What causes a high monocyte count?

Causes of High Monocyte Count

Monocytosis (absolute monocyte count >0.8-1.0 × 10⁹/L) results from either reactive conditions—most commonly infections, inflammatory disorders, and recovery from bone marrow suppression—or clonal hematologic malignancies, particularly chronic myelomonocytic leukemia (CMML) and other myeloid neoplasms. 1

Reactive (Non-Clonal) Causes

Infectious Etiologies

• Chronic infections are the most common infectious cause, including tuberculosis, subacute bacterial endocarditis, and parasitic infections such as Strongyloides 1, 2
• Ehrlichiosis (E. chaffeensis, E. ewingii) characteristically presents with monocytosis alongside leukopenia, thrombocytopenia, and elevated hepatic transaminases 1
• Viral infections including HIV and hepatitis C can cause monocytosis that may be clinically indistinguishable from primary hematologic disorders 3
• Recovery phase of acute infections commonly triggers reactive monocytosis 2, 4

Inflammatory and Autoimmune Conditions

• Systemic lupus erythematosus (SLE) and other autoimmune disorders frequently cause monocytosis 3
• Adult-onset Still's disease demonstrates monocytosis as part of its inflammatory profile 3
• Inflammatory bowel disease and rheumatoid arthritis are associated with elevated monocyte counts 3
• Chronic inflammatory states activate innate immunity, driving monocyte production and recruitment 4

Malignancy-Associated Monocytosis

• Solid tumors can cause paraneoplastic monocytosis through cytokine production 1
• Lymphoproliferative disorders including chronic lymphocytic leukemia (CLL) may present with monocytosis; elevated absolute monocyte count in CLL correlates with inferior outcomes and accelerated disease progression 3, 5
• Monocyte count is highest in malignant pericardial effusions (79 ± 27%) compared to other causes 3

Other Reactive Causes

• Recovery from bone marrow suppression following chemotherapy or severe infection 1, 2
• Medications including corticosteroids (paradoxically can cause both increase and decrease), lithium, and certain immunosuppressants 2
• Physical and emotional stress, including seizures, anesthesia, or overexertion 2
• Hypothyroidism shows elevated monocyte percentages in pericardial effusions (74 ± 26%) 3

Clonal (Neoplastic) Causes

Chronic Myelomonocytic Leukemia (CMML)

• CMML is the primary clonal cause requiring 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
• Bone marrow evaluation reveals dysplasia in one or more myeloid lineages and often demonstrates mutations in TET2, SRSF2, ASXL1, or RAS genes 1

Other Myeloid Neoplasms

• Acute myeloid leukemia (AML) with monocytic differentiation (M4 and M5 subtypes) 1
• Juvenile myelomonocytic leukemia (JMML) in pediatric populations 1
• Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase fusion genes may present with monocytosis 1
• Myelodysplastic syndromes (MDS) can show monocytosis, though absolute monocyte count typically remains <1 × 10⁹/L 1

Critical Diagnostic Approach

Initial Evaluation

• Obtain detailed history focusing on infections (especially travel-related parasitic infections), medications, autoimmune symptoms, constitutional symptoms (fever, weight loss, night sweats), and family history of hematologic malignancies 1
• Physical examination must assess spleen size (moderate/massive splenomegaly suggests malignancy rather than reactive causes), lymphadenopathy, hepatomegaly, and cutaneous lesions 3, 1
• Complete blood count with differential to determine absolute monocyte count (not just percentage) and assess for concurrent cytopenias or other abnormalities 1

Peripheral Blood Smear Examination

• Mandatory evaluation by qualified hematologist/pathologist to assess monocyte morphology, presence of dysgranulopoiesis, promonocytes, blasts, and immature forms 3, 1
• Look for morulae in monocytes (suggests ehrlichiosis) and rouleaux formation (suggests plasma cell dyscrasia) 1
• Exclude pseudo-monocytosis from EDTA-dependent platelet agglutination 3

When to Pursue Bone Marrow Evaluation

Bone marrow aspiration and biopsy are indicated for: 1

• Persistent unexplained monocytosis without clear reactive cause
• Absolute monocyte count ≥1 × 10⁹/L sustained over time
• Concurrent cytopenias or other blood count abnormalities
• Constitutional symptoms or organomegaly
• Dysplastic features on peripheral smear

Bone marrow workup must include: 1

• Morphologic assessment of blast percentage and dysplasia
• Gomori's silver staining for fibrosis
• Conventional cytogenetics to exclude t(9;22), t(5;12), and other translocations
• Molecular testing for CMML-associated mutations (TET2, SRSF2, ASXL1, RAS)
• Flow cytometry to exclude lymphoproliferative disorders

Common Pitfalls to Avoid

• Failing to distinguish relative from absolute monocytosis—always calculate absolute monocyte count, as percentage alone can be misleading when total WBC is abnormal 1
• Missing underlying infections—particularly tuberculosis, ehrlichiosis, and parasitic infections that require specific testing 1
• Overlooking medication effects—corticosteroids and other drugs commonly alter monocyte counts 2
• Not recognizing transient elevations—exercise, stress, and diurnal variations can temporarily increase monocytes; serial measurements are more informative than single values 6
• Delaying bone marrow evaluation in persistent cases—waiting too long to investigate unexplained persistent monocytosis can delay diagnosis of CMML or other myeloid neoplasms 1
• Ignoring concurrent laboratory abnormalities—anemia, thrombocytopenia, or other cytopenias significantly increase suspicion for primary bone marrow disorders 3, 2