What are the diagnostic criteria for hypoglobulinemia?

Diagnostic Criteria for Hypogammaglobulinemia

Hypogammaglobulinemia is defined as serum IgG <450-500 mg/dL (or <7 g/L) plus IgA or IgM below the 5th percentile for age, with impaired specific antibody production and exclusion of secondary causes. 1, 2

Laboratory Thresholds

• IgG <450-500 mg/dL is the primary diagnostic threshold for hypogammaglobulinemia in adults 2
• In European literature, IgG <7 g/L is the equivalent cutoff used 3
• All three immunoglobulin classes (IgG, IgA, IgM) must be measured simultaneously, not just total protein or calculated globulin 2, 3
• Age-adjusted reference ranges are critical—immunoglobulin levels 2 standard deviations below the mean for age define abnormality in children 4

Essential Functional Testing

• Specific antibody responses to both protein antigens and polysaccharide antigens must be documented to confirm functional antibody deficiency, as immunoglobulin levels alone are insufficient 2, 5
• Testing pre-existing antibodies to vaccines previously received is necessary to assess immune function 2
• Impaired vaccine response is a key diagnostic criterion that guides treatment decisions regarding immunoglobulin replacement therapy 5

Critical Distinction: Primary vs Secondary Causes

Check albumin and total protein levels immediately—this single step distinguishes primary immunodeficiency from secondary protein loss syndromes 2, 6:

• Low albumin + low total protein = secondary hypogammaglobulinemia from protein loss (nephrotic syndrome, protein-losing enteropathy, lymphatic disorders) 2
• Normal albumin + normal total protein = primary immunodeficiency (CVID, agammaglobulinemia) because only immunoglobulin production is affected 2

Mandatory Secondary Cause Exclusion

Before diagnosing primary immunodeficiency, exclude 2, 6:

• Nephrotic syndrome: 24-hour urine protein, urine protein/creatinine ratio, urinalysis for proteinuria 2
• Protein-losing enteropathy: chronic diarrhea history, stool alpha-1 antitrypsin clearance, intestinal imaging 2, 6
• Medication-induced: antiepileptics (phenytoin, carbamazepine, valproic acid), rituximab/anti-CD20 therapies, corticosteroids, sulfasalazine, gold, penicillamine, hydroxychloroquine 2, 6, 3
• Hematologic malignancies: B-cell lymphomas, multiple myeloma, thymoma (Good syndrome) 2, 6
• Cryoglobulinemia: can cause false hypogammaglobulinemia on testing 3

Distinguishing Primary Immunodeficiency Subtypes

B-cell enumeration by flow cytometry is essential to distinguish between diagnoses 2, 5:

Agammaglobulinemia

• Absent or severely reduced B cells (<2% of lymphocytes) 2, 6
• Very low or undetectable immunoglobulins (typically IgG <100 mg/dL) 6
• Presents in first 2 years of life with severe recurrent bacterial respiratory infections 6

Common Variable Immunodeficiency (CVID)

• Normal or only moderately reduced B-cell numbers 1, 2
• IgG <450-500 mg/dL plus IgA or IgM below 5th percentile 2
• Typically diagnosed at age ≥4 years 2, 6
• History of recurrent bacterial respiratory infections 2
• May have autoimmune complications, granulomatous disease, or lymphoproliferation 2
• Approximately 13% of CVID patients have <3% B cells among peripheral blood lymphocytes 5

Unspecified Hypogammaglobulinemia

• Diagnosis of exclusion when patient has: (1) significant morbidity from infections, (2) abnormal immunoglobulin levels not conforming to other diagnoses, (3) normal cellular immunity, (4) no other potential immune deficiency diagnosis, and (5) no conditions predisposing to humoral immunodeficiency 1, 5

Additional Immunologic Workup

• T-cell evaluation including complete blood count with differential and lymphocyte subset analysis (CD4, CD8, CD19) to identify combined immunodeficiency 2, 5
• T-cell abnormalities are frequently found in CVID despite being classified as predominantly humoral immunodeficiency 5
• Thoracoabdominal CT scan to rule out thymoma and identify deep tumor syndrome 3

Severity Stratification and Urgent Management

• IgG <300-400 mg/dL with recurrent infections requires urgent immunoglobulin replacement therapy to reduce risk of life-threatening infections from encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae) 2, 6
• Antibiotic prophylaxis should be initiated while awaiting definitive diagnosis 2
• Patients with ≥2 severe recurrent infections by encapsulated bacteria require IVIG regardless of exact IgG level 6

Common Pitfalls to Avoid

• Relying on calculated globulin alone: calculated globulin ≤20 g/L has only 5.8% sensitivity for hypogammaglobulinemia, though 82.5% positive predictive value when present 7
• Failing to repeat testing: transient hypogammaglobulinemia exists, so persistence should be confirmed at distance with repeat IgG, IgA, IgM measurement 3, 4
• Overlooking medication history: drug-induced hypogammaglobulinemia is frequently reversible with cessation of the offending agent 6, 3
• Ignoring functional assessment: serum levels alone are inadequate—specific antibody responses are more predictive of infection risk 2, 5