What is the diagnostic approach for Immunoglobulin G (IgG) deficiency?

Diagnostic Approach for IgG Deficiency

The diagnostic approach for IgG deficiency should begin with measuring serum immunoglobulin levels (IgG, IgA, and IgM) and assessing specific antibody responses to both protein and polysaccharide antigens. 1

Initial Laboratory Evaluation

• Measure total serum immunoglobulin levels (IgG, IgA, and IgM) as the first step in evaluating suspected antibody deficiency 1
• If total IgG is normal but clinical suspicion remains high, consider measuring all four IgG subclasses (IgG1, IgG2, IgG3, and IgG4) 1, 2
• Abnormal IgG subclass levels should be confirmed with at least one additional measurement at least one month apart from the first 1
• Assess functional antibody production by measuring specific antibody responses to both protein antigens (e.g., tetanus toxoid) and polysaccharide antigens (e.g., pneumococcal vaccines) 1, 2

Interpretation of IgG Subclass Testing

• Normal IgG subclass values are defined as within 2 standard deviations of the mean, with approximately 2.5% of the healthy population naturally having levels below this range for at least one subclass 2
• IgG1 comprises approximately 60% of total IgG, so "selective" IgG1 deficiency is usually (but not always) associated with low total IgG 1
• IgG4 is present in very low concentrations in children younger than 10 years, so IgG4 deficiency should not be diagnosed before age 10 1
• Low IgG2 levels are sometimes associated with low IgG4 and/or low IgA levels 1

Assessing Specific Antibody Responses

• For pneumococcal polysaccharide responses in patients >6 years old:
  • Mild impairment: Concentration >1.3 mg/mL for >70% of serotypes with a 2-fold increase for <70% of serotypes 1
  • Moderate impairment: Concentration >1.3 mg/mL for <70% of serotypes 1
  • Severe impairment: Concentration >1.3 mg/mL for ≤2 serotypes 1
• Memory impairment: Loss of protective antibody levels within 6 months 1

Diagnostic Categories Based on Laboratory Findings

• Normal: Normal levels of IgG, IgA, IgM, IgG subclasses, and normal vaccine responses 1
• Specific Antibody Deficiency (SAD): Normal immunoglobulin levels but impaired response to vaccines 1
• IgG Subclass Deficiency (IGGSD): Normal total IgG, IgA, and IgM, but one or more low IgG subclasses and impaired vaccine responses 1
• Selective IgA Deficiency (SIGAD): Absent IgA with normal IgG and IgM 1
• Combined deficiencies: Various combinations of the above 1

Clinical Correlation

• The clinical significance of IgG subclass levels should be evaluated in the context of:
  • Presence of recurrent respiratory or other infections 2, 3
  • Quality of life impact from infections 2, 4
  • Response to standard antibiotic therapy 2
  • Evidence of end-organ damage (e.g., bronchiectasis) 2, 5

Important Considerations and Pitfalls

• Medication use should be investigated as certain drugs can cause secondary IGGSD (antiepileptics, gold, penicillamine, hydroxychloroquine, NSAIDs) 1, 2
• Some patients with IGGSD may evolve into more severe phenotypes like Common Variable Immunodeficiency (CVID) over time 1, 2
• IgG replacement therapy should not be initiated based solely on laboratory values without clinical correlation 2, 6
• Isolated low subclass levels may not be clinically significant if vaccine responses are normal and the patient has no history of recurrent infections 2, 4
• Consider referral to a clinical immunologist if the diagnosis remains unclear despite initial testing or if specialized testing (e.g., flow cytometry) is needed 1, 7

When to Consider Further Evaluation

• Recurrent sinopulmonary infections, particularly with encapsulated bacteria 2, 5
• Infections that negatively affect quality of life despite aggressive antibiotic therapy 2, 4
• Bronchiectasis or other evidence of end-organ damage 2, 7
• Family history of immunodeficiency 5, 7