What disorders are associated with decreased secretory Immunoglobulin A (sIgA)?

Disorders Associated with Decreased Secretory IgA (sIgA)

Decreased sIgA is most prominently associated with selective IgA deficiency (SIGAD), common variable immunodeficiency (CVID), and IgG subclass deficiency with concurrent IgA deficiency, which collectively predispose patients to recurrent sinopulmonary infections, autoimmune diseases, allergic disorders, and gastrointestinal pathology. 1

Primary Immunodeficiency Disorders

Selective IgA Deficiency (SIGAD)

• SIGAD is the most common primary immunodeficiency, occurring in 1:300-700 live births in white populations (though much rarer in Asian populations at 1:18,000) 2, 3
• Defined as serum IgA <7 mg/dL with normal IgG and IgM levels, normal vaccine responses, and exclusion of secondary causes in patients >4 years of age 2
• Approximately two-thirds of patients have detectable but very low IgA levels; one-third have completely absent IgA 2
• 20-25% of patients with partial IgA deficiency will progress to complete SIGAD or evolve into CVID, particularly those with family history 4, 2

Common Variable Immunodeficiency (CVID)

• CVID presents with variable reduction in 2 or more major immunoglobulin classes, including IgA, with impaired specific antibody responses 1
• Sinusitis was one of the most frequent presenting infections in the French national study of primary hypogammaglobulinemia, with 36% of CVID patients having sinusitis 1
• CVID shares genetic susceptibility with SIGAD, representing a spectrum of the same underlying disorder 2

IgG Subclass Deficiency with Concurrent IgA Deficiency

• IgG subclass deficiency may coexist with IgA deficiency, creating increased susceptibility to infections with encapsulated bacteria 5
• Approximately 4% of IgA-deficient patients develop concurrent IgG subclass deficiency 6
• This combination is associated with more severe clinical phenotypes including recurrent pneumonia and bronchiectasis 6

Agammaglobulinemia

• Both X-linked (Bruton agammaglobulinemia) and autosomal forms result in extremely low or absent immunoglobulins including IgA 1
• X-linked form accounts for 85% of agammaglobulinemia cases 1

Syndromic Immunodeficiencies with Decreased sIgA

Wiskott-Aldrich Syndrome

• Presents with varying degrees of immunoglobulin alterations including decreased IgA 1
• Associated with susceptibility to entire spectrum of pathogenic organisms 1

DiGeorge Syndrome

• Variable immunoglobulin levels including IgA deficiency depending on specific genetic defect 1
• Impaired specific antibody responses common 1

Ataxia-Telangiectasia

• Laboratory abnormalities include alterations in immunoglobulin levels with impaired specific antibody responses 1
• IgA deficiency frequently observed 1

Hyper-IgE Syndromes

• Can present with variable immunoglobulin abnormalities including decreased IgA 1

Secondary Causes of Decreased sIgA

Medication-Induced IgA Deficiency

• Antiepileptic drugs, gold, penicillamine, hydroxychloroquine, and NSAIDs can cause secondary IgA deficiency 5
• Drug-induced IgA deficiency may be reversible upon cessation of the offending agent 2
• Antibiotics can disrupt the microbiome, influencing IgA levels 7

Infectious Causes

• HIV infection is associated with CRS or recurrent acute rhinosinusitis in 30-68% of patients, often with concurrent IgA deficiency 1
• Other infections can cause secondary hypogammaglobulinemia 2

Malignancy

• Malignancies can cause secondary IgA deficiency 2, 7
• Patients with SIGAD have increased risk of developing malignancy (1.5% in pediatric cohorts) 6

Clinical Manifestations by System

Respiratory Tract

• Recurrent sinopulmonary infections occur in approximately 18-19% of IgA-deficient patients 4
• Recurrent upper respiratory tract infections affect 17.5% of pediatric patients 6
• Recurrent pneumonia occurs in 6% of patients, with 30% of these developing secondary bronchiectasis 6
• Recurrent ear infections affect 11.8% of patients, with some developing secondary deafness 6
• Viral respiratory infections, particularly rhinovirus, occur more frequently 4

Gastrointestinal Tract

• Celiac disease occurs in 6.57% of SIGAD patients 8
• Chronic diarrhea affects 6.5% of patients 6
• Gastrointestinal infections, particularly Giardia lamblia, show increased prevalence 7
• Inflammatory bowel disease (Crohn's disease and ulcerative colitis) occurs in 4.01% 8

Autoimmune Diseases

• Overall autoimmune manifestations occur in 11.5-22% of IgA-deficient patients 6, 8
• Rheumatoid arthritis: 3.80% prevalence 8
• Type 1 diabetes mellitus: significant association 9
• Systemic lupus erythematosus: strong association 9
• Thyroid disease (both hyper- and hypothyroidism): strong association 7, 9
• Juvenile idiopathic arthritis and ankylosing spondylitis: strong associations 9
• Vitiligo, immune thrombocytopenic purpura, and autoimmune hemolytic anemia: weaker associations 9

Allergic Diseases

• Atopic disease is present in 18-19% of IgA-deficient patients 4, 6
• Asthma: 19.06% prevalence 8
• Allergic rhinitis: 15.46% prevalence 8
• Allergic conjunctivitis: 11.68% prevalence 8
• Allergic inflammation predisposes to secondary respiratory infections 4

Critical Clinical Pitfalls

Transfusion Reactions

• Patients with very low or absent IgA may develop anti-IgA antibodies, creating risk for anaphylactic reactions to blood products 4
• IgA-deficient blood products should be used when available for transfusions 4

Diagnostic Considerations

• Most clinical laboratories cannot accurately measure IgA levels below 7 mg/dL; only specialized laboratories can determine if IgA is truly absent versus present at very low levels 2
• Patients with IgA levels between 7 mg/dL and the lower limit of normal should NOT be diagnosed with SIGAD 2
• Medication history is essential as drug-induced IgA deficiency may be reversible 2

Disease Evolution

• Regular monitoring is essential as some patients progress from partial IgA deficiency to SIGAD or CVID over time 4, 2
• Repeat immunoglobulin levels and specific antibody testing if clinical status changes 4