How to work up a patient with hypogammaglobulinemia on Serum Protein Electrophoresis (SPEP)?

Workup of Hypogammaglobulinemia on SPEP

When hypogammaglobulinemia is detected on SPEP, immediately confirm the finding with quantitative immunoglobulin levels (IgG, IgA, IgM) and perform immunofixation electrophoresis to exclude occult monoclonal proteins, which are present in up to 24% of cases. 1

Initial Confirmation and Characterization

• Repeat testing is essential because transient hypogammaglobulinemia occurs frequently and should not trigger extensive workup 2, 3
• Order quantitative immunoglobulin levels (IgG, IgA, IgM) on a separate blood draw to confirm the SPEP finding and characterize the pattern 2, 3
• Perform immunofixation electrophoresis (IFE) on all confirmed cases because monoclonal proteins are present in 10-24% of patients with isolated hypogammaglobulinemia on SPEP, even when no discrete peak is visible 1
• Check serum free light chains (kappa and lambda) to further evaluate for occult plasma cell disorders 2

Rule Out Secondary Causes First

Secondary immunodeficiencies are 30 times more common than primary immunodeficiencies in adults, so this must be your initial focus 2

Protein Loss Syndromes

• 24-hour urine protein with urine protein electrophoresis to exclude nephrotic syndrome and light chain myeloma 2, 3
• Consider protein-losing enteropathy if chronic diarrhea is present 2, 3

Hematologic Malignancies

• Peripheral blood immunophenotyping to detect circulating B-cell clones suggesting lymphoid malignancy 2
• CT chest/abdomen/pelvis to identify thymoma (associated with Good syndrome), lymphadenopathy, splenomegaly, or occult malignancy 2, 3

Medication-Induced

• Review medication history for:
  • Anti-CD20 agents (rituximab) - the most common drug cause in rheumatology patients 2, 3
  • Corticosteroids 2
  • Antiepileptic drugs 2, 3
  • Other immunosuppressive agents 2, 3
• Drug-induced hypogammaglobulinemia typically shows preserved IgA levels and lacks switched memory B-cell deficiency, distinguishing it from primary immunodeficiency 2

Cryoglobulinemia

• Check for cryoglobulins if a monoclonal component is present, as cryoglobulins can cause falsely low gamma globulin readings on SPEP 2

Assess Clinical Significance

Infection History

• Document frequency and severity of sinopulmonary infections (sinusitis, pneumonia, otitis, bronchitis) - the most common manifestations 4
• Recurrent infections requiring antibiotics ≥3 times per year suggests clinically significant immunodeficiency 5
• Note that severe infections may be absent even with profound hypogammaglobulinemia (IgG <3 g/L) 6

Associated Conditions

• Screen for autoimmune diseases, particularly hypothyroidism (present in 50% of patients) 4
• Assess for allergic conditions: rhinitis (87.5%) and asthma (37.5%) are common 4
• Evaluate for bronchiectasis with high-resolution chest CT if chronic respiratory symptoms exist 4

Evaluate for Primary Immunodeficiency

If secondary causes are excluded, consider primary immunodeficiency:

Functional Antibody Assessment

• Measure specific antibody responses to pneumococcal polysaccharide vaccine (Pneumovax 23) before and 4-6 weeks after vaccination 7
• Note that vaccine responses correlate poorly with long-term prognosis and need for immunoglobulin replacement 6

Lymphocyte Subset Analysis

• Flow cytometry for B-cell subsets including total B cells, switched memory B cells (CD27+IgM-IgD-), and unswitched memory B cells (CD27+IgD+IgM+) 7
• Reduced switched memory B cells suggest immunoglobulin class-switch defects 7

Diagnostic Considerations

• Common Variable Immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency in adults, typically presenting in the 20s-30s 2, 3
• Good syndrome (thymoma with hypogammaglobulinemia) presents around age 40 years 3
• Unspecified hypogammaglobulinemia is a diagnosis of exclusion requiring: significant infection morbidity, abnormal immunoglobulin levels not fitting other diagnoses, normal cellular immunity, and no other predisposing conditions 7

Treatment Thresholds

Indications for Immunoglobulin Replacement

• IgG <400-500 mg/dL (4-5 g/L) with recurrent infections (≥3 events/year) 5
• Consider higher threshold of 650 mg/dL for patients on B-cell depleting therapies 5
• Severe asymptomatic hypogammaglobulinemia (IgG <3 g/L) warrants treatment despite favorable natural history data, due to potential risk of catastrophic infections 6

Dosing When Treatment Indicated

• IVIG: 0.4-0.6 g/kg every 3-4 weeks 5, 4
• SCIG: equivalent weekly dose (divide monthly dose by 4) 5, 8
• Target trough IgG level: 600-800 mg/dL 5

Common Pitfalls

• Do not assume all hypogammaglobulinemia requires immunoglobulin replacement - moderate asymptomatic hypogammaglobulinemia (IgG 3.0-6.9 g/L) has excellent prognosis without treatment 6
• Do not skip immunofixation - up to 24% of isolated hypogammaglobulinemia cases harbor occult monoclonal proteins 1
• Do not rely solely on vaccine responses to guide treatment decisions, as they correlate poorly with clinical outcomes 6
• Recognize that 18-42% of patients with hypogammaglobulinemia spontaneously normalize their IgG levels (transient hypogammaglobulinemia of adulthood), particularly those who are asymptomatic 6
• Average time from symptom onset to diagnosis is 6-10 years - maintain high clinical suspicion to avoid preventable sequelae 4