What is neutropenia?

What is Neutropenia?

Neutropenia is a condition defined by an absolute neutrophil count (ANC) below 1,000 cells/mm³, with severe neutropenia occurring at counts below 500 cells/mm³ and profound neutropenia at counts below 100 cells/mm³. 1

Core Definition and Clinical Thresholds

• Neutropenia begins at ANC <1,000 cells/mm³, though increased infection susceptibility becomes clinically apparent at this level 1
• Severe neutropenia is defined as ANC <500 cells/mm³, representing the threshold where infection risk substantially increases 1
• Profound neutropenia occurs at ANC <100 cells/mm³, carrying the highest infection risk with approximately 10-20% of these patients developing bloodstream infections 1, 2
• The duration of neutropenia matters critically: protracted neutropenia lasting ≥7-10 days significantly amplifies infection risk regardless of the absolute count 1, 2

Primary Causes

• Chemotherapy-induced myelosuppression is the most common cause of clinically significant neutropenia, particularly in cancer patients 2, 3
• Bone marrow infiltration by malignancy directly impairs neutrophil production 3
• Infections (bacterial, viral, fungal) can cause neutropenia through increased consumption or impaired production 3
• Congenital disorders affecting neutrophil production, differentiation, or survival represent rare but important causes 4
• Drug-induced neutropenia from medications beyond chemotherapy (antibiotics, anticonvulsants, antithyroid drugs) occurs frequently 4

Why Neutropenia Matters: Infection Risk

The infection risk is inversely proportional to the neutrophil count, with the greatest danger occurring when counts fall below 100 cells/mm³ 1, 2, 3. This relationship exists because:

• Neutrophils are the body's primary defense against bacterial and fungal pathogens 5
• Approximately 50-60% of febrile neutropenic patients have an established or occult infection 2, 3
• At counts below 100 cells/mm³, at least 20% of patients develop bacteremia 1

Common Infection Sites and Pathogens

Primary anatomic sites of infection include:

• The alimentary tract (where chemotherapy-induced mucosal damage allows organism invasion) 1, 2, 3
• Sinuses and lungs 2, 3
• Skin and soft tissues, particularly at vascular catheter sites and bone marrow aspiration sites 1
• The perineum and perianal region 1

Causative organisms vary by timing:

• Early infections (<7 days) are predominantly bacterial: gram-negative organisms (E. coli, Klebsiella, Pseudomonas aeruginosa) and gram-positive organisms (coagulase-negative staphylococci, S. aureus, viridans streptococci) 1, 2
• Later infections (>7 days) involve antibiotic-resistant bacteria, yeasts (particularly Candida species), and molds (Aspergillus, Mucor, Fusarium) 1, 2

Clinical Presentation: The Diagnostic Challenge

A critical pitfall: symptoms and signs of inflammation are often minimal or absent in severely neutropenic patients 1. This creates diagnostic challenges:

• Cellulitis may present without typical erythema, warmth, or induration 1
• Pneumonia may occur without infiltrates visible on chest radiography 1
• Meningitis may develop without pleocytosis in cerebrospinal fluid 1
• Urinary tract infections may lack pyuria 1

Specific Clinical Entities to Recognize

Ecthyma gangrenosum is a characteristic cutaneous vasculitis:

• Begins as painless erythematous macules that rapidly become painful and necrotic within 12-24 hours 1, 2, 3
• Classically associated with Pseudomonas aeruginosa but can occur with other organisms 1
• Lesions preferentially occur in the groin, axilla, or trunk and can enlarge from 1 cm to >10 cm in under 24 hours 1

Neutropenic enterocolitis (typhlitis) presents as:

• Acute abdominal pain in neutropenic cancer patients 2, 3
• Typically occurs 1-2 weeks after chemotherapy initiation 2

Febrile Neutropenia: When to Act Urgently

Febrile neutropenia is defined as:

• A single oral temperature ≥38.3°C (101°F), OR 1
• Temperature ≥38.0°C (100.4°F) sustained over 1 hour 1
• Occurring with ANC <500 cells/mm³ or <1,000 cells/mm³ with predicted decline to ≤500 cells/mm³ 1

This constitutes a medical emergency requiring empirical broad-spectrum antibiotics within 2 hours 2, as approximately 50-60% of these patients have an active infection 2, 3.

Risk Stratification

High-risk features include:

• Profound neutropenia (ANC <100 cells/mm³) 1
• Protracted neutropenia expected to last ≥7-10 days 1
• Age ≥65 years 1
• Poor performance status (ECOG ≥2) 1
• Albumin <35 g/L 1
• Prior febrile neutropenia episode (increases risk four-fold in subsequent cycles) 1

Low-risk patients may be candidates for oral antibiotic therapy or early transition from intravenous to oral therapy after 48 hours of stability 1.

Management Principles

Immediate actions when neutropenia is discovered:

• Obtain blood cultures from peripheral vein (and from central venous catheter if present) before antibiotics 1
• Examine carefully for subtle signs of infection at high-risk sites: periodontium, pharynx, esophagus, lungs, perineum, skin (especially catheter sites), and nail beds 1
• Culture any suspicious sites 1

Empirical antibiotic therapy should cover both gram-negative and gram-positive organisms, with specific regimens chosen based on local resistance patterns 1, 2.

Granulocyte colony-stimulating factor (G-CSF) is indicated for:

• Primary prophylaxis when chemotherapy regimens carry >50% risk of severe neutropenia 1, 6
• Treatment of established severe neutropenia with complications 1, 6
• Dose: 5 mcg/kg/day subcutaneously starting 24-72 hours after chemotherapy until ANC recovery 1