What Causes Lymphocytosis?

Patient Presentation
A 15-month-old female came to clinic for her health maintenance examination. She was doing well except for some upper respiratory infection symptoms for several days. She also had missed some health maintenance visits and was behind on her immunizations. The pertinent physical exam showed a smily, interactive female with obvious rhinorrhea. Growth was symmetric at 75%. Her examination was otherwise normal.

The diagnosis of a healthy female was made. The laboratory evaluation included screening tests for lead and a complete blood count. The patient was sent home, and later the laboratory called because her white blood cell count was 18.3 x 1000/mm2, her lymphocyte count was 9100 cells/microL and the technician was very concerned that the lymphocytes looked like potential blast cells. The red blood cells and platelets were normal. The pathologist reviewed the smear the following day and determined that the lymphocytes were not consistent with blasts, but were large cells with increased cytoplasm consistent with reactive lymphocytes, i.e. “atypical lymphocytes”. After discussion, the pathologist and clinician felt that the reaction was probably due to the upper respiratory tract infection that she had, and the clinician monitored the patient clinically.

Lymphocytes are an important part of the cellular and humoral immunity. Absolute lymphocyte count (ALC) is usually used to determine ranges of normal for lymphocytes. The ALC is higher in neonates and young children (up to 8000 cells/microL) but in those > 12 years of age is normally > 4000 cells/microL. Lymphopenia is usually defined as < 1000-1500 cells/microL. Infants again usually have higher counts or < 2500 cells/microL. Remember normal leukocyte count is 4.5-11.0 x 1000/mm2 with about 22-44% overall being lymphocytes.

Reactive lymphocytosis is when a patient without an underlying hematological problem has a problem associated with lymphocytosis and the lymphocyte count normalizes or is expected to normalize within 2 months. Common causes are viral infections and pertussis. These cells show two different patterns: 1. the lymphocytes are small but normal-appearing (associated with infections or pertussis), or 2. are large cells with irregular nuclei and increased basophilic cytoplasm (often caused by Epstein Barr virus) and are often described as “atypical” lymphocytes.

Learning Point
The differential diagnosis of lymphocytosis includes:
(Some of the most common entities are denoted with *)

  • Infectious
    • General acute infections
    • Bacterial
      • Bartonella
      • Brucellosis
      • *Pertussis
      • Paratyphoid
      • Typhoid
      • Syphilis
      • Tuberculosis
    • Viral
      • Adenovirus
      • Coxsackie
      • Cytomegalovirus
      • *Epstein Barr Virus
      • Hepatitis
      • Herpes
      • Human T-lymphotrophic virus type 1
      • Measles
      • Mumps
      • Poliovirus
      • Varicella
    • Other
      • Babesiosis
      • Toxoplasmosis
  • Endocrine
    • Hypoadrenalism
    • Hyperthyroidism
  • Gastrointestinal
    • Ulcerative colitis
  • Hematologic
    • Agranulocytosis
    • Aplastic anemia
    • Hypereosinophilia syndrome
    • Leukocyte adhesion deficiency
    • *Leukemia
    • Sickle cell anemia
  • Immune
    • Idiopathic thrombotic purpura
    • Serum sickness
  • Miscellaneous
    • Alcohol
    • Smoking
    • Down syndrome
    • Post-splenectomy
    • Stress lymphocytosis

The differential diagnosis of lymphocytopenia includes:

  • Infections, acute
    • General acute infections
    • Tuberculosis
  • Immunodeficiency
    • AIDS
    • Congenital defects of cellular immunity
    • Cancer
  • Immune
    • Systemic lupus erythematosis
  • Endocrine
    • ACTH
  • Lymphatic circulation defects
    • Intestinal lymphangectasia
    • Intestinal mucosal disorders
    • Thoracic duct drainage problem
  • Medications
    • Corticosteroids
    • Epinephrine
    • Immunosuppressive medication
  • Miscellaneous
    • Renal failure
    • Hemorrhage
    • Trauma

Questions for Further Discussion
1. What is in the differential diagnosis of neutrophilia or neutropenia?
2. What causes eosinophilia? see What Causes Eosinophilia?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Blood Disorders

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

Bakerman S. Bakerman’ ABC’s of Interpretive Laboratory Data. Interpretive Laboratory Data, Scottsdale AZ. 4th edit. pp. 576-577.

Coates TD. Approach to the patient with lymphocytosis or lymphocytopenia. UpToDate. (rev. 2/18/2013, cited 4/1/2013)

Inoue S. Leukocytosis Differential Diagnosis. Medscape. (rev. 7/12/2013, cited 4/1/2013)

ACGME Competencies Highlighted by Case

  • Patient Care
    1. When interacting with patients and their families, the health care professional communicates effectively and demonstrates caring and respectful behaviors.
    2. Essential and accurate information about the patients’ is gathered.
    3. Informed decisions about diagnostic and therapeutic interventions based on patient information and preferences, up-to-date scientific evidence, and clinical judgment is made.
    4. Patient management plans are developed and carried out.
    7. All medical and invasive procedures considered essential for the area of practice are competently performed.
    8. Health care services aimed at preventing health problems or maintaining health are provided.
    9. Patient-focused care is provided by working with health care professionals, including those from other disciplines.

  • Medical Knowledge
    10. An investigatory and analytic thinking approach to the clinical situation is demonstrated.
    11. Basic and clinically supportive sciences appropriate to their discipline are known and applied.

  • Systems Based Practice
    24. Cost-effective health care and resource allocation that does not compromise quality of care is practiced.


    Donna M. D’Alessandro, MD
    Professor of Pediatrics, University of Iowa Children’s Hospital