Agranulocytosis
Synonyms and Keywords: Agranulosis, granulocytopenia, neutropenia

# Overview
Agranulocytosis is defined as marked reduction in the number of granulocytes (Neutrophils, Basophils, Eosinophils) below an absolute count of 500 cells/mcL. It is a rare condition with incidence of 1 to 5 cases per million population per year. Agranulocytosis results in frequent chronic bacterial infections of skin, lung, and throat. Patients can present with sepsis and fever. Among many risk factors, medications, combination therapy with ACE inhibitors and interferon, cytotoxic chemotherapy, hematologic malignancies, and autoimmune disorders are the more common. On the basis of etiology agranulocytosis can be classified as congenital and acquired. Common causes of acquired agranulocytosis include medications like clozapine, sulfasalazine, and thioamide, infections, nutritional deficiencies, myelodysplasia, collagen vascular diseases, and white cell aplasia. Agranulocytosis needs to be differentiated from bacterial sepsis, aplastic anemia, acute myeloid leukemia, acute lymphoblastic leukemia, cytomegalovirus, folic acid deficiency, and Hodgkin lymphoma. The negative prognostic factors in the course of agranulocytosis are age > 65, septic shock, bacteremia, systemic infections, renal, cardiac and respiratory diseases.The mainstay of treatment of agranulocytosis is medical therapy, including, discontinuation of offending agent, treating infections with broad spectrum antibiotics, and using granulocyte-colony stimulating factor.

# Historical Perspective
- Agranulocytosis was first noted around the beginning of the 20th century on review of blood cell differentials described in patients with lupus, other autoimmune disorders, and with various drug toxicities.

# Classification
Agranulocytosis can be classified as congenital or acquired. Each class can be classified to further subgroups as follows:
- Kostmann's syndrome
- Reticular dysgenesis
- Shwachman-Diamond syndrome
- Chediak-Higashi syndrome
- Dyskeratosis congenita
- Drug induced
Clozapine
Sulfasalazine
Thioamide
- Clozapine
- Sulfasalazine
- Thioamide
- Infection
Viral infections including:
Hepatitis B
Hepatitis C
Epstein-Barr virus
HIV
Bacterial
Rickettsial
- Viral infections including:
Hepatitis B
Hepatitis C
Epstein-Barr virus
HIV
- Hepatitis B
- Hepatitis C
- Epstein-Barr virus
- HIV
- Bacterial
- Rickettsial
- Collagen vascular diseases
SLE
Felty's syndrome
- SLE
- Felty's syndrome
- White cell aplasia
- Nutritional deficiency
Vitamin B12 deficiency
Folic acid deficiency
- Vitamin B12 deficiency
- Folic acid deficiency
- Myelodysplasia
- Hypoplasia
Aplastic anemia
Fanconi's anemia
- Aplastic anemia
- Fanconi's anemia
- Leukemia

# Pathophysiology
Agranulocytosis develops as a result of the following mechanisms:
- Immune mediated destruction of granulocytes
The drugs or its active metabolite act as hapten, and binds to neutrophil membrane.
Autoantibodies are produced as a result of this binding.
This results in destruction of sensitized neutrophils by phagocytosis.
Most common drugs are propylthiouracil, amodiaquine, mono-desethyl amodiaquine, and flecainide.
- The drugs or its active metabolite act as hapten, and binds to neutrophil membrane.
- Autoantibodies are produced as a result of this binding.
- This results in destruction of sensitized neutrophils by phagocytosis.
- Most common drugs are propylthiouracil, amodiaquine, mono-desethyl amodiaquine, and flecainide.
- Direct damage of granulocytes
Some drugs release chemically active metabolites.
These metabolites bind to cytoplasmic proteins or proteins in the nucleus.
This results in direct toxicity and destruction of granulocytes.
Chlorpromazine, dapsone, clozapine, and procainamide are few examples of these drugs.
Granulocytes oxidize clozapine releasing nitrenium ions.
Nitrenium ions bind irreversibly to granulocytes and its precursor cells resulting in toxic destruction of these cells.
- Some drugs release chemically active metabolites.
- These metabolites bind to cytoplasmic proteins or proteins in the nucleus.
- This results in direct toxicity and destruction of granulocytes.
- Chlorpromazine, dapsone, clozapine, and procainamide are few examples of these drugs.
- Granulocytes oxidize clozapine releasing nitrenium ions.
- Nitrenium ions bind irreversibly to granulocytes and its precursor cells resulting in toxic destruction of these cells.

# Causes
Agranulocytosis can be congenital or acquired. Common causes of acquired agranulocytosis include:
- Medications
Clozapine
Deferiprone
Sulfasalazine
Ticlopidine
Rituximab
Quinine
Trimethoprim-sulfamethoxazole
- Clozapine
- Deferiprone
- Sulfasalazine
- Ticlopidine
- Rituximab
- Quinine
- Trimethoprim-sulfamethoxazole
- Chemotherapy
- Bone marrow transplant
- Systemic lupus erythematosus (SLE)
- Rheumatoid arthritis
- HIV
- Hepatitis
- Leukemia
- Myelodysplasia

# Differentiating Agranulocytosis from Other Diseases
Consider the following differential when evaluating a patient with agranulocytosis:
- Bacterial sepsis
- Aplastic anemia
- Acute myeloid leukemia
- Acute lymphoblastic leukemia
- Cytomegalovirus
- Folic acid deficiency
- Hodgkin lymphoma
- Non-Hodgkin lymphoma
- Wegener granulomatosis

# Epidemiology and Demographics
- Agranulocytosis is an extremely rare condition.
- The overall incidence rate is 7.2 per million per year.
- It can occur in all races and any age group.
- The acquired type of agranulocytosis is more common in older individuals. While inherited type is commonly seen in children.
- The risk of agranulocytosis is seen higher in women.

# Risk Factors
Risk factors for agranulocytosis include:
- Acquired conditions
Medications
Infectious mononucleosis
Combination therapy with ACE inhibitors and interferon
Cytotoxic chemotherapy
Hematologic malignancies
Autoimmune disorders
- Medications
- Infectious mononucleosis
- Combination therapy with ACE inhibitors and interferon
- Cytotoxic chemotherapy
- Hematologic malignancies
- Autoimmune disorders
- Genetic susceptibility
Association between HLA-B38, DQW3 haplotype, and clozapine induced agranulocytosis is seen in Ashkenazi Jews.
HLA DRB1*08032 allele has a strong susceptibility to methimazole induced agranulocytosis.
- Association between HLA-B38, DQW3 haplotype, and clozapine induced agranulocytosis is seen in Ashkenazi Jews.
- HLA DRB1*08032 allele has a strong susceptibility to methimazole induced agranulocytosis.

# Screening
There are no routine screening recommendations for agranulocytosis. It is typically identified incidentally on routine blood work or while monitoring after cytotoxic therapy.

# Natural History, Complications, and Prognosis

## Natural History
- Neutropenia, and progression to agranulocytosis, occurs in either a dose-dependent or idiosyncratic process dependent upon the etiology.
- Neutropenia caused by cytotoxic chemotherapy or malignant bone marrow infiltration is typically dose-dependent or related to tumor burden, as opposed to idiosyncratic, and  immune-mediated neutropenia that occurs independently.

## Complications
The major complications of agranulocytosis are as follows:
- Septicemia
- Bacterial infections
- Fungal infections
- Pneumonia
- Fever
- Mouth ulcers

## Prognosis
The negative prognostic factors for agranulocytosis are:
- Neutrophil count at the time of diagnosis <0.1  109 cells/L
- Age > 65 years old
- Severe infections like septic shock, bacteremia
- Pre existence of systemic infections, renal, cardiac and respiratory diseases

# Diagnosis

## Diagnostic Study of Choice
The diagnosis of agranulocytosis is based on the laboratory finding when the number of granulocytes (Neutrophils, Basophils, Eosinophils) is below an absolute count of 500 cells/mcL.

## History and Symptoms
History of patients with agranulocytosis should focus on any history of:
- Malignancy
- Infection
- Autoimmune disorders
- Medications
Common symptoms include:
- Fever
- Symptoms of frequent infections
- Unusual redness, pain, or swelling around a wound
- Mouth ulcers
- Diarrhea
- Burning sensation when urinating
- Sore throat
- Shortness of breath
- Shaking chills

## Physical Examination
Common signs of agranulocytosis may include:
- Fever
- Tachycardia
- Hypotension
- Tachypnea
- Hypoxia
- Jaundice
- Wheezes
- Rales
- Joint swelling or deformity
- Rashes

## Laboratory Findings
The following tests should be performed after careful medication history:
- CBC
- Differential WBC
- Peripheral blood smear
Some patients may need:
- Liver function tests
- Rheumatoid factor
- Peripheral blood flow cytometry
- Antinuclear antibody (ANA)
- Serum immunoglobulin study
- Vitamin B12 and Folate levels
- HIV testing

## Electrocardiogram
There are no ECG findings associated with agranulocytosis.

## X-ray
There are no x-ray findings associated with agranulocytosis. However, an x-ray may be helpful in the diagnosis of underlying cause or complications of agranulocytosis.

## Echocardiography or Ultrasound
There are no echocardiography/ultrasound findings associated with agranulocytosis.

## CT scan
There are no CT scan findings associated with agranulocytosis. However, a CT scan may be helpful in the diagnosis of underlying cause or complications of agranulocytosis.

## MRI
There are no MRI findings associated with agranulocytosis. However, a MRI may be helpful in the diagnosis of underlying cause or complications of agranulocytosis.

## Other Imaging Findings
There are no other imaging findings associated with agranulocytosis.

## Other Diagnostic Studies
There are no other diagnostic studies associated with agranulocytosis.

# Treatment

## Medical Therapy
- Discontinuation of the offending agent
Identifying and removing the offending agents
It takes about 1-3 weeks for neutropenia to resolve after stopping the offending drug.
- Identifying and removing the offending agents
- It takes about 1-3 weeks for neutropenia to resolve after stopping the offending drug.
- Treat the associated infections and conditions
In cases of febrile neutropenia, empiric antibiotics should be administered intravenously as early as possible.
Before starting the antibiotics, blood, urine and sputum cultures should be withdrawn.
Antibiotic coverage should be bactericidal for most common pathogens.
Central venous catheters and other indwelling devices should be removed when possible if there is suspicion for infection or with positive blood cultures.
- In cases of febrile neutropenia, empiric antibiotics should be administered intravenously as early as possible.
- Before starting the antibiotics, blood, urine and sputum cultures should be withdrawn.
- Antibiotic coverage should be bactericidal for most common pathogens.
- Central venous catheters and other indwelling devices should be removed when possible if there is suspicion for infection or with positive blood cultures.
- Use of granulocyte-colony stimulating factor
Granulocyte-colony stimulating factor (G-CSF) has shown excellent results in patients with drug induced agranulocytosis and severe infection.
It is mostly beneficial in patients with neutropenia secondary to chemotherapy.
- Granulocyte-colony stimulating factor (G-CSF) has shown excellent results in patients with drug induced agranulocytosis and severe infection.
- It is mostly beneficial in patients with neutropenia secondary to chemotherapy.
- Immune suppression
In neutropenia with autoimmune diseases, prednisone is used for immunosuppression.
- In neutropenia with autoimmune diseases, prednisone is used for immunosuppression.
- Bone marrow transplant
When other treatments do not work, bone marrow transplant is an option.
It is more successful in patients aged <40 years old in good health.
- When other treatments do not work, bone marrow transplant is an option.
- It is more successful in patients aged <40 years old in good health.

## Surgery
There are no surgical treatments for agranulocytosis. However, in patients with neutropenic fever, surgical intervention may be necessary depending on the source of infection.

## Primary Prevention
Primary prevention of agranulocytosis is dependent upon:
- Avoiding certain medications
- Occasionally, when agranulocytosis is anticipated, such as in the setting of cytotoxic chemotherapy, recombinant G-CSF (granulocyte-colony stimulating factor) can be considered to speed myeloid reconstitution.

## Secondary Prevention
Effective measures for the secondary prevention of agranulocytosis include early detection and treatment of underlying conditions.