What additional investigations should be performed for a patient with low immunoglobulin G (IgG) levels?

Further Investigations for Low IgG

Confirm the low IgG with a repeat measurement at least one month apart, then immediately assess functional antibody responses to both protein and polysaccharide antigens—this functional testing is the cornerstone of determining whether the low IgG is clinically significant. 1

Initial Confirmatory Testing

• Repeat quantitative IgG measurement after at least one month to exclude transient decline or laboratory error before proceeding with an extensive workup. 1

• Measure serum total protein and albumin concurrently; if both are low alongside IgG, this pattern indicates secondary hypogammaglobulinemia from protein-losing states (nephrotic syndrome, protein-losing enteropathy, lymphatic disorders) rather than primary immunodeficiency. 1, 2

• Complete immunoglobulin panel including quantitative IgA, IgM, and all four IgG subclasses (IgG1, IgG2, IgG3, IgG4) to characterize the pattern of deficiency. 1, 3

Functional Antibody Assessment (Critical Step)

This is the most important investigation—laboratory values alone cannot determine clinical significance. 3

Protein Antigen Response (T-cell Dependent)

• Measure specific IgG antibodies to tetanus and diphtheria toxoids to evaluate T-cell-dependent immunity; these responses are preserved in most cases except severe panhypogammaglobulinemia. 3, 1

Polysaccharide Antigen Response (T-cell Independent)

• Measure baseline pneumococcal antibody levels against the 23-valent pneumococcal polysaccharide vaccine serotypes. 3

• Administer the 23-valent pneumococcal polysaccharide vaccine if baseline levels are low or if the patient has recurrent infections. 3

• Remeasure serotype-specific IgG concentrations 4–8 weeks post-vaccination to assess B-cell function. 3, 1

• Define impaired response as failure to achieve protective antibody levels (>1.3 mg/mL) to more than 70% of serotypes tested in adults and older children (>6 years). 3, 1

Important caveat: The pneumococcal antibody assay has significant laboratory-to-laboratory variability and measures antibody quantity, not functional killing capacity—interpret results in the clinical context of documented pneumococcal disease, not in isolation. 3

Cellular Immune Assessment

• B-cell phenotyping by flow cytometry to enumerate total B cells (CD19+), CD27+ memory B cells, and class-switched memory B cells; absent B cells suggest X-linked agammaglobulinemia, while normal or reduced B cells with impaired function suggest CVID. 1, 4

• Lymphocyte subset analysis including CD4+ and CD8+ T-cell counts to exclude combined immunodeficiency. 1

• Complete blood count with differential to detect lymphopenia, neutropenia (suggesting primary immunodeficiency), lymphocytosis (B-cell lymphoproliferative disease), or eosinophilia. 3

Exclude Secondary Causes

This step is frequently overlooked but essential—many cases of hypogammaglobulinemia are iatrogenic or secondary. 1, 2

• Comprehensive medication review for immunosuppressive drugs including:

  • Antiepileptics (phenytoin, carbamazepine, valproic acid, zonisamide) 2
  • Disease-modifying agents (gold salts, penicillamine, hydroxychloroquine) 1, 4
  • Biologics (rituximab and anti-CD20 therapies—21% develop IgG <5 g/L on long-term use) 2
  • NSAIDs 1, 4

• Screen for HIV infection as a cause of secondary immunodeficiency. 1, 4

• Serum protein electrophoresis with immunofixation to detect monoclonal proteins and immune paresis associated with lymphoproliferative disorders (multiple myeloma, Waldenström macroglobulinemia, chronic lymphocytic leukemia, MGUS). 3, 2

• Evaluate for occult malignancy, particularly lymphoma and thymoma (Good syndrome), which can cause secondary hypogammaglobulinemia. 1, 2

Pattern Recognition for Differential Diagnosis

The combination of immunoglobulin levels and functional responses guides diagnosis:

• Low IgG with normal IgA/IgM and normal vaccine responses: Consider secondary hypogammaglobulinemia, unspecified hypogammaglobulinemia, or transient hypogammaglobulinemia of infancy—observation without treatment is appropriate if asymptomatic. 1

• Low IgG with normal IgA/IgM but impaired vaccine responses: Suggests specific antibody deficiency or evolving CVID—requires close monitoring. 1

• Low IgG with low IgA ± IgM, reduced IgG subclasses, and impaired vaccine responses: Consistent with CVID (requires reduction in ≥2 immunoglobulin isotypes plus defective vaccine responses). 1, 4

• Low IgG with low IgA and normal/elevated IgM: Indicates hyper-IgM syndrome (class-switch defect). 1

• Absent or markedly low all immunoglobulins with absent B cells: Points to X-linked agammaglobulinemia. 1, 2

Critical Pitfalls to Avoid

• Never diagnose immunodeficiency on a single low IgG value—transient decreases occur with infections, surgery, and other stressors. 1

• Never initiate immunoglobulin replacement therapy based solely on laboratory abnormalities without documented clinical disease (recurrent infections causing morbidity or established organ damage such as bronchiectasis). 3, 1, 4

• Always check albumin and total protein—this simple step distinguishes protein-loss syndromes from true immunodeficiency and is frequently forgotten. 1, 2

• Do not rely on pneumococcal antibody responses alone—the assay is imprecise, and many healthy individuals have suboptimal responses; clinical correlation with documented pneumococcal infections is essential. 3

• Recognize that IgG subclass deficiencies without functional antibody defects rarely require treatment—many healthy individuals lack specific subclasses entirely. 3