Antibody Deficiencies: XLA, CVID, IgA Deficiency, Subclass Deficiencies

X-linked agammaglobulinemia (Bruton) · Autosomal recessive agammaglobulinemia · Transcobalamin II deficiency · Common variable immune deficiency (CVID) · Selective IgA deficiency · IgG subclass deficiency · Specific antibody deficiency (SAD)
🧬 Key concepts: XLA (BTK, absent B cells, low all immunoglobulins). CVID (low IgG, IgA, poor vaccine response, autoimmune). IgA deficiency (most common, often asymptomatic). IgG subclass deficiency (recurrent infections, normal total IgG).

📖 Defects of antibody production: classification & features

🧬 X-linked agammaglobulinemia (XLA, Bruton)
BTK mutation. Absent B cells, very low IgG, IgA, IgM. Recurrent encapsulated bacteria (sinopulmonary, sepsis). Onset after maternal IgG wanes (6-9 months). IVIG replacement.
🩺 Common variable immune deficiency (CVID)
Low IgG and IgA, variable IgM. Poor vaccine response. Recurrent sinopulmonary infections, autoimmune cytopenias, granulomatous disease, lymphoma risk. IVIG.
⚠️ IgA deficiency
Most common PID (1:500). Often asymptomatic. Can cause recurrent sinopulmonary infections, GI infections, allergic/autoimmune conditions. Anaphylaxis risk with blood products (anti-IgA antibodies).
🔬 IgG subclass & specific antibody deficiencies
IgG2 subclass (polysaccharide response). Normal total IgG. Specific antibody deficiency (impaired response to vaccines despite normal immunoglobulins). IVIG may help.
⚠️ Red flags for antibody deficiency: Recurrent sinopulmonary infections (otitis, sinusitis, pneumonia), severe infections, failure to thrive, family history, low or absent immunoglobulins, poor vaccine response.

🩺 Diagnostic approach to antibody deficiencies

1
Screening labs – Serum immunoglobulins (IgG, IgA, IgM). Quantitative immunoglobulins. Lymphocyte subsets (B cells CD19+). Vaccine antibody titers (tetanus, pneumococcal, Hib).
2
XLA suspicion – Male, absent B cells (<2%), very low all immunoglobulins. BTK gene sequencing.
3
CVID diagnosis – Low IgG (plus low IgA), poor vaccine response, exclusion of other causes. Age >4 years.
4
IgA deficiency – IgA <7 mg/dL (undetectable) with normal IgG, IgM. Confirm with repeat testing.
5
Specific antibody deficiency (SAD) – Normal immunoglobulins, poor response to pneumococcal polysaccharide vaccine. Test after age 2 years.
📌 Clinical pearl: A male infant with recurrent sinopulmonary infections starting after 6 months of age → suspect XLA until proven otherwise. Check B-cell count and immunoglobulins.

📋 Stepwise management of antibody deficiencies

1
XLA & CVID – Immunoglobulin replacement therapy (IVIG or subcutaneous). Target trough IgG >500 mg/dL. Prophylactic antibiotics (TMP-SMX) if breakthrough infections. Treat infections promptly.
2
IgA deficiency (asymptomatic) – No treatment. Avoid immunoglobulin products containing IgA due to risk of anaphylaxis (use IgA-depleted IVIG if needed).
3
IgG subclass deficiency (with recurrent infections) – Trial of prophylactic antibiotics, IVIG if severe and unresponsive.
4
Specific antibody deficiency (SAD) – Pneumococcal vaccination (PCV13, PPSV23). If poor response, consider IVIG.
5
General measures – Avoid live vaccines (if severe antibody deficiency? Actually in XLA/CVID live vaccines are generally avoided except measles if on IVIG?). In XLA, live vaccines not contraindicated because T cells normal? Actually live vaccines are generally safe in isolated antibody deficiencies except oral polio (shedding). Check guidelines.
🚨 Anaphylaxis risk in IgA deficiency: Patients with undetectable IgA may have anti-IgA antibodies. If IVIG needed, use IgA-depleted product (Gammagard S/D, etc.).

🧠 Reflex prompts: antibody deficiencies

🧬 9-month-old male with recurrent pneumonia, sinusitis, and very low IgG, IgA, IgM. B cells absent. Diagnosis?
X-linked agammaglobulinemia (Bruton, BTK mutation). IVIG replacement.
🩺 25-year-old with recurrent sinopulmonary infections, low IgG, low IgA, poor pneumococcal vaccine response. Diagnosis?
Common variable immune deficiency (CVID). IVIG, monitor for autoimmune disease.
⚠️ 30-year-old with recurrent URIs, found to have undetectable IgA, normal IgG. Most likely diagnosis?
Selective IgA deficiency (most common PID). Usually asymptomatic; caution with blood products.
🔬 Child with recurrent otitis media, normal IgG, IgA, IgM, but poor response to polysaccharide vaccine. Diagnosis?
Specific antibody deficiency (SAD). Consider IVIG if severe.
💊 What is first-line treatment for XLA and CVID?
Immunoglobulin replacement therapy (IVIG or subcutaneous), 400-600 mg/kg every 3-4 weeks.
🩸 What is the risk of giving standard IVIG to a patient with undetectable IgA?
Anaphylaxis due to anti-IgA antibodies. Use IgA-depleted IVIG.
🧪 Most common primary immunodeficiency disorder?
Selective IgA deficiency (1 in 500).
🧬 Which gene is mutated in X-linked agammaglobulinemia?
BTK (Bruton tyrosine kinase).
🩺 What is a common autoimmune manifestation in CVID?
Autoimmune cytopenias (ITP, autoimmune hemolytic anemia), inflammatory bowel disease.
💊 What is the target trough IgG level for IVIG replacement?
Typically >500 mg/dL to prevent breakthrough infections.