What is Selective IgA (Immunoglobulin A) Deficiency?

What is Selective IgA Deficiency?

Selective IgA deficiency (SIgAD) is the most common primary immunodeficiency, defined as a serum IgA level less than 7 mg/dL in patients older than 4 years with normal IgG and IgM levels, after excluding other causes of hypogammaglobulinemia. 1

Epidemiology and Prevalence

• SIgAD affects approximately 1 in 300 to 700 white individuals in the United States, making it the most frequently encountered primary antibody deficiency 1, 2
• The condition is significantly rarer in Asian populations, occurring in approximately 1 in 18,000 individuals 1
• There is a family history of either SIgAD or Common Variable Immunodeficiency (CVID) in 20-25% of affected patients 1
• The prevalence may be slightly higher in males 1

Diagnostic Criteria

The diagnosis requires:

• Serum IgA level less than 7 mg/dL (most clinical laboratories cannot measure below this threshold, though specialty laboratories can) 1
• Normal serum IgG and IgM levels 1
• Patient age greater than 4 years 1
• Exclusion of other causes of hypogammaglobulinemia 1

Important diagnostic nuance: Approximately two-thirds of patients with IgA levels below 7 mg/dL have detectable but very low IgA; in one-third, IgA appears completely absent 1. Patients with IgA levels greater than 7 mg/dL but below the normal range should NOT be diagnosed with SIgAD, as there are no consistently identified clinical associations with these intermediate levels 1.

Pathophysiology

• The underlying mechanism involves defective terminal differentiation of B cells and impaired switching to IgA-producing plasma cells 2
• T-cell populations and function remain normal in patients with SIgAD 1
• Some patients demonstrate lower proportions of switched memory B cells, which correlates with higher rates of pneumonia, bronchiectasis, and autoimmune disease 1
• Impaired specific antibody responses, particularly to pneumococcal polysaccharide antigens, are commonly seen 1

Clinical Manifestations

Most patients with SIgAD are asymptomatic, but symptomatic patients can present with a spectrum of complications 1, 2:

Infections (Most Common)

• Recurrent sinopulmonary infections are the predominant infectious complication 3, 4
• Respiratory tract infections occur in approximately 50-65% of symptomatic patients 3, 4
• Gastrointestinal infections, with particular susceptibility to Giardia lamblia 5
• Chronic diarrhea affects approximately 6.5% of patients 3

Allergic Diseases

• Atopy occurs frequently, affecting 18-26% of patients with SIgAD 3, 4
• Asthma prevalence reaches approximately 19% 4
• Allergic rhinitis affects approximately 15% 4
• The relationship between SIgAD and allergic disease is well-supported, though prevalence varies by study 6

Autoimmune Disorders

• Autoimmune manifestations occur in 11-22% of patients 3, 4
• Celiac disease is particularly common, affecting approximately 6.6% of patients 3
• Other associations include inflammatory bowel disease (4%), rheumatoid arthritis (3.8%), Type 1 diabetes, systemic lupus erythematosus, thyroid disorders, and juvenile chronic arthritis 3, 5, 4

Malignancy

• Rare but documented, occurring in approximately 1.5% of pediatric patients 3

Secondary Causes to Exclude

A thorough medication history is essential, as SIgAD can be acquired and potentially reversible with drug cessation 1:

• Antiepileptic drugs: phenytoin, carbamazepine, valproic acid, zonisamide 1, 7
• Disease-modifying agents: sulfasalazine, gold, penicillamine, hydroxychloroquine 1, 7
• Nonsteroidal anti-inflammatory drugs (NSAIDs) 1, 7

Associated Immunologic Abnormalities

• IgG subclass deficiency occurs in approximately 8-9% of patients with SIgAD 1
• Combined IgA and IgG subclass deficiency is found in only 1.4% 1
• Some patients demonstrate impaired specific antibody production despite normal total immunoglobulin levels 1

Risk of Progression

Critical monitoring consideration: Some patients with SIgAD can evolve into CVID later in life 1, 7. This underscores the importance of long-term surveillance for:

• Development of IgG or IgM deficiency 1
• Worsening infection patterns 1
• New autoimmune manifestations 1
• Opportunistic infections suggesting more severe immunodeficiency 1

Transfusion Considerations

Patients with IgA deficiency are considered at risk for anaphylactic reactions to blood products due to possible anti-IgA antibodies 1. However, the actual risk to individual patients is likely small 1. Practice varies, but some centers will:

• Transfuse products from IgA-deficient donors 1
• Wash red blood cells and platelets before transfusion 1
• This precaution is most relevant for patients with complete IgA absence who may develop anti-IgA IgE antibodies 5

Management Principles

There is no definitive cure for SIgAD 1. Management focuses on:

For Recurrent Infections

• Aggressive antimicrobial therapy for acute infections 1
• Prophylactic antibiotics for patients with frequent infections affecting quality of life 1

For Atopic Disease

• Aggressive treatment of allergic conditions is essential, as allergic inflammation predisposes to respiratory tract infections (especially sinusitis and otitis media) 1
• Standard allergy diagnostic techniques and all applicable treatment modalities should be employed 1

IgG Replacement Therapy

• Use of IVIG in SIgAD is controversial and rarely indicated 1
• The majority of patients will have minimal (if any) clinical response 1
• May be considered in rare patients with recurrent infections that negatively affect quality of life when aggressive antibiotic therapy and prophylaxis fail or cause intolerable side effects 1
• The lack of clear correlation between impaired vaccine response and infection frequency in SIgAD patients makes the rationale for IVIG questionable 1

Long-term Monitoring

• Patients should be monitored over time for development of complications including progression to more severe immunodeficiency, new autoimmune diseases, and malignancy 1