Lymphopenia, Constitutional and Acquired

Qian-Yun Zhang, MD, PhD

Key Facts

Terminology

Lymphopenia is defined as absolute lymphocyte count < 1,000/µL in adults or < 2,000/µL in children

Etiology/Pathogenesis

SCID is immunodeficiency with defects in both humoral and cell-mediated immunity
DiGeorge syndrome results from malformation of 3rd and 4th pharyngeal pouches
ICL has unknown etiology; may represent various disorders and is likely multifactorial
HIV/AIDS infections cause lymphopenia by several mechanisms
Autoimmune disorders are linked to lymphopenia as a consequence of self-destruction
Chemotherapy causes destruction of lymphocytes

Clinical Issues

HIV infection is most common cause of lymphopenia
SCID is associated with excessive number of severe infections since infancy
DGS is associated with T-cell immunodeficiency
Clinical presentation of ICL patients can range from asymptomatic to life-threatening infections mimicking AIDS
Bone marrow transplantation cures SCID
Thymus transplantation in patient with complete DiGeorge anomaly corrects severe immunodeficiency
Antiretroviral drugs, such as reverse transcriptase inhibitors, protease inhibitors, CCR5 inhibitors, and fusion inhibitors, target various stages of life-cycle and result in lifelong viral suppression

This peripheral blood smear from a patient with severe combined immunodeficiency shows pancytopenia, anisopoikilocytosis, and polychromasia of the red blood cells. A single neutrophil is seen in this microphotograph.

This peripheral blood smear from a patient with severe combined immunodeficiency status post bone marrow transplantation reveals normal CBC and differential counts.

TERMINOLOGY

Synonyms

Lymphocytopenia

Definitions

Absolute lymphocyte count < 1,000/µL in adults or < 2,000/µL in children

ETIOLOGY/PATHOGENESIS

Congenital Immunodeficiency Disorders

Severe combined immunodeficiency disease (SCID)
- Immunodeficiency with defects in both humoral and cell-mediated immunity
- Pathogenesis
  - Impaired precursor survival due to mutations in adenylate kinase 2 gene or deficiency of adenosine deaminase
  - Defects in cytokine-mediated signaling due to mutations in IL-2 receptor gamma gene or IL-7 receptor gene
  - Deficiency of the common gamma chain of T-cell growth factor receptor and other growth factor receptors
  - Defect in immune recognition receptors on T- and B-cells due to mutations in RAG1, RAG2 genes
  - Defects in CD3 development due to mutations CD3 complex genes
  - Defects in T-cell development/signaling due to ZAP70 or STAT5B gene mutations, or major histocompatibility complex (MHC) class II deficiency
DiGeorge syndrome (DGS)
- Results from deletion of chromosome 22q11.2
- Transcription factor gene TBX1 may be responsible at molecular level
- Malformation of 3rd and 4th pharyngeal pouches, which give rise to thymus, parathyroid glands, part of aortic arch and face
- 22q11.2 deletion may also give rise to velocardiofacial syndrome, with congenital heart diseases as major manifestations

Idiopathic CD4 T-lymphocytopenia (ICL)

Unknown etiology; may represent various disorders and is likely multifactorial
- Diminished generation of T-cell precursors
- Increased T-cell apoptosis
- Failure of T-cell development
- Defective cytokine production
- CD4 autoantibody

Acquired Immunodeficiency Disorders

HIV infection/AIDS causes lymphopenia by several mechanisms
- Transmitted through sexual or parental exposure to HIV-containing fluids or maternal-fetal transmission
- HIV viruses cause destruction of CD4(+) lymphocytes
- HIV-mediated destruction of mucosal barriers
- Damage of thymus and other lymphoid tissues
Other viral infections
Bacterial infections
Systemic disorders linked to lymphopenia via diverse mechanisms
- Nutritional deficiencies
- Protein-losing disease; GI or renal diseases, burns
- Malignancy
Autoimmune disorders are linked to lymphopenia as consequence of self-destruction
Therapy causes lymphocyte destruction
- Radiation/chemotherapy
- Antilymphocyte globulin

CLINICAL ISSUES

Epidemiology

Incidence
- SCID is rare; X-linked or autosomal recessive inheritance
- DGS affects 1 in 2,000-4,000 live births
- Idiopathic CD4 lymphocytopenia (ICL) is rare; can be seen in any age
- HIV infection is most common cause of sustained lymphopenia