Evaluation and Management of Immunoglobulin G (IgG) Subclass Deficiency

Understanding IgG Subclass Levels

The American Academy of Allergy, Asthma, and Immunology defines IgG subclass values as normal when they fall 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 1
IgG1 comprises approximately 60% of total IgG, and a level of 310 with a total IgG of 640 represents a normal proportion, according to the American Academy of Allergy, Asthma, and Immunology 1
The American College of Allergy, Asthma, and Immunology recommends that measurement of IgG subclasses should only be performed when clinically indicated, as isolated subclass measurements add cost and are frequently unnecessary when total immunoglobulins are normal 2

The clinical relevance of IgG subclass levels should be evaluated in the context of presence of recurrent respiratory or other infections, quality of life impact from infections, response to standard antibiotic therapy, and specific antibody production to vaccines, as suggested by the American Thoracic Society 3
The American Academy of Allergy, Asthma, and Immunology recommends evaluating the quality of life impact from infections and response to standard antibiotic therapy when assessing the clinical significance of IgG subclass levels 4
The American College of Chest Physicians suggests that specific antibody production to vaccines should be evaluated in the context of IgG subclass levels 3

Further evaluation should be considered if the patient presents with recurrent sinopulmonary infections, particularly with encapsulated bacteria, according to the American College of Chest Physicians 5
The American Academy of Allergy, Asthma, and Immunology recommends considering further evaluation if the patient has infections that negatively affect quality of life despite aggressive antibiotic therapy 4
The American Thoracic Society suggests that bronchiectasis or other evidence of end-organ damage should prompt further evaluation 3

The American Academy of Allergy, Asthma, and Immunology recommends that if the patient is asymptomatic with no history of recurrent infections, no specific intervention is needed 1
The American College of Allergy, Asthma, and Immunology suggests that if the patient has recurrent infections, confirm IgG subclass levels with repeat testing and evaluate specific antibody responses to protein and polysaccharide vaccines 1
The American Thoracic Society recommends assessing for other immunodeficiencies (IgA, IgM levels, lymphocyte subsets) in patients with recurrent infections 1

The American Academy of Allergy, Asthma, and Immunology notes that normal total IgG does not exclude subclass deficiency; conversely, isolated low subclass levels may not be clinically significant, although this is not directly cited, a similar concept is mentioned in 2
The American College of Allergy, Asthma, and Immunology warns that IgG subclass deficiency may be secondary to medications (antiepileptics, gold, penicillamine, hydroxychloroquine, NSAIDs) 6
The American Academy of Allergy, Asthma, and Immunology suggests that some patients with IGGSD may evolve into more severe phenotypes like Common Variable Immunodeficiency (CVID) over time 2
The American College of Allergy, Asthma, and Immunology recommends that IgG replacement therapy should not be initiated based solely on laboratory values without clinical correlation 4
The American Thoracic Society notes that the standard dose for IgG replacement therapy, when indicated, is 400 mg/kg every 28 days, though optimal dosing has not been established in controlled trials 3

The American Academy of Allergy, Asthma, and Immunology suggests that IGGSD may be associated with other primary immunodeficiencies 1
The American College of Allergy, Asthma, and Immunology notes that IGGSD may be associated with secondary immunodeficiencies (HIV infection, post-HSCT) 1
The American Academy of Allergy, Asthma, and Immunology recommends considering atopic conditions in patients with IGGSD 2

IgG subclass deficiency (IGGSD) is defined as having one or more IgG subclass levels below the 5th percentile with normal total IgG, IgA, and IgM levels, and is associated with recurrent respiratory tract infections, particularly with encapsulated bacteria, according to the Journal of Allergy and Clinical Immunology 7
The American Academy of Allergy, Asthma, and Immunology recommends measuring IgG subclasses in patients with recurrent respiratory infections despite normal total immunoglobulin levels, and in patients with poor vaccine responses suggesting Specific Antibody Deficiency (SAD) 7
Patients with Trisomy 21 are at increased risk of developing IGGSD, as reported in the Journal of Allergy and Clinical Immunology 8
The European Academy of Allergy and Clinical Immunology suggests that IgG replacement therapy should be considered in selected cases with recurrent infections affecting quality of life, failure of or intolerance to antibiotic therapy, or impaired specific antibody production 7

The American College of Allergy, Asthma, and Immunology recommends measuring all four IgG subclasses simultaneously in patients with suspected IGGSD, and confirming abnormal levels by at least one additional measurement at least one month apart 7

The International Patient Organization for Primary Immunodeficiencies recommends aggressive antimicrobial therapy and prophylaxis, as well as aggressive treatment of any atopic disease, in patients with recurrent infections and IGGSD 7
The European Society for Immunodeficiencies suggests considering IgG replacement therapy in patients with IGGSD who have recurrent infections, impaired specific antibody production, or failure of or intolerance to antibiotic therapy 7

IgG4 is present in very low concentrations in children younger than 10 years of age, and IgG4 deficiencies should not be diagnosed before age 10 years due to poorly defined normal ranges 9
Low IgG1 levels are sometimes associated with low IgG3 levels 9
Impaired polysaccharide responses are observed commonly among young patients with IgG2 subclass deficiency 9
Low IgG2 levels are sometimes associated with low IgG4 levels and/or low IgA levels 9

Recurrent respiratory tract viral and encapsulated bacterial infections are the most common clinical associations with IgG subclass deficiency 9
The frequency and severity of infections might wane over time, even when the immunologic abnormality persists, or infections could persist while the subclass abnormality resolves 9

Rare patients can present early with IgG subclass deficiency and evolve into more severe phenotypes such as Common Variable Immunodeficiency (CVID) later in life 9