What causes elevated monocytes?

Causes of Elevated Monocytes

Elevated monocytes result from two major categories: reactive (benign) conditions including chronic infections, inflammatory diseases, and tissue injury, or clonal hematologic malignancies, particularly chronic myelomonocytic leukemia (CMML), which must be systematically excluded when monocytosis persists beyond 3 months. 1

Reactive (Benign) Causes

Infectious Etiologies

• Chronic infections are the most common infectious triggers, particularly tuberculosis and bacterial endocarditis 1
• Monocyte recruitment occurs during viral, bacterial, fungal, and protozoal infections as part of normal host defense mechanisms 2

Inflammatory and Autoimmune Conditions

• Adult-onset Still's disease presents with marked leukocytosis including monocytosis, often with white blood cell counts >15×10⁹ cells/L 3, 1
• Inflammatory bowel disease (both Crohn's disease and ulcerative colitis) causes chronic monocyte elevation 1
• Systemic lupus erythematosus and rheumatoid arthritis involve aberrant monocyte activation and expansion of specific monocyte subsets 4
• Chronic inflammatory conditions of any cause trigger monocyte expansion through persistent cytokine stimulation 1

Cardiovascular Disease

• Atherosclerosis and coronary artery disease are associated with elevated monocyte counts, as monocytes play a pathogenic role in plaque formation 1

Malignancy

• Solid tumors spontaneously elevate CD16+ monocyte populations in the majority of cancer patients (35 of 44 patients across various tumor types) 5
• Monocyte elevation in cancer patients appears to represent a host immune response to malignancy, with CD16+ monocytes accounting for 46% ± 22% of total monocytes versus 5% ± 3% in controls 5
• This elevation is independent of infection or intercurrent illness and correlates with the underlying malignancy itself 5

Other Reactive Causes

• Tissue injury and repair from any cause can lead to monocytosis 1
• Hormonal fluctuations during menstruation may cause transient monocytosis due to approximately ten-fold changes in estradiol levels affecting immune cell production 6

Clonal (Malignant) Causes

Chronic Myelomonocytic Leukemia (CMML)

• CMML is the primary hematologic malignancy causing persistent monocytosis and requires specific diagnostic exclusion 1
• WHO 2008 criteria include: persistent peripheral blood monocytosis (>1×10⁹/L), absence of Philadelphia chromosome or BCR-ABL1 fusion gene, and <20% blasts in blood and bone marrow 1
• Molecular mutations commonly found include TET2, SRSF2, ASXL1, and RAS 1

COVID-19-Related Monocytosis

• Monocyte and macrophage hyperactivation contributes to increased circulating pro-inflammatory cytokines (TNF-α, IL-6, IL-1, IFN-γ) in COVID-19 patients, particularly those in intensive care 3
• This represents part of the systemic inflammatory response syndrome (SIRS) associated with severe disease 3

Diagnostic Approach Algorithm

Initial Evaluation

• Absolute monocyte count >1×10⁹/L persisting beyond 3 months requires hematologic workup 1
• Complete blood count with differential and peripheral blood smear examination to assess for dysplasia, additional cytopenias, or circulating blasts 1

When to Pursue Malignancy Workup

• Persistent monocytosis without clear reactive cause mandates bone marrow evaluation 1
• Essential workup includes bone marrow aspiration and biopsy with conventional cytogenetics 1
• Molecular testing for BCR-ABL1 and mutations in TET2, SRSF2, ASXL1, and RAS genes is necessary 1

Common Pitfalls

• Failing to distinguish between transient reactive monocytosis and persistent elevation requiring malignancy evaluation
• Not recognizing that cancer patients may have spontaneously elevated monocytes as a host response, which differs from CMML
• Overlooking chronic infections like tuberculosis or endocarditis as treatable causes