What is the initial workup for a patient with suspected hypogammaglobulinemia?

Initial Workup for Suspected Hypogammaglobulinemia

Begin with quantitative measurement of serum immunoglobulin levels (IgG, IgA, IgM) and functional antibody assessment to both protein and polysaccharide antigens. 1

Step 1: Initial Laboratory Testing

Quantitative Immunoglobulin Measurement

• Measure serum IgG, IgA, and IgM levels using age-adjusted reference ranges 1
• Hypogammaglobulinemia is defined as IgG <400-500 mg/dL in adults 2, 3
• For children, use age-specific cutoffs (e.g., >450-500 mg/dL for children ≥4 years) 4
• Confirm abnormal results with repeat testing to exclude laboratory error 4

Serum Protein Assessment

• Measure total protein and albumin levels concurrently 1, 3
• Low albumin with low immunoglobulins suggests secondary hypogammaglobulinemia from protein loss (nephrotic syndrome, protein-losing enteropathy, lymphatic disorders) rather than primary immunodeficiency 1, 3
• Primary immunodeficiencies typically have normal albumin and total protein 3

Functional Antibody Assessment

• Measure specific antibody responses to protein antigens (tetanus, diphtheria toxoid) 1
• Assess polysaccharide antigen responses using pneumococcal vaccine titers 1
• For children <6 years: adequate response is concentration >1.3 mg/mL for >50% of serotypes with 2-fold increase 1
• For patients ≥6 years: adequate response is concentration >1.3 mg/mL for >70% of serotypes 1
• Document pre-existing antibodies to previously received vaccines 3

Step 2: B-Cell and T-Cell Enumeration

Flow Cytometry Analysis

• Perform B-cell enumeration (CD19+ cells) to distinguish between diagnoses 1, 3
• Absent or severely reduced B cells (<3%) suggests agammaglobulinemia 1
• Normal or moderately reduced B cells suggests Common Variable Immunodeficiency (CVID) 1, 3
• Measure T-cell subsets (CD4, CD8) and lymphocyte differential to identify combined immunodeficiency 1, 3

Advanced B-Cell Phenotyping (if CVID suspected)

• Consider B-cell subset analysis including switched memory B cells (IgD-CD27+), marginal zone B cells, transitional B cells, and CD21low cells 1
• Use age-adjusted values for B-cell subsets in children 1

Step 3: Exclude Secondary Causes

Protein Loss Syndromes

• 24-hour urine protein and urine protein/creatinine ratio to exclude nephrotic syndrome 3
• Stool alpha-1 antitrypsin clearance if chronic diarrhea present to exclude protein-losing enteropathy 3

Medication Review

• Identify use of immunosuppressive agents (rituximab, anti-CD20 antibodies, corticosteroids, antiepileptics, gold) 1, 3, 5
• Drug-induced hypogammaglobulinemia typically shows preserved IgA and no switched memory B-cell deficit 5

Hematologic Malignancies

• Blood immunophenotyping to detect circulating B-cell clones 5
• Consider thoracoabdominal CT to exclude thymoma, lymphoma, or deep tumor syndrome 5
• Evaluate for B-cell lymphomas, chronic lymphocytic leukemia, or multiple myeloma 1, 6

Urinary Protein Electrophoresis

• Perform to exclude light chain myeloma 5

Step 4: Age-Specific Considerations

Children Under 4 Years

• Do not diagnose CVID before age 4 years as transient hypogammaglobulinemia of infancy is common 1, 4
• Transient hypogammaglobulinemia typically resolves by mean age 27 months, with all cases normalizing by 59 months 4
• Monitor IgG levels serially rather than immediately treating 4

Adults

• CVID is the most common symptomatic primary immunodeficiency in adults 5
• Consider transient hypogammaglobulinemia of adulthood if IgG spontaneously normalizes 7

Critical Diagnostic Patterns

Pattern Recognition from Initial Labs 1

Low IgG only with normal IgA/IgM:

• Check vaccine responses and IgG subclasses
• If vaccine response impaired: specific antibody deficiency or IgG subclass deficiency
• If normal total protein/albumin low: secondary hypogammaglobulinemia

Low IgG and IgA, normal/high IgM:

• Suggests Hyper-IgM syndrome 1
• Requires evaluation of CD40L expression

Low IgG, IgA, and IgM with normal/low B cells:

• CVID if B cells normal or moderately reduced 1, 3
• Agammaglobulinemia if B cells absent/severely reduced 1, 3

Absent IgG, IgA, and IgM:

• Agammaglobulinemia or severe CVID 1
• Cellular immunity should be evaluated 1

Common Pitfalls to Avoid

• Do not rely solely on total IgG levels—functional antibody assessment is essential for diagnosis 1, 2
• Do not assume all hypogammaglobulinemia requires immunoglobulin replacement—verify infection history and severity 2, 3
• Do not overlook secondary causes—they are 30 times more common than primary immunodeficiencies 5
• Do not diagnose IgG subclass deficiency without documenting impaired vaccine responses, as isolated subclass deficiencies may not be clinically significant 1, 4
• Do not delay evaluation in patients with severe hypogammaglobulinemia (IgG <300 mg/dL) and recurrent infections—these patients require urgent assessment and potential immunoglobulin replacement 3