What are the potential causes of granulocytosis and neutropenia?

Causes of Granulocytosis and Neutropenia

Granulocytosis and neutropenia represent opposite ends of the granulocyte count spectrum, with each having distinct etiologies that require prompt identification to reduce morbidity and mortality.

Causes of Neutropenia

Neutropenia is defined as an absolute neutrophil count (ANC) below 1500 cells/mm³, with severe neutropenia being less than 500 cells/mm³ 1.

Congenital Causes:

• Severe congenital neutropenia (SCN) 2
• Cyclic neutropenia
• Kostmann syndrome
• Shwachman-Diamond syndrome
• Dyskeratosis congenita

Acquired Causes:

1. Drug-induced neutropenia:

   • Chemotherapeutic agents
   • Antibiotics (beta-lactams, sulfonamides)
   • Antithyroid medications
   • Antipsychotics
   • Anticonvulsants

2. Infectious causes:

   • Viral infections (HIV, hepatitis, CMV)
   • Bacterial infections (typhoid fever, tuberculosis)
   • Parasitic infections (malaria)

3. Immune-mediated neutropenia:

   • Autoimmune neutropenia
   • Large granular lymphocyte (LGL) syndrome 2
   • Systemic lupus erythematosus
   • Rheumatoid arthritis

4. Hematologic disorders:

   • Myelodysplastic syndromes
   • Aplastic anemia
   • Leukemias
   • Hairy cell leukemia
   • Vitamin B12 or folate deficiency

5. Splenic sequestration:

   • Hypersplenism

6. Bone marrow infiltration:

   • Metastatic cancer
   • Hematologic malignancies

Causes of Granulocytosis

Granulocytosis refers to an abnormally high number of granulocytes (primarily neutrophils) in the blood.

Physiologic Causes:

• Stress response
• Exercise
• Pregnancy
• Post-surgical state

Pathologic Causes:

1. Infections:

   • Bacterial infections (particularly pyogenic)
   • Fungal infections
   • Tuberculosis

2. Inflammatory conditions:

   • Adult-onset Still's disease 3
   • Vasculitis
   • Inflammatory bowel disease
   • Rheumatoid arthritis

3. Malignancies:

   • Leukemias (particularly chronic myeloid leukemia)
   • Myeloproliferative disorders
   • Solid tumors producing colony-stimulating factors 4
   • Anaplastic large cell lymphoma of T-cell lineage 5

4. Medications:

   • Corticosteroids
   • Lithium
   • Granulocyte colony-stimulating factor (G-CSF)
   • Granulocyte-macrophage colony-stimulating factor (GM-CSF) 3

5. Tissue damage:

   • Burns
   • Myocardial infarction
   • Trauma

6. Metabolic disorders:

   • Diabetic ketoacidosis
   • Uremia

Clinical Significance

Neutropenia:

• The risk of infection increases dramatically when ANC falls below 500/mcL 3
• When ANC falls below 100/mcL, approximately 10-20% of patients will develop bloodstream infections 1
• Primary infection sites include the alimentary tract, sinuses, lungs, and skin 3
• Common pathogens include gram-positive cocci, gram-negative bacilli, fungi (Candida, Aspergillus), and viruses 3

Granulocytosis:

• May indicate underlying infection, inflammation, or malignancy
• Tumor-associated granulocytosis often parallels tumor growth and can be associated with poor prognosis 4
• May be caused by colony-stimulating factors produced by neoplastic cells 4

Diagnostic Approach

1. Complete blood count with differential
2. Peripheral blood smear to assess morphology
3. Bone marrow examination if cause is not apparent
4. Specific testing based on suspected etiology:
   • Microbiology cultures for infection
   • Autoimmune markers for immune-mediated causes
   • Imaging studies for occult malignancy
   • Medication review for drug-induced causes

Management Considerations

• For neutropenia: prompt evaluation of fever (>38.5°C) and early initiation of empiric antibiotics for febrile neutropenia 1
• Growth factors (G-CSF) may be indicated for severe neutropenia or high-risk febrile neutropenia 1
• For granulocytosis: treatment of the underlying cause is the primary approach
• Patients with certain types of chronic neutropenia may have an increased risk of developing myelodysplastic syndrome and acute myeloid leukemia 1

Remember that the clinical presentation of infection in neutropenic patients may be muted due to lack of neutrophils, with fever often being the only sign 3.