T-Cell Deficiency Disorders, Inherited

Diagnosis

Indications for Testing

  • Recurrent infections, particularly with opportunistic organisms

Laboratory Testing

  • Initial testing
    • HIV testing
      • Infants ≤15 months – PCR qualitative or quantitative
      • Adults – screen for antibodies; confirm positive results with Western blot
    • CBC with differential – profound thrombocytopenia with small, nonfunctioning platelets suggests Wiskott-Aldrich syndrome
    • Immunoglobulin quantitative – if low, proceed with B-cell immunodeficiency testing

    • Sweat chloride – if positive, proceed with cystic fibrosis  genetic testing
    • T-cell immunodeficiency profile testing
      • T-cell testing at minimum should include CD4, CD45RA, CD45RO, CD8, CD4:8 ratio, CD3, CD19, and NK-cell
      • If abnormal, proceed with lymphocyte antigen and mitogen test
  • Cell-mediated immune screen – lymphocyte mitogen stimulated ATP production (LMPS); rapid overnight test
    • Lymphocyte antigen and mitogen proliferation test
      • Measures tritiated thymidine (3H-TdR) uptake by lymphocytes in response to stimulus (requires 5-7 days)
      • Low with low T-cells confirms T-cell disorder
    • Lymphocyte antigen and mitogen stimulation with cytokines
  • Further specific genetic testing based on the results of the above testing

Differential Diagnosis

Clinical Background

Cell-mediated immunity is accomplished by T-lymphocytes (T-cells) and their effector response and interactions with other immune cells.

T-cell immunodeficiency diseases include the following

  • Adenosine deaminase deficiency
  • Ataxia telangiectasia
  • Chronic mucocutaneous candidiasis
  • DiGeorge syndrome
  • Purine nucleoside phosphorylase deficiency
  • Severe combined immunodeficiencies (SCID)
  • Wiskott-Aldrich syndrome (WAS)

Epidemiology

  • Incidence – rare (<1/1,000,000)
  • Age – most common during neonatal period and infancy
    •  Adult onset rare
  • Sex – M:F, equal, except X-linked diseases
    • M>F for X-linked SCID and WAS

Inheritance

  • Autosomal recessive for all diseases except X-linked SCID and WAS

Pathophysiology

  • Defective lymphocyte responses to stimulants may occur
    • Nonspecific mitogens (phytohemagglutinin, concanavalin A and pokeweed mitogen)
    • Specific antigens, such as Candida or tetanus
  • Characterized by increased susceptibility to infections from opportunistic organisms

Clinical Presentation

  • Ataxia telangiectasia
    • Recurrent infections – sinopulmonary are most common
    • Progressive cerebellar dysfunction
    • Oculocutaneous telangiectasia
    • Cancer risk 35-40% in affected individuals
      • Increased risk of solid tumors in older population
      • Leukemia and lymphoma in children
      • Risk four times greater than general population, especially for breast cancer
  • Chronic mucocutaneous candidiasis
    • Persistent or recurrent Candida infections of the skin, nails and mucous membranes
    • Often have an associated autoimmune disease
    • May be associated with multiple endocrinopathies
  • DiGeorge syndrome
    • Recurrent infections – fungal, viral, bacterial, Pneumocystis
    • Congenital heart disease
    • Hypocalcemic tetany
    • Abnormal facies
    • Palatal abnormalities
    • Thymic hypoplasia
  • SCID
    • Early onset of severe infections (intracellular bacterial, viral, fungal, Pneumocystis)
    • Growth failure
    • Persistent diarrhea
    • Graft-versus-host disease upon exposure to maternal lymphocytes or blood transfusions
    • Earliest onset in X-linked SCID, adenosine deaminase (ADA) deficiency, purine nucleoside phosphorylase deficiency (PNP), ZAP70 defects, and T- and B-cell variants
    • Refer to T- and B-cell Variants of SCID table in the SCID ARUP Consult topic
  • WAS
    • Recurrent infections – viral, pneumococcal
    • Eczema
    • Associated autoimmune disease common

Treatment

  • Patients with severe T-cell defects, such as SCID, may be appropriate candidates for bone marrow or stem cell transplants and possibly gene therapy
  • Evaluation in the first 2-3 months of life – treatment may decrease morbidity and mortality

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Human Immunodeficiency Virus 1 (HIV-1) by Qualitative PCR 0093061
Method: Qualitative Polymerase Chain Reaction

Initial testing for infants ≤15 months

Qualitative screen for presence of HIV-1 infection

   
Human Immunodeficiency Virus 1 RNA Quantitative Real-Time PCR 0055598
Method: Quantitative Real-Time Polymerase Chain Reaction

Initial testing for infants ≤15 months

Quantitative screen for presence of HIV-1 infection

   
Human Immunodeficiency Virus Types 1 and 2 (HIV-1, HIV-2) Antibodies by CIA with Reflex to HIV-1 Antibody Confirmation by Western Blot 2005377
Method: Qualitative Chemiluminescent Immunoassay/Qualitative Western Blot

Initial testing for adults

Screen for antibodies against HIV-1 and HIV-2

If test is repeatedly reactive, confirmation will be made by Western Blot

   
CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Initial testing

Assess for thrombocytopenia

   
Immunoglobulins (IgA, IgG, IgM), Quantitative 0050630
Method: Quantitative Nephelometry

Initial test in the workup of immunoglobulin disorders

In adults and older children with suspected hypogammaglobulinemia, order in conjunction with serum protein electrophoresis and immunofixation

 

If results low, proceed to B-cell immunodeficiency testing

CD4+ T-Cell Recent Thymic Emigrants (RTEs) 2010179
Method: Quantitative Flow Cytometry

Assess thymic function in suspected SCID, DiGeorge syndrome and other T-cell immune deficiency disorders

Evaluate immune reconstitution during highly active antiviral therapy (HAART) in HIV patients and post chemotherapy and hematopoietic cell transplant

   
Lymphocyte Subset Panel 6 - Total Lymphocyte Enumeration with CD45RA and CD45RO 0095862
Method: Quantitative Flow Cytometry

Useful for assessing primary T-cell immunodeficiency disorders

Test enumerates the percent and absolute cell count of lymphocyte subsets in whole blood for CD4  (helper T cells), CD45RA (naive helper T cells), CD45RO (memory helper T cells), CD8 (cytotoxic T cells), CD4: CD8 ratio, CD3 (total T cells), CD19 (B cells), NK cells

   
Lymphocyte Subset Panel 7 - Congenital Immunodeficiencies 0095899
Method: Quantitative Flow Cytometry

Acceptable lymphocyte subset panel for the investigation of primary immunodeficiency disorders

Test enumerates the percent and absolute cell count of lymphocyte subsets in whole blood for CD4  (helper T cells), CD45RA (naive helper T cells), CD45RO (memory helper T cells), CD8 (cytotoxic T cells), CD4: CD8 ratio, CD2, CD3 (total T cells), HLA-DR, CD19 (B cells), NK cells

 

Severe deficiencies in T cells should initiate differential workup based on deficiency

Lymphocyte Antigen and Mitogen Proliferation Panel 0096056
Method: Cell Culture

Test for lymphocyte proliferation in response to the following

  • Phytohemagglutinin 
  • Concanavalin A
  • Pokeweed mitogen
  • Candida antigen
  • Tetanus antigens

Use to evaluate T-cell mediated immune deficiency

Bacterial or endotoxin contamination of sample profoundly affects test results

T-cell immunodeficiency profile (short and extended)

In addition, evaluate chronic infection based on clinical history and in conjunction with other tests

Chromosome Analysis - Breakage, Ataxia Telangiectasia, Whole Blood 2005749
Method: Giemsa Band

May be useful in diagnosing ataxia telangiectasia; not recommended for diagnosing Fanconi anemia or similar breakage syndromes

Carriers are not detected by this test

 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Lymphocyte Antigen and Mitogen Proliferation Panel with Cytokine Response to Mitogens, 12 Cytokines 0051584
Method: Cell Culture/Multiplex Bead Assay

Test for lymphocyte cytokine responses to

  • Phytohemagglutinin
  • Concanavalin A
  • Pokeweed mitogen
  • Candida antigen
  • Tetanus antigens 

Use to evaluate chronic infections

Lymphocyte Antigen and Mitogen Proliferation Panel with Cytokine Response to Mitogens, Monokines 0051587
Method: Cell Culture/Multiplex Bead Assay
Lymphocyte Antigen and Mitogen Proliferation Panel with Cytokine Response to Mitogens, TH2 Cytokines 0051586
Method: Cell Culture/Multiplex Bead Assay
Lymphocyte Antigen and Mitogen Proliferation Panel with Cytokine Response to Mitogens, TH1 Cytokines 0051585
Method: Cell Culture/Multiplex Bead Assay
Lymphocyte Antigen Proliferation  0096055
Method: Cell Culture

Rapid test for Candida and tetanus antigens

Use to evaluate chronic infections