At a Glance

Lymphocytosis is defined as a peripheral blood lymphocyte count greater than 2SD above the mean for the patient population. As lymphocyte counts vary with age, the diagnosis must be made using age specific normal ranges. In adults, an absolute lymphocyte count greater than 4000 per microliter is generally considered lymphocytosis.

Note that a finding of “lymphocytosis” should not be based on a differential count reported in percentages. Depending on the total white cell count (WBC), an elevation in the percentage of lymphocytes may reflect either true lymphocytosis (high WBC) or neutropenia (normal or low WBC). Therefore, the diagnosis of lymphocytosis should be based on an absolute lymphocyte count either provided directly by the performing laboratory or calculated (ALC = WBC x % lymphocytes x 100).

Causes of non-neoplastic lymphocytosis include acute viral illness (CMV, EBV, HIV), chronic viral infections (hepatitis A, B, or C), chronic infections (tuberculosis, brucellosis, syphilis), protozoan infections (toxoplasmosis), and rarely bacterial infections (B. pertussis). Lymphocytosis may also be associated with drug reactions, connective tissue disorders, thyrotoxicosis, and Addison’s disease.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

In a patient without an obvious cause for lymphocytosis (e.g., signs or symptoms of viral infection or allergy), it is most appropriate to simply repeat a complete blood count (CBC) on a new sample to confirm that lymphocytosis is truly present. Although uncommon, sample mislabeling or laboratory error may result in an erroneous lymphocytosis that may simply disappear on repeat testing.

If lymphocytosis is present on repeat testing, the next step is to thoroughly review the remainder of the CBC for other abnormalities and ask the laboratory to review a well-made peripheral smear for lymphocyte, red cell, other leukocyte, and platelet morphology.

Review of CBC

In particular, it is important to assess the appearance of the lymphocytes. Lymphocytosis with a spectrum of lymphocyte morphology (e.g., small mature forms, atypical forms, prolymphocytes, immunoblasts, etc.) suggests a reactive process. Conversely, a monomorphic appearance to the lymphoid population (blasts, mature lymphocytes) suggests a clonal lymphoproliferation.

In children, lymphocytosis associated with anemia or thrombocytopenia mandates an evaluation for acute lymphoblastic leukemia, as the morphology of lymphoblasts may be subtle and there may be a spectrum of lymphoid morphology present. The association with other cytopenias may suggest marrow replacement and warrants evaluation.

Additionally, it is important to look for any of the following in association with the lymphocytosis: neutropenia, eosinophilia, monocytopenia, anemia, or thrombocytopenia.

Review of the Peripheral Smear

General assessment includes evidence of red cell or platelet clumping that may cause spurious leukocytosis and lymphocytosis. Leukocyte morphology has a general appearance of the lymphocyte population (monomorphic (clonal) versus polymorphic (reactive)), and presence of abnormal neutrophils, monocytes, and eosinophils exists. Within red cell morphology, there are nucleated red cells (marrow infiltration), dysplastic forms (myelodysplasia), spherocytes (microangiopathic processes, DIC, burns, immune hemolysis), and schistocytes (TTP, HUS, DIC, endocarditis, other microangiopathic processes). Platelet morphology includes large platelets (marrow recovery) and abnormal platelet shape or granulation (myelodysplasia).

History and Physical Examination

A thorough history and physical exam may be useful in identifying the cause of monocytosis.

Such a history may contain:

acute onset, suggesting a infective process

collagen vascular disorders, such as rheumatoid arthritis or polymyositis

gastrointestinal (GI) disorders, such as sprue, ulcerative colitis, and Crohn’s disease

solid tumors


evidence of or exposure to tuberculosis, rickettsia, or protozoan parasites

full medication history, especially marrow suppressants

evidence of chronic infection, weight loss, fevers, and night sweats


Physical examination may show:

choriza, cough, fever, pharyngitis

adenopathy, especially cervical, epitrochlear

splenomegaly or evidence of splenectomy


In an asymptomatic or mildly symptomatic patient with findings suggesting a viral infection and no associated CBC or peripheral smear abnormalities, the laboratory evaluation could justifiably stop with a plan to repeat testing if symptoms develop and/or worsen in several weeks to determine if the lymphocytosis is persistent. If lymphocytosis persists, assessment of the patient for chronic infectious, autoimmune, or hematologic disorders may be warranted.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

The DRESS Syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) may also demonstrate an atypical lymphocytosis. Implicated drugs include phenobarbital, carbamazepine, phenytoin, lamotrigine, minocycline, sulfonamides, allopurinol, modafonil, and dapsone.

Other drug hypersensitivity reactions (e.g., ethitoin, PAS, sulfasalazine, ginseng) may have an associated lymphocytosis.

What Lab Results Are Absolutely Confirmatory?

A repeat CBC with leukocyte differential is confirmatory.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

General Assessment
  • AST and/or ALT to identify systemic and/or hepatic damage

  • Serum sodium and potassium levels

Findings suggesting acute viral infection
  • Monospot, CMV IgM

  • HIV Antibody

  • with upper respiratory symptoms consider Direct Fluorescent Antigen (DFA) testing for common respiratory viruses

Whooping cough
  • Upper respiratory culture

  • Bordetella spp. PCR

Chronic infection
  • PPD, Quantiferon testing and/or Chest x-ray to r/o tuberculosis

  • Brucella serology

  • VDRL or RPR

  • Toxoplasma serology

Miscellaneous as suggestive by history and physical exam findings
  • TSH level

  • Cortisol and/or ACTH Stimulation testing