Diagnostic Approach for IgG Deficiency

Initial Laboratory Evaluation

The American Academy of Allergy, Asthma, and Immunology recommends measuring total serum immunoglobulin levels (IgG, IgA, and IgM) as the first step in evaluating suspected antibody deficiency 1, 2
If total IgG is normal but clinical suspicion remains high, consider measuring all four IgG subclasses (IgG1, IgG2, IgG3, and IgG4) 3, 5
Abnormal IgG subclass levels should be confirmed with at least one additional measurement at least one month apart from the first 3, 5
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, 5

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 4
IgG1 comprises approximately 60% of total IgG, so "selective" IgG1 deficiency is usually (but not always) associated with low total IgG 3, 5
IgG4 is present in very low concentrations in children younger than 10 years, so IgG4 deficiency should not be diagnosed before age 10 3, 5

For pneumococcal polysaccharide responses in patients >6 years old, mild impairment is defined as concentration >1.3 mg/mL for >70% of serotypes with a 2-fold increase for <70% of serotypes 1, 5
Moderate impairment is defined as concentration >1.3 mg/mL for <70% of serotypes 1, 5
Severe impairment is defined as concentration >1.3 mg/mL for ≤2 serotypes 1, 5

Normal: Normal levels of IgG, IgA, IgM, IgG subclasses, and normal vaccine responses 1, 2
Specific Antibody Deficiency (SAD): Normal immunoglobulin levels but impaired response to vaccines 1, 2
IgG Subclass Deficiency (IGGSD): Normal total IgG, IgA, and IgM, but one or more low IgG subclasses and impaired vaccine responses 1, 2

Medication use should be investigated as certain drugs can cause secondary IGGSD (antiepileptics, gold, penicillamine, hydroxychloroquine, NSAIDs) 6, 4
Some patients with IGGSD may evolve into more severe phenotypes like Common Variable Immunodeficiency (CVID) over time 5, 4