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Lymphocytopenia

by Mary Territo, MD

Lymphocytopenia is a total lymphocyte count of < 1000/μL in adults or < 3000/μL in children < 2 yr. Sequelae include opportunistic infections and an increased risk of malignant and autoimmune disorders. If the CBC reveals lymphocytopenia, testing for immunodeficiency and analysis of lymphocyte subpopulations should follow. Treatment is directed at the underlying disorder.

The normal lymphocyte count in adults is 1000 to 4800/μL; in children < 2 yr, 3000 to 9500/μL. At age 6 yr, the lower limit of normal is 1500/μL. Both B and T cells are present in the peripheral blood; about 75% of the lymphocytes are T cells and 25% B cells. Because lymphocytes account for only 20 to 40% of the total WBC count, lymphocytopenia may go unnoticed when WBC count is checked without a differential.

Almost 65% of blood T cells are CD4+ (helper) T cells. Most patients with lymphocytopenia have a reduced absolute number of T cells, particularly in the number of CD4+ T cells. The average number of CD4+ T cells in adult blood is 1100/μL (range, 300 to 1300/μL), and the average number of cells of the other major T-cell subgroup, CD8+ (suppressor) T cells, is 600/μL (range, 100 to 900/μL).

Etiology

Lymphocytopenia can be

  • Acquired

  • Inherited

Acquired lymphocytopenia

Acquired lymphocytopenia can occur with a number of other disorders (see Table: Causes of Lymphocytopenia). The most common causes include

  • Protein-energy undernutrition

  • AIDS and certain other viral infections

Protein-energy undernutrition is the most common cause worldwide. AIDS is the most common infectious disease causing lymphocytopenia, which arises from destruction of CD4+ T cells infected with HIV. Lymphocytopenia may also reflect impaired lymphocyte production arising from destruction of thymic or lymphoid architecture. In acute viremia due to HIV or other viruses, lymphocytes may undergo accelerated destruction from active infections with the virus, may be trapped in the spleen or lymph nodes, or may migrate to the respiratory tract.

Iatrogenic lymphocytopenia is caused by cytotoxic chemotherapy, radiation therapy, or the administration of antilymphocyte globulin (or other lymphocyte antibodies). Long-term treatment for psoriasis using psoralen and ultraviolet A irradiation may destroy T cells. Glucocorticoids can induce lymphocyte destruction.

Lymphocytopenia may occur with autoimmune diseases such as SLE, RA, myasthenia gravis, and protein-losing enteropathy.

Inherited lymphocytopenia

Inherited lymphocytopenia (see Table: Causes of Lymphocytopenia) most commonly results from

  • Severe combined immunodeficiency disorder

  • Wiskott-Aldrich syndrome

It may occur with inherited immunodeficiency disorders (see Immunodeficiency Disorders) and disorders that involve impaired lymphocyte production. Other inherited disorders, such as Wiskott-Aldrich syndrome, adenosine deaminase deficiency, and purine nucleoside phosphorylase deficiency, may involve accelerated T-cell destruction. In many disorders, antibody production is also deficient.

Causes of Lymphocytopenia

Mechanism

Examples

Acquired

AIDS

Other infectious disorders, including hepatitis, influenza, TB, typhoid fever, and sepsis

Dietary deficiency in patients with ethanol abuse, protein-energy undernutrition, or zinc deficiency

Iatrogenic after use of cytotoxic chemotherapy, glucocorticoids, high-dose psoralen and ultraviolet A radiation therapy, immunosuppressants, radiation therapy, or thoracic duct drainage

Systemic disorders with autoimmune features (eg, aplastic anemia, Hodgkin lymphoma, myasthenia gravis, protein-losing enteropathy, RA, renal failure, sarcoidosis, SLE, thermal injury)

Hereditary

Aplasia of lymphopoietic stem cells

Ataxia-telangiectasia

Cartilage-hair hypoplasia syndrome

Idiopathic CD4+ T lymphocytopenia

Immunodeficiency with thymoma

Severe combined immunodeficiency associated with a defect in the IL-2 receptor γ-chain, deficiency of ADA or PNP, or an unknown defect

Wiskott-Aldrich syndrome

ADA = adenosine deaminase; PNP = purine nucleoside phosphorylase.

Symptoms and Signs

Lymphocytopenia per se generally causes no symptoms. However, findings of an associated disorder may include

  • Absent or diminished tonsils or lymph nodes, indicative of cellular immunodeficiency

  • Skin abnormalities (eg, alopecia, eczema, pyoderma, telangiectasia)

  • Evidence of hematologic disease (eg, pallor, petechiae, jaundice, mouth ulcers)

  • Generalized lymphadenopathy and splenomegaly, which may suggest HIV infection

Lymphocytopenic patients experience recurrent infections or develop infections with unusual organisms. Pneumocystis jirovecii, cytomegalovirus, rubeola, and varicella pneumonias often are fatal. Lymphocytopenia is also a risk factor for the development of cancers and for autoimmune disorders.

Diagnosis

  • Clinical suspicion (repeated or unusual infections)

  • CBC with differential

  • Measurement of lymphocyte subpopulations and immunoglobulin levels

Lymphocytopenia is suspected in patients with recurrent viral, fungal, or parasitic infections but is usually detected incidentally on a CBC. P. jirovecii, cytomegalovirus, rubeola, or varicella pneumonias with lymphocytopenia suggest immunodeficiency. Lymphocyte subpopulations are measured in patients with lymphocytopenia. Measurement of immunoglobulin levels should also be done to evaluate antibody production. Patients with a history of recurrent infections undergo complete laboratory evaluation for immunodeficiency (see Approach to the Patient With Suspected Immunodeficiency), even if initial screening tests are normal.

Treatment

  • Treatment of associated infections

  • Treatment of underlying disorder

  • Sometimes IV immune globulin

  • Possibly hematopoietic stem cell transplantation

In acquired lymphocytopenias, lymphocytopenia usually remits with removal of the underlying factor or successful treatment of the underlying disorder. IV immune globulin is indicated if patients have chronic IgG deficiency, lymphocytopenia, and recurrent infections. Hematopoietic stem cell transplantation can be considered for all patients with congenital immunodeficiencies and may be curative (see Hematopoietic Stem Cell Transplantation).

Key Points

  • Lymphocytopenia is most often due to AIDS or undernutrition, but it also may be inherited or caused by various infections, drugs, or autoimmune disorders.

  • Patients have recurrent viral, fungal, or parasitic infections.

  • Lymphocyte subpopulations and immunoglobulin levels should be measured.

  • Treatment is usually directed at the cause, but occasionally, IV immune globulin or, in patients with congenital immunodeficiency, stem cell transplantation is helpful.

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