Primary Immunodeficiency Disorders

Monogenic causes grouped by inheritance

• X-linked defects (boys, maternal uncles affected): BTK in X-linked agammaglobulinemia (blocks pre-B to mature B-cell transition), IL2RG in X-linked SCID (the most common SCID form; T−B+NK− phenotype), CD40LG in X-linked hyper-IgM (no class switching, so IgM high and IgG/IgA low), WAS in Wiskott-Aldrich, and CYBB (gp91^phox) in the majority of chronic granulomatous disease
• Autosomal recessive defects: adenosine deaminase and purine nucleoside phosphorylase deficiency (toxic dATP/deoxynucleoside accumulation is lymphotoxic), RAG1/RAG2 (failed V(D)J recombination), JAK3, ZAP70, ITGB2 in leukocyte adhesion deficiency type 1 (CD18 absent), p47^phox CGD, and most terminal complement component deficiencies
• Autosomal dominant / de novo: dominant-negative STAT3 in hyper-IgE (Job) syndrome; FOXP3 (X-linked) in IPEX with loss of regulatory T cells
• Contiguous gene deletion: 22q11.2 microdeletion (DiGeorge/velocardiofacial), usually de novo, disrupting third and fourth pharyngeal pouch development — thymus, parathyroids, and conotruncus
• Polygenic/undefined: common variable immunodeficiency and selective IgA deficiency are mostly sporadic with only a minority carrying identified risk alleles (e.g., *TNFRSF13B*/TACI); the two cluster in the same families, and IgA deficiency can evolve into CVID

Non-modifiable risk factors examiners plant in the stem

• Consanguinity or a prior sibling/infant death from infection — points to an autosomal recessive combined immunodeficiency
• Male sex plus an affected maternal male relative — X-linked pedigree
• Abnormal newborn TREC screen (now on the HRSA/ACHDNC Recommended Uniform Screening Panel nationwide) or absent thymic shadow on infant chest film

Modifiable exposures that convert latent risk into catastrophe

• Live vaccines — rotavirus, BCG, MMR, varicella, live attenuated influenza, and oral polio are contraindicated in SCID and other profound T-cell defects per CDC/ACIP and IDSA guidance on the immunocompromised host
• Non-irradiated, non-leukoreduced, CMV-untested blood products — risk of transfusion-associated GVHD and CMV in T-cell deficiency
• Delayed recognition, breastfeeding from a CMV-seropositive mother in SCID, and tobacco smoke or untreated sinopulmonary infection accelerating bronchiectasis in antibody deficiency
• Distractor: secondary causes (HIV, rituximab, chronic corticosteroids, protein-losing enteropathy, nephrotic syndrome, malignancy) must be excluded before labeling a hypogammaglobulinemia "primary"

• B-cell defects (X-linked agammaglobulinemia, CVID, IgA deficiency): Impaired antibody production leads to defective opsonization and complement activation; infections typically involve encapsulated organisms (S. pneumoniae, H. influenzae) and enteroviruses; defects range from absent B cells to normal B-cell numbers with impaired differentiation to plasma cells

• T-cell defects (DiGeorge syndrome, SCID): Thymic hypoplasia or aplasia results in absent or severely reduced T-cell numbers; impaired cell-mediated immunity compromises defense against viruses, fungi, Pneumocystis, and intracellular bacteria; also prevents effective B-cell help, causing secondary antibody defects in SCID

• Combined immunodeficiency (SCID): Mutations in genes encoding IL-2 receptor gamma chain (most common X-linked form), adenosine deaminase (ADA), or purine nucleoside phosphorylase (PNP) lead to toxic metabolite accumulation in lymphocytes; results in profoundly impaired T-cell, B-cell, and NK cell function

• Phagocytic defects (Chronic Granulomatous Disease, Leukocyte Adhesion Deficiency): Impaired neutrophil respiratory burst (CGD via NADPH oxidase mutations) or adhesion molecule expression (LAD via integrin defects) prevents effective pathogen killing and chemotaxis; results in infections with catalase-positive organisms (S. aureus, Serratia, Burkholderia, Aspergillus, Nocardia) and delayed wound healing

• Complement deficiencies (C1q through C9, Factor H, Factor I): Absent complement components eliminate classical or alternative pathway activation, preventing opsonization, C3b deposition, and membrane attack complex formation; C3/C5 deficiencies and terminal pathway defects cause susceptibility to Neisseria meningitidis and other encapsulated organisms

• NK cell defects: Impaired recognition and elimination of virally infected and malignant cells; increased susceptibility to herpesviruses (CMV, EBV) and lymphomas

• Recurrent infections with specific pathogen patterns reflecting immune defect: B-cell defects present with respiratory/GI infections (bacteria); T-cell defects present with opportunistic infections (PCP, CMV, candidiasis); phagocytic defects present with catalase-positive organisms and severe local infections; complement deficiencies present with meningitis and sepsis

• Age of onset provides crucial diagnostic clue: Antibody deficiencies typically manifest after 6 months of age (when maternal antibodies wane); T-cell deficiencies present in infancy with failure to thrive, chronic diarrhea, and opportunistic infections; phagocytic defects may present with omphalitis or abscesses in newborn period

• Failure to thrive, chronic diarrhea, poor growth—cardinal signs of early T-cell or combined immunodeficiency in infants; weight loss and malabsorption from recurrent GI infections are common in antibody deficiencies

• Recurrent otitis media, sinusitis, bronchitis progressing to bronchiectasis in antibody deficiencies; atypical presentation without fever or local symptoms may occur in severe T-cell defects

• Skin manifestations: Severe eczema (Hyper-IgE syndrome), delayed umbilical cord separation (LAD), skin abscesses and draining lymph nodes (CGD), candidiasis of mouth/esophagus (T-cell defects)

• Lymphoid architecture abnormalities: Absent/hypoplastic thymus (DiGeorge, SCID), absent/reduced lymph nodes and tonsils (XLA, CVID), splenomegaly (some forms of CVID, hyper-IgM syndrome)

• Autoimmune phenomena paradoxically occur in some PIDs (CVID, IPEX, Hyper-IgM) due to impaired regulatory T-cell function or defective tolerance mechanisms

• Bacterial meningitis with unusual organisms (Neisseria meningitidis in complement deficiency) or recurrent meningitis should raise suspicion for underlying immunodeficiency

• Clinical suspicion based on "WARNING signs": Warts (common in many PIDs), Autoimmunity, Recurrent infections (>4 per year in children, >2 per year in adults), Recurrent pneumonia, Growth failure, Infections unusual for age/severity, Needing antibiotics >2 months/year, Deep skin/organ abscesses, Persistent thrush, Persistent diarrhea, Failure to thrive

• Quantitative immunoglobulin levels (IgG, IgA, IgM): Markedly low IgG suggests antibody deficiency (XLA, CVID); absent IgA suggests selective IgA deficiency; abnormal distribution (very high IgM, low IgG) suggests Hyper-IgM syndrome; must correct for age as norms vary in children

• Lymphocyte enumeration and subset analysis via flow cytometry: Absent CD19+ B cells or CD3+ T cells; reduced CD4+ count (<500 suggests cellular immunity defect); NK cell numbers; used to classify severity in SCID and T-cell deficiencies

• Complement pathway testing: CH50 (classical pathway screening), AP50 (alternative pathway), individual component levels; identify specific deficiency (e.g., C3 level in C3 deficiency, Factor H in Factor H deficiency)

• Dihydrorhodamine (DHR) or nitroblue tetrazolium (NBT) flow cytometry: Gold standard for CGD diagnosis; detects absent respiratory burst capacity in neutrophils; NBT turns blue with functional respiratory burst

• Leukocyte adhesion molecule testing (anti-CD11/CD18 antibodies by flow cytometry): Absent beta-2 integrins diagnostic of LAD-1

• Genetic testing: Increasingly available; identifies mutations in specific genes (BTLA in XLA, PIK3CD in activated PI3K syndrome, ADA in some SCID cases, NADPH oxidase components in CGD); confirms diagnosis and guides counseling

• Specific antibody response testing: Assess post-vaccination titers to pneumococcal/meningococcal vaccines; failure to mount response suggests impaired B-cell function even with normal immunoglobulin levels

• T-cell function assays (proliferation to mitogens, lymphocyte transformation test): Assess T-cell responsiveness to stimulation; abnormal response supports T-cell deficiency diagnosis

• Newborn screening: Now includes severe combined immunodeficiency (SCID) in many US states via T-cell receptor excision circle (TREC) testing; allows early identification before onset of infections

• Immunoglobulin replacement (IV or subcutaneous): First-line for antibody deficiencies (XLA, CVID, selective IgA deficiency); IVIg typically 400-600 mg/kg monthly; SCIg 100-150 mg/kg weekly; goal is trough IgG level >400-500 mg/dL (higher in CVID with infection history); reduces infection frequency by 50-75%

• Antibiotic prophylaxis: Trimethoprim-sulfamethoxazole for PCP prophylaxis in T-cell defects with CD4 <200; itraconazole for candidiasis prophylaxis; long-term penicillin V in CGD/LAD to prevent S. aureus infections; consider prophylaxis against Encapsulated organisms if asplenic or complement-deficient

• **Hematopoi

Emergencies — recognize on sight

• Disseminated live-vaccine infection or Pneumocystis pneumonia in an infant with SCID: absent T cells permit uncontrolled replication of BCG, rotavirus, or vaccine poliovirus; signaled by a hypoxic infant with diffuse interstitial infiltrates and a normal-to-low lymphocyte count. Requires isolation, IVIG, high-dose TMP-SMX, and urgent transplant referral
• Transfusion-associated GVHD or maternal T-cell engraftment in SCID: infused allogeneic T cells are not rejected; rash, hepatitis, diarrhea, and pancytopenia after a non-irradiated transfusion
• Hypocalcemic seizures in DiGeorge syndrome: parathyroid aplasia; low calcium with low PTH and a prolonged QT
• Fulminant meningococcemia/purpura fulminans in terminal complement (C5–C9) deficiency: no membrane attack complex, so serogroup-specific killing fails; recurrent Neisseria disease is the signature
• Enteroviral meningoencephalitis or vaccine-associated paralytic poliomyelitis in XLA: neutralizing antibody is the sole effective defense against enteroviruses

Chronic disease complications

• Bronchiectasis and obstructive lung disease from repeated encapsulated-organism pneumonias in XLA/CVID — chronic productive cough with tram-track and signet-ring findings on high-resolution CT
• CVID-specific sequelae: granulomatous-lymphocytic interstitial lung disease, nodular lymphoid hyperplasia with chronic Giardia diarrhea, autoimmune cytopenias (ITP, autoimmune hemolytic anemia), and markedly increased risk of non-Hodgkin lymphoma and gastric adenocarcinoma
• CGD sequelae: obstructing granulomas of the pylorus or bladder, hepatic abscess, invasive Aspergillus, and an inflammatory bowel disease–like colitis from dysregulated, ineffective inflammation
• Hyper-IgE syndrome: pneumatoceles after staphylococcal pneumonia, later colonized by Aspergillus

Treatment-related complications

• Immunoglobulin replacement: infusion-rate–related headache, aseptic meningitis, hemolysis from passive isohemagglutinins, acute kidney injury with sucrose-stabilized products, and thromboembolism — the FDA carries a boxed warning for thrombosis and renal dysfunction
• Anaphylaxis to IgA-containing products in IgA-deficient patients with anti-IgA IgE — treat with epinephrine 0.3 mg IM; use washed red cells and IgA-depleted products thereafter
• TMP-SMX prophylaxis: cytopenias, hyperkalemia, hypersensitivity reactions including SJS/TEN
• Hematopoietic stem cell transplant: GVHD, conditioning toxicity, and delayed immune reconstitution; earlier retroviral gene-therapy protocols for X-linked SCID caused insertional leukemia, now mitigated by self-inactivating lentiviral vectors

• Positive newborn TREC screen is the single most tested "next step" chain: confirm with flow cytometry for CD3/CD4/CD8, CD19, and CD16/56, then immediately institute protective isolation, no live vaccines, only irradiated/leukoreduced/CMV-safe blood, IVIG, and TMP-SMX prophylaxis, with referral for allogeneic HSCT — outcomes are best when transplant occurs in the first months of life, before infection supervenes
• XLA versus CVID: a boy who becomes ill after 6 months of age (maternal IgG wanes) with absent tonsils and no palpable lymph nodes, low all isotypes, and absent CD19+ B cells with normal T cells is Bruton agammaglobulinemia (BTK). CVID presents in the second to fourth decade with normal B-cell numbers but failure to differentiate into plasma cells, plus bronchiectasis, Giardia, autoimmune cytopenias, and lymphoma risk
• Selective IgA deficiency is the most common PID and is usually asymptomatic — two boards hooks: anaphylaxis to blood products/IVIG from anti-IgA antibodies, and a false-negative IgA tissue transglutaminase in celiac disease (order IgG-based serology, or check total IgA first)
• DiGeorge = CATCH-22: conotruncal defect (truncus arteriosus, interrupted aortic arch), abnormal facies, thymic aplasia with absent thymic shadow, cleft palate, hypocalcemia — confirm with chromosomal microarray or FISH for the 22q11.2 deletion
• CGD: catalase-positive organisms (S. aureus, Serratia, Burkholderia, Nocardia, Aspergillus); diagnose with the dihydrorhodamine flow-cytometric burst assay (NBT is the older test); prophylaxis is TMP-SMX plus itraconazole plus interferon-gamma
• **Recurrent Neisseria meningitidis disease = terminal complement deficiency**: screen with CH50; CDC/ACIP recommends both MenACWY and serogroup B vaccination for these patients
• The commonest distractor is a normal child: a toddler in daycare with frequent viral URIs, normal growth, and no deep-seated or opportunistic infection needs no immune workup. Likewise, always exclude secondary causes — HIV, rituximab, steroids, protein loss — before calling hypogammaglobulinemia primary
• Absent lymph nodes/tonsils implies a B-cell or combined defect; delayed umbilical separation without pus implies leukocyte adhesion deficiency; retained primary teeth with cold abscesses and eosinophilia implies hyper-IgE (Job) syndrome