What are the European Society for Immunodeficiencies (ESID) criteria for diagnosing Selective Immunoglobulin A (IgA) Deficiency?

European Society for Immunodeficiencies (ESID) Criteria for Selective IgA Deficiency

The ESID diagnostic criteria for Selective IgA Deficiency require: serum IgA level less than 0.07 g/L (7 mg/dL) in patients older than 4 years, with normal IgG and IgM levels, normal vaccine responses, and exclusion of secondary causes of hypogammaglobulinemia. 1

Core Diagnostic Requirements

The diagnosis mandates all of the following criteria be met:

Age Criterion

• Patient must be older than 4 years of age 2, 1
• This age cutoff is critical because IgA levels may be physiologically low in younger children and continue to mature through early childhood 3

Quantitative IgA Threshold

• Serum IgA must be less than 7 mg/dL (0.07 g/L) 2, 1
• This represents a very low or absent level of circulating IgA 2
• Approximately two-thirds of patients with IgA <7 mg/dL have detectable but very low levels; one-third have completely absent IgA 2

Other Immunoglobulin Levels

• IgG levels must be normal for age 2, 1
• IgM levels must be normal for age 2, 1
• This distinguishes selective IgA deficiency from more severe combined immunodeficiencies like CVID 3

Functional Antibody Responses

• Normal vaccine responses must be demonstrated 1
• This confirms that the B-cell system can mount appropriate antibody responses to antigens despite the IgA deficiency 1

Exclusion of Secondary Causes

• Other causes of hypogammaglobulinemia must be excluded 2, 1
• This includes ruling out medication-induced IgA deficiency (antiepileptics, gold, penicillamine, hydroxychloroquine, NSAIDs) 4, 3
• Secondary causes such as HIV infection, post-hematopoietic stem cell transplantation, and malignancies must be excluded 4

Critical Diagnostic Pitfalls

The 7 mg/dL Threshold is Absolute

• Patients with IgA levels between 7 mg/dL and the lower limit of normal should NOT be diagnosed with selective IgA deficiency 2
• These patients may be referred to as having "partial IgA deficiency," but this is a distinct entity without consistently identified clinical associations 2, 1
• It is inappropriate to label these patients as having SIGAD 2

Laboratory Capability Matters

• Most clinical laboratories cannot accurately measure IgA levels below 7 mg/dL 2
• Only specialized laboratories with methods capable of detecting very low IgA concentrations can determine whether IgA is truly absent or present at detectable but very low levels 2
• This technical limitation is important for confirming the diagnosis 2

Medication History is Essential

• Always investigate current and recent medication use 2, 3
• Drug-induced IgA deficiency may be reversible upon cessation of the offending agent 3
• Failure to identify medication-related causes can lead to incorrect diagnosis of primary immunodeficiency 3

Clinical Context and Monitoring

Most Patients Are Asymptomatic

• 75-90% of patients with SIGAD have no clinical symptoms 1
• The diagnosis may be an incidental laboratory finding 3
• Asymptomatic patients do not require specific treatment but should maintain up-to-date vaccinations 1

Long-Term Surveillance is Required

• Patients must be monitored over time for development of complications 2
• Clinical manifestations can include respiratory and gastrointestinal infections, atopy, autoimmune diseases, celiac disease, and malignancy 2
• Some patients with SIGAD will evolve to CVID later in life, necessitating ongoing immunologic surveillance 2, 4, 3

Familial Clustering

• 20-25% of patients have a family history of either SIGAD or CVID 2, 3
• This shared genetic susceptibility suggests these conditions may represent a spectrum of the same underlying disorder 3

Ethnic and Demographic Considerations

• Prevalence varies dramatically by ethnicity: 1 in 300-700 among white populations versus approximately 1 in 18,000 in Asian populations 2, 3
• Male predominance may exist, though data are limited 2, 3