What is the likely cause of monoblasts on a peripheral blood smear in a 54-year-old male presenting with malaise, cough, upper respiratory symptoms, COVID-19 reverse transcription polymerase chain reaction (rRT‑PCR) positivity and pneumonia?

Monoblasts on Peripheral Blood Smear in COVID-19 Pneumonia

The presence of monoblasts on the peripheral blood smear in this COVID-19 positive patient with pneumonia most likely represents reactive monocytosis with immature monocytic forms rather than acute monocytic leukemia, though the latter must be urgently excluded through bone marrow examination and flow cytometry.

Primary Differential Diagnosis

The finding of monoblasts requires immediate consideration of two main possibilities:

1. Acute Monocytic Leukemia (AML-M5)

• This is the most critical diagnosis to exclude as it directly impacts mortality
• Requires urgent bone marrow biopsy with flow cytometry and cytogenetics
• True monoblasts (>20% in bone marrow) indicate acute leukemia requiring immediate hematology consultation 1

2. Reactive Monocytosis with Left Shift (Most Likely)

• COVID-19 infection causes significant alterations in monocyte populations and morphology 2, 3
• Studies demonstrate that COVID-19 patients show increased classical (CD14++CD16-) and intermediate (CD14+CD16+) monocytes during acute infection 2
• Abnormal monocyte morphology is well-documented in COVID-19, particularly in hospitalized patients 3
• The combination of viral pneumonia and bacterial superinfection can drive marked monocytic response

Clinical Approach Algorithm

Step 1: Immediate Hematology Review

• Have an experienced hematopathologist review the peripheral smear
• Distinguish true monoblasts (large cells with fine chromatin, prominent nucleoli, abundant cytoplasm) from reactive monocytes with immature features
• Assess for other concerning features: circulating blasts, dysplasia, cytopenias

Step 2: Complete Blood Count Analysis

• COVID-19 typically causes lymphopenia and neutrophilia in severe disease 3, 4
• True leukemia usually presents with anemia, thrombocytopenia, or marked leukocytosis
• Check for cytopenias that would favor malignancy over reactive process

Step 3: Risk Stratification

• If true monoblasts are confirmed (>5% of WBCs) → urgent bone marrow biopsy within 24-48 hours
• If reactive monocytes with left shift → monitor CBC daily and reassess smear in 48-72 hours 3

Step 4: Evaluate for Bacterial Superinfection

• COVID-19 pneumonia patients are at high risk for bacterial superinfections 5
• Consider lower respiratory tract sampling (tracheal aspirate or bronchoalveolar lavage) if clinically indicated 5
• Bacterial pneumonia can drive significant reactive monocytosis

Key Distinguishing Features

Favoring Reactive Process:

• Monocytosis with morphologic abnormalities but <5% blasts
• Preservation of other cell lines
• Clinical context of acute viral/bacterial infection
• Abnormal monocyte morphology (increased RNA content, morphologic changes) consistent with COVID-19 3

Favoring Acute Leukemia:

• True monoblasts >5% on peripheral smear
• Associated cytopenias (anemia, thrombocytopenia)
• Constitutional symptoms predating acute illness
• Absence of improvement with infection treatment

Critical Pitfalls to Avoid

1. Do not dismiss monoblasts as purely reactive without hematology consultation - this could delay diagnosis of acute leukemia with catastrophic consequences for mortality

2. Do not delay bone marrow biopsy if true blasts are present - even in the setting of active COVID-19 infection, acute leukemia diagnosis cannot wait 1

3. Do not attribute all findings to COVID-19 - while COVID-19 causes significant monocyte abnormalities 2, 3, the presence of true blasts mandates malignancy workup

4. Screen for SARS-CoV-2 before any planned bone marrow procedure as recommended for all patients with hematological malignancies undergoing procedures 1, 5

Monitoring Strategy

• Daily CBC with manual differential to track numerical and morphologic changes 3
• Repeat peripheral smear review in 48-72 hours if initial assessment suggests reactive process
• Monitor for resolution of monocytic abnormalities with treatment of underlying infection
• Persistent or worsening blast count mandates bone marrow examination regardless of infection status

The clinical context strongly suggests reactive monocytosis given the acute COVID-19 pneumonia presentation, but the presence of monoblasts on peripheral smear is never normal and requires definitive exclusion of acute leukemia through bone marrow examination if confirmed by expert review.