Drug-induced agranulocytosis

# Overview
- Leukopenia refers to a low white blood count (WBC) that may be due to lymphopenia as well as neutropenia, while granulocytopenia refers to a reduced number of granulocytes (neutrophils, eosinophils, and basophils). - Neutropenia is defined as an absolute neutrophil count (ANC) of less than 1500/L.
ANC  =  WBC (cells/L)  x  percent (PMNs  +  bands)    100.
Neutrophilic metamyelocytes and younger forms are not included in this calculation.
- Neutrophilic metamyelocytes and younger forms are not included in this calculation.
- The risk of infection begins to increase at an ANC below 1000/L.
- Agranulocytosis refers to severe neutropenia (ie, ANC less than 500/L).
- Drug-induced neutropenia or agranulocytosis occurs as an idiosyncratic reaction.
- In research protocols, the definition excludes known cytotoxic agents or diseases that can cause neutropenia and requires that the offending drug be administered within four weeks of the onset of neutropenia.

# Epidemiology and Demographics
- Agranulocytosis has a reported incidence from approximately 1 to 10 cases per million population per year.
- An association with drug use can be found in about 70 percent of cases.
- Only 10 percent of cases occurred in children and young adults.
- More than 50 percent of cases occur in patients over age fifty.
- There is a 2:1 female:male ratio of cases.

# Risk Factors
- The International Aplastic Anemia and Agranulocytosis Study noted the following risk factors for agranulocytosis:
- Age
- Female gender
- Epstein-Barr virus (EBV) infection
- Renal failure
- In a study of 11,555 patients receiving clozapine, the risk of agranulocytosis was significantly higher among women.
- Other risk factors for agranulocytosis include:
Underlying autoimmune disease
Combination therapy with an angiotensin converting enzyme inhibitor and interferon
There is some suggestion of genetic susceptibility with certain HLA serotypes having a higher incidence after exposure to clozapine and methimazole.
- Underlying autoimmune disease
- Combination therapy with an angiotensin converting enzyme inhibitor and interferon
- There is some suggestion of genetic susceptibility with certain HLA serotypes having a higher incidence after exposure to clozapine and methimazole.

# Pathophysiology & Etiology
- Most cases of neutropenia are due to decreased granulocyte production or less commonly increased destruction. - Acquired neutropenia is most often due to accelerated turnover, usually resulting from immunologic mechanisms.
- Discontinuation of the drug generally results in correction of the ANC within 30 days.
- Numerous drugs have been implicated based on case reports, registries, cohort studies, and population and case control studies.
- There are a number of drugs which are considered to have a high risk association for agranulocytosis based upon definite and unequivocal evidence This list excludes drugs that produce agranulocytosis on the basis of bone marrow suppression.
- Among the drugs that are more commonly associated with agranulocytosis are clozapine, the thionamides (antithyroid drugs), sulfasalazine, and ticlopidine.  Other drugs with multiple reports of agranulocytosis include the ACE inhibitors, H2 blockers, nonsteroidal antiinflammatory drugs, antiarrhythmic drugs such as tocainide, procainamide, and flecainide, aminoglutethimide, and dapsone.
- The highest relative risks for development of agranulocytosis are for antithyroid drugs, sulfasalazine, trimethoprim-sulfamethoxazole combined with analgesics or clomipramine.
Clozapine
Clozapine, a tricyclic dibenzodiazepine, is used only for schizophrenia unresponsive to other therapies due to its propensity for agranulocytosis . The cumulative risk of agranulocytosis is approximately 0.8 to 1.5 percent at one year, with little further increase over time. The majority of cases (84 percent) occur within the first three months of therapy, which constitutes the rationale for monitoring the white blood cell count, especially soon after therapy has been instituted.
Thionamides
The prevalence of agranulocytosis with thionamide therapy (eg, methimazole (MMI) and propylthiouracil (PTU) ranges from 0.2 to 0.5 percent.  It has been shown that agranulocytosis is independent of dose, age, duration of treatment, or second exposure to the thionamide.  Controversy exists as to the value of monitoring white blood cell counts.
Sulfasalazine
Sulfasalazine causes leukopenia, in 1 to 2 percent of patients.  The leukopenia is usually mild and transient, but life-threatening agranulocytosis can occur.  Some feel that benign leukopenia can be treated with dose reduction, while agranulocytosis caused by a hypersensitivity reaction necessitates drug discontinuation.  The estimated frequency of agranulocytosis is 0.6 percent in patients with arthritis and 0.06 percent in inflammatory bowel disease.  Serious episodes of agranulocytosis are usually observed within the first three months and often within the first six weeks of therapy. Other sulfa drugs, such as trimethoprim-sulfamethoxazole, are common causes of agranulocytosis
Ticlopidine
Ticlopidine causes neutropenia at a rate of approximately 2.4 percent, usually within the first three months of therapy. Severe hematological reactions in addition to neutropenia and thrombocytopenia from Ticlodipine include thrombotic thrombocytopenic purpura-hemolytic uremic syndrome and aplastic anemia.Data from between 1992 and 1997 revealed 116 cases of agranulocytosis associated with ticlopidine with 22 deaths.
- Clozapine
Clozapine, a tricyclic dibenzodiazepine, is used only for schizophrenia unresponsive to other therapies due to its propensity for agranulocytosis . The cumulative risk of agranulocytosis is approximately 0.8 to 1.5 percent at one year, with little further increase over time. The majority of cases (84 percent) occur within the first three months of therapy, which constitutes the rationale for monitoring the white blood cell count, especially soon after therapy has been instituted.
- Clozapine, a tricyclic dibenzodiazepine, is used only for schizophrenia unresponsive to other therapies due to its propensity for agranulocytosis . The cumulative risk of agranulocytosis is approximately 0.8 to 1.5 percent at one year, with little further increase over time. The majority of cases (84 percent) occur within the first three months of therapy, which constitutes the rationale for monitoring the white blood cell count, especially soon after therapy has been instituted.
- Thionamides
The prevalence of agranulocytosis with thionamide therapy (eg, methimazole (MMI) and propylthiouracil (PTU) ranges from 0.2 to 0.5 percent.  It has been shown that agranulocytosis is independent of dose, age, duration of treatment, or second exposure to the thionamide.  Controversy exists as to the value of monitoring white blood cell counts.
- The prevalence of agranulocytosis with thionamide therapy (eg, methimazole (MMI) and propylthiouracil (PTU) ranges from 0.2 to 0.5 percent.  It has been shown that agranulocytosis is independent of dose, age, duration of treatment, or second exposure to the thionamide.  Controversy exists as to the value of monitoring white blood cell counts.
- Sulfasalazine
Sulfasalazine causes leukopenia, in 1 to 2 percent of patients.  The leukopenia is usually mild and transient, but life-threatening agranulocytosis can occur.  Some feel that benign leukopenia can be treated with dose reduction, while agranulocytosis caused by a hypersensitivity reaction necessitates drug discontinuation.  The estimated frequency of agranulocytosis is 0.6 percent in patients with arthritis and 0.06 percent in inflammatory bowel disease.  Serious episodes of agranulocytosis are usually observed within the first three months and often within the first six weeks of therapy. Other sulfa drugs, such as trimethoprim-sulfamethoxazole, are common causes of agranulocytosis
- Sulfasalazine causes leukopenia, in 1 to 2 percent of patients.  The leukopenia is usually mild and transient, but life-threatening agranulocytosis can occur.  Some feel that benign leukopenia can be treated with dose reduction, while agranulocytosis caused by a hypersensitivity reaction necessitates drug discontinuation.  The estimated frequency of agranulocytosis is 0.6 percent in patients with arthritis and 0.06 percent in inflammatory bowel disease.  Serious episodes of agranulocytosis are usually observed within the first three months and often within the first six weeks of therapy. Other sulfa drugs, such as trimethoprim-sulfamethoxazole, are common causes of agranulocytosis
- Ticlopidine
Ticlopidine causes neutropenia at a rate of approximately 2.4 percent, usually within the first three months of therapy. Severe hematological reactions in addition to neutropenia and thrombocytopenia from Ticlodipine include thrombotic thrombocytopenic purpura-hemolytic uremic syndrome and aplastic anemia.Data from between 1992 and 1997 revealed 116 cases of agranulocytosis associated with ticlopidine with 22 deaths.
- Ticlopidine causes neutropenia at a rate of approximately 2.4 percent, usually within the first three months of therapy. Severe hematological reactions in addition to neutropenia and thrombocytopenia from Ticlodipine include thrombotic thrombocytopenic purpura-hemolytic uremic syndrome and aplastic anemia.Data from between 1992 and 1997 revealed 116 cases of agranulocytosis associated with ticlopidine with 22 deaths.

# Pathogenesis
- There are two basic mechanisms by which drugs cause neutropenia and agranulocytosis:
Immune mediated destruction of circulating neutrophils by drug-dependent or drug-induced antibodies
Direct toxic effects upon marrow granulocytic precursors. Drugs including clozapine, sulfonamides, dapsone, and indomethacin are oxidized by the NADPH oxidase/myeloperoxidase system found in neutrophils and monocytes.  This metabolism generates reactive metabolites which generate antibodies or have direct marrow effects.
- Immune mediated destruction of circulating neutrophils by drug-dependent or drug-induced antibodies
- Direct toxic effects upon marrow granulocytic precursors. Drugs including clozapine, sulfonamides, dapsone, and indomethacin are oxidized by the NADPH oxidase/myeloperoxidase system found in neutrophils and monocytes.  This metabolism generates reactive metabolites which generate antibodies or have direct marrow effects.
- Clozapine is oxidized by granulocytes to a nitrenium ion formed by chlorination of the nitrogen bridge between the two aromatic rings. This metabolite binds covalently and irreversibly and is toxic to neutrophils and bone marrow unit-granulocyte/macrophage (CFU-GM) stem cells.

# History and Symptoms
- Most cases of severe neutropenia or agranulocytosis present within the first six months and usually within the first three months after beginning the offending drug. Many patients are asymptomatic at the time that severe neutropenia is detected.  The clinical presentation depends in part upon the etiology and pathogenesis of the agranulocytosis:
- Immune forms may present days to weeks after beginning the drug and are often acute with explosive symptoms. Rechallenge, or inadvertent subsequent administration, is associated with a prompt recurrence with even small doses.
- The presentation in toxic forms may be delayed for months. The neutropenia is often asymptomatic or presents with an insidious onset. Rechallenge requires both a latent period and high doses before recurrence is observed.
- The classic presentation in symptomatic patients is severe sore throat and fever. The total white blood cell count may be normal but the peripheral smear reveals the absence of neutrophil and band forms. Bone marrow aspiration and biopsy findings vary with the cause of the agranulocytosis: normal or mildly reduced cellularity with myeloid aplasia or hypoplasia if the drug is acting as a toxin; myeloid arrest at a later stage of myeloid maturation is seen if the damage is antibody-mediated and directed predominantly at circulating neutrophils.

# Treatment
- Prophylactic monitoring of the white blood cell count and differential has been primarily evaluated with drugs associated with the highest risk of agranulocytosis, thionamides and clozapine. An approach to patients taking a thionamide is to have a white blood cell count with differential at the earliest sign of a sore throat or other infection, and to discontinue the drug until the result is available.
- Clozapine
Weekly monitoring of the white blood cell count and differential is currently required in the United States. In the first 1.5 years of release, the cumulative incidence of agranulocytosis was 0.9 percent. Among the 73 patients who developed this complication, two died of infectious causes.
- Weekly monitoring of the white blood cell count and differential is currently required in the United States. In the first 1.5 years of release, the cumulative incidence of agranulocytosis was 0.9 percent. Among the 73 patients who developed this complication, two died of infectious causes.
- If the inciting drug is known, drug withdrawal is necessary whether or not the patient is symptomatic.  Treat as usual febrile neutropenia.  Consider anti-neutrophil antibody testing and/or bone marrow biopsy.  The neutropenia usually resolves within one to three weeks after cessation of drug therapy but there is substantial variability. In one study of 63 episodes in 61 patients, for example, the mean time to recovery was 12 days but the range was 3 to 56.

# Future or Investigational Therapies
- Granulocyte colony-stimulating factor  A number of uncontrolled case studies have reported shorter recovery times compared with historic controls while others show no change with the use of granulocyte or granulocyte-macrophage colony-stimulating factor (G-CSF or GM-CSF) in infected patients with drug-induced agranulocytosis.
- Although their efficacy is not proven, growth factors have minimal toxicity and most patients with agranulocytosis receive these drugs.  G-CSF selectively targets granulocyte colony forming unit stem cells and seems better tolerated. G-CSF is usually given (at the recommended dose of 5 g/kg per day) subcutaneously to patients with an ANC less than 1000/L who have fever or other signs of infection or any patient with an ANC less than 500/L which persists for longer than five days after the suspect drug has been withdrawn.