What is the diagnosis and treatment for Agranulocytosis (a potentially life-threatening reduction in white blood cells)?

From the Guidelines

Agranulocytosis is a life-threatening condition that requires immediate discontinuation of the suspected medication and prompt medical attention, with treatment including broad-spectrum antibiotics, granulocyte colony-stimulating factors, and supportive care. Agranulocytosis is characterized by severely reduced neutrophil counts (below 500 cells/mm³), leaving patients vulnerable to life-threatening infections. It typically results from medication side effects, with common culprits including clozapine, carbamazepine, methimazole, propylthiouracil, and certain antibiotics like trimethoprim-sulfamethoxazole 1. Management of agranulocytosis involves immediate discontinuation of the suspected medication and prompt medical attention, with treatment including broad-spectrum antibiotics (such as piperacillin-tazobactam 4.5g IV every 6 hours plus vancomycin 15-20mg/kg IV every 8-12 hours) for febrile patients, granulocyte colony-stimulating factors like filgrastim (5-10 μg/kg/day subcutaneously) to stimulate neutrophil production, and supportive care including isolation to prevent infection.

Key Considerations

• Regular complete blood count monitoring is essential for patients on high-risk medications, with weekly monitoring recommended for the first month of clozapine therapy 1.
• Agranulocytosis develops because these medications either directly damage neutrophil precursors in the bone marrow or trigger immune-mediated destruction of neutrophils, resulting in the dangerous neutropenia that characterizes this condition.
• Other medications like deferiprone also carry a risk of agranulocytosis, with a reported incidence of approximately 1% of treated patients (0.6 cases per 100 patient-years of treatment) 1.

Monitoring and Prevention

• The neutrophil count should be monitored every week to detect early signs of agranulocytosis, particularly in patients treated with deferiprone 1.
• Temporary discontinuation or dose adjustment may be beneficial for common adverse events, whereas in the case of agranulocytosis or neutropenia, the drug should be stopped immediately, and patients should contact their physician 1.
• Patients should also be advised to report immediately to their physician any symptoms indicative of infection, such as fever, sore throat, and flulike symptoms 1.

From the FDA Drug Label

Pediatric patients with congenital types of neutropenia (Kostmann's syndrome, congenital agranulocytosis, or Schwachman-Diamond syndrome) have developed cytogenetic abnormalities and have undergone transformation to MDS and AML while receiving chronic NEUPOGEN treatment The FDA drug label mentions congenital agranulocytosis as a condition where patients have developed cytogenetic abnormalities and undergone transformation to MDS and AML while receiving chronic NEUPOGEN treatment.

• The relationship of these events to NEUPOGEN administration is unknown. However, it does not provide information on the incidence of agranulocytosis as an adverse effect of filgrastim treatment 2.

From the Research

Definition and Causes of Agranulocytosis

• Agranulocytosis is a rare, severe, and unpredictable idiosyncratic reaction associated with drug therapy that can lead to life-threatening illness 3.
• It is characterized by a neutrophil count below 0.5 × 10(9)/l, and can be caused by various drugs, including dipyrone, captopril, clozapine, anti-thyroid agents, sulphonamides, and dapsone 4, 3.

Clinical Presentation and Management

• Idiosyncratic drug-induced agranulocytosis remains a potentially serious adverse event owing to the frequency of severe sepsis with severe deep tissue infections, septicemia, and septic shock in approximately two-thirds of all hospitalized patients 5.
• Modern management with broad-spectrum antibiotics and hematopoietic growth factors, particularly granulocyte colony-stimulating factor (G-CSF), is likely to improve prognosis 5.
• The use of G-CSF in the treatment of non-chemotherapy drug-induced agranulocytosis has been shown to shorten the time to recovery in patients with agranulocytosis 6.

Treatment and Outcome

• Recombinant human granulocyte-colony-stimulating factor (rh-G-CSF) has been used effectively in the treatment of drug-induced agranulocytosis, with neutrophil counts recovering between day 6 and 12 after administration 4.
• The mortality rate from idiosyncratic drug-induced agranulocytosis is currently approximately 5% with appropriate management 5.
• G-CSF has been used as an adjunctive therapy with discontinuation of the offending drug, barrier nursing, and a broad-spectrum antibiotic regimen to treat neutropenic sepsis 7.

Risk Factors and Prevention

• Old age (>65 years), septicemia or shock, metabolic disorders such as renal failure, and a neutrophil count below 0.1 × 10(9)/l are currently consensually accepted as poor prognostic factors 5.
• The risk of agranulocytosis is multiplied between 25 and 33 fold in patients with dermatitis herpetiformis (DH) compared with normal patients 3.
• Monitoring of neutrophil cell population in the first 3 months of therapy may be necessary in high-risk patients, such as those with DH 3.