What is the differential diagnosis (DDx) for a patient with leukocytosis characterized by elevated absolute neutrophils and elevated absolute monocytes?

Differential Diagnosis for Leukocytosis with Elevated Absolute Neutrophils and Elevated Absolute Monocytes

The combination of elevated absolute neutrophils and monocytes most commonly indicates bacterial infection, chronic inflammatory conditions, or chronic myelomonocytic leukemia (CMML), with the clinical context and peripheral blood smear being critical to distinguish between these entities. 1, 2

Primary Diagnostic Categories

Infectious Etiologies

• Bacterial infections are the most common cause when leukocytosis exceeds 14,000 cells/mm³ with neutrophilia 1, 3
• Look specifically for: severe bacterial infections affecting lungs, skin, or viscera; signs of sepsis including hemodynamic instability, altered mental status, or organ dysfunction 1, 3
• Mycobacterial or Salmonella infections can present with this pattern and warrant specific consideration 1
• Fungal infections, particularly in immunocompromised patients, may produce combined neutrophil and monocyte elevation 1

Chronic Inflammatory Conditions

• Inflammatory bowel disease, vasculitis, and other chronic inflammatory states commonly produce this dual elevation 3, 4
• These conditions typically show persistent rather than acute leukocytosis 4
• Autoimmune disorders may present with leukocytosis and should be considered when infection is excluded 5

Hematologic Malignancies

Chronic Myelomonocytic Leukemia (CMML)

• CMML is the prototypical malignancy presenting with persistent monocytosis (>1×10⁹/L) combined with neutrophilia 1
• Key diagnostic features include: peripheral blood monocytes >1×10⁹/L, bone marrow blasts <20%, dysplasia in one or more myeloid lineages, and absence of BCR-ABL fusion gene 1
• Flow cytometry showing monocyte repartitioning can distinguish CMML from reactive causes 2
• CMML patients often present with splenomegaly, and the condition is more common in older adults (median age 65-70 years) 1

Other Myeloproliferative Neoplasms

• Leukocyte adhesion defects present with marked leukocytosis even without active infection 1
• Acute myeloid leukemia (AML) may present with leukocytosis, particularly with excessive leukocytosis and clinical signs of leukostasis 1
• Plasma cell leukemia can present with leukocytosis, elevated LDH, and aggressive clinical features 1

Physiologic and Reactive Causes

• Stress responses from surgery, trauma, burns, myocardial infarction, or emotional stress can cause acute leukocytosis with neutrophilia 3, 4
• Physical exercise can double the peripheral white blood cell count within hours 4
• Medications, particularly corticosteroids and G-CSF, commonly cause neutrophilia and can mask fever 3, 4
• Smoking, obesity, and asplenia are chronic causes of leukocytosis 4

Diagnostic Approach Algorithm

Step 1: Assess Clinical Context

• Determine if presentation is acute (hours to days) versus chronic (weeks to months) 6, 7
• Identify fever, hemodynamic instability, altered mental status, or organ dysfunction suggesting sepsis 1, 3
• Look for constitutional symptoms (fever, weight loss, night sweats, fatigue) suggesting malignancy 7, 4
• Examine for organomegaly (splenomegaly, hepatomegaly, lymphadenopathy) which suggests CMML or other hematologic malignancy 1

Step 2: Evaluate Laboratory Parameters

• If WBC >14,000 cells/mm³ or left shift (band neutrophils >16% or >1,500 cells/mm³): high probability of bacterial infection requiring immediate evaluation 1, 3
• If monocytes persistently >1×10⁹/L: strongly consider CMML and obtain peripheral blood smear 1, 2
• Check LDH (elevated in aggressive malignancies like plasma cell leukemia and AML) 1
• Assess for anemia, thrombocytopenia, or dysplasia on peripheral smear 1, 7

Step 3: Peripheral Blood Smear Examination

• Critical for distinguishing reactive from malignant causes 6, 7, 4
• Look for: immature cells (blasts, promyelocytes, promonocytes), dysplastic features, toxic granulations, left shift 1, 7
• Abnormal peripheral smear with constitutional symptoms mandates evaluation for malignancy 7

Step 4: Directed Testing Based on Clinical Suspicion

If Infection Suspected:

• Blood cultures, urinalysis, chest imaging, and site-specific cultures 1
• Consider mycobacterial and fungal studies if appropriate risk factors present 1

If CMML or Hematologic Malignancy Suspected:

• Bone marrow aspiration and biopsy with conventional cytogenetics 1
• Molecular testing to exclude BCR-ABL (chronic myeloid leukemia) and PDGFRA/PDGFRB rearrangements 1
• Flow cytometry for monocyte immunophenotyping 1, 2
• Consider molecular mutation analysis (TET2, SRSF2, KRAS, NRAS) if CMML suspected, though not yet standard for routine diagnosis 1

If Chronic Inflammatory Condition Suspected:

• Inflammatory markers (ESR, CRP), autoimmune serologies, imaging as clinically indicated 3, 4

Critical Pitfalls to Avoid

• Do not dismiss persistent monocytosis >1×10⁹/L as reactive without excluding CMML, as this is the defining feature of this malignancy 1, 2
• Do not attribute leukocytosis solely to corticosteroids or stress without reviewing the peripheral smear for dysplasia or immature cells 3, 4
• Do not delay hematology referral if constitutional symptoms, organomegaly, or abnormal peripheral smear are present, as acute leukemias require urgent management 1, 7
• In the absence of fever, leukocytosis, or left shift, additional diagnostic tests may have low yield unless specific clinical manifestations of focal infection exist 1
• Patients with marked leukocytosis at presentation may require emergency leukapheresis if clinical signs of leukostasis are present 1