What is the diagnosis for a patient with hypoproteinemia, hypoalbuminemia, and low levels of IgA, IgG, and IgM?

Laboratory Interpretation and Diagnosis

This laboratory pattern—hypoproteinemia (total protein 5.7 g/dL), hypoalbuminemia (albumin 3.9 g/dL), and pan-hypogammaglobulinemia (IgA 30 mg/dL, IgG 258 mg/dL, IgM 6 mg/dL)—most likely represents secondary hypogammaglobulinemia due to protein loss rather than a primary immunodeficiency, and requires immediate evaluation for protein-losing conditions before considering primary immunodeficiency diagnoses. 1, 2

Critical Diagnostic Distinction

The key to diagnosis is the concurrent low total protein and albumin levels, which strongly suggest secondary hypogammaglobulinemia from protein loss through the gastrointestinal tract, lymphatics, or kidney. 1, 2

Why This Matters Clinically:

• When IgG, IgA, and IgM are all low AND total protein/albumin are also low, this pattern is consistent with secondary hypogammaglobulinemia 1, 2
• Primary immunodeficiencies (like CVID or agammaglobulinemia) typically have normal albumin and total protein levels because only immunoglobulin production is affected 1
• The extremely low IgG level (258 mg/dL, normal >700 mg/dL) combined with low albumin creates urgent infection risk regardless of etiology 2, 3

Immediate Evaluation Required

Before diagnosing any primary immunodeficiency, you must exclude these secondary causes: 1, 4

Protein-Losing Conditions to Rule Out:

• Nephrotic syndrome: Check 24-hour urine protein, urine protein/creatinine ratio, urinalysis for proteinuria 1, 4
• Protein-losing enteropathy: Assess for chronic diarrhea, stool alpha-1 antitrypsin clearance, intestinal imaging 1, 4
• Lymphatic disorders: Evaluate for lymphangiectasia, lymphatic obstruction 1

Other Secondary Causes:

• Medications: Review for immunosuppressive drugs (rituximab, corticosteroids, anticonvulsants, gold) 1, 4, 5
• Hematologic malignancies: Screen for B-cell lymphomas, multiple myeloma, chronic lymphocytic leukemia with complete blood count, peripheral smear, serum protein electrophoresis 1, 2, 4
• Bone marrow failure: Evaluate complete blood count for cytopenias 1

If Secondary Causes Are Excluded

Only after ruling out secondary causes should you consider primary immunodeficiency diagnoses. 1, 2

Differential Diagnosis for Primary Immunodeficiency:

The pattern of low IgG, IgA, and IgM with normal or low B cells suggests either: 1, 2

1. Common Variable Immunodeficiency (CVID) - most likely if:

   • Patient age ≥4 years (CVID not diagnosed before age 4) 1
   • B-cell numbers normal or only moderately reduced (>3% of lymphocytes) 1, 2
   • History of recurrent bacterial respiratory infections 2
   • May have autoimmune complications, granulomatous disease, or lymphoproliferation 2

2. Agammaglobulinemia or Severe CVID - consider if:

   • B cells are absent or severely reduced (<2% of lymphocytes) 1, 2
   • More severe presentation with early-onset infections 1

Essential Next Steps for Primary Immunodeficiency Workup:

• B-cell enumeration by flow cytometry: Distinguishes CVID (normal/reduced B cells) from agammaglobulinemia (absent B cells) 1, 2
• Specific antibody responses: Test responses to protein antigens (tetanus, diphtheria) and polysaccharide antigens (pneumococcal vaccine) to document functional antibody deficiency 1
• T-cell evaluation: Complete blood count with differential, lymphocyte subset analysis (CD3, CD4, CD8), as significant humoral deficiency may indicate combined immunodeficiency 1
• Vaccine titers: Measure pre-existing antibodies to vaccines received (if applicable) 1

Urgent Clinical Management

Regardless of whether this is primary or secondary immunodeficiency, the IgG level of 258 mg/dL places this patient at high risk for severe bacterial infections and requires urgent intervention. 2, 3

Immediate Actions:

• Consider urgent immunoglobulin replacement therapy: Patients with IgG <300 mg/dL are at high risk for life-threatening infections 2, 3
• Antibiotic prophylaxis: Consider while awaiting definitive diagnosis and treatment initiation 1
• Avoid live vaccines: Immunoglobulin therapy interferes with live virus vaccine responses 3
• Monitor for infections: Particularly respiratory tract infections from encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae) 1, 2

Target IgG Levels with Replacement:

• Maintain IgG trough levels ≥500 mg/dL to reduce infection risk to background 5
• Higher levels (700-800 mg/dL) may be necessary with comorbidities or ongoing infections 2, 5

Common Pitfalls to Avoid

• Do not diagnose primary immunodeficiency without measuring total protein and albumin - this is the critical step to identify secondary causes 1, 2
• Do not delay treatment while completing workup - with IgG this low, infection risk is immediate 2, 3
• Do not assume all low immunoglobulins are primary immunodeficiency - medication history (especially rituximab) is essential 4, 5
• Do not diagnose CVID in children <4 years old - transient hypogammaglobulinemia of infancy is more likely 1