What are the causes of monocytosis?

Causes of Monocytosis

Monocytosis (absolute monocyte count >1.0 × 10⁹/L) 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 including tuberculosis, bacterial endocarditis, and parasitic infections are common triggers of sustained monocytosis 1, 2, 3
• Viral infections such as HIV, hepatitis C, and post-transfusion cytomegalovirus (CMV) can produce monocytosis clinically indistinguishable from primary hematologic disorders 1, 2
• Ehrlichiosis presents with the triad of monocytosis, leukopenia, and thrombocytopenia alongside elevated hepatic transaminases, with morulae visible within monocytes on peripheral smear 1, 2
• Listeria monocytogenes causes severe septicemia and meningitis with considerable mortality, particularly in immunosuppressed patients 3

Inflammatory and Autoimmune Conditions

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

Cardiovascular and Tissue Injury

• Atherosclerosis and coronary artery disease are associated with elevated monocyte counts due to the pathogenic role of monocytes in plaque formation 3, 4
• Tissue injury and chronic inflammation of any cause can trigger monocytosis through persistent cytokine stimulation 3

Other Reactive Causes

• Solid tumors can produce reactive monocytosis 5, 2
• Recovery from bone marrow suppression represents a physiologic cause of transient monocytosis 2
• Splenectomy is a recognized cause of reactive monocytosis 5
• Allergic disorders and drug reactions are less common but recognized causes 2

Clonal (Neoplastic) Causes

Chronic Myelomonocytic Leukemia (CMML)

• CMML is the prototypical clonal disorder requiring: (1) persistent peripheral blood monocytosis >1.0 × 10⁹/L, (2) absence of Philadelphia chromosome or BCR-ABL1 fusion gene, (3) no PDGFRA or PDGFRB rearrangements, (4) <20% blasts in peripheral blood and bone marrow, and (5) either dysplasia in ≥1 hematopoietic lineage, clonal cytogenetic abnormality, or monocytosis persisting >3 months without another identifiable cause 5, 1, 2
• Common cytogenetic abnormalities in CMML include chromosome 7 lesions (monosomy or deletions), trisomy 8, and complex karyotypes 5, 1
• Molecular mutations are present in approximately 93% of CMML patients, most commonly involving TET2, SRSF2, ASXL1, and RAS pathway genes 1, 2

Myelodysplastic Syndromes (MDS)

• MDS can present with monocytosis, though the absolute monocyte count typically remains <1.0 × 10⁹/L 1, 2
• Dysplastic features including dyserythropoiesis, macrocytosis, monocytosis, pseudo Pelger-Huët anomaly, or predominance of small megakaryocytes with monolobated nuclei suggest MDS rather than other myeloproliferative disorders 5, 2

Other Myeloid Neoplasms

• Acute myeloid leukemia with monocytic differentiation presents with monocytosis and typically a more acute clinical presentation 2
• Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase fusion genes (involving PDGFRA, PDGFRB) may present with neutrophilia, basophilia, thrombocytosis, monocytosis, and myeloid immaturity 1, 2
• Myeloproliferative neoplasm (MPN) overlap syndromes can manifest with monocytosis 1

Critical Diagnostic Thresholds

The absolute monocyte count >1.0 × 10⁹/L defines monocytosis and serves as the key threshold for further evaluation, not relative percentages 1, 2, 3. Persistent monocytosis ≥1.0 × 10⁹/L lasting >3 months after exclusion of reactive etiologies warrants bone marrow examination 1. Sustained monocytosis (at least two measurements over 3 months) significantly increases the risk of CMML, though the absolute risk remains low at 0.1% even in these cases 6.

Common Pitfalls to Avoid

• Failing to calculate absolute monocyte count from the differential—relative percentages are insufficient and can lead to unnecessary workup or missed diagnoses 1, 2, 3
• Premature bone marrow biopsy when the absolute monocyte count is <1.0 × 10⁹/L and no dysplasia is present—reactive causes must be excluded first 1
• Missing underlying infections such as ehrlichiosis, CMV, or Listeria by attributing monocytosis solely to inflammatory conditions without adequate investigation 1, 2, 3
• Incomplete molecular workup—omission of BCR-ABL1 testing can miss atypical presentations of chronic myeloid leukemia 1, 2
• Ignoring transient post-treatment changes—monocytosis can occur during immune response initiation and is typically not clinically significant 3