Selective IgA Deficiency

Selective IgA deficiency is the commonest primary antibody deficiency. It is defined as serum IgA under 0.07 g/L with normal IgG and IgM, in a person older than 4 years, once secondary causes are excluded.

Pathophysiology. B cells fail to mature into IgA-secreting plasma cells, so mucosal secretory IgA is low. The cause is usually polygenic, with strong HLA associations (the HLA-DR3, DQ2 and B8 haplotypes). Variants in TNFRSF13B, the gene for TACI, occur in a minority.

Prevalence is about 1 in 300 to 1 in 700 in people of European ancestry and much lower in East Asian populations. Over 85% of affected people have no symptoms and are found by chance.

Drugs can induce it (phenytoin, carbamazepine, valproate, sulfasalazine, penicillamine, gold salts), as can congenital rubella and chromosome 18q deletion.

A small number progress to common variable immunodeficiency, with IgG falling over years.

• Often none
• Recurrent sinusitis, otitis media, bronchitis and pneumonia, with bronchiectasis in a few
• Recurrent giardiasis, chronic diarrhoea, nodular lymphoid hyperplasia of the gut
• Coeliac disease (about 10 times more frequent than in the general population) and inflammatory bowel disease
• Atopy: asthma, allergic rhinitis, food allergy
• Autoimmune disease: systemic lupus erythematosus, immune thrombocytopenia, autoimmune thyroid disease, type 1 diabetes, rheumatoid arthritis, vitiligo
• Anaphylaxis during transfusion or immunoglobulin infusion in the few who make anti-IgA antibodies

• Serum IgA, IgG and IgM by nephelometry, repeated after at least 4 weeks to confirm.
• Specific antibody responses to tetanus toxoid and pneumococcal polysaccharide, and IgG subclasses, when infections are recurrent.
• B cell subsets (class switched memory B cells) to detect early common variable immunodeficiency.
• Coeliac screen: IgA-based tests are falsely negative, so use IgG anti-tissue transglutaminase and IgG deamidated gliadin peptide antibodies, then duodenal biopsy if positive. A negative HLA-DQ2 and DQ8 type excludes coeliac disease.
• Stool Giardia antigen or PCR on three samples with chronic diarrhoea.
• Anti-IgA antibodies before planned transfusion or immunoglobulin therapy, or after any unexplained transfusion reaction.
• Exclude secondary causes: drug history, and other antibody deficiencies.

Differential diagnosis.

• Transient hypogammaglobulinaemia of infancy (low IgA under 4 years may recover)
• Early common variable immunodeficiency
• IgG subclass deficiency
• Drug induced low IgA
• Ataxia telangiectasia (low IgA, ataxia, raised alpha fetoprotein)
• Congenital rubella and 18q deletion
• Specific antibody deficiency with normal immunoglobulins

No treatment is needed without symptoms. Counsel that the condition is usually benign and that coeliac disease and autoimmunity can appear later.

• Infections: treat early with antibiotics chosen by culture, using longer courses (10 to 14 days) for chest infection. Treat sinus disease and atopy fully.
• Prophylaxis for recurrent infection, for 6 to 12 months and then reviewed:
  • Azithromycin 500 mg orally three times weekly or 250 mg once daily in adults (children 10 mg/kg three times weekly, maximum 500 mg). Before starting, check QTc under 450 ms on ECG, send sputum for non-tuberculous mycobacteria, and avoid other QT-prolonging drugs. Stop for hearing loss, tinnitus or diarrhoea that persists.
  • Amoxicillin 500 mg orally once daily at night in adults is an alternative.
• Giardiasis: tinidazole 2 g orally as a single dose (children 50 mg/kg, maximum 2 g). Repeat after 1 week if symptoms or cysts persist. Confirm clearance by stool PCR.
• Vaccines: one dose of pneumococcal conjugate vaccine, then pneumococcal polysaccharide vaccine at least 8 weeks later, with yearly inactivated influenza, Haemophilus influenzae type b and COVID-19 vaccines. Live vaccines are allowed when T cells are normal and no immunosuppressive drug is used.
• Coeliac disease: lifelong gluten free diet with dietitian support.
• Immunoglobulin replacement is not given for IgA deficiency alone, since it supplies IgG and not IgA, and it can cause anaphylaxis in patients with anti-IgA antibodies. It is reserved for coexisting specific antibody failure with serious infection: intravenous immunoglobulin 400 to 600 mg/kg every 3 to 4 weeks, or subcutaneous immunoglobulin 100 to 150 mg/kg weekly, adjusted to a trough IgG of at least 6 g/L, usually 7 to 9 g/L. Use an IgA-depleted product in anyone with anti-IgA antibodies.
• Blood products in a patient with anti-IgA antibodies or a past reaction: washed red cells and platelets, or components from IgA-deficient donors. For a transfusion reaction with anaphylaxis, stop the infusion and give adrenaline 0.5 mg intramuscularly (0.5 mL of 1 mg/mL; children 0.01 mg/kg, maximum 0.5 mg), repeated after 5 minutes if needed.

Special groups.

• Children under 4 years: label as probable deficiency and recheck, since levels can rise.
• Pregnancy: no change in management. Tell the obstetric team if anti-IgA antibodies are present.

Monitoring. Review yearly for infections, weight and autoimmune symptoms. Repeat IgG, IgA and IgM yearly for 2 to 3 years, then when symptoms change, to detect falling IgG. Repeat IgG-based coeliac serology every 2 to 3 years or with symptoms.

Referral and escalation. Refer to immunology for recurrent or severe infection, falling IgG or IgM, poor vaccine response, autoimmunity, or anti-IgA antibodies. Urgent for anaphylaxis during transfusion.