Lymphocytes Lymphocytes The immune system consists of cellular components and molecular components that work together to destroy antigens. (See also Overview of the Immune System.) Although some antigens (Ags) can... read more 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.
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 Causes of Lymphocytopenia 
).
The most common causes include
Protein-energy undernutrition
HIV infection
COVID-19
Certain other viral infections
Protein-energy undernutrition Protein-Energy Undernutrition (PEU) Protein-energy undernutrition (PEU), previously called protein-energy malnutrition, is an energy deficit due to deficiency of all macronutrients. It commonly includes deficiencies of many micronutrients... read more 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 Human Immunodeficiency Virus (HIV) Infection Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more 
routinely have lymphocytopenia, which arises from destruction of CD4+ T cells infected with the HIV virus (1 Etiology references Lymphocytopenia is a total lymphocyte count of < 1000/mcL ( 1 × 109/L) in adults or < 3000/mcL (< 3 × 109/L) in children < 2 years. Sequelae include opportunistic... read more ). 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 COVID-19 COVID-19 is an acute, sometimes severe, respiratory illness caused by the novel coronavirus SARS-CoV-2. Prevention is by vaccination and infection control precautions (eg, face masks, handwashing... read more also frequently have lymphocytopenia (35 to 83% of patients) (2 Etiology references Lymphocytopenia is a total lymphocyte count of < 1000/mcL ( 1 × 109/L) in adults or < 3000/mcL (< 3 × 109/L) in children < 2 years. Sequelae include opportunistic... read more ). 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 Overview of Lymphoma Lymphomas are a heterogeneous group of tumors arising in the reticuloendothelial and lymphatic systems. The major types are Hodgkin lymphoma Non-Hodgkin lymphoma See table Comparison of Hodgkin... read more , sarcoidosis Sarcoidosis Sarcoidosis is an inflammatory disorder resulting in noncaseating granulomas in one or more organs and tissues; etiology is unknown. The lungs and lymphatic system are most often affected, but... read more 
, autoimmune diseases such as systemic lupus erythematosus Systemic Lupus Erythematosus (SLE) Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more 
, rheumatoid arthritis Rheumatoid Arthritis (RA) Rheumatoid arthritis is a chronic systemic autoimmune disease that primarily involves the joints. Rheumatoid arthritis causes damage mediated by cytokines, chemokines, and metalloproteases.... read more 
, or myasthenia gravis Myasthenia Gravis Myasthenia gravis is characterized by episodic muscle weakness and easy fatigability caused by autoantibody- and cell-mediated destruction of acetylcholine receptors. It is more common among... read more , and protein-losing enteropathy caused by gastrointestinal disease or constrictive pericarditis Constrictive pericarditis Pericarditis is inflammation of the pericardium, often with fluid accumulation in the pericardial space. Pericarditis may be caused by many disorders (eg, infection, myocardial infarction, trauma... read more 
.
Iatrogenic lymphocytopenia is caused by cytotoxic chemotherapy, radiation therapy, or the administration of antilymphocyte globulin (or other lymphocyte antibodies such as rituximab). Long-term treatment for psoriasis using psoralen and ultraviolet A irradiation may destroy T cells. Long-term glucocorticoid therapy can induce lymphocyte destruction, as can Cushing syndrome Cushing Syndrome Cushing syndrome is a constellation of clinical abnormalities caused by chronic high blood levels of cortisol or related corticosteroids. Cushing disease is Cushing syndrome that results from... read more 
.
Inherited lymphocytopenia
Inherited lymphocytopenia (see table Causes of Lymphocytopenia Causes of Lymphocytopenia ) most commonly occurs in
It may occur with inherited immunodeficiency disorders Overview of Immunodeficiency Disorders Immunodeficiency disorders are associated with or predispose patients to various complications, including infections, autoimmune disorders, and lymphomas and other cancers. Primary immunodeficiencies... read more and disorders that involve impaired lymphocyte production (3 Etiology references Lymphocytopenia is a total lymphocyte count of < 1000/mcL ( 1 × 109/L) in adults or < 3000/mcL (< 3 × 109/L) in children < 2 years. Sequelae include opportunistic... read more ). Other inherited disorders, such as Wiskott-Aldrich syndrome Wiskott-Aldrich Syndrome Wiskott-Aldrich syndrome is an immunodeficiency disorder that involves a combined B- and T-cell defect and is characterized by recurrent infection, eczema, and thrombocytopenia. (See also Overview... read more , adenosine deaminase deficiency Adenosine deaminase deficiency Purines are key components of cellular energy systems (eg, ATP, NAD), signaling (eg, GTP, cAMP, cGMP), and, along with pyrimidines, RNA and DNA production. Purines and pyrimidines may be synthesized... read more , and purine nucleoside phosphorylase deficiency Purine nucleoside phosphorylase deficiency Purines are key components of cellular energy systems (eg, ATP, NAD), signaling (eg, GTP, cAMP, cGMP), and, along with pyrimidines, RNA and DNA production. Purines and pyrimidines may be synthesized... read more , 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.
Etiology references
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. 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. 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 Cellular immunity deficiencies Immunodeficiency disorders are associated with or predispose patients to various complications, including infections, autoimmune disorders, and lymphomas and other cancers. Primary immunodeficiencies... read more
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 Symptoms and Signs Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more
or Hodgkin lymphoma Hodgkin Lymphoma Hodgkin lymphoma is a localized or disseminated malignant proliferation of cells of the lymphoreticular system, primarily involving lymph node tissue, spleen, liver, and bone marrow. Symptoms... read more 
Patients with lymphocytopenia experience recurrent infections or develop infections with unusual organisms. Pneumocystis jirovecii Pneumocystis jirovecii Pneumonia Pneumocystis jirovecii is a common cause of pneumonia in immunosuppressed patients, especially in those infected with human immunodeficiency virus (HIV) and in those receiving systemic... read more 
, cytomegalovirus Cytomegalovirus (CMV) Infection Cytomegalovirus (CMV, human herpesvirus type 5) can cause infections that have a wide range of severity. A syndrome of infectious mononucleosis that lacks severe pharyngitis is common. Severe... read more , rubeola Measles Measles is a highly contagious viral infection that is most common among children. It is characterized by fever, cough, coryza, conjunctivitis, an enanthem (Koplik spots) on the oral mucosa... read more 
, and varicella Chickenpox Chickenpox is an acute, systemic, usually childhood infection caused by the varicella-zoster virus (human herpesvirus type 3). It usually begins with mild constitutional symptoms that are followed... read more 
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 Approach to the Patient With Suspected Immunodeficiency Immunodeficiency typically manifests as recurrent infections. However, recurrent infections are more likely to have causes other than immunodeficiency (eg, inadequate treatment, resistant organisms... read more , 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 Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more 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.
Drugs Mentioned In This Article
| Drug Name | Select Trade |
|---|---|
rituximab |
RIABNI, Rituxan, RUXIENCE, truxima |
adenosine |
Adenocard, Adenoscan |
