What does low secretory Immunoglobulin A (IgA) mean in a patient with a history of autoimmune disorders or recurrent infections?

What Does Low Secretory IgA Mean?

Low secretory IgA indicates a deficiency in the primary antibody that protects mucosal surfaces, most commonly representing selective IgA deficiency (SIGAD), which predisposes patients to recurrent sinopulmonary and gastrointestinal infections, autoimmune disorders, and allergic diseases. 1, 2

Defining the Deficiency

• Selective IgA deficiency is diagnosed when serum IgA is less than 7 mg/dL in patients older than 4 years, with normal IgG and IgM levels, normal vaccine responses, and exclusion of secondary causes. 2
• Approximately two-thirds of patients with IgA <7 mg/dL have detectable but very low levels; one-third have completely absent IgA. 2
• This is the most common primary immunodeficiency, affecting 1 in 300-700 white individuals but only 1 in 18,000 Asians. 2, 3

Clinical Significance and Manifestations

Infection Risk

• Recurrent sinopulmonary infections (sinusitis, bronchitis, pneumonia) and gastrointestinal infections are the hallmark manifestations, though many patients remain asymptomatic. 1, 4
• The majority of immunodeficient patients with recurrent sinusitis have defects in humoral immunity, with SIGAD being one of the most common. 1
• Patients with IgA deficiency plus additional immune defects (IgG subclass deficiency or defective specific antibody production) have significantly higher rates of lower respiratory tract infections and bronchiectasis compared to isolated IgA deficiency. 4

Autoimmune and Allergic Associations

• Autoimmune diseases occur in approximately 20-30% of symptomatic IgA-deficient patients, with thyroiditis, celiac disease, inflammatory bowel disease, and arthritis being most common. 4, 5
• Allergic disorders (asthma, atopic dermatitis, allergic rhinoconjunctivitis) are highly prevalent, affecting up to 84% of symptomatic patients during follow-up. 4
• The 8.1 MHC haplotype has been significantly associated with autoimmunity in IgA deficiency. 5

Diagnostic Workup Algorithm

Initial Assessment

• Confirm the diagnosis with at least two measurements showing IgA <7 mg/dL taken at least one month apart. 6, 2
• Measure total IgG, IgM, and IgG subclasses (IgG1-4) to identify combined deficiencies. 1
• Most clinical laboratories cannot accurately measure IgA below 7 mg/dL; specialized laboratories are needed to determine if IgA is truly absent. 2

Functional Assessment

• Measure specific antibody responses to pneumococcal polysaccharide vaccine (23-valent) before and 4 weeks after immunization to assess functional antibody production. 1
• Test responses to protein antigens (tetanus, diphtheria) to evaluate overall humoral immunity. 1
• Approximately 25% of IgA-deficient patients are hyporesponsive to polysaccharide vaccines, and these patients are at higher risk for bronchiectasis. 4

Exclude Secondary Causes

• Review medication history for drugs causing IgA deficiency: antiepileptics, gold, penicillamine, hydroxychloroquine, and NSAIDs. 6
• Exclude HIV infection, protein-losing enteropathy, and other secondary causes of hypogammaglobulinemia. 1, 2

Risk Stratification

High-Risk Features (Require Aggressive Management)

• IgA deficiency combined with IgG subclass deficiency (especially IgG2) or defective specific antibody production. 1, 4
• Poor response to pneumococcal polysaccharide vaccine (concentration >1.3 mg/mL for <70% of serotypes in patients >6 years). 1
• Development of bronchiectasis or chronic lung disease. 4
• Recurrent infections requiring hospitalization or IV antibiotics. 1

Lower-Risk Features

• Isolated IgA deficiency with normal IgG subclasses and normal vaccine responses. 4
• Asymptomatic or minimal symptoms. 3, 7

Management Strategy

For Symptomatic Patients with Recurrent Infections

• Initiate aggressive antibiotic treatment for acute infections using longer courses (3-6 weeks) than in immunocompetent patients. 6
• Implement prophylactic antibiotics for patients with recurrent sinopulmonary infections that negatively impact quality of life. 1, 6
• Consider conjugate pneumococcal vaccines (PCV13, PCV15, PCV20) to enhance immunity, as patients may respond normally to conjugated antigens despite poor polysaccharide responses. 1

For High-Risk Patients

• IVIG therapy should be considered when recurrent infections persist despite aggressive antibiotic therapy, significantly affect quality of life, or evidence of permanent organ damage (bronchiectasis) is present. 1, 6
• Do NOT initiate IVIG based solely on laboratory values without documented clinical disease. 6

For Autoimmune or Allergic Manifestations

• Aggressively treat concurrent atopic disease, as this may reduce infection frequency. 6
• Screen for and manage specific autoimmune conditions (thyroid disease, celiac disease, inflammatory bowel disease). 5

Critical Pitfalls to Avoid

• Never diagnose IgA deficiency based on a single laboratory value—always confirm with repeat testing and correlate with clinical symptoms. 6, 2
• Patients with IgA levels between 7 mg/dL and the lower limit of normal should NOT be diagnosed with selective IgA deficiency. 2
• Do not administer blood products containing IgA to patients with undetectable IgA, as they may develop anti-IgA antibodies and risk anaphylaxis. 1
• IgG4 deficiency should not be diagnosed in children under 10 years, as levels are normally very low. 1

Long-Term Monitoring

• Monitor patients longitudinally, as 10-20% may progress to common variable immunodeficiency (CVID) later in life. 2, 3
• Reassess immune function regularly with repeat immunoglobulin measurements and vaccine responses. 6
• Some patients experience resolution of infections over time even when the immunologic abnormality persists. 1, 6
• Familial clustering occurs in 20-25% of cases, suggesting shared genetic susceptibility with CVID. 2