Severe Combined Immunodeficiencies

Indications for Testing

Early onset viral, fungal or P. jiroveci infections

Laboratory Testing

Initial testing
- CBC – presence of lymphopenia
- HIV molecular PCR testing in infants ≤15 months – rule out HIV infection
- Cell-mediated immune function (results within 24 hours) – recommended to determine necessity of immediate prophylactic treatment for children
- T-cell and B-cell immunodeficiency profile testing
- Quantitative immunoglobulins
- Lymphocyte antigen and mitogen proliferation with cytokine response – will be abnormal
  - Test requires at least 7 days for results
Molecular diagnosis is available for prenatal testing
Second-line testing
- Analyte/enzyme testing – adenosine deaminase, purine nucleoside phosphorylase
- Genetic testing – ADA, PNP, IL2RG

Severe combined immunodeficiencies (SCID) consist of a group of genetic disorders characterized by blocking T-lymphocyte differentiation in function and often are associated with abnormal development of other lymphocyte lineages (B-cells and NK-cells).

Epidemiology

Incidence – 1/75,000-100,000
Age – onset usually in infancy
Sex – M;F, equal, except for X-linked forms

Identified Forms of SCID

X-linked SCID – 50-60% of SCID
Adenosine deaminase (ADA) deficiency – 30% of SCID

T- and B-cell variants

T- and B-cell Variants of SCID
Variant	T-cell	B-cell	NK-cell	Comment
IL2RG	–	+	–
JAK3	–	+	–
IL7R	–	+	+	T-cell growth IL7
IL2RA	–	+	+
PTPRC (CD45)	–	+	+	T-cell receptors only
CD3D or CD3δ	–	+	+	T-cell receptors only
Winged Helix Nude (WHN)	–	+	+
ADA	–	–	–	Adenosine is toxic to all cells; depresses all cells
RAG1/2	–	–	+	Recombinant of T- and B-cell receptors
DCCRE1C (Artemis)	–	–	+	Recombinant of T- and B-cell receptors
CD3ε	+ but dysfunctional	+	+
NP (PNP)	–	+	–
ZAP70	CD4 (+) CD8 (–) Lymphocytes	–	+

Inheritance

All but the X-linked forms are autosomal recessive

Pathophysiology

Block in T-lymphocyte differentiation or growth and variable abnormal development of other lymphocyte lineages

Clinical Presentation

Early onset of severe infections (earliest are Pneumocystis jiroveci viral, also fungal followed in many cases at 4-6 months by bacterial infection)
Growth failure
Persistent diarrhea
Desquamative skin rash, elevated liver enzymes, and GI bleeding
Occurrence of graft-versus-host disease upon exposure to maternal lymphocytes, during delivery, or by non-irradiated blood transfusion

Treatment

Prophylaxis for P. jiroveci, fungal infections, and in some cases bacterial infections
Allogeneic bone marrow transplant
For ADA deficiency – exogenous enzyme replacement
Gene therapy for X-linked SCID and ADA deficiency

Tests generally appear in the order most useful for common clinical situations

Test name: CBC with Platelet Count & Automated Differential

ARUP #: 0040003

Methodology: Automated Cell Count with Flow Cell Differential

Use:

Determine presence of lymphopenia

Test name: Human Immunodeficiency Virus Type 1 (HIV-1) Antibody with Reflex to Human Immunodeficiency Virus Type 1 (HIV-1) Antibody Confirmation by Western Blot

ARUP #: 2005375

Methodology: Qualitative Chemiluminescent Immunoassay/Qualitative Western Blot

Use:

Rule out HIV

Test name: Cell-Mediated Immune Function Screen

ARUP #: 0051273

Methodology: Cell Culture/Quantitative Chemiluminescence

Use:

May be useful as a screen for immunodeficiency

Limitations:

Time sensitive

Assay does not directly quantify level of immunosuppression

Test name: Lymphocyte Subset Panel 7 - Congenital Immunodeficiencies

ARUP #: 0095899

Methodology: Quantitative Flow Cytometry

Use:

Determine presence of T-cell deficiency

Measures percentage and absolute numbers of CD4 (helper T-cells), CD45RA (naive helper T-cells), CD45RO (memory helper T-cells), CD8 (suppressor T-cells), CD4: CD8 ratio, CD2, CD3 (total T-cells), HLA-DR, CD19 (B-cells), NK-cells

Test name: B-Cell Immunodeficiency Profile

ARUP #: 0095940

Methodology: Quantitative Flow Cytometry

Use:

Determine presence of B-cell deficiency

Measures circulating B-cells (CD19), their surface immunoglobulins (total Ig, IgG, IgD, IgM, and IgA), and HLA-DR

Test name: Immunoglobulins (IgA, IgG, IgM), Quantitative

ARUP #: 0050630

Methodology: Quantitative Nephelometry

Use:

Screen for immunodeficiency

Determine immunoglobulin concentration

Test name: Lymphocyte Antigen & Mitogen Proliferation Panel

ARUP #: 0096056

Methodology: Cell Culture

Use:

Screen for immunodeficiencies

Panel includes testing for phytohemagglutinin, concanavalin A, pokeweed mitogen, Candida antigen, and tetanus antigen

Limitations:

Time sensitive

Test name: Lymphocyte Antigen and Mitogen Proliferation Panel with Cytokine Response to Mitogens, 12 Cytokines

ARUP #: 0051584

Methodology: Cell Culture/Multi-Analyte Fluorescence Detection

Use:

Screen for inheritance of immunodeficiencies

Components include cytokine production by mononuclear cells in response to mitogen stimulation, which include: interleukin 2, interleukin 2 receptor, interleukin 12, interferon gamma, interleukin 4, interleukin 5, interleukin 10, interleukin 13, interleukin 1 beta, interleukin 6, interleukin 8, and tumor necrosis factor alpha

Limitations:

Time sensitive

Additional Tests Available

Test name: Adenosine Deaminase, RBC

ARUP #: 0083001

Methodology: Quantitative Spectrophotometry

Comments:

May be used as a marker of SCID; lack of ADA allows deoxyadenosine to accumulate and kill lymphocytes

Test name: Interleukin 2 Receptor (Soluble) by MAFD

ARUP #: 0051529

Methodology: Quantitative Multi-Analyte Fluorescent Detection

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