Lymphocytopenia

ByDavid C. Dale, MD, University of Washington
Reviewed/Revised Apr 2023
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Lymphocytopenia is a total lymphocyte count of < 1000/mcL ( < 1 × 10/L) in adults or < 3000/mcL (< 3 × 10/L) in children < 2 years. Sequelae include opportunistic infections and an increased risk of malignant and autoimmune disorders. If the complete blood count reveals lymphocytopenia, testing for immunodeficiency and analysis of lymphocyte subpopulations should follow, usually after the patient has recovered from any acute event. Treatment is directed at the underlying disorder.

Lymphocytes are components of the cellular immune system and include T cells, B cells, and natural killer (NK) cells, all of which are present in the peripheral blood; about 75% of the lymphocytes are T cells, 20% B cells, and 5% NK cells. Because lymphocytes account for only 20 to 40% of the total white blood cell (WBC) count, lymphocytopenia may go unnoticed if the WBC count is checked without a differential.

The normal lymphocyte count in adults is 1000 to 4800/mcL (1 to 4.8 × 109/L; in children < 2 years, the normal count is 3000 to 9500/mcL (3 to 9.5 × 109/L). At age 6 years, the lower limit of normal is 1500/mcL (1.5 × 109/L). Different laboratories may have slightly different normal values.

Almost 65% of blood T cells are CD4+ (helper) T cells. Thus, 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/mcL (range, 300 to 1300/mcL [1.1 × 109/L with a range of 0.3 to 1.3 × 109/L]), and the average number of cells of the other major T-cell subgroup, CD8+ (suppressor) T cells, is 600/mcL (range, 100 to 900/mcL).

It is important to note that the lymphocytes in the blood represent only a small proportion of the total lymphocyte pool, and the lymphocyte count may not always correlate with the composition and numbers of lymphocytes in other lymphoid (eg, nodes, spleen) and non-lymphoid (eg, lung, liver) tissues. Similarly, deficiencies of particular subsets of lymphocytes (eg, CD8+, B, NK cells) can also be missed.

Clinical Calculators

Etiology of Lymphocytopenia

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

  • HIV infection

  • COVID-19

  • Certain other viral infections

Protein-energy undernutrition is the most common cause worldwide.

Lymphocytopenia is often transient when caused by many viral and bacterial infections, sepsis, corticosteroid treatment, and stress responses.

Patients with HIV infection routinely have lymphocytopenia, which arises from destruction of CD4+ T cells infected with the HIV virus (1). 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 infection with the virus, may be trapped in the spleen or lymph nodes, or may migrate to the respiratory tract.

Patients with COVID-19 also frequently have lymphocytopenia (35 to 83% of patients) (2). Lower lymphocyte counts portend a poor prognosis and an increased likelihood of requiring ICU admission and of dying from the disease. The cause of the lymphocytopenia is not completely understood, but COVID-19 can directly infect lymphocytes, and a cytokine-related apoptosis of the cells is likely.

Lymphocytopenia may occur with lymphomas, sarcoidosis, autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, or myasthenia gravis, and protein-losing enteropathy caused by gastrointestinal disease or constrictive pericarditis.

Cushing syndrome.

Inherited lymphocytopenia

Inherited lymphocytopenia (see table Causes of Lymphocytopenia) most commonly occurs in

It may occur with inherited immunodeficiency disorders and disorders that involve impaired lymphocyte production (3). Other inherited disorders, such as Wiskott-Aldrich syndrome, , and purine nucleoside phosphorylase deficiency, may involve accelerated T-cell destruction. WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is a rare inherited disorder with neutropenia and lymphocytopenia due to abnormal leukocyte migration with retention of mature neutrophils in the bone marrow. In many of these disorders, antibody production is also deficient.

Table

Etiology references

  1. 1. Moir S, Chun TW, Fauci AS: Pathogenic mechanisms of HIV disease. Annu Rev Pathol 6:223-6248, 2011. doi: 10.1146/annurev-pathol-011110-130254

  2. 2. Agbuduwe C, Basu S: Haematological manifestations of COVID-19: From cytopenia to coagulopathy. Eur J Haematol 105(5):540-546, 2020. doi: 10.1111/ejh.13491

  3. 3. Puck JM: Newborn screening for severe combined immunodeficiency and T-cell lymphopenia Immunol Rev 287(1):241-252, 2019. doi: 10.1111/imr.12729.

Symptoms and Signs of Lymphocytopenia

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, warts)

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

  • Generalized lymphadenopathy and splenomegaly, which may suggest HIV infection or Hodgkin lymphoma

Patients with lymphocytopenia 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 of Lymphocytopenia

  • Clinical suspicion (repeated or unusual infections)

  • Complete blood count (CBC) with differential

  • Measurement of lymphocyte subpopulations and immunoglobulin levels

Lymphocytopenia is suspected in patients with recurrent viral, bacterial, fungal, or parasitic infections but is usually detected incidentally with 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 should undergo complete laboratory evaluation for immunodeficiency, even if initial screening test results are normal.

Treatment of Lymphocytopenia

  • Treatment of associated infections

  • Treatment of underlying disorder

  • Sometimes IV or subcutaneous 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 or subcutaneous immune globulin is indicated if patients have chronic immunoglobulin G deficiency, lymphocytopenia, and recurrent infections. Hematopoietic stem cell transplantation can be considered for all patients with congenital immunodeficiencies and may be curative.

Avoid giving live vaccines (because of the risk of causing infection) in these patients. Inactive or recombinant vaccines are safe, but their efficacy is variable depending on type and severity of the lymphocytopenia.

Key Points

  • Lymphocytopenia is most often due to AIDS, and recently COVID-19, or undernutrition, but it also may be inherited or caused by various infections, drugs, or autoimmune disorders.

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

  • Lymphocyte subpopulations and immunoglobulin levels should be measured.

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

  • Avoid giving live vaccines in these patients.

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