What is the role of antibodies (immunoglobulins) in a patient with a history of recurrent infections and immune deficiency?

Role of Antibodies in Patients with Recurrent Infections and Immune Deficiency

Antibodies (immunoglobulins) serve as the cornerstone of humoral immunity by providing passive protection against recurrent bacterial infections in patients with primary antibody deficiencies, and immunoglobulin replacement therapy is the definitive treatment for patients with documented hypogammaglobulinemia and severe recurrent infections. 1

Fundamental Functions of Antibodies

Antibodies protect against infections through multiple mechanisms beyond simple pathogen binding:

• Neutralization: Antibodies prevent pathogen entry into host cells by blocking viral attachment and bacterial toxins 2
• Opsonization and phagocytosis: Antibodies tag pathogens for destruction by innate immune cells, driving clearance of bacteria, viruses, fungi, and parasites 2
• Complement activation: Immune complexes formed by antibodies activate the complement cascade, leading to pathogen lysis 2
• Antibody-dependent cellular cytotoxicity: Antibodies mark infected cells for elimination by NK cells and other effector cells 2

Diagnostic Evaluation of Antibody Deficiency

When evaluating patients with recurrent infections, a stepwise diagnostic approach is essential:

Initial Screening Tests

• Measure serum immunoglobulin levels (IgG, IgA, IgM) as the first step, with hypogammaglobulinemia defined as IgG <500 mg/dL or ≥2 standard deviations below age-adjusted mean 1, 3
• Assess specific antibody responses to both protein antigens (tetanus, diphtheria) and polysaccharide antigens (pneumococcal vaccine), as global immunoglobulin levels can appear normal despite functional antibody defects 1
• Perform lymphocyte phenotyping including CD19+ B cells, CD4+ and CD8+ T cells, and memory B-cell subsets to characterize the immune defect 1, 3

Critical Pitfall

Normal total IgG levels are a critical exclusion criterion for standard immunoglobulin replacement therapy - patients with normal or borderline IgG levels should not receive this expensive treatment without documented functional antibody deficiency and severe infections 3, 4

Specific Antibody Deficiency Considerations

For patients with normal immunoglobulin levels but recurrent infections:

• Specific antibody deficiency (SAD) is characterized by inadequate IgG antibody responses to pneumococcal polysaccharide vaccine despite normal IgG, IgA, IgM, and IgG subclass levels 1, 5
• Diagnosis requires demonstration of poor response to at least 6 serotypes from the 23-valent pneumococcal polysaccharide vaccine, with both pre- and post-vaccination titers measured by the same laboratory 1, 5
• Functional testing using opsonophagocytic assays provides more valuable information than simple antibody concentration measurements 3

Treatment Algorithm for Antibody Deficiency

First-Line Conservative Management

Before considering immunoglobulin replacement, aggressive conservative measures must be attempted and documented as failed:

• Prophylactic antibiotics as the initial approach for recurrent sinopulmonary infections 4, 6
• Treatment of underlying atopic disease (asthma, allergic rhinitis) as allergic inflammation predisposes to respiratory infections 4
• Review medication history for drugs causing secondary antibody deficiency 4

Indications for Immunoglobulin Replacement Therapy

Immunoglobulin replacement is indicated only when ALL of the following criteria are met:

• Documented hypogammaglobulinemia: Significant reduction in ≥2 immunoglobulin isotypes (not borderline values), typically IgG <400-500 mg/dL 4, 6, 7
• Severe recurrent infections: At least 2-3 severe bacterial infections per year requiring hospitalization or culture-proven bacterial infections 3, 6
• Failure of conservative management: Aggressive antibiotic prophylaxis has been tried and failed 3, 4
• Impaired functional antibody responses: Poor response to pneumococcal polysaccharide vaccine 1, 3

Dosing and Monitoring

When immunoglobulin replacement is indicated:

• Initial dose: 400-600 mg/kg every 3-4 weeks intravenously, or 100-150 mg/kg weekly subcutaneously 6, 7, 8
• Target trough levels: IgG >500-800 mg/dL for common variable immunodeficiency, >500 mg/dL for agammaglobulinemia 6, 7
• Clinical response is paramount: Reduction in infection frequency is more important than achieving specific IgG levels 6, 7
• Monitor trough levels before each infusion during dose adjustment, then every 3-6 months once stable 6, 8

Special Populations

Transient Hypogammaglobulinemia of Infancy

• Characterized by low IgG levels (and sometimes IgA/IgM) during infancy with normal vaccine responses and spontaneous resolution by age 2-5 years 1
• Management: Most cases require only observation and aggressive treatment of infections; immunoglobulin replacement rarely needed 1
• Reassessment: Consider suspending immunoglobulin therapy after 3-6 months to reassess immune function 6

Specific Antibody Deficiency

• Immunoglobulin replacement is Category C1 (last resort) - antibiotic prophylaxis is equally or more effective 4
• Most patients with selective antibody deficiency will have minimal clinical response to IgG replacement 4
• Consider conjugate pneumococcal vaccines as they may overcome the polysaccharide response defect 1

Vaccination Considerations in Antibody Deficiency

Patients on Immunoglobulin Replacement

• Inactivated vaccines are not routinely administered during immunoglobulin therapy as patients lack antibody response capability 1
• Exception: Influenza vaccine can be administered to patients with residual antibody production, as T-cell responses may contribute to protection 1
• Live vaccines should be avoided due to preexisting neutralizing antibody from administered immunoglobulin and unknown safety risks 1

Pre-Treatment Assessment

• All inactivated vaccines can be administered as part of immune response assessment prior to starting immunoglobulin therapy 1
• Live oral polio vaccine is absolutely contraindicated in patients with major antibody deficiencies due to risk of vaccine-associated paralytic poliomyelitis 1

Critical Warnings

The placebo effect is substantial in immunoglobulin therapy - passive immunization at regular intervals may be credited as miraculous recovery without objective benefit 4

Resource stewardship is essential - without carefully controlled clinical trials demonstrating benefit, inappropriate immunoglobulin use results in significant expenditures for patients who may not need it 4

Patients with asymptomatic hypogammaglobulinemia and normal antibody responses should NOT receive immunoglobulin replacement - this represents overtreatment of healthy individuals 4