Causes of Low WBC and Low Absolute Neutrophils
Leukopenia with neutropenia results from either decreased bone marrow production, increased peripheral destruction, or redistribution of neutrophils, with the most common causes being chemotherapy-induced bone marrow suppression, medications (especially antibiotics), infections, autoimmune disorders, and hematologic malignancies. 1, 2
Primary Etiologic Categories
Decreased Bone Marrow Production
- Chemotherapy and cytotoxic agents are the most frequent cause, with standard-dose chemotherapy causing febrile neutropenia in 10-57% of patients and AML induction/consolidation causing it in 35-48% 1
- Hematologic malignancies including chronic lymphocytic leukemia (CLL), hairy cell leukemia, and acute leukemias cause marrow infiltration and failure 3, 1
- Stem cell transplantation (both autologous and allogeneic) regularly causes profound neutropenia 1
- Megaloblastic anemia from vitamin B12 or folate deficiency impairs myeloid cell maturation 4
Increased Peripheral Destruction or Utilization
- Severe infections consume neutrophils faster than they can be produced, with bacterial sepsis being particularly common 3, 5, 4
- Autoimmune neutropenia from antibodies directed against neutrophils causes accelerated destruction 2, 4
- Hypersplenism sequesters and destroys neutrophils in an enlarged spleen 4
Medication-Induced Neutropenia
- Beta-lactam antibiotics (especially penicillinase-resistant penicillins, ticarcillin, moxalactam, cefoxitin) cause immunologic destruction of peripheral neutrophils, particularly at high doses (≥150 mg/kg/day in pediatrics) 6
- Purine analogs (cladribine, pentostatin) used in CLL and hairy cell leukemia produce profound and prolonged immunosuppression lasting over a year 3
- Anti-CD20 monoclonal antibodies (rituximab, obinutuzumab) reduce both B cells and granulocytes 3
- Recovery typically occurs within days after discontinuing the offending medication 6
Viral Infections
- Acute viral infections (EBV, CMV, HSV, VZV, respiratory viruses) cause transient neutropenia with relative or absolute reduction in neutrophils 7
- These typically present with fever, constitutional symptoms, and self-limited course 7
Congenital and Hereditary Disorders
- Primary neutropenia syndromes are rare but may be hereditary and associated with other developmental defects, particularly in children 5, 4
- Intrinsic marrow defects cause impaired proliferation and maturation of myeloid progenitor cells 2
Critical Risk Stratification
Severity Classification
- Mild neutropenia: ANC 1.0-1.5 × 10⁹/L 8
- Moderate neutropenia: ANC 0.5-1.0 × 10⁹/L 8
- Severe neutropenia: ANC <0.5 × 10⁹/L, with greatest infection risk when ANC <100/mcL 3, 1, 8
Duration Matters
- Prolonged neutropenia (>7 days) significantly increases infection risk and mortality 3, 1, 8
- The rate of neutrophil count decline correlates with bone marrow reserve and infection severity 3, 1
Essential Diagnostic Workup
Immediate evaluation should include:
- Complete blood count with differential to calculate absolute neutrophil count 8, 7
- Peripheral blood smear examination to assess cell morphology 5
- Comprehensive medication review, particularly recent antibiotics and chemotherapy 2, 6
- Assessment for fever (>38.5°C for >1 hour), which constitutes a medical emergency when ANC <0.5 × 10⁹/L 1, 8, 7
Additional testing based on clinical context:
- Bone marrow aspirate/biopsy with cytogenetics if etiology unclear or malignancy suspected 5, 2
- Viral serologies (EBV, CMV, HSV, VZV) if acute infection suspected 7
- Serum immunoglobulins and protein electrophoresis if recurrent infections present 7
- Blood cultures, urine cultures, and chest X-ray before initiating antibiotics in febrile patients 8
Critical Clinical Pitfalls
Signs and symptoms of infection are often absent or muted in severely neutropenic patients due to lack of inflammatory cells, leaving patients with infections but without typical cellulitis, pulmonary infiltrates, CSF pleocytosis, or pyuria 3. Fever remains the primary early indicator 3.
Approximately 50-60% of febrile neutropenic patients have an established or occult infection, with 10-20% developing bloodstream infections when ANC <100/mcL 3, 1. Primary infection sites include the alimentary tract (mouth, pharynx, esophagus, colon, rectum), sinuses, lungs, and skin 3.
Gram-positive organisms (coagulase-negative staphylococci, S. aureus, viridans streptococci, enterococci) and gram-negative organisms (E. coli, Klebsiella, Enterobacter, P. aeruginosa) are the most common initial pathogens 3, 1. Antibiotic-resistant bacteria, fungi (especially Candida and Aspergillus), and viruses cause subsequent infections 3.
Empirical broad-spectrum antibiotics must be initiated within 2 hours of fever presentation in neutropenic patients, as earlier administration is associated with fewer complications 1, 8. For severe neutropenia (ANC <0.5 × 10⁹/L), implement prophylactic fluoroquinolone therapy in high-risk patients 8.