What is gamma globulin deficiency?

Gamma Globulin Deficiency

Gamma globulin deficiency, also known as hypogammaglobulinemia or agammaglobulinemia in severe cases, is a primary immunodeficiency disorder characterized by markedly reduced or absent immunoglobulin (antibody) levels, resulting in recurrent bacterial infections due to impaired B-cell function or development. 1, 2

Definition and Classification

Gamma globulin deficiency encompasses a spectrum of antibody deficiency disorders:

• Agammaglobulinemia represents the most severe form, characterized by serum IgG levels typically <100 mg/dL, IgM <20 mg/dL, IgA <10 mg/dL, and peripheral blood CD19+ B-cell counts <2%. 1
• Hypogammaglobulinemia refers to reduced but not absent immunoglobulin levels, with the primary defect involving B cells' inability to produce adequate amounts of immunoglobulins. 3
• Approximately 85% of agammaglobulinemia cases are X-linked (XLA) due to mutations in the Bruton tyrosine kinase (BTK) gene, affecting primarily males with a characteristic X-linked inheritance pattern involving maternal male relatives. 1, 2

Clinical Presentation

The hallmark clinical features include:

• Recurrent bacterial respiratory tract infections (occurring in 88% of patients) typically present in the first 2 years of life, with Streptococcus pneumoniae and Haemophilus influenzae as the most common pathogens. 1, 2
• Upper respiratory tract involvement occurs in 75% and lower respiratory tract in 65% of patients. 2
• Gastrointestinal infections with giardiasis occur in 35% of patients, often presenting with chronic diarrhea and malabsorption causing greasy, foul-smelling stool. 2
• Some patients present with overwhelming infection, often with associated neutropenia. 1

Pathognomonic Physical Findings

• Absent or markedly small tonsils and lymph nodes on physical examination distinguish agammaglobulinemia from other forms of antibody deficiency. 1, 2
• This finding is highly specific and should immediately raise suspicion for severe antibody deficiency. 2

Specific Complications

• CNS enteroviral (ECHO virus) infections are specific to agammaglobulinemia and can cause serious morbidity or mortality, though occurrence has decreased with routine IgG replacement therapy. 1, 2
• Ecthyma or pyoderma gangrenosum caused by Helicobacter species, silent bacteremia with Helicobacter or Campylobacter jejuni, and Pseudomonas sepsis can occur. 1

Diagnostic Criteria

The combination of undetectable or very low serum immunoglobulin concentrations with normal T-cell numbers and function in a patient with recurrent bacterial infections is diagnostic. 1, 2

Essential Laboratory Evaluation

• Measure serum immunoglobulin levels (IgG, IgA, IgM) - expect severely reduced or undetectable levels. 1, 4
• Perform flow cytometry for CD19+ B cells - expect <2% of lymphocytes in agammaglobulinemia. 1, 2
• Confirm T-cell enumeration shows normal numbers and function to distinguish from combined immunodeficiency. 2, 4
• Test specific antibody responses to protein and polysaccharide antigens to document functional antibody deficiency. 4

Critical Diagnostic Distinction

• Check serum total protein and albumin levels - concurrent low total protein and albumin strongly suggest secondary hypogammaglobulinemia from protein loss (nephrotic syndrome, protein-losing enteropathy, lymphatic disorders) rather than primary immunodeficiency. 4
• Primary immunodeficiencies typically have normal albumin and total protein levels because only immunoglobulin production is affected. 4

Differential Diagnosis

• Common Variable Immunodeficiency (CVID) is most likely if patient age is ≥4 years, B-cell numbers are normal or only moderately reduced, and there is a history of recurrent bacterial respiratory infections. 4
• Severe Combined Immunodeficiency (SCID) presents with opportunistic infections (Pneumocystis, fungal, viral) within the first 3-6 months of life, not just bacterial infections. 2
• Isolated IgA deficiency is the mildest antibody deficiency with normal or near-normal IgG and IgM levels and less severe clinical manifestations. 2

Management

Agammaglobulinemia should be managed aggressively with antimicrobials, IgG replacement therapy, and careful attention to pulmonary status. 1

Immediate Treatment Priorities

• Initiate IgG replacement therapy immediately upon diagnosis without waiting for genetic confirmation to prevent further infections and complications. 2, 4
• Patients with IgG <300-400 mg/dL are at high risk for severe bacterial infections and require urgent immunoglobulin replacement therapy. 4
• Administer aggressive antimicrobial therapy for current infections and consider antibiotic prophylaxis while awaiting definitive treatment. 2, 4

Immunoglobulin Replacement Protocols

• Intravenous immunoglobulin (IVIG) should be administered at 0.2-0.4 g/kg body weight every 3-4 weeks. 4
• IVIG is more effective than intramuscular administration to achieve higher total IgG serum levels (5.2 ± 1.2 vs 3.5 ± 1.6 g/L) in a shorter period of time (2.1 ± 1.6 months vs 6.3 ± 2.8 months) with fewer secondary effects. 5
• Subcutaneous immunoglobulin (SCIG) may provide more stable IgG levels with fewer systemic side effects. 4
• Monitor IgG trough levels monthly during initial therapy, then every 6-12 months once stable. 4

Special Considerations for Severe Complications

• Enteroviral meningoencephalitis should be treated with high doses of IVIG (maintaining IgG trough levels >1000 mg/dL) with measurable antibody to the infecting virus. 1
• The IVIG product or lot should be selected to contain relatively high-titer antibody to the particular infecting ECHO virus. 1

Pulmonary Management

• Monitor pulmonary status carefully to prevent bronchiectasis, which develops in 10-20% of patients despite treatment. 2
• Patients with chronic bronchial suppuration require the greatest doses of immunoglobulin and shorter interdose time intervals (19.2 ± 3.1 vs 23.6 ± 3.6 days). 5
• Adjuvant treatment with respiratory physical measures and antibiotics are required in patients with chronic bronchial suppuration to avoid progressive alteration of respiratory function. 5
• Lung transplantation should be considered for patients with agammaglobulinemia and life-threatening chronic lung disease. 1

Common Pitfalls to Avoid

• Do not delay diagnosis waiting for B-cell enumeration if immunoglobulin levels are in the agammaglobulinemic range—the clinical picture is sufficient to initiate treatment. 2
• Do not confuse with transient hypogammaglobulinemia of infancy, which would not present with undetectable levels of all three immunoglobulin classes. 2
• Patients with very low or absent IgA may develop anti-IgA antibodies, creating risk for anaphylactic reactions to blood products. 4
• Review medication history for drugs that can cause secondary hypogammaglobulinemia (phenytoin, carbamazepine, valproic acid, sulfasalazine, gold, penicillamine, hydroxychloroquine, NSAIDs). 4