What is the clinical significance of nucleated red blood cells (NRBCs) in the peripheral blood of patients across different age groups and medical conditions?

Clinical Significance of Nucleated Red Blood Cells (NRBCs)

The presence of NRBCs in peripheral blood of adults is always pathological and serves as both a diagnostic marker for hematological disorders and a powerful prognostic indicator of mortality in critically ill patients, with higher NRBC counts correlating directly with increased risk of death.

Diagnostic Significance in Hematological Disorders

Primary Hematological Conditions

• NRBCs indicate dysplastic erythropoiesis in myelodysplastic syndromes (MDS), serving as a key diagnostic feature 1
• In acute myeloid leukemia (AML), complete remission requires disappearance of NRBCs from peripheral blood (in non-splenectomized patients), along with normalization of other blood parameters 2
• NRBCs appear in nearly all onco-hematological diseases at diagnosis but are typically absent at remission, making them useful for monitoring treatment response 3
• The presence of NRBCs alongside teardrop cells and other dysplastic features (pseudo-Pelger-Huët cells, hypogranulation) strongly suggests MDS or MDS/myeloproliferative neoplasm overlap syndromes 4

Underlying Mechanisms

• NRBCs appear due to either increased erythropoiesis, bone marrow micro-architectural damage from inflammation, or decreased tissue oxygenation 5
• Under normal circumstances, NRBCs cannot cross the blood-marrow barrier because they do not distort easily; their presence indicates barrier disruption 5
• Common pathogenic causes include anemia, myelofibrosis, thalassemia, miliary tuberculosis, bone marrow malignancies (myelomas, leukemias, lymphomas), and prolonged hypoxemia 6

Prognostic Significance in Critical Illness

Mortality Prediction

• In ICU patients, NRBC presence carries a 30% mortality rate compared to 14% in NRBC-negative patients (p<0.001) 6
• A cutoff of ≥2.5 NRBCs predicts mortality with 91% sensitivity in critically ill patients 6
• The mortality rate increases proportionally with rising NRBC concentrations 5
• NRBCs typically appear 1-3 days before death in critically ill patients, making them an early warning sign 5

Disease-Specific Mortality Patterns

• Among NRBC-positive ICU patients, malignancy carries 100% mortality, followed by sepsis at 58.8% 6
• NRBCs serve as prognostic markers in neonatal hypoxia, asphyxia, sepsis, trauma, ARDS, acute pancreatitis, and severe cardiovascular disease 7
• The overall incidence of NRBCs in ICU-admitted patients is 62.5%, with 72.8% of NRBC-positive patients recovering after treatment 6

Diagnostic Approach

Initial Detection

• Complete blood count with peripheral blood smear examination is essential for diagnosing NRBCs 1
• Most automated hematology analyzers (such as Sysmex XE2100 and XN-9000) can detect and quantify NRBCs, though manual confirmation on peripheral smear remains important 6, 3
• NRBCs falsely elevate automated white blood cell counts, requiring manual correction when present 8

Further Workup When NRBCs Detected

• Bone marrow examination (aspiration and biopsy with reticulin stain) is necessary when myelofibrosis or MDS is suspected 4
• Flow cytometry helps distinguish clonal from reactive causes of NRBC release 1
• Cytogenetic and molecular testing are essential for MDS/myeloproliferative neoplasm diagnosis, as chromosomal abnormalities occur in up to 80% of MDS patients 4
• Conventional cytogenetic analysis cannot be replaced by molecular tests or FISH alone and should be completed before starting treatment 9

Contextual Interpretation

• Look for accompanying dysplastic features: cytopenias with dysplasia suggest MDS, while leukocytosis with monocytosis suggests chronic myelomonocytic leukemia 4
• Distinguish from microangiopathic hemolytic anemia by checking for schistocytes, which point toward MAHA rather than marrow pathology 4
• Anemia with reticulocytosis suggests hemolytic processes (autoimmune hemolytic anemia or MAHA) rather than primary marrow disorders 4

Critical Clinical Pitfalls

Common Misinterpretations

• Do not dismiss NRBCs as merely reflecting anemia or hypoxia—their presence in adults always warrants investigation for underlying serious pathology 5
• The absence of NRBCs does not rule out hematological disease, as they are not present in all patients even at diagnosis 3
• NRBCs are physiological only in neonates and during pregnancy; any other context requires explanation 8

Laboratory Considerations

• Cutoff values for correcting WBC counts vary widely (1,5,10,20, or 50), with 5 and 10 being most common, but these are largely subjective 8
• Screening for NRBCs aids in early identification of high-risk patients requiring intensive care 5
• The same physician should ideally interpret both bone marrow aspirate smears and core biopsy samples for optimal diagnostic accuracy 9

Treatment Planning Implications

• In AML, chemotherapy should be postponed until satisfactory material for all diagnostic tests has been obtained 9
• Patients with excessive leukocytosis may require emergency leukapheresis before induction chemotherapy 9
• Treatment should occur in centers offering multidisciplinary approaches with full hematology services, bone marrow transplant units, infectious disease units, and adequate transfusion services 9