What can cause low secretory Immunoglobulin A (sIgA) levels?

Causes of Low Secretory IgA (sIgA)

Low sIgA is most commonly caused by selective IgA deficiency (SIGAD), a primary immunodeficiency affecting approximately 1 in 300-700 white individuals, though medication-induced deficiency and other secondary causes must be systematically excluded. 1

Primary Causes

Selective IgA Deficiency (SIGAD)

• SIGAD is defined as serum IgA <7 mg/dL with normal IgG and IgM levels in patients older than 4 years, making it the most common primary immunodeficiency disorder. 1
• This results from inherited genetic defects affecting B lymphocyte differentiation and maturation, preventing terminal differentiation into IgA-producing plasma cells. 2, 3
• Familial clustering occurs in 20-25% of cases, with family members having either SIGAD or Common Variable Immunodeficiency (CVID), indicating shared genetic susceptibility. 1, 2
• Prevalence varies dramatically by ethnicity: 1 in 300-700 among white Americans versus approximately 1 in 18,000 in Asian populations. 2, 4

Evolution to More Severe Immunodeficiency

• Low sIgA may be an early manifestation of Common Variable Immunodeficiency (CVID) or other immunodeficiencies such as IgG subclass deficiencies, requiring long-term monitoring. 1, 2
• Some patients with SIGAD will evolve to CVID over time, necessitating periodic reassessment. 2

Secondary/Acquired Causes

Medication-Induced IgA Deficiency

• Several medications cause reversible IgA deficiency with subsequent low sIgA, including:
  • Antiepileptic drugs 1, 2
  • Anti-inflammatory drugs (NSAIDs) 1, 2
  • Immunomodulators 1
  • Disease-modifying agents 5, 2
  • Antibiotics (through microbiome disruption) 6
• Discontinuation of offending medications may reverse the IgA deficiency in many cases, making thorough medication review essential. 5, 2

Other Secondary Causes

• Viral infections can cause secondary IgA deficiency. 4
• Malignancies may be associated with secondary IgA deficiency. 6
• Microbiome disruption from antibiotics can influence IgA levels. 6

Associated Conditions That May Present with Low sIgA

IgG Subclass Deficiencies

• IgA deficiency associated with IgG2 or IgG4 deficiency represents a more severe immunologic defect than isolated SIGAD and requires differentiation. 1, 6
• Some IgA-deficient individuals have reduced antibody responses to immunizations or bacterial polysaccharides despite normal total IgG and IgM levels. 7

Autoimmune Diseases

• Celiac disease is the most common autoimmune association with IgA deficiency and should be specifically tested for using IgG-based antibody tests (since standard IgA-based tests will be falsely negative). 1, 4
• Other autoimmune associations include thyroid disorders, type 1 diabetes, and systemic lupus erythematosus. 1, 6

Critical Diagnostic Considerations

Age-Related Factors

• Diagnosis requires age >4 years, as IgA levels may be physiologically low in younger children, making early diagnosis unreliable. 2

Partial vs. Complete Deficiency

• Partial IgA deficiency (serum IgA >0.05 g/L but 2 SD below normal) presents with detectable but low secretory IgA levels at mucosal surfaces. 8
• Complete IgA deficiency shows no detectable salivary or fecal sIgA and only minimal urinary sIgA. 8

Important Clinical Caveats

• More than 50% of patients with SIGAD remain asymptomatic despite the immunologic defect, so low sIgA alone does not necessarily predict clinical disease. 2, 4
• When symptoms occur, patients are at increased risk for gastrointestinal and respiratory infections (particularly Giardia lamblia), autoimmune diseases, and rarely malignancy. 1, 6
• Measurement of total serum IgA is essential when evaluating low sIgA in stool, as this distinguishes primary from secondary causes and guides management. 1