What is the differential diagnosis and recommended workup for an adult with leukocytosis (white blood cell count 12.7 ×10⁹/L), neutrophilia (absolute neutrophil count 8,712/µL), and elevated hemoglobin (19.1 g/dL) and hematocrit (56.1%)?

Differential Diagnosis and Workup for Leukocytosis with Neutrophilia and Polycythemia

This patient requires immediate evaluation for polycythemia vera (PV) given the markedly elevated hemoglobin (19.1 g/dL) and hematocrit (56.1%), combined with leukocytosis and neutrophilia—a classic triad for this myeloproliferative neoplasm. 1, 2

Immediate Diagnostic Priority: Polycythemia Vera

The combination of hemoglobin >18.5 g/dL in men (or >16.5 g/dL in women) with hematocrit >56% meets the major criterion for PV and mandates JAK2 mutation testing as the next step. 1, 2

Key Laboratory Features Supporting PV:

• Hemoglobin 19.1 g/dL and hematocrit 56.1% exceed diagnostic thresholds (men: Hb >18.5 g/dL, Hct >49%; women: Hb >16.5 g/dL, Hct >48%) 1, 2
• Leukocytosis (WBC 12.7 × 10⁹/L) with neutrophilia (ANC 8,712/µL) is present in the majority of PV patients, with thrombocytosis also common 2
• Approximately 95% of PV patients carry JAK2V617F mutation, making this the most specific diagnostic test 1, 2

Mandatory Workup for PV:

• JAK2V617F mutation testing by RT-PCR (first-line) 1, 2
• Serum erythropoietin level (typically low/suppressed in PV, serving as a minor criterion) 1
• Bone marrow biopsy with cytogenetics to confirm panmyelosis with prominent erythroid and megakaryocytic proliferation, and to detect abnormal karyotype (present in 15-20% of cases) 1, 2
• Complete metabolic panel to assess for secondary causes of erythrocytosis 1
• Arterial oxygen saturation to exclude hypoxia-driven secondary polycythemia 1

Secondary Consideration: Exclude Infection

While PV is the primary concern, the absolute neutrophil count of 8,712/µL warrants assessment for occult bacterial infection, particularly given that neutrophilia can occur in both conditions. 3, 4

Critical Infection Assessment:

• Check vital signs immediately: fever ≥38.3°C, hypotension, tachycardia, tachypnea, altered mental status 3, 4
• Manual differential count is mandatory to assess for left shift (≥16% bands, likelihood ratio 4.7 for bacterial infection) and absolute band count ≥1,500 cells/mm³ (likelihood ratio 14.5) 3, 5
• Blood cultures if any systemic signs present 3, 4
• Urinalysis with culture to exclude urinary tract infection 5
• Lactate level: if >3 mmol/L, indicates severe sepsis requiring immediate antibiotics 4, 5

Infection Likelihood in This Case:

• The neutrophil count of 8,712/µL is elevated but not extreme, and without fever or systemic signs, infection is less likely than PV 3
• If patient is hemodynamically stable and asymptomatic, complete PV workup first before empiric antibiotics 5

Tertiary Consideration: Other Myeloproliferative Neoplasms

Chronic myeloid leukemia (CML) must be excluded, though less likely given the absence of extreme leukocytosis. 1

Features That Would Suggest CML:

• Basophilia is highly specific for CML when present with leukocytosis 4
• WBC counts typically >20 × 10⁹/L, often >50 × 10⁹/L at diagnosis 1
• BCR-ABL1 fusion gene testing (RT-PCR or FISH) is diagnostic if CML suspected 1, 4
• Peripheral smear showing immature granulocytes (metamyelocytes, myelocytes, promyelocytes) 1

Adult-Onset Still's Disease (AOSD)

AOSD is a remote consideration given the laboratory findings, but should be considered if fever, rash, or arthritis develop. 1

AOSD Laboratory Pattern:

• Leukocytosis with striking neutrophilia (50% have WBC >15 × 10⁹/L, 37% have WBC >20 × 10⁹/L) 1
• Elevated ESR and CRP in virtually all patients 1
• Markedly elevated ferritin (>1,000 ng/mL, often >5,000 ng/mL) with high sensitivity for AOSD 1
• However, AOSD does not cause polycythemia—this patient's elevated hemoglobin/hematocrit excludes AOSD as the primary diagnosis 1

Critical Pitfalls to Avoid

• Do not dismiss the polycythemia as secondary or spurious—hemoglobin 19.1 g/dL and hematocrit 56.1% are too elevated for physiologic causes and demand JAK2 testing 1, 2
• Do not rely on automated differential alone—manual review is essential to identify left shift, toxic granulations, and dysplasia 4, 5
• Do not ignore elevated neutrophils when total WBC is only mildly elevated—left shift can occur with normal or near-normal WBC and still indicate serious bacterial infection 3, 5
• Do not delay antibiotics if sepsis criteria are present (fever, hypotension, lactate >3 mmol/L)—initiate within 1 hour of recognition 4, 5

Recommended Diagnostic Algorithm

Step 1: Immediate Assessment

• Vital signs and clinical examination for signs of infection or thrombosis 3, 4
• Manual differential count to assess for left shift and immature forms 3, 4

Step 2: If Hemodynamically Stable and Afebrile

• JAK2V617F mutation testing (first priority) 1, 2
• Serum erythropoietin level 1
• Peripheral blood smear review for dysplasia, basophilia, or immature granulocytes 1, 4
• Basic metabolic panel, liver function tests 1

Step 3: If JAK2 Positive or High Clinical Suspicion for PV

• Bone marrow biopsy with cytogenetics and molecular studies 1, 2
• Assess for thrombosis risk factors (age >60 years, prior thrombosis history) 2
• Initiate phlebotomy to target hematocrit <45% and aspirin 81 mg daily if no contraindications 2

Step 4: If JAK2 Negative

• Consider exon 12 JAK2 mutations (present in ~3% of JAK2V617F-negative PV) 1, 2
• Reassess for secondary causes of polycythemia (sleep apnea, chronic lung disease, renal tumors) 1
• BCR-ABL1 testing if CML suspected 1, 4

Step 5: If Infection Suspected

• Blood cultures, urinalysis with culture, site-specific cultures 3, 5
• Chest imaging if respiratory symptoms 5
• Empiric antibiotics only if sepsis criteria met 4, 5