What is the significance of nucleated red blood cells (nRBCs) in peripheral blood?

Significance of Nucleated Red Blood Cells (nRBCs) in Peripheral Blood

The presence of nucleated red blood cells (nRBCs) in the peripheral blood of adults is a pathological finding that indicates serious underlying conditions and is associated with poor prognosis and increased mortality.

Definition and Normal Values

• Nucleated red blood cells (nRBCs) are immature erythrocyte precursors that normally reside in the bone marrow and are not found in the peripheral blood of healthy adults 1, 2
• While nRBCs may be present in the blood of neonates, their presence in adults always indicates a pathological condition 3
• Modern hematology analyzers can detect very low levels of nRBCs, with updated reference intervals suggesting values up to 0.10 × 10^6/μL may be considered normal 4

Pathophysiological Mechanisms

• The appearance of nRBCs in peripheral blood may be caused by:
  • Increased erythropoiesis due to severe anemia or hypoxemia 2, 3
  • Bone marrow architectural damage from inflammation 3
  • Decreased tissue oxygenation 3
  • Failure of the blood-marrow barrier allowing premature release of immature cells 3

Clinical Significance in Various Conditions

Hematological Disorders

• nRBCs may appear in peripheral blood in:
  • Myelodysplastic syndromes (MDS) - a sign of dysplastic erythropoiesis 5
  • Leukemias and lymphomas with bone marrow involvement 1, 6
  • Myelofibrosis 1
  • Thalassemia 1
  • Multiple myeloma 1

Critical Illness

• The incidence of nRBCs in ICU-admitted patients can be as high as 62.5% 1
• Mortality is significantly higher in NRBC-positive critically ill patients (30%) compared to NRBC-negative patients (14%) 1
• A cutoff of 2.50 nRBCs has been associated with high mortality risk with 91% sensitivity 1
• nRBCs typically appear 1-3 days before death in critically ill patients 3

Specific Conditions Associated with nRBCs

• Sepsis (associated with 58.8% mortality when nRBCs are present) 1
• Malignancy (100% mortality reported in one study) 1
• Acute respiratory distress syndrome (ARDS) 2
• Severe cardiovascular disease 2
• Acute pancreatitis 2, 3
• Trauma 2
• Liver cirrhosis 3

Diagnostic Approach

• Complete blood count with peripheral blood smear examination is essential 5
• Peripheral blood smear should be carefully examined for:
  • Presence and quantification of nRBCs 6
  • Other morphological abnormalities that may indicate specific conditions 5
• Bone marrow examination may be necessary to determine the underlying cause 5
• Flow cytometry can help distinguish clonal from reactive causes of nRBCs 5

Prognostic Value

• nRBCs are an independent predictor of poor outcome 3
• Mortality increases with increasing nRBC concentration 3
• The presence of nRBCs can serve as an early warning sign, allowing for timely intervention in critically ill patients 2, 3

Clinical Implications

• Detection of nRBCs should prompt a thorough investigation for underlying conditions 1, 2
• Regular monitoring of nRBC counts in critically ill patients may help predict clinical deterioration 1
• Early identification of patients with nRBCs may allow for more aggressive management strategies 3

Common Pitfalls and Caveats

• Do not confuse nRBCs with other abnormal cells in peripheral blood such as blasts or lymphoma cells 5
• Automated hematology analyzers may have different thresholds for detecting nRBCs; confirmation with manual microscopy is recommended in critical cases 4, 6
• Transient appearance of polyclonal nRBCs can occur in non-malignant conditions such as severe sepsis, infectious mononucleosis, and serum sickness 5
• The absence of nRBCs does not rule out serious underlying conditions 1