What is immunoglobulin G (IgG) deficiency?

What is IgG Deficiency?

IgG deficiency is a condition where immunoglobulin G levels fall below age-specific normal ranges, either as total IgG or specific IgG subclasses (IgG1-4), leading to impaired antibody responses and recurrent bacterial infections, particularly of the respiratory tract. 1

Types of IgG Deficiency

Transient Hypogammaglobulinemia of Infancy (THI)

• THI occurs when infants fail to produce adequate IgG after maternal antibodies degrade (half-life ~21 days), with levels remaining below normal until early childhood, typically correcting by 27 months of age (range up to 59 months). 1
• This condition predominantly affects males (60%) and presents with bacterial sinopulmonary infections, though severe infections like sepsis or meningitis are uncommon. 1
• Specific antibody production is usually preserved, and cellular immunity remains intact, distinguishing it from more severe immunodeficiencies. 1

IgG Subclass Deficiency (IGGSD)

• IGGSD is defined as one or more IgG subclass levels below the 5th percentile while total IgG, IgA, and IgM remain normal, associated with recurrent respiratory infections from encapsulated bacteria. 2
• Approximately 2.5% of healthy individuals naturally have subclass levels below normal range without clinical consequences, making clinical correlation essential before diagnosing disease. 2, 3

Subclass-Specific Patterns:

• IgG1 deficiency (comprises ~60% of total IgG): Often occurs with other immunoglobulin disturbances and may represent early common variable immunodeficiency (CVID). 2, 4
• IgG2 deficiency: Frequently associated with impaired polysaccharide responses, commonly combined with IgG4 and/or IgA deficiency. 2, 3
• IgG3 deficiency: Most common isolated subclass deficiency (56.4% in one cohort), often associated with low IgG1 levels. 2, 5, 6
• IgG4 deficiency: Should not be diagnosed before age 10 years due to naturally low concentrations and poorly defined normal ranges in children. 2

Clinical Manifestations

Infection Patterns

• Recurrent upper and lower respiratory tract infections (sinusitis, bronchitis, pneumonia) from encapsulated bacteria (H. influenzae, pneumococci) are the hallmark presentation. 2, 6, 4
• Recurrent sinusitis is the most common presenting symptom (83.6% in one pediatric cohort). 6
• Infection frequency and severity may wane over time even when immunologic abnormality persists, or conversely, infections may persist while subclass levels normalize. 2

Associated Conditions

• Atopic diseases and autoimmune disorders (autoimmune hemolytic anemia, inflammatory bowel disease) occur in approximately 20% of patients. 1
• Patients with Trisomy 21 have increased risk of developing IGGSD. 2
• Rare patients may evolve from IgG subclass deficiency into more severe phenotypes like CVID over time. 2, 3

Diagnostic Approach

Laboratory Evaluation

• Confirm deficiency with at least two measurements taken one month apart to exclude transient decreases or laboratory error. 2, 3, 5
• Measure all four IgG subclasses simultaneously when IGGSD is suspected. 2
• Assess specific antibody responses to pneumococcal vaccines (protein and polysaccharide antigens), as functional antibody production is more predictive of infection risk than absolute subclass levels. 2, 3
• Enumerate lymphocyte subsets by flow cytometry to exclude combined immunodeficiencies. 1, 2

Functional Antibody Testing

• For patients ≥6 years, administer 23-valent pneumococcal polysaccharide vaccine (PPSV23) and measure serotype-specific antibodies at 4 weeks. 2
• Severe impairment: protective concentration (≥1.3 mg/mL) achieved for ≤2 serotypes. 2
• Moderate impairment: protective concentration for <70% of serotypes. 2
• Mild impairment: protective concentration for >70% of serotypes without ≥2-fold rise. 2

Exclude Secondary Causes

• Review medications: antiepileptics, gold salts, penicillamine, hydroxychloroquine, NSAIDs. 2, 5
• Evaluate for malignancy (especially lymphoma), protein-losing conditions, HIV infection, or post-hematopoietic stem cell transplant. 2

Management Algorithm

Asymptomatic Patients

• No intervention is needed if the patient has no history of recurrent infections, regardless of laboratory values. 2, 3

Symptomatic Patients with Recurrent Infections

First-Line Management:

• Aggressive antimicrobial therapy with longer antibiotic courses than in immunocompetent patients. 2, 5
• Prophylactic antibiotics for patients experiencing ≥4 infections per year despite standard treatment. 2
• Administer PCV13 if not previously given; consider two-dose schedule to maximize protective immunity. 2
• Aggressively treat concurrent atopic disease, as it may exacerbate infection risk. 2, 3

Indications for IgG Replacement Therapy:

Initiate IVIG (400-600 mg/kg every 3-4 weeks) when ALL of the following are present: 2, 3, 7

1. Documented severe or moderate impairment of specific antibody production to polysaccharide antigens
2. Recurrent infections substantially impairing quality of life despite prophylaxis and optimized vaccination
3. Failure of or intolerance to prophylactic antibiotic regimens
4. Evidence of end-organ damage (e.g., bronchiectasis)

Monitoring During IgG Replacement

• Monitor trough IgG levels: target >5 g/L for agammaglobulinemia, 3 g/L above baseline for CVID. 7
• When IgA or IgM levels are also low at therapy initiation, monitor them regularly—increases into normal range indicate recovery and may allow discontinuation. 1, 3
• Consider stopping IVIG after 3-6 months to reassess humoral immune function if clinical improvement occurs. 1, 3

Critical Pitfalls to Avoid

• Never initiate IgG replacement therapy based solely on laboratory values without documented functional antibody deficiency and clinically significant recurrent infections. 2, 3, 5
• Do not diagnose IgG subclass deficiency based on a single laboratory measurement—always confirm with repeat testing. 2, 3, 5
• Normal total IgG does not exclude subclass deficiency; conversely, isolated low subclass levels may not be clinically significant. 2
• Remain vigilant for evolution toward more severe immunodeficiency phenotypes during long-term follow-up. 2, 3, 5