Lymphocytosis

WBCs develop from stem cells in the bone marrow and are called leukocytes when circulating in the bloodstream. Lymphocytes are 1 of the 5 subclasses of WBCs. Lymphocytosis is an increase in the number or proportion of the lymphocyte subclass of WBCs, often as a result of an immune response to infection (known as reactive lymphocytosis). Common presentations include fever, lymphadenopathy, and upper respiratory symptoms. Usually transient, lymphocytosis resolves on its own in most cases after resolution of the infection. In other situations, it may signal a lymphoproliferative disorder (known as clonal lymphocytosis). Diagnosis is based on peripheral blood smear, flow cytometry, and potentially, a bone marrow biopsy. Management depends on the underlying cause.

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Overview

Definition

Lymphocytosis refers to elevated levels of lymphocytes. This elevation most often results from increased production.

  • Lymphocytes:
    • Agranulocytic WBCs 
    • Circulating immunocompetent cells that can recognize antigens in the blood 
    • Leave the bloodstream through lymph nodes, then can reenter the blood
    • Vary in size from small (6–8 µm) to large (18 µm)
    • Lymphocytes are 1 of the 5 subclasses of WBCs:
      • Neutrophils (approximately 56%)
      • Lymphocytes (approximately 34%)
      • Monocytes (approximately 4%)
      • Eosinophils (approximately 3%)
      • Basophils (approximately 0.3%)
  • Lymphocytosis corresponds to an absolute lymphocyte count (ALC):
    • > 4000 lymphocytes/µL for adults 
    • > 8000 lymphocytes/µL for children < 12 years
    • Equation: ALC = WBC (cells/µL) × (% lymphocytes ÷ 100)
    • ALC is used to quantitate lymphocytes in peripheral blood (rather than the percentage of lymphocytes in the WBC differential count).
    • Normal values for ALC may vary in different laboratories.
  • Of note: The term leukocytosis refers to elevated levels of WBCs in general.

Lymphocyte subsets

  • T cells:
    • Represent 60%–80% of lymphocytes 
    • Responsible for cell-mediated immunity, which focuses on the active destruction of infected or cancerous cells
    • Types of T lymphocytes:
      • Cytotoxic T cells: bind directly to cells containing antigens and destroy them
      • Helper T cells (CD4+): stimulate the production of antibodies by B cells and produce substances that activate other T cells
      • Suppressor T cells (CD8+): suppress the response of B and T cells to antigens
  • B cells:
    • 10%–20% of lymphocytes
    • Responsible for humoral immunity (antibody production)
      • Focus on identifying antigens prior to cell infection 
      • Create antibodies to antigens
  • Natural killer (NK) cells:
    • 5%–10% of lymphocytes
    • Responsible for immunologic surveillance: lyse host cells altered by infection or malignancy
  • Memory cells:
    • B or T lymphocytes that recognize previously encountered antigens
    • Direct an immune response more quickly on subsequent exposures  
    • Stored in lymph nodes and spleen
    • Can provide lifelong immunity against certain pathogens (e.g., measles and mumps)

Epidemiology

  • Lymphocytosis is most commonly seen between ages 15 and 45.
  • Most often is due to a viral infectious process

Etiology and Pathophysiology

Lymphocytosis may result from an increased production of lymphocytes (most common) or several additional mechanisms.

Increased production of lymphocytes

The production of lymphocytes may be increased because of:

  • Response to an infectious process:
    • Viral (most common)
    • Bacterial 
    • Parasitic
  • Lymphoproliferative disorders:
    • Monoclonal B-cell lymphocytosis (MBL)
    • CLL
    • Large granular lymphocytic (LGL) leukemia
    • Non-Hodgkin lymphoma
    • ALL
    • Persistent polyclonal B-cell lymphocytosis
  • Drug hypersensitivity reactions, most commonly to:
    • Phenytoin
    • Allopurinol
    • Carbamazepine
    • Vancomycin 
    • Sulfa drugs
  • Chronic inflammation, for example:
    • Arthritis
    • Autoimmune disorders
  • Other causes:
    • Hyperthyroidism
    • Severe medical stress:
      • Trauma
      • Cardiac emergencies
      • Status epilepticus
Table: Infectious processes associated with lymphocytosis
Type of infectionMicrobes/conditions
Viral
  • Members of herpesvirus family:
    • EBV
    • CMV
    • Varicella
    • Others
  • HIV, acute infections
  • Measles
  • Mumps
  • Rubella
  • Influenza
  • Viral hepatitis
  • Adenovirus
  • Coxsackie B virus
  • Enteroviruses, including poliovirus
Bacterial
  • Pertussis
  • Tuberculosis
  • Brucellosis
  • Syphilis
  • Cat scratch disease (Bartonella henselae)
Parasitic
  • Toxoplasmosis
  • Malaria
  • Babesiosis

Other mechanisms of lymphocytosis

  • Redistribution of lymphocytes from bone marrow or secondary lymphoid organs: seen after splenectomy
  • Decreased extravasation of lymphocytes from peripheral blood to lymphoid organs: seen in pertussis infections
  • Decreased cell death from impaired apoptosis: seen in some lymphoproliferative disorders
  • Unclear mechanisms: malignant thymoma

Pathophysiology

The pathophysiology depends on the underlying etiology. Increased production of lymphocytes may be due to a clonal process or a reactive process.

  • Clonal lymphocytosis:  
    • Seen in patients with a lymphoproliferative disorder
    • Due to abnormal lymphocyte proliferation, usually owing to genetic mutations
    • Involves expansion of a single clone (monoclonal) or related cells 
  • Reactive lymphocytosis:
    • Seen in patients without a lymphoproliferative disorder
    • Due to “normal” lymphocyte proliferation in response to infection or inflammation (i.e., the lymphocytosis is part of an immune response)
    • For further details on the immune response, see:
      • Innate immunity
      • Adaptive immunity
      • Cellular immunity
      • Humoral immunity
    • Polyclonal expansion is seen in 1 or more subsets of lymphocytes (e.g., T cells, B cells, or NK cells).
    • Lymphocytosis should normalize < 2 months after resolution of the acute medical condition that triggered the reactive lymphocytosis.

Clinical Presentation

The clinical presentation depends on the primary cause (i.e., infections or lymphoproliferative disorders). Lymphocytosis can be an asymptomatic incidental finding.

Presentations associated with infection

Signs and symptoms may include:

  • Fever
  • Lymphadenopathy 
  • Hepatosplenomegaly
  • Upper respiratory symptoms:
    • Sore throat
    • Nasal congestion/rhinorrhea
    • Cough
  • Rashes
  • Fatigue
  • Arthralgias and myalgias

Presentations associated with lymphoproliferative disorders

Signs and symptoms may include:

  • Low-grade fever
  • Night sweats
  • Weight loss
  • Diffuse or localized lymphadenopathy
  • Splenomegaly
  • Shortness of breath
  • Itching
  • Signs/symptoms related to bone marrow infiltration: 
    • Anemia: pallor, fatigue, dyspnea
    • Thrombocytopenia: easy bruising or bleeding, purpura

Diagnosis and Management

The initial workup for lymphocytosis involves a comprehensive history and physical examination, CBC, and peripheral blood smear. If the diagnosis is still uncertain, or if findings are worrisome for malignancy, clonality should be established using flow cytometry.

Historical factors to consider

  • History or clinical evidence of infection and/or inflammation, for example:
    • New-onset fever and rash
    • Symptoms of upper respiratory infection (URI)
    • History of arthritis
    • Recent trauma
  • Clinical stability/acuity of illness
  • Rapidity of onset
  • Surgical or functional asplenia
  • Medications

CBC findings

CBC findings associated with lymphocytosis include:

  • Changes from prior CBCs 
  • ↑ Eosinophils or basophils, which may indicate:
    • Infection and/or inflammation
    • Allergic conditions
    • Drug hypersensitivities
  • ↑ Neutrophils and/or monocytes, which may indicate:
    • Infections and/or inflammation
    • Severe medical stress
    • Asplenia
  • Anemia, which may indicate:
    • Bone marrow infiltration
    • Anemia of chronic disease associated with chronic inflammatory conditions or infections
    • Hemolytic anemia associated with CLL or LGL leukemia
  • Serious or multiple hematologic abnormalities (e.g., ALC > 50,000 cells/µL) require more urgent evaluation.

Peripheral blood smear

Peripheral blood smear for lymphocyte morphology may show:

  • Atypical lymphocytes (also known as Downey cells):
    • Characteristics: more prominent nucleoli and more abundant cytoplasm
    • Seen in infectious mononucleosis due to EBV or CMV, toxoplasmosis, and viral hepatitis
  • Lymphocytes with hair-like projections → seen in hairy cell leukemia
  • Lymphocytes with azurophilic granules → seen in LGL leukemia
  • Lymphoblasts → seen in ALL
  • Smudge cells and lymphoblasts → seen in CLL
Peripheral blood smear with occasional small lymphocytes

Peripheral blood smear showing a lymphocyte with hair-like cytoplasmic projections (known as “hairy cells”) in hairy cell leukemia

Image: “Peripheral blood smear” by Department of Pathology and Laboratory Medicine and Department of Hematology-Oncology, Tufts Medical Center, Tufts University Medical School, Washington Street 800, Boston, MA 02111, USA. License: CC BY 3.0

Flow cytometry

  • Determines the clonality and immunophenotype of a lymphocytosis 
  • Important in diagnosing malignancy: All malignant lymphocytosis is clonal (though not all clonal lymphocytosis is malignant).
  • Indications:
    • Suspicion for malignancy (e.g., lymphoblasts on peripheral smear)
    • ALC > 30,000 cells/µL without a known cause 
    • Lymphadenopathy
    • Hepatosplenomegaly
    • Cytopenias

Additional tests

Additional tests may be required based on the provisional diagnosis:

  • Viral serologies
  • Bone marrow biopsy
  • Imaging tests
  • Specialized tests for clonality include:
    • Flow cytometry (first-line test)
    • Molecular and genetic testing (e.g., PCR and DNA sequencing)
    • Chromosome analysis

Persistent lymphocytosis

If lymphocytosis persists for ≥ 3 months and the cause is unclear, a further workup should be completed. This workup should include:

  • Serial CBCs with differential 
  • Chemistries (to evaluate liver and kidney function)
  • Erythrocyte sedimentation rate (ESR) and CRP
  • Peripheral blood smear (if not already done)
  • Peripheral blood flow cytometry (if not already done)

Management

Management of lymphocytosis is related to the underlying etiology. 

  • Infectious etiologies: 
    • Usually transient and asymptomatic: In most cases, lymphocytosis resolves on its own after resolution of the infection.
    • Observation and supportive care
    • Antibiotics as normally indicated for bacterial infections.
  • Lymphoproliferative disorders:
    • Management by a hematology-oncology specialist
    • Management may involve:
      • Chemotherapy
      • Immunotherapy
      • Radiation therapy
      • Bone marrow transplantation

Differential Diagnosis

  • Infectious causes (see table under “Etiology and Pathophysiology”)
  • ALL: cancer of the blood and bone marrow resulting from abnormal proliferation of lymphocytes. There are > 10 subtypes of ALL. ALL is rare, with < 6000 adults and children diagnosed in the United States each year, though ALL is the most common childhood cancer.
  • CLL: most common leukemia in adults. CLL is a monoclonal B-cell proliferation that infiltrates the bone marrow and/or lymph nodes. The B cells arrest before maturation, and many patients have hypogammaglobulinemia resulting in recurrent infections. CLL is mainly found on incidental blood work showing lymphocytosis, though patients may also present with lymphadenopathy, hepatosplenomegaly, or skin manifestations. Peripheral blood smears show smudge cells. 
  • MBL: condition characterized by elevation of monoclonal B cells persisting ≥ 3 months. The monoclonal B cells are phenotypically similar to those in CLL (though found at levels below the threshold for CLL), in the absence of other features typically found in lymphoproliferative disorders (e.g., splenomegaly, lymphadenopathy, or other cytopenias). MBL may progress to CLL.
  • Congenital polyclonal B-cell lymphocytosis: rare congenital disorder of children that presents in infancy with significant lymphocytosis and splenomegaly due to polyclonal B-cell expansion. The lymphocytosis may become indistinguishable from CLL later in life. 
  • Persistent polyclonal B-cell lymphocytosis: rare syndrome characterized by polyclonal B-cell expansion, splenomegaly, and/or lymphadenopathy. This disorder is typically diagnosed in young to middle-aged women who smoke cigarettes. The pathogenesis is unknown.
  • LGL leukemia: relatively rare atypical lymphocytosis characterized by large lymphocytes with slightly eccentric nuclei and abundant pale-blue cytoplasm containing many azurophilic granules. Phenotypically, the granules are clonal lymphocytes. These patients usually present in middle age with splenomegaly and autoimmune manifestations. While there may be an absolute lymphocytosis in LGL leukemia, there is frequently a neutropenia and/or normal total lymphocyte count with an increased percentage of cytotoxic T cells.
  • Malignant thymoma: malignant tumor of the thymus gland. Malignant thymoma typically affects middle-aged adults and may be associated with paraneoplastic autoimmune syndromes. The cause of the lymphocytosis is unclear, but the morphology appears normal. This condition is associated with polyclonal T-cell lymphocytosis and resolves following successful treatment of the tumor.

References

  1. Davids, M.S. (2020). Approach to the adult with lymphocytosis or lymphocytopenia.  UpToDate.  Accessed April 22, 2021, from https://www.uptodate.com/contents/approach-to-the-adult-with-lymphocytosis-or-lymphocytopenia
  2. Coates, T.D. (2020). Approach to the child with lymphocytosis or lymphocytopenia.  UpToDate. Accessed April 22, 2021, from https://www.uptodate.com/contents/approach-to-the-child-with-lymphocytosis-or-lymphocytopenia
  3. Teggatz, J.R., Parkin, J., Peterson, L. (1987). Transient atypical lymphocytosis in patients with emergency medical conditions. Archives of Pathology and Laboratory Medicine 111:712–714.
  4. Snow, A.L., Xiao, W., et al. (2012). Congenital B cell lymphocytosis explained by novel germline CARD11 mutations. Journal of Experimental Medicine 209:2247–2261.
  5. Dasanu, C.A., Codreanu, I. (2012). Persistent polyclonal B-cell lymphocytosis in chronic smokers: more than meets the eye. Connecticut Medicine 76(2):69–72.

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