Immunodeficiency Conditions - Classification

Immunodeficiency Conditions - Classification

• Immunodeficiencies can be categorized as primary (often genetic) or secondary (caused by another condition).
• Primary immunodeficiencies encompass those affecting the specific immune system (e.g., T cells, B cells) or the innate/nonspecific immune system (e.g., complement, neutrophils).
• Secondary immunodeficiencies are triggered by factors like viral infections (HIV, CMV, EBV), chronic infections, malignancies, therapies, drugs, radiation, and other non-immunological diseases.
• Genetic causes include autosomal recessive, autosomal dominant, and X-linked inheritance patterns. Gene deletions and rearrangements are also possible mechanisms.
• Biochemical/metabolic deficiencies include adenosine deaminase deficiency, purine nucleoside phosphorylase (PNP) deficiency, biotin-dependent multiple carboxylase deficiency, and deficient membrane glycoproteins.
• Vitamin or mineral deficiencies can also lead to immunodeficiencies (e.g., zinc, B12, biotin).

Clinical Features of Immunodeficiency: Recurrent Infections

• Recurrent infections use a flexible definition.
• Two or more major or one major and recurring minor infections within a year might suggest immunodeficiency.
• Unusual organisms (e.g., Aspergillus, Pneumocystis) could indicate immunodeficiency.
• Unusual infection sites (e.g., liver abscess, osteomyelitis) and chronic infections (e.g., sinusitis) are indicators.
• Structural damage (e.g., bronchiectasis) also suggests immunodeficiency.

Algorithm for Evaluation of Recurrent Infections

• Stage 1: general evaluation includes history, physical exam, height and weight, and exclusion of other potential causes.
• Stage 2: immunologic tests include immunoglobulin levels (IgG, IgA, IgM), IgE (if allergic symptoms are present), specific antibody responses (to tetanus, diphtheria, pneumococcal vaccines), IgG subclass analysis, lymphocyte markers (CD3/CD4/CD8), and complement screening (CH50, C3, C4).

X-linked Agammaglobulinemia (Bruton's Disease)

• This is the first recognized immunodeficiency disease.
• Genetic disorder caused by mutations in the BTK gene on the X chromosome (Xq21.3-22).
• Defects prevent B-cell maturation from pro-B to pre-B cells.
• Presents with high incidence of recurrent bacterial infections after early childhood.
• Diagnosis involves low or absent B cells and reduced IgG levels; T and NK cell counts/function are typically normal.

Wiskott-Aldrich Syndrome (WAS)

• An X-linked disorder affecting the WASP gene (Xp11.23).
• Characterized by thrombocytopenia (small platelets), eczema, and progressive immune deficiency.
• Diagnosis involves clinical features, identification of low or absent WASP, and immunological analysis.
• Immunological components like T cells, IgA, IgG, IgE may be affected.
• Symptoms include easy bruising, eczema, and recurrent infections (bacterial, fungal, viral, protozoal).

Ataxia Telangiectasia (AT)

• Autosomal recessive condition (11q22.23), affecting the ATM gene.
• Characterized by progressive cerebellar ataxia, normal intellect, typical telangiectasia (especially on ear lobes and conjunctivae), recurrent bacterial sinopulmonary infections, and an increased risk of cancer due to DNA repair defects.
• Immunological findings can include variable immunoglobulins (IgG2/IgG4, IgA, IgE reduced), reduced T cell numbers, and elevated alpha-fetoprotein (AFP).
• Presentation includes ataxia, difficulty with coordination, balance, slurred speech, and slowed eye movements.

DiGeorge Syndrome

• Results from a microdeletion of 22q11.2.
• Often presents with a triad of hypoplastic thymus, cardiac anomalies, and hypocalcemia.
• Immunological effects include possible deficiency of T cells or other immune components.
• Symptoms include heart defects and immune deficiency leading to recurrent infections. Diagnosis involves tests like cardiac echo, endocrine testing (checking calcium, phosphorus), and checking immune function (including the thymus).