What is the difference between Immunoglobulin G (IGG), Immunoglobulin M (IGM), Immunoglobulin A (IGA), and Immunoglobulin E (IGE) testing in patients with suspected immune system disorders or infections?

Understanding Immunoglobulin Testing: IgG, IgM, IgA, and IgE

Each immunoglobulin class serves distinct diagnostic purposes: IgM indicates acute/recent infection, IgG reflects past infection or immunity, IgA assesses mucosal immunity and specific deficiencies, and IgE evaluates allergic responses and certain immunodeficiencies. 1

Immunoglobulin Distribution and Basic Function

In normal serum, immunoglobulins comprise approximately 80% IgG, 15% IgA, 5% IgM, and trace amounts of IgE, with each class produced by plasma cells as the terminal stage of B-cell differentiation 1. These quantitative tests detect abnormal levels to diagnose conditions causing excess, deficiency, or combined patterns of immunoglobulin abnormalities 1.

IgM Testing: Acute Infection Marker

Primary Diagnostic Role

• IgM antibodies appear first during acute infections, making them the primary marker for recent or active disease 2
• For viral encephalitis, CSF IgM testing is specifically recommended for suspected flavivirus infections 2
• In dengue/Zika diagnosis, positive IgM on either assay (with appropriate PRNT confirmation) indicates recent infection within the past 12 weeks 2

Critical Limitations

• IgM testing for Helicobacter pylori is explicitly not recommended due to low specificity and sensitivity, with only FDA-approved IgG tests considered reliable 2
• IgM for pertussis diagnosis is not mentioned in ACCP guidelines, which instead recommend IgG and IgA antibodies to pertussis toxin 3
• IgM can persist for extended periods in some infections (e.g., toxoplasmosis), limiting its utility for distinguishing acute from chronic disease in certain contexts 4

Timing Considerations

• False negatives occur if specimens are collected ≤7 days after illness onset, before detectable antibody response develops 2
• Antibiotics, bismuth, or proton pump inhibitors can reduce bacterial load and produce false negative results 2

IgG Testing: Past Infection and Immunity

Diagnostic Applications

• IgG indicates past infection or established immunity, typically appearing 10-14 days after illness onset and persisting for years 2
• For viral encephalitis, intrathecal IgG synthesis peaks after one month and helps establish diagnosis when CSF is sampled after day 10-12 of illness 2
• Paired acute and convalescent sera demonstrating fourfold IgG increase (collected 3-4 weeks apart) is the accepted serologic criterion for pertussis diagnosis, with 99% specificity and 63% sensitivity 3

Subclass Testing

• IgG subclass deficiencies (particularly IgG2) are clinically significant in patients with chronic or recurrent respiratory infections, even when total IgG is normal 5
• Five of 47 patients with chronic respiratory infection and five of 53 with recurrent infection had IgG2 concentrations >3 standard deviations below normal, with total IgG remaining in normal range in 13 of 14 cases 5

Critical Pitfalls

• Serology remains positive long after infection eradication (a "serologic scar"), making IgG unsuitable for confirming eradication 2
• For hypersensitivity pneumonitis, serum antigen-specific IgG testing alone cannot confirm or rule out diagnosis due to lack of standardized preparations, techniques, and validation 2
• Panels combining IgG, IgA, and IgM provide no added benefit over IgG alone and often consist of non-FDA-approved tests 2

IgA Testing: Mucosal Immunity and Specific Infections

When to Measure IgA

• IgA antibodies to pertussis toxin or filamentous hemagglutinin are recommended alongside IgG for pertussis diagnosis, with paired sera showing fourfold increase 3
• For toxoplasmosis in pregnancy, IgA antibodies appear about one week after IgM and were detected in 75% of women with seroconversion 4
• IgA testing is useful for congenital toxoplasmosis during serological reactivation, particularly when IgM results are equivocal 4

IgA Deficiency Considerations

• Selective IgA deficiency is common and was found in five patients with respiratory infections who had normal IgG subclasses 5
• Three patients with IgG2 deficiency also had concomitant IgA deficiency (<0.01 g/L) 5
• The majority of patients with selective IgA deficiency will have minimal clinical response to IgG replacement therapy 6

IgE Testing: Allergy and Immunodeficiency

Diagnostic Utility

• Low or undetectable IgE (<2 IU/mL) is highly specific for Common Variable Immunodeficiency (CVID), occurring in 75.6% of CVID patients versus only 3.3% of the general population 7
• Conversely, high IgE (>180 IU/mL) is very uncommon in CVID (0.3% of patients) 7
• IgE >2 IU/mL occurs in 91.2% of patients with secondary hypogammaglobulinemia, making undetectable IgE suggestive of primary humoral immunodeficiency 7

Clinical Associations

• IgE deficiency is associated with impaired vaccine response and increased malignancy risk, particularly in patients without allergic comorbidities and those with non-CVID humoral immunodeficiency 8
• Allergen-specific IgE is undetectable in 96.5% of CVID patients 7
• For toxoplasmosis, specific IgE antibodies were detected in 85% of women with seroconversion and appear useful for differentiating acute from chronic infection 4

Immunoglobulin Replacement Therapy Considerations

When Replacement Is NOT Indicated

• Normal total IgG levels are a critical exclusion criterion for standard immunoglobulin replacement therapy 6
• Asymptomatic hypogammaglobulinemia with normal antibody responses does not warrant replacement 6
• For selective antibody deficiency, antibiotic prophylaxis might be equally effective as replacement therapy 6

When to Consider Replacement

• Hypogammaglobulinemia defined as significant reduction in ≥2 isotypes (not borderline values) justifies consideration 6
• IgG <400 mg/dL with recurrent infections may warrant replacement 9
• Documented severe or recurrent infections negatively affecting quality of life, plus failure of aggressive antibiotic therapy/prophylaxis 6

First-Line Management

• Aggressive antimicrobial therapy and prophylactic antibiotics should be attempted before considering immunoglobulin replacement 6
• Treat underlying atopic disease aggressively, as allergic inflammation predisposes to respiratory infections 6
• Review medication history, as certain drugs can cause secondary antibody deficiency 6

Practical Testing Algorithm

Initial Workup for Suspected Immunodeficiency

1. Measure total serum IgG, IgA, IgM, and IgE as the minimum bundle of etiological tests 6, 1
2. If IgG is globally low, evaluate for CVID or secondary causes (medications, protein loss, HIV) 3
3. Measure specific antibody responses to vaccines when evaluating low IgG 3
4. Consider IgG subclass testing if recurrent respiratory infections occur despite normal total IgG 5

Infection Diagnosis Strategy

• For acute infections: Prioritize IgM testing with appropriate timing (>7 days after symptom onset) 2
• For confirming past infection: Use IgG testing, recognizing it cannot distinguish recent from remote infection 2
• For pertussis: Order paired IgG and IgA to pertussis toxin, not IgM 3
• For suspected CVID: Include IgE measurement, as undetectable levels are highly specific 7