What is the initial work up for a patient presenting with neutropenia?

Initial Work-Up for Neutropenia

Begin with a complete blood count (CBC) with differential and platelet count, peripheral blood smear examination, and comprehensive metabolic panel including hepatic transaminases and total bilirubin to establish the severity and context of neutropenia. 1

Immediate Laboratory Assessment

Essential Initial Tests

• CBC with differential leukocyte count and platelet count to calculate the absolute neutrophil count (ANC) and assess for concurrent cytopenias 1
• Peripheral blood smear review to evaluate neutrophil morphology, identify dysplastic features, and assess for blasts or atypical cells 1, 2
• Comprehensive metabolic panel including serum creatinine, blood urea nitrogen, electrolytes, hepatic transaminase enzymes, and total bilirubin 1

Blood Cultures and Infection Work-Up (If Febrile)

• At least 2 sets of blood cultures from separate venipunctures; if a central venous catheter is present, obtain one set from each lumen and one from a peripheral site 1
• Limit blood culture volumes to <1% of total blood volume (approximately 70 mL/kg) in patients weighing <40 kg 1
• Culture specimens from other sites of suspected infection as clinically indicated 1

Risk Stratification

Define Neutropenia Severity

Neutropenia severity directly correlates with infection risk and guides management intensity:

• Mild neutropenia: ANC 1.0-1.5 × 10⁹/L 2, 3
• Moderate neutropenia: ANC 0.5-1.0 × 10⁹/L 2, 3
• Severe neutropenia: ANC <0.5 × 10⁹/L (highest infection risk) 2, 4, 5
• Profound neutropenia: ANC <100 cells/mm³ (critical risk) 1

Assess Duration and Clinical Context

• Acute neutropenia (evolving over days): typically drug-induced, viral infection, or immune-mediated; often self-limited 2
• Chronic neutropenia (lasting ≥3 months): suggests underlying hematologic disorder, congenital defect, or chronic immune process requiring extensive evaluation 2, 4

High-Risk vs. Low-Risk Classification (If Febrile)

High-risk patients require immediate hospitalization and IV antibiotics if they have 1:

• Anticipated prolonged neutropenia (>7 days duration) and profound neutropenia (ANC <100 cells/mm³)
• Hemodynamic instability or hypotension
• Pneumonia or new pulmonary infiltrates
• New-onset abdominal pain or gastrointestinal symptoms
• Neurologic or mental status changes
• Oral/gastrointestinal mucositis interfering with swallowing
• MASCC score <21 1

Low-risk patients may be candidates for outpatient oral therapy if they have 1:

• Anticipated brief neutropenia (<7 days)
• Few or no comorbidities
• MASCC score ≥21
• Clinically stable presentation

Imaging Studies

Chest Radiography

• Obtain chest radiograph for any patient with respiratory signs or symptoms (cough, dyspnea, hypoxemia) 1
• Consider chest CT if clinical suspicion for pulmonary infection remains high despite normal chest radiograph, as inflammatory signs may be attenuated in neutropenic patients 1

Additional Imaging

• Abdominal CT if abdominal pain, distension, or diarrhea present to evaluate for neutropenic enterocolitis (typhlitis), showing bowel wall thickening, pericolic fluid, or pneumatosis intestinalis 6
• Sinus imaging if facial pain or nasal symptoms suggest sinusitis 1

Clinical History and Physical Examination Specifics

Critical Historical Elements

• Medication review: chemotherapy agents, antibiotics (especially beta-lactams), antithyroid drugs, anticonvulsants, immunosuppressants 2, 3
• Timing and pattern: acute onset suggests drug or infection; chronic suggests intrinsic marrow disorder 2, 4
• Infection history: recurrent skin infections, oral ulcers, pneumonias, or perirectal abscesses suggest chronic severe neutropenia 4, 5
• Family history: congenital neutropenia syndromes may have familial patterns 2, 5
• Autoimmune symptoms: arthritis, rash, serositis suggesting systemic lupus erythematosus or rheumatoid arthritis 2
• HIV risk factors and viral exposure history 7

Focused Physical Examination

• Oral cavity: examine for ulcers, gingivitis, periodontitis (common in chronic severe neutropenia) 1, 4, 5
• Skin: inspect for cellulitis, abscesses, catheter site infections, perirectal inflammation 1
• Pharynx and sinuses: assess for pharyngitis or sinus tenderness 1
• Lungs: auscultate for pneumonia (though signs may be subtle in neutropenic patients) 1
• Abdomen: palpate for hepatosplenomegaly, tenderness, or peritoneal signs 1
• Lymph nodes: assess for lymphadenopathy suggesting lymphoproliferative disorder 1

Common Pitfalls to Avoid

• Do not dismiss mild neutropenia (ANC 1.0-1.5 × 10⁹/L): even subnormal counts carry increased risk for viral infections (OR 2.32) and haematological malignancies (OR 3.23) 7
• Do not delay blood cultures in febrile neutropenic patients: obtain cultures immediately before initiating empirical antibiotics, as progression can be rapid 1
• Do not overlook signs of infection in neutropenic patients: inflammatory signs are often attenuated or absent; subtle findings like mild pain or low-grade fever may represent serious infection 1
• Do not assume benign etiology without bone marrow evaluation in chronic severe neutropenia: moderate-severe neutropenia carries 46-fold increased odds of haematological malignancy and >50% absolute risk of mortality 7
• Do not start G-CSF before confirming diagnosis in suspected chronic neutropenia: premature treatment may impair diagnostic evaluation of underlying conditions 8

When to Proceed to Bone Marrow Evaluation

Obtain bone marrow aspirate and biopsy with cytogenetics for 1, 2, 4, 5:

• Severe chronic neutropenia (ANC <0.5 × 10⁹/L lasting >3 months)
• Unexplained neutropenia with concurrent cytopenias
• Peripheral blood smear showing dysplastic features or blasts
• Clinical suspicion for myelodysplastic syndrome, acute leukemia, or aplastic anemia
• Failure to identify reversible cause after initial work-up

Bone marrow examination evaluates 1, 5:

• Cellularity and myeloid maturation arrest patterns
• Cytogenetic abnormalities
• Infiltrative processes (malignancy, granulomas, fibrosis)
• Maturation defects in congenital neutropenia syndromes

Additional Diagnostic Considerations

Autoimmune and Infectious Serologies

• Antinuclear antibodies (ANA), rheumatoid factor if autoimmune disorder suspected 2
• HIV testing given strong association (neutropenia increases HIV odds significantly) 7
• Viral serologies (EBV, CMV, hepatitis) if acute viral infection suspected 7, 2

Nutritional Deficiencies

• Vitamin B12 and folate levels if macrocytic indices or megaloblastic features present 2
• Copper levels if history of zinc supplementation or gastric surgery 2

The lower the ANC, the greater the urgency for comprehensive evaluation: severe neutropenia (ANC <0.5 × 10⁹/L) carries absolute risks exceeding 40% for haematological malignancy and 50% for all-cause mortality, necessitating aggressive diagnostic pursuit 7.