Should a patient with low Immunoglobulin A (IgA) levels, negative Immunoglobulin G (IgG) and tissue transglutaminase (tTG) tests, be referred to an immunologist for further evaluation?

Immunology Referral for Low IgA

Referral to an immunologist is not necessary for isolated low IgA with negative celiac serology (IgG and tTG), unless the patient has recurrent sinopulmonary or gastrointestinal infections, autoimmune disease, or other clinical features suggesting immunodeficiency. 1

Diagnostic Criteria for Selective IgA Deficiency

Before considering immunology referral, confirm whether the patient meets criteria for selective IgA deficiency (SIGAD):

• IgA must be <7 mg/dL to diagnose SIGAD—patients with IgA between 7 mg/dL and the lower limit of normal do NOT have selective IgA deficiency 1
• IgG and IgM levels must be normal for age to distinguish SIGAD from more severe combined immunodeficiencies like common variable immunodeficiency (CVID) 1
• Patient must be >4 years old, as IgA levels are normally low in younger children 1
• Exclude secondary causes including medications (immunosuppressants, anticonvulsants), HIV infection, and other causes of hypogammaglobulinemia 1

Clinical Context Determines Need for Referral

Refer to immunology if:

• Recurrent sinopulmonary infections (sinusitis, bronchitis, pneumonia) that significantly impact quality of life 1
• Recurrent gastrointestinal infections or chronic diarrhea 1
• Autoimmune diseases including type 1 diabetes, autoimmune thyroid disease, inflammatory bowel disease, or rheumatologic conditions 1
• Severe allergic manifestations or atopy requiring specialized management 1
• Family history of SIGAD or CVID (present in 20-25% of cases) 1
• Concern for evolution to CVID, which occurs in some SIGAD patients over time 1

Do NOT refer if:

• Asymptomatic with isolated low IgA and normal IgG/IgM levels 1
• No history of recurrent infections or autoimmune disease 1
• The low IgA was discovered incidentally during celiac disease screening with negative results 2, 1

Celiac Disease Considerations

The negative IgG and tTG results effectively rule out celiac disease in this context:

• Negative tTG IgA with normal total IgA has excellent negative predictive value for celiac disease 2
• If the patient is IgA deficient (IgA <7 mg/dL), IgG-based testing is required including IgG deamidated gliadin peptide (DGP-IgG) with 93.6% sensitivity and 99.4% specificity, or IgG tissue transglutaminase 2, 3
• The negative IgG result suggests either adequate IgG-based testing was performed or the patient does not have IgA deficiency requiring alternative testing 2

Practical Management Algorithm

Step 1: Confirm IgA level is truly low (<7 mg/dL for SIGAD diagnosis) 1

Step 2: Measure IgG and IgM levels to exclude combined immunodeficiency 1

Step 3: Assess clinical symptoms:

• If symptomatic (recurrent infections, autoimmune disease, severe allergies) → Refer to immunology 1
• If asymptomatic → No referral needed; provide reassurance and monitoring plan 1

Step 4: If referring to immunology, additional workup will include:

• IgG subclasses (IgG1-4) to identify combined deficiencies 1
• Specific antibody responses to pneumococcal polysaccharide vaccine (23-valent) before and 4 weeks after immunization 1
• Responses to protein antigens (tetanus, diphtheria) 1

Critical Safety Considerations

• Document IgA deficiency prominently in the medical record, as patients with undetectable IgA may develop anti-IgA antibodies and risk anaphylaxis with blood products containing IgA 1
• Most individuals with SIGAD are asymptomatic (prevalence 1:300-700 in white populations) and require no specific treatment 1
• Monitor over time for development of infections, autoimmune diseases, or evolution to CVID, even if initially asymptomatic 1