Immunodeficiencies

Framework: the organism names the broken arm

Pattern recognition. Immunodeficiency vignettes pair an infection pattern with one buzzword (absent tonsils, delayed cord separation, giant granules) that usually names both the disease and the gene. Start by asking which arm of immunity has failed:

• B-cell (antibody) defects: encapsulated bacteria (S. pneumoniae, H. influenzae), enteroviruses, and Giardia. Symptoms begin after about 6 months of age, once maternal IgG wanes.
• T-cell defects: viruses (CMV, EBV, VZV), fungi including Candida, and Pneumocystis (PCP).
• Phagocyte defects: catalase-positive organisms such as S. aureus and Nocardia, plus pyogenic bacteria.
• Complement defects: terminal complement (C5–C9) deficiency gives recurrent Neisseria infection.

B-cell (humoral) defects

X-linked (Bruton) agammaglobulinemia. A defective BTK (Bruton tyrosine kinase) gene halts B-cell maturation, so mature B cells never reach the blood. Boys are well until about 6 months, then develop recurrent bacterial (pneumococcal, Haemophilus) and enteroviral infections. All immunoglobulin classes are low, and tonsils and lymph nodes are absent or scanty because germinal centers never form. Treatment is immunoglobulin replacement. No live vaccines: enteroviruses and polio vaccine strains can disseminate.

Selective IgA deficiency. The most common primary immunodeficiency: IgA <7 mg/dL with normal IgG and IgM. Most patients are asymptomatic; others have sinopulmonary and GI infections, atopy, autoimmune disease, or celiac disease. Some form anti-IgA antibodies and develop anaphylaxis to IgA-containing blood products, so they need washed or IgA-deficient products. IgA-based celiac serology is falsely negative, so IgG-based tests are used.

Common variable immunodeficiency (CVID). B cells are present but fail to differentiate into plasma cells, so immunoglobulins fall. It affects both sexes and presents later (ages 15–35) with recurrent sinopulmonary infections and a markedly increased risk of autoimmune disease, bronchiectasis, and lymphoma.

T-cell defects

DiGeorge syndrome (22q11.2 deletion). Failed development of the 3rd and 4th pharyngeal pouches causes thymic aplasia (↓ T cells, absent thymic shadow) and parathyroid aplasia (low PTH, hypocalcemia, neonatal tetany). Infections are viral, fungal, and PCP, and conotruncal heart defects (tetralogy of Fallot, truncus arteriosus) are typical. CATCH-22: Cardiac defects, Abnormal facies, Thymic aplasia, Cleft palate, Hypocalcemia, chromosome 22.

IL-12 receptor deficiency. Autosomal recessive loss of IL-12 signaling blunts Th1 differentiation and IFN-γ, causing disseminated mycobacterial and fungal infection, sometimes first recognized after BCG vaccination.

Chronic mucocutaneous candidiasis. T-cell dysfunction in the AIRE or IL-17 pathway allows persistent but noninvasive Candida infection of skin and mucosa. AIRE mutations also cause autoimmune polyendocrine syndrome type 1 (candidiasis, hypoparathyroidism, adrenal insufficiency).

Hyper-IgE (Job) syndrome. An autosomal dominant STAT3 mutation impairs Th17 differentiation, so neutrophils are not recruited. Abscesses are "cold," lacking warmth and redness because neutrophils never arrive. FATED: coarse Facies, cold staphylococcal Abscesses, retained primary Teeth, very high IgE, and Dermatologic eczema; bone fractures and eosinophilia also occur.

Combined B- and T-cell defects

SCID, the "bubble boy" defect. Most often X-linked, from a defective IL-2 receptor common γ chain (shared by several cytokine receptors), or autosomal recessive adenosine deaminase (ADA) deficiency, in which toxic deoxyadenosine metabolites kill lymphocytes. T cells are absent, with variable loss of B and NK cells. Infants have failure to thrive, chronic diarrhea, thrush, and opportunistic infections, and the thymic shadow is absent. Newborn screening detects low T-cell receptor excision circles (TRECs). Treatment is bone marrow transplant; avoid live vaccines.

Ataxia-telangiectasia. An autosomal recessive ATM mutation impairs repair of DNA double-strand breaks. Triad: cerebellar Ataxia, spider Angiomas (telangiectasias), and IgA deficiency. Elevated serum AFP is the classic lab clue in a child with ataxia; patients are radiosensitive and at increased risk of lymphoma and leukemia.

Wiskott-Aldrich syndrome. An X-linked recessive WAS mutation leaves T cells unable to reorganize the actin cytoskeleton. WATER: Wiskott-Aldrich = Thrombocytopenia with small platelets, Eczema, Recurrent pyogenic infections. IgM is low while IgE and IgA are high; autoimmune disease and malignancy risks are increased.

Hyper-IgM syndrome. Most often X-linked loss of CD40 ligand on helper T cells: B cells never receive the CD40 signal to class-switch, so IgM is high while IgG, IgA, and IgE are low. Because CD40L also helps activate macrophages, severe pyogenic infections are joined by opportunistic Pneumocystis, Cryptosporidium, and CMV.

Phagocyte defects

Chronic granulomatous disease (CGD). Defective NADPH oxidase abolishes the respiratory burst, so phagocytes cannot make reactive oxygen species. Catalase-negative microbes are still killed because host myeloperoxidase can use the H₂O₂ they generate; catalase-positive organisms destroy their own H₂O₂ and survive: S. aureus, Serratia, Burkholderia cepacia, Nocardia, Aspergillus. The X-linked form is most common. Diagnose with abnormal dihydrorhodamine (DHR) flow cytometry or nitroblue tetrazolium (NBT) dye test; prophylaxis is TMP-SMX plus itraconazole, and IFN-γ reduces infections.

Chédiak-Higashi syndrome. An autosomal recessive LYST mutation disrupts microtubule-dependent phagolysosome fusion, giving giant granules in leukocytes, partial albinism, peripheral neuropathy, and recurrent pyogenic infection.

Leukocyte adhesion deficiency type 1 (LAD-1). Defective CD18, part of the integrin LFA-1, stops neutrophils from adhering to endothelium and migrating into tissue: infections without pus, delayed umbilical cord separation (>30 days), and neutrophilia because the cells stay in the blood.

Buzzword → diagnosis: absent tonsils → Bruton; transfusion anaphylaxis → IgA deficiency; tetany plus truncus arteriosus → DiGeorge; cold abscesses and retained teeth → Job; ataxia with high AFP → ataxia-telangiectasia; small platelets and eczema → Wiskott-Aldrich; delayed cord separation → LAD-1.