What causes low Secretory Immunoglobulin A (SIGA) levels in stool?

Causes of Low Secretory IgA (SIgA) in Stool

Low SIgA in stool is most commonly caused by selective IgA deficiency (SIGAD), defined as serum IgA <7 mg/dL with normal IgG and IgM levels, but medication-induced IgA deficiency should always be investigated first as it is reversible with drug cessation. 1, 2

Primary Immunodeficiency Causes

Selective IgA Deficiency (SIGAD) is the most common primary immunodeficiency and the leading cause of low stool SIgA:

• Affects approximately 1 in 300-700 white individuals in the United States (much rarer in Asian populations at 1:18,000) 1, 2
• Defined as serum IgA <7 mg/dL with normal IgG and IgM levels in patients older than 4 years 1, 2
• Family history of SIGAD or Common Variable Immunodeficiency (CVID) present in 20-25% of cases 1
• Note that approximately two-thirds of patients with IgA <7 mg/dL have detectable low levels, while one-third have completely absent IgA 1

Common Variable Immunodeficiency (CVID):

• Low SIgA may be an early manifestation before progression to full CVID 2
• Some patients with SIGAD develop CVID later in life 1
• CVID patients frequently have gastrointestinal complications including small intestinal bacterial overgrowth (SIBO), which can further compromise mucosal immunity 3

Associated IgG Subclass Deficiencies:

• IgA deficiency may occur with concurrent IgG2 or IgG4 deficiency or specific antibody deficiency 4
• These patients require differentiation from isolated SIGAD as management differs 4

Secondary/Acquired Causes

Medication-Induced IgA Deficiency (reversible with drug cessation):

• Antiepileptics: phenytoin, carbamazepine, valproic acid, zonisamide 1, 2, 5
• Anti-inflammatory drugs: sulfasalazine, NSAIDs, hydroxychloroquine 1, 5
• Other medications: gold, penicillamine 1, 5
• A thorough medication history is essential as this cause is reversible 1, 2

Celiac Disease:

• Strong association between celiac disease and IgA deficiency 1, 2
• Selective IgA deficiency occurs in 2.6% of celiac patients compared to 0.14-0.2% in general population 1
• Critical pitfall: IgA-based celiac testing (tissue transglutaminase IgA, endomysial antibodies) will be falsely negative in IgA-deficient patients 1
• Total IgA level must be measured when testing for celiac disease 1, 2

Microbiome Disruption:

• Antibiotics can disrupt the microbiome and influence IgA levels 4
• The gut microbiota plays an essential role in regulating SIgA production 6

Infections:

• Certain infections can temporarily suppress SIgA production 7
• Gastrointestinal infections, particularly with Giardia lamblia, are both a consequence and potential contributor to low SIgA 2, 4

Integrin-Blocking Therapies:

• Vedolizumab (anti-α4β7), ontamalimab (anti-MAdCAM-1), and etrolizumab (anti-β7) can lower SIgA levels 8
• A single dose of vedolizumab lowers stool SIgA and weakens oral immunization responses in healthy volunteers 8
• These therapies compromise de novo recruitment of IgA-producing plasma cells to intestinal lamina propria 8

Other Secondary Causes:

• Malignancies 4
• Systemic infections 4

Clinical Implications and Risk Assessment

Infection Risk:

• Increased susceptibility to sinopulmonary infections with bacteria and viruses 2, 4
• Predilection for gastrointestinal infections, particularly Giardia lamblia 2, 4, 9
• Impaired specific antibody responses, especially to pneumococcal polysaccharide 1

Autoimmune Disease Risk:

• Increased risk of multiple autoimmune conditions including systemic lupus erythematosus, thyroid disorders (hyper- and hypothyroidism), Type 1 diabetes, and celiac disease 2, 4
• Atopic disease occurs frequently with SIGAD and should be treated aggressively 1

Rare but Important Complications:

• Risk of anaphylaxis to blood products containing IgA in patients with complete IgA deficiency who develop anti-IgA IgE antibodies 1, 4
• Rarely, malignancy 4

Diagnostic Approach

Essential Initial Testing:

• Measure total serum IgA to confirm deficiency (<7 mg/dL for SIGAD diagnosis) 1, 2, 7
• Measure serum IgG and IgM to ensure they are normal (required for SIGAD diagnosis) 1, 2
• Comprehensive medication review looking specifically for causative drugs 1, 2, 5

Additional Testing to Consider:

• Celiac disease screening with tissue transglutaminase IgA AND total IgA (if IgA deficient, use IgG-based celiac tests) 1, 2
• Specific antibody responses to pneumococcal polysaccharide vaccine 1
• Evaluation for IgG subclass deficiencies if recurrent infections present 4
• Stool testing for infectious causes, particularly Giardia 2, 9

Management Considerations

For Medication-Induced IgA Deficiency:

• Discontinue causative medication if possible, as this is often reversible 1, 2

For Confirmed SIGAD with Recurrent Infections:

• Aggressive antimicrobial therapy or prophylactic antibiotics for recurrent sinopulmonary infections 1, 2
• Longer-term prophylactic antibiotics may benefit patients with frequent infections 1

Monitoring and Follow-up:

• Regular monitoring for development of infections, autoimmune diseases, and progression to CVID 2, 4
• Patient education about specific complications and when to seek care 4

Special Precautions:

• Consider using IgA-deficient blood products or washed cells for transfusions in patients with complete IgA deficiency, though individual risk is likely small 1
• Very rarely, supplemental IgG infusions may be indicated for severe cases with recurrent infections 4