Neutropenia

Definition

ANC = (% neutrophils + % bands) × total WBC ÷ 100

Severity Classification

Pathophysiology

1. Decreased production - proliferation or maturation defects (e.g., chemotherapy, aplastic anemia, congenital disorders)
2. Increased peripheral destruction - immune-mediated (antibodies against neutrophils) or consumption in overwhelming sepsis
3. Altered distribution - shift from circulating pool to marginating pool (e.g., sepsis-induced complement activation causes increased margination)
4. Combinations of the above

Bone Marrow Morphology (Robbins Basic Pathology)

• Compensatory hypercellularity when destruction exceeds production, or in ineffective granulopoiesis (e.g., megaloblastic anemia)
• Selective loss of granulocytic precursors with preserved erythroid and megakaryocytic elements - seen in drug-induced selective suppression
• Panhypocellularity with myelotoxic chemotherapy agents

Causes / Etiology

Congenital Neutropenias

• Goldman-Cecil Medicine, p. 1767-1768

Acquired (Secondary) Neutropenias

• Predictable, dose-dependent: antineoplastics, AZT, ganciclovir, TMP-SMX, chloramphenicol, allopurinol
• Idiosyncratic immune-mediated: clozapine, carbimazole/methimazole/PTU (antithyroids), quinidine, procainamide, sulfasalazine, levamisole (cocaine adulterant)
• Typically presents 1-2 weeks after drug initiation; recovery within 3-10 days of stopping. Mortality from drug-induced agranulocytosis is 2.5-10%. G-CSF speeds recovery.

• Viral: varicella, measles, rubella, EBV, CMV, HIV, hepatitis A/B, parvovirus, influenza
• Atypical: M. tuberculosis, ehrlichiosis, rickettsia, tularemia, brucellosis
• Overwhelming sepsis: consumption of marrow neutrophil reserves + margination from complement activation (mainly in neonates and elderly)

• Primary autoimmune neutropenia (infants/children - usually benign, self-resolving)
• Secondary: Felty syndrome (RA + splenomegaly + neutropenia), SLE, Sjögren syndrome
• Large granular lymphocyte (LGL) leukemia - cytotoxic T cells/NK cells suppress myelopoiesis
• Alloimmune neonatal neutropenia (maternal-fetal antigen incompatibility)

• Aplastic anemia, myelodysplastic syndrome (MDS), acute leukemia
• Marrow infiltration by metastatic carcinoma
• Radiation injury

• B12, folate (cause ineffective granulopoiesis - often pancytopenia)
• Copper deficiency

• Splenomegaly causes sequestration and accelerated neutrophil removal

• Diagnosis of exclusion after excluding all above causes with bone marrow biopsy

Diagnostic Approach

1. Fever/localizing signs? - If ANC <500/µL: admit for IV antibiotics + consider G-CSF
2. Stop potential drugs, look for toxins
3. Is neutropenia new or chronic?

• New + family history → test for ELANE mutation → consider cyclic neutropenia or familial neutropenia
• If cyclic pattern on serial CBCs → cyclic neutropenia

1. Single lineage vs multilineage?

• Pancytopenia → check B12/folate (megaloblastic anemia) → autoimmune disease? → bone marrow exam
• Isolated neutropenia → bone marrow exam: morphology, cytogenetics, flow cytometry

1. Bone marrow findings:

• Abnormal cytogenetics → myelodysplasia
• LGL on flow → LGL leukemia
• All normal → chronic idiopathic neutropenia

Clinical Features

• Infections are the dominant manifestation - especially gram-positive and gram-negative bacteria, and fungi
• Classic sites: gingiva, buccal mucosa, pharynx, floor of mouth, skin, perianal region, lungs
• Ulcerating, necrotizing oral lesions ("agranulocytic angina") - contain large masses of organisms without pus (no neutrophils to form pus)
• Systemic: malaise, chills, fever
• Fever may be the ONLY sign of infection - normal inflammatory response (redness, swelling, purulence) is absent without neutrophils
• Hypothermia on presentation (<36.5°C) may indicate higher mortality than fever

Febrile Neutropenia - Emergency Management

• Single temperature ≥ 38.3°C, OR
• Temperature ≥ 38.0°C sustained for ≥1 hour
• In a patient with ANC <500/µL (or ANC expected to drop below 500 within 48 hours)

Evaluation

• At least 2 sets of blood cultures before starting antibiotics (one from each lumen of central lines; one peripheral)
• Cultures from suspected sites (sputum, urine, wound)
• CBC, BMP, LFTs, chest X-ray
• Avoid digital rectal exam and rectal temperatures (risk of bacteremia from disrupted rectal flora)
• CT if clinically indicated

Treatment

• Empiric broad-spectrum IV antibiotics within 30-60 minutes of presentation
• Monotherapy with an anti-pseudomonal beta-lactam is standard: piperacillin-tazobactam, cefepime, meropenem, or imipenem
• Pseudomonas aeruginosa is the key organism to always cover
• Add vancomycin if: catheter-related infection, skin/soft tissue infection, hemodynamic instability, MRSA colonization
• Add antifungal coverage if: fever persists >4-7 days despite antibiotics, or high-risk setting
• G-CSF may be added in high-risk cases (Goldman-Cecil Medicine, p. 1769-1770; Rosen's Emergency Medicine)

MASCC Risk Score

Treatment of Non-Febrile Neutropenia

Cyclic Neutropenia - Key Points

• Autosomal dominant, ELANE mutation
• ~21-day cycle; nadir lasts 4-6 days
• Stomatitis, pharyngitis, lymphadenitis, cellulitis during nadirs
• Risk of serious infections (Clostridium septicum bacteremia is classic)
• Managed with G-CSF; NOT associated with AML/MDS transformation (unlike severe congenital neutropenia)
• Goldman-Cecil Medicine, p. 1767

Key Points Summary

• ANC <500/µL: markedly increased infection risk; fever = emergency
• Drug-induced neutropenia is the most common cause overall
• Viral infections cause transient self-limited neutropenia
• Always check for Duffy-null genetic background in asymptomatic patients of African/Middle Eastern descent before labeling as neutropenic
• Fever may be the only sign of severe infection - empiric antibiotics must not be delayed
• G-CSF is the cornerstone of treatment for congenital and chemotherapy-related neutropenia
• No role for low-bacterial diet in neutropenic cancer patients