IgG Subclass Deficiency

IgG subclass deficiency is a low level of one or more IgG subclasses (IgG1, IgG2, IgG3, IgG4), usually with normal total IgG, under the age specific 5th percentile of the laboratory. It matters only when it comes with recurrent infection and poor antibody responses.

Pathophysiology. IgG1 and IgG3 respond to protein antigens, and IgG2 (with some IgG4) responds to polysaccharide antigens of encapsulated bacteria. Isolated low IgG2 impairs defence against Streptococcus pneumoniae and Haemophilus influenzae.

Low subclasses are common in healthy people, so a laboratory value alone is not a diagnosis.

Associations are IgA deficiency, atopy, ataxia telangiectasia, HIV infection in children, long term anticonvulsants and corticosteroids, and common variable immunodeficiency.

• Recurrent otitis media, sinusitis, bronchitis and pneumonia
• Bronchiectasis in prolonged disease
• Persistent cough, wheeze and poor response to asthma treatment
• Chronic rhinosinusitis with nasal polyps
• Many patients are asymptomatic

• Total IgG, IgA, IgM and IgG subclasses, repeated at least 4 weeks later and compared with age matched reference intervals.
• Specific antibody titres before and 4 to 6 weeks after tetanus toxoid and pneumococcal polysaccharide vaccines. An impaired response (not rising by at least 2 fold, or under the protective titre) with recurrent infections supports the diagnosis.
• IgE and eosinophils, with skin or serum allergy tests, to find atopy.
• Lymphocyte subsets and B cell phenotype, to exclude common variable immunodeficiency.
• Chest imaging, spirometry and high resolution CT with recurrent chest infection, to find bronchiectasis.
• CT of the sinuses and ENT review for chronic sinus disease.
• Exclude HIV and secondary causes (drugs, protein loss, lymphoproliferative disease).

Differential diagnosis.

• Common variable immunodeficiency
• Selective IgA deficiency
• Specific antibody deficiency
• Atopy with chronic rhinosinusitis
• Asthma
• Cystic fibrosis and primary ciliary dyskinesia
• Anatomical airway disease and aspiration
• Secondary hypogammaglobulinaemia

Treat only patients with infections and proven poor antibody responses.

• Reduce exposure and treat associated disease: treat atopy, sinus disease and reflux. Intranasal mometasone 2 sprays (100 micrograms) in each nostril once daily can be used for chronic rhinosinusitis.
• Vaccination: pneumococcal conjugate vaccine, then pneumococcal polysaccharide vaccine at least 8 weeks later, and yearly inactivated influenza vaccine. Recheck titres 4 to 6 weeks later.
• Prompt, longer antibiotic courses by culture result for each exacerbation.
• Prophylaxis for 6 to 12 months for frequent infections: azithromycin 500 mg orally three times weekly or 250 mg once daily in adults (children 10 mg/kg three times weekly, maximum 500 mg), after ECG shows QTc under 450 ms and sputum is clear of non-tuberculous mycobacteria. Alternative: amoxicillin 500 mg orally once daily at night in adults.
• Immunoglobulin replacement only if infections continue despite 6 months of prophylaxis and antibody responses are impaired: intravenous immunoglobulin 400 to 600 mg/kg every 3 to 4 weeks, or subcutaneous immunoglobulin 100 to 150 mg/kg weekly, with trough IgG of at least 6 g/L, usually 7 to 9 g/L. Use a time limited course of 12 months, then stop for 3 to 6 months to judge continued need.
• Bronchiectasis: airway clearance with physiotherapy and early treatment of exacerbations.

Special groups.

• Children: subclass levels mature with age, and many outgrow the deficiency. Recheck at 6 to 12 months before long term treatment and avoid immunoglobulin unless infections are severe.

Monitoring. Review at 3 months after any change, then every 6 to 12 months. Repeat total IgG and subclasses yearly to detect falling IgG (progression to common variable immunodeficiency). Spirometry yearly with chest disease.

Referral and escalation. Refer to immunology for recurrent infection with low subclasses, poor vaccine response, bronchiectasis, or falling total IgG. Urgent for invasive infection.