Lymphocytosis is a finding on a Complete Blood Count (CBC) test where the number of lymphocytes circulating in the blood exceeds the established reference range. Lymphocytes are a type of white blood cell that forms a major part of the adaptive immune system, recognizing and eliminating pathogens. An elevated count often signals an active immune response. While this finding is often temporary and related to a common infection, a persistent increase requires further medical investigation.
Defining Lymphocytosis and Normal Ranges
Lymphocytosis is defined by an elevation in the absolute lymphocyte count (ALC), the total number of these cells in a specific volume of blood. For adults, the threshold for lymphocytosis is typically an ALC greater than 4.0 x 10⁹/L, or 4,000 cells per microliter (µL) of blood. The normal ALC range for adults usually falls between 1,000 and 4,800 cells/µL.
Relative lymphocytosis occurs when the percentage of lymphocytes is high, but the absolute count remains normal. This often happens because other white blood cells, such as neutrophils, have decreased, making the lymphocyte percentage appear disproportionately high. However, the absolute count is the clinically significant measure that prompts further evaluation, as it reflects an actual increase in the number of lymphocytes.
Common Causes of Elevated Lymphocytes
The causes of elevated lymphocytes are categorized into two groups: reactive (temporary) and clonal (chronic or potentially malignant). Most cases are reactive, indicating the immune system is fighting an infection or responding to stress. Viral infections are the most frequent cause, including Epstein-Barr Virus (EBV), which causes infectious mononucleosis, and Cytomegalovirus (CMV).
Other common viral culprits include HIV during the acute infection phase, and Hepatitis A, B, and C. Certain bacterial infections, which typically increase other white blood cells, are exceptions that can trigger lymphocytosis, such as Bordetella pertussis (whooping cough) and Bartonella henselae (cat-scratch disease). Severe physiological stress or reactions to specific medications can also temporarily elevate counts.
The second category involves clonal or lymphoproliferative disorders, caused by the uncontrolled proliferation of an abnormal line of lymphocytes. Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in adults and a frequent cause of persistent lymphocytosis. Other causes include certain types of Non-Hodgkin Lymphoma (NHL) that involve the blood, or the precursor condition Monoclonal B Lymphocytosis (MBL). If lymphocytosis is persistent and unexplained by infection, the focus shifts to ruling out these chronic conditions.
Diagnostic Evaluation and Next Steps
After an initial finding of lymphocytosis, the first step is to repeat the CBC to confirm the elevation and check for changes in other blood cell lines, such as red blood cells or platelets. A thorough medical history is collected, focusing on recent illnesses, travel, and symptoms, which helps determine if the cause is reactive or chronic. A recent flu-like illness, for example, suggests a temporary, reactive cause.
The peripheral blood smear (PBS) review involves examining the blood under a microscope. This evaluation looks for atypical or reactive lymphocytes, characteristic of viral infections like mononucleosis, or specific abnormal cells associated with a clonal disorder. The appearance of these cells can provide immediate clues, such as the presence of “smudge cells” often seen in CLL.
If lymphocytosis is persistent, significantly high, or the PBS suggests an abnormality, flow cytometry is performed. This specialized testing analyzes the surface markers of the lymphocytes to determine the specific cell type (T-cell, B-cell, or NK-cell) and whether they are monoclonal. Monoclonal cells, which originate from a single abnormal cell, are strongly indicative of a lymphoproliferative disorder like CLL. Flow cytometry distinguishes between a reactive increase and a potentially malignant clonal expansion.
When High Lymphocytes Require Urgent Attention
For most adults, lymphocytosis is temporary, indicating the immune system is working, and the count will return to normal once the infection resolves. However, certain signs and symptoms accompanying a persistent or unexplained elevation warrant urgent consultation with a healthcare provider or hematologist. These red flags suggest the possibility of a chronic underlying process.
Systemic symptoms, called “B symptoms,” are a significant concern and include unexplained weight loss, drenching night sweats, and persistent fever. Noticeably enlarged lymph nodes (lymphadenopathy) in the neck, armpits, or groin that do not shrink after a few weeks are another indicator. An enlarged spleen (splenomegaly), which may cause discomfort or fullness in the upper left abdomen, requires prompt evaluation. In these scenarios, immediate diagnostic follow-up is necessary to identify and manage the underlying condition.