What is Combined Immunodeficiency Disorder?

What is Combined Immunodeficiency Disorder?

Combined immunodeficiency disorders (CID) are inherited genetic conditions characterized by defects in both T-cell and B-cell function, resulting in severe susceptibility to recurrent, severe infections that are often life-threatening without prompt treatment. 1

Classification and Spectrum

Combined immunodeficiencies exist on a spectrum from most severe to less severe forms:

• Severe Combined Immunodeficiency (SCID) represents the most extreme form, with complete absence of specific immunity and susceptibility to the entire range of pathogens, including opportunistic organisms. 1
• Less severe combined immunodeficiencies include conditions like hyper-IgM syndromes and other T- and B-cell defects that cause significant but incomplete immune dysfunction. 1

Combined B- and T-cell defects account for approximately 10-20% of all primary immunodeficiencies, making them less common than pure antibody deficiencies but more severe. 1

Core Immunologic Features

The hallmark of combined immunodeficiency is impairment of both adaptive immune arms:

• T-cell dysfunction is always present, with very low or absent T-cell counts and profoundly reduced proliferation to mitogens and antigens. 2
• B-cell abnormalities occur due to both lack of T-cell help and intrinsic B-cell defects, resulting in hypogammaglobulinemia and poor antibody production. 2
• NK cell involvement varies depending on the specific genetic defect, with some forms affecting T, B, and NK cells (T-B-NK-), while others primarily affect T and B cells (T-B-NK+). 2

Clinical Presentation

Patients with combined immunodeficiency typically present with:

• Recurrent severe infections that are repetitive, refractory to therapy, and caused by both common pathogens and opportunistic organisms. 1, 3
• Early onset symptoms in SCID include chronic diarrhea, failure to thrive, thrush, skin rashes, and persistent infections unresponsive to standard treatments. 1, 3
• Autoimmune manifestations such as cytopenias, inflammatory arthropathies, and vasculitides due to immune dysregulation. 1
• Increased malignancy risk, particularly hematologic malignancies like lymphoma and leukemia. 1

Genetic Basis

Over 20 different genes can cause combined immunodeficiency, affecting various stages of lymphocyte development:

• X-linked SCID (IL2RG gene) is the most common form, characterized by T-B+NK- phenotype. 1, 2
• Adenosine deaminase (ADA) deficiency causes T-B-NK- phenotype with the most profound lymphopenia. 2
• RAG1/2 deficiencies result in T-B-NK+ phenotype due to defective V(D)J recombination. 2
• Other defects include JAK3, IL-7Rα, CD3 complex components, and DNA repair enzymes. 1

Laboratory Diagnosis

Key diagnostic findings include:

• Lymphopenia and leukopenia on complete blood count. 2
• Low or absent immunoglobulins (IgA, IgM, with variable IgG due to maternal transfer). 2
• Severely reduced or absent T cells on flow cytometry, with variable B and NK cell numbers depending on the specific defect. 2
• Profoundly reduced T-cell proliferation to mitogens and antigens. 2
• Very low or absent TRECs (T-cell receptor excision circles) used in newborn screening programs. 2

Critical Management Principles

SCID is an urgent medical emergency requiring immediate intervention, as these infants can succumb to severe infection at any time. 1

Initial management includes:

• Supportive care with antimicrobials and IgG replacement therapy. 1
• Infection control measures including avoidance of live vaccines, irradiated blood products only, and isolation from infectious exposures. 1
• Definitive treatment with hematopoietic stem cell transplantation (HSCT) should be pursued as quickly as possible, with significantly better outcomes when performed before 3.5 months of age. 1, 2
• Gene therapy is becoming an effective option for certain forms of SCID, particularly ADA deficiency and X-linked SCID. 3, 4

Important Distinctions

Combined immunodeficiency must be distinguished from:

• Pure antibody deficiencies (like X-linked agammaglobulinemia) where T-cell numbers and function are normal. 5, 6
• Secondary immunodeficiencies due to drugs, infections (HIV), malnutrition, or other acquired causes. 1
• Syndromic forms like DiGeorge syndrome, Wiskott-Aldrich syndrome, and ataxia-telangiectasia that have additional non-immunologic features. 1, 7

Prognosis

Without treatment, severe combined immunodeficiency is fatal within the first two years of life. 8, 4 However, with early diagnosis through newborn screening and prompt HSCT or gene therapy, patients can achieve immune reconstitution and lead relatively normal lives, though lifelong medical follow-up remains necessary. 3, 4