What are the causes of monocytosis (elevated monocyte count)?

Monocytosis Causes

Monocytosis results from either reactive (benign) conditions or clonal hematologic malignancies, with chronic myelomonocytic leukemia (CMML) being the most critical diagnosis to exclude in persistent cases. 1, 2

Reactive (Non-Clonal) Causes

Infectious Etiologies

• Chronic bacterial infections: Tuberculosis and bacterial endocarditis are classic triggers of persistent monocyte elevation 2, 3
• Viral infections: HIV and hepatitis C produce monocytosis that may be clinically indistinguishable from primary hematologic disorders 1, 3
• Ehrlichiosis (E. chaffeensis, E. ewingii): Presents with monocytosis alongside leukopenia, thrombocytopenia, and elevated hepatic transaminases; morulae visible within monocytes on peripheral smear 1, 3
• Listeria monocytogenes: Causes severe septicemia and meningitis with considerable mortality, particularly in immunosuppressed patients—requires immediate lumbar puncture if neurological symptoms present 2
• Parasitic infections: Strongyloidiasis and other parasitic exposures, especially with travel history 1
• Post-transfusion CMV: Mononucleosis syndrome occurring approximately 1 month after transfusion, presenting with high fever, atypical lymphocytosis, and mild liver function test elevations 4

Inflammatory and Autoimmune Conditions

• Inflammatory bowel disease (Crohn's disease and ulcerative colitis): Causes chronic monocyte elevation 1, 2, 3
• Systemic lupus erythematosus and other autoimmune disorders frequently cause monocytosis 1, 3
• Adult-onset Still's disease: Presents with marked leukocytosis including monocytosis, often with WBC >15×10⁹/L 2, 3
• Rheumatoid arthritis: Associated with elevated monocyte counts 1, 3

Cardiovascular and Tissue Injury

• Atherosclerosis and coronary artery disease: Associated with elevated monocyte counts due to their pathogenic role in plaque formation 2
• Tissue injury and chronic inflammation of any cause triggers monocytosis through persistent cytokine stimulation 2

Other Reactive Causes

• Recovery from bone marrow suppression: Represents a physiologic cause of transient monocytosis 1, 3
• Solid tumors: Can produce reactive monocytosis 1, 3
• Allergic disorders and drug reactions: Less common but recognized causes 4

Clonal (Neoplastic) Causes

Primary Myeloid Malignancies

• Chronic myelomonocytic leukemia (CMML): The prototypical disorder requiring persistent peripheral blood monocytosis ≥1×10⁹/L, absence of Philadelphia chromosome or BCR-ABL1 fusion gene, and <20% blasts in peripheral blood and bone marrow 1, 2, 3
• Myelodysplastic syndromes (MDS): Can present with monocytosis, though absolute monocyte count typically remains <1×10⁹/L; presence of dyserythropoiesis, macrocytosis, pseudo Pelger-Huet anomaly, or predominance of small megakaryocytes with monolobated nuclei suggests MDS 4, 1, 3
• Acute myeloid leukemia with monocytic differentiation: Presents with monocytosis and typically more acute clinical presentation 3
• Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase (TK) fusion genes: May present with neutrophilia, basophilia, thrombocytosis, monocytosis, and myeloid immaturity 4, 1, 3

Secondary Hematologic Malignancies

• Chronic lymphocytic leukemia (CLL): Elevated absolute monocyte count correlates with inferior outcomes and accelerated disease progression 1
• Plasma cell dyscrasias: Rouleaux formation on peripheral smear suggests this diagnosis 1

Diagnostic Approach Algorithm

Initial Assessment

1. Confirm absolute monocytosis: Calculate absolute monocyte count from CBC with differential (>0.8-1.0×10⁹/L) 1, 2, 3
2. Obtain focused history: Travel exposure, new medications, recurrent infections, family history of hematologic malignancies, constitutional symptoms (fever, night sweats, weight loss), bleeding or bruising 1, 3
3. Targeted physical examination: Assess spleen size, cutaneous lesions, lymphadenopathy, signs of organ damage 1, 3

Laboratory Evaluation

• Peripheral blood smear examination: Assess monocyte morphology, dysgranulopoiesis, promonocytes, blasts, neutrophil precursors, rouleaux formation (suggests plasma cell dyscrasia), and morulae in monocytes (suggests ehrlichiosis) 1, 3
• Comprehensive metabolic panel: Including calcium, albumin, creatinine, and liver function tests 1, 3
• If plasma cell dyscrasia suspected: Serum protein electrophoresis with immunofixation, serum-free light chains, 24-hour urine collection for electrophoresis and immunofixation, and CD138 stains 1

Indications for Bone Marrow Evaluation

Bone marrow aspiration and biopsy are indicated for: 1, 2, 3

• 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 Studies

• Morphologic assessment: Percentage of blasts (including myeloblasts, monoblasts, and promonocytes), marrow cellularity, presence of dysplasia 1, 2, 3
• Gomori's silver impregnation staining: For fibrosis assessment 1, 2, 3
• Conventional cytogenetic analysis: To identify clonal abnormalities and exclude t(9;22) Philadelphia chromosome, BCR-ABL1 fusion gene, t(5;12) translocation, del(5q), t(3;3)(q21;q26), or inv(3)(q21q26) 4, 1, 2, 3
• Molecular testing: For mutations commonly found in CMML (TET2, SRSF2, ASXL1, RAS) 1, 2, 3

Critical Pitfalls to Avoid

• Failing to distinguish absolute from relative monocytosis: Can lead to unnecessary workup or missed diagnoses 1, 2, 3
• Not performing comprehensive bone marrow evaluation in persistent unexplained monocytosis delays diagnosis of treatable malignancies like CMML 1, 2, 3
• Missing underlying infections or malignancies by attributing monocytosis solely to inflammatory conditions without adequate investigation 1, 2, 3
• Overlooking molecular testing to exclude specific myeloid neoplasms in persistent cases 1, 2
• Ignoring transient post-treatment changes: Monocytosis can occur during immune response initiation and is typically not clinically significant 2
• In immunosuppressed patients with monocytosis and neurological symptoms: Failure to perform immediate lumbar puncture to exclude Listeria monocytogenes meningitis can be fatal 2