What is expected in a blood smear of a patient with likely infectious mononucleosis (Infectious Mononucleosis), specifically a condition characterized by Atypical Lymphocytosis?

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From the Guidelines

The expected finding in a blood smear of a patient with likely infectious mononucleosis is atypical lymphocytosis, characterized by the presence of larger than normal lymphocytes with abundant cytoplasm and irregular, indented nuclei, as noted in the study by 1. In infectious mononucleosis, which is typically caused by Epstein-Barr virus (EBV), the immune system responds by producing reactive or atypical lymphocytes. These atypical lymphocytes represent activated T cells responding to the viral infection. This finding is so characteristic that it serves as an important diagnostic clue when combined with clinical symptoms like sore throat, fever, fatigue, and lymphadenopathy. Some key points to consider in the diagnosis of infectious mononucleosis include:

  • The presence of an elevated white blood cell count with an increased percentage of atypical lymphocytes, as mentioned in the study by 1.
  • The detection of heterophile antibodies, which usually become detectable between the sixth and tenth day following symptom onset, as noted in the study by 1.
  • The use of EBV antibody testing for IgG and IgM to viral capsid antigen (VCA) and Epstein-Barr nuclear antigen (EBNA) to confirm the diagnosis, as recommended in the study by 1. It is essential to differentiate infectious mononucleosis from other conditions that may present with similar symptoms, such as chronic lymphocytic leukemia (CLL), as discussed in the studies by 1, 1, 1, and 1. However, the presence of atypical lymphocytosis in a blood smear is a key feature that can help distinguish infectious mononucleosis from other conditions, as noted in the study by 1. Therefore, the presence of atypical lymphocytosis in a blood smear is a critical diagnostic finding in patients with suspected infectious mononucleosis, as supported by the study by 1.

From the Research

Blood Smear Characteristics in Infectious Mononucleosis

In a patient with likely infectious mononucleosis, the blood smear is expected to show:

  • Atypical lymphocytosis, which is a common peripheral blood abnormality seen in Epstein-Barr virus (EBV)-associated acute infectious mononucleosis 2
  • Increased numbers of absolute lymphocytes, atypical lymphocytes, CD8+ cells, NK cells, gammadelta T cells, CD8+/CD45RO+ cells, CD8+/CD57- cells, and CD8+/CD28+ cells 2
  • A marked increase in activated CD8-positive T cells, a moderate increase in NK cells, and no increase in CD4-positive T cells and B cells 2
  • Atypical lymphocytes constituting more than 10% of the total lymphocyte count 3
  • Peripheral blood leukocytosis with lymphocytes making up at least 50% of the white blood cell differential count 3

Key Features of Atypical Lymphocytosis

The key features of atypical lymphocytosis in infectious mononucleosis include:

  • Absolute lymphocytosis with >10% atypical lymphocytes 2
  • Increased numbers of CD3+/CD8+, CD3-/CD16/56+, CD3+/gammadelta+, CD8+/CD48-, CD8+/CD57-, CD8+/CD95+, CD4+/CCR5+ CD4+/CD7-, CD4+/CD43-, CD4+/CD48-, and CD4+/CD62L- subsets 2
  • No change in absolute CD4+ T cell and CD19+ B cell counts 2

Diagnostic Considerations

The diagnosis of infectious mononucleosis should be considered in patients with:

  • Fever, sore throat, and significant fatigue, palatal petechiae, posterior cervical or auricular adenopathy, marked adenopathy, or inguinal adenopathy 4
  • Atypical lymphocytosis of at least 20 percent or atypical lymphocytosis of at least 10 percent plus lymphocytosis of at least 50 percent 4
  • Positive heterophile antibody test or serologic testing for antibodies to viral capsid antigens 3

References

Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

Research

Infectious Mononucleosis: An Updated Review.

Current pediatric reviews, 2024

Research

Epstein-Barr virus infectious mononucleosis.

American family physician, 2004

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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