What is the diagnostic approach for selective antibody deficiency?

Diagnostic Approach for Selective Antibody Deficiency

Selective antibody deficiency (SAD) is diagnosed when a patient has recurrent respiratory infections, normal serum immunoglobulin levels (IgG, IgA, IgM), but demonstrates impaired antibody responses to polysaccharide antigens after pneumococcal vaccination. 1, 2

Initial Laboratory Assessment

Measure baseline serum immunoglobulin levels to confirm they are within normal limits for age:

• IgG, IgA, and IgM must all be normal (this distinguishes SAD from other antibody deficiencies like CVID or agammaglobulinemia) 1, 2
• If IgG subclasses are measured and found to be low, this may coexist with SAD but does not define it 1, 3
• Measure total serum protein and albumin to exclude secondary hypogammaglobulinemia from protein loss 1, 4

Functional Antibody Testing: The Definitive Diagnostic Step

Administer the 23-valent pneumococcal polysaccharide vaccine (PPSV-23) and measure serotype-specific antibody responses:

Pre-vaccination Testing

• Measure baseline antibody titers to pneumococcal serotypes before vaccination 1, 2
• This establishes whether the patient has pre-existing immunity 5

Post-vaccination Testing

• Measure antibody titers 4-8 weeks after PPSV-23 vaccination 1, 4
• Test responses to at least 7-12 pneumococcal serotypes (commonly 4, 6B, 9V, 14, 18C, 19F, 23F) 3

Interpretation Criteria for SAD Diagnosis

According to the American Academy of Allergy, Asthma, and Immunology (AAAAI) criteria:

For children under 6 years:

• Abnormal response = concentration >1.3 µg/mL for <50% of serotypes tested 1

For adults and children over 6 years:

• Abnormal response = concentration >1.3 µg/mL for <70% of serotypes tested 1
• Alternatively, failure to achieve protective titers (>1.3 µg/mL) for at least 50% of serotypes indicates SAD 2, 3

A critical caveat: The antibody concentration measured by ELISA does not necessarily reflect functional antibody activity (opsonophagocytic capacity), which is a significant limitation of current diagnostic methods 1

Additional Protein Antigen Assessment

Measure antibody responses to protein antigens to assess overall B-cell function:

• Diphtheria, tetanus, pertussis titers 1, 4
• Conjugated pneumococcal or Haemophilus influenzae vaccine responses 1, 4
• These are typically normal in SAD but help exclude broader antibody deficiencies 2

Flow Cytometry for B-Cell Phenotyping

Perform B-cell subset analysis when SAD is confirmed or suspected:

• Total B-cell count (should be normal in SAD) 1
• Switched memory B cells (CD27+IgD-) may be reduced in SAD patients 3, 6
• Marginal zone B cells and transitional B cells may be decreased in non-responders 6
• This helps distinguish SAD from early CVID and provides prognostic information 1, 7

Excluding Coexisting or Alternative Diagnoses

Rule out IgG subclass deficiency:

• Measure IgG1, IgG2, IgG3, IgG4 levels 1
• IgG2 and IgG3 deficiencies commonly coexist with SAD (63% of SAD patients have combined deficiencies) 3
• Post-vaccination responses to serotypes 4/9V/18C correlate with IgG2 levels, while responses to 6B/9V/14 correlate with IgG3 3

Assess for selective IgA deficiency:

• IgA <7 mg/dL with normal IgG and IgM defines selective IgA deficiency 4
• SAD can coexist with selective IgA deficiency 6

Consider T-cell evaluation if clinical features suggest combined immunodeficiency:

• CD4, CD8, NK cell enumeration by flow cytometry 1, 4
• T-cell abnormalities may contribute to poor polysaccharide responses 6

Clinical Context Required for Diagnosis

Document recurrent respiratory infections:

• Recurrent sinusitis, otitis media, bronchitis, or pneumonia 2, 5
• Infections with encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae) are characteristic 2
• The diagnosis requires both laboratory findings AND clinical manifestations 2

Critical Diagnostic Pitfalls

Do not diagnose SAD based solely on low baseline pneumococcal titers without post-vaccination testing—many healthy individuals have low baseline titers but respond appropriately to vaccination 5

Recognize that SAD may represent early or evolving CVID:

• Patients with SAD should be monitored longitudinally for progression to CVID 1, 7
• Repeat immunoglobulin levels periodically to detect declining IgG or IgA 7

Understand the limitations of current testing:

• ELISA-measured antibody concentrations do not reflect functional opsonophagocytic activity 1
• Laboratory-to-laboratory variability in pneumococcal antibody assays creates diagnostic uncertainty 1
• The definition of "adequate response" remains controversial among clinical immunologists 2

Avoid overdiagnosis:

• Not all patients with borderline responses require immunoglobulin replacement therapy 1
• Antibiotic prophylaxis may be equally effective as immunoglobulin replacement for SAD 1
• Treatment decisions should be based on infection severity and frequency, not laboratory values alone 2