What is the approach to evaluating elevated Immunoglobulin E (IgE) levels?

From the Guidelines

Evaluating elevated Immunoglobulin E (IgE) levels requires a comprehensive approach, including a detailed clinical history, physical examination, and targeted laboratory testing to identify the underlying cause, as elevated IgE can result from various conditions, including allergic diseases, parasitic infections, certain malignancies, and primary immunodeficiencies. The diagnosis of atopic dermatitis, for example, remains clinical, and while elevated total and/or allergen-specific serum IgE levels are commonly associated with the disease, they are not present in about 20% of affected individuals 1.

Key Components of Evaluation

• Obtain a detailed clinical history focusing on allergic conditions, family history, recurrent infections, and environmental exposures
• Perform a physical examination to look for signs of atopic diseases, skin manifestations, and evidence of chronic infections
• Conduct laboratory testing, including:
  • Complete blood count with differential to assess for eosinophilia
  • Specific IgE testing for common allergens
  • Skin prick testing to identify allergen sensitivities
• Consider additional tests based on clinical presentation, such as pulmonary function tests for asthma evaluation, stool examination for parasitic infections, and genetic testing for primary immunodeficiency syndromes like hyper-IgE syndrome (Job's syndrome)
• Imaging studies, such as chest X-ray or CT scan, may be necessary if pulmonary involvement is suspected

Importance of Clinical Judgment

The workup should be tailored to the patient's clinical presentation, and understanding the specific cause of elevated IgE helps direct appropriate treatment and management strategies. While biomarkers such as serum levels of CD30, Macrophage-Derived Chemoattractant (MDC), interleukins (IL), and Thymus and Activation-Regulated Chemokine (TARC) have been studied, none have shown reliable sensitivity or specificity for atopic dermatitis to support general clinical use for diagnosis or monitoring 1.

Consultation and Management

Consider consultation with an allergist/immunologist for complex cases. The management of elevated IgE levels depends on the underlying cause and may involve allergen immunotherapy, pharmacological treatment, or other interventions. The effectiveness of immunotherapy can be determined by objective measures, such as clinical symptom scores and the amount of medication required to control symptoms, as well as improvement in disease-specific quality of life 1.

From the FDA Drug Label

Determine dosage of XOLAIR by serum total IgE level (IU/mL) measured before the start of treatment, and by body weight (kg) Total IgE levels are elevated during treatment and remain elevated for up to one year after the discontinuation of treatment. Interruptions lasting one year or more: Re-test total serum IgE levels for dose determination

The approach to evaluating elevated Immunoglobulin E (IgE) levels is to:

• Measure serum total IgE level before the start of treatment
• Use the measured IgE level to determine the dosage of XOLAIR
• Re-test total serum IgE levels after interruptions in treatment lasting one year or more to re-determine the dosage 2
• Note that total IgE levels may remain elevated for up to one year after discontinuation of treatment, and therefore should not be used to reassess the dosing regimen during this time 2

From the Research

Approach to Evaluating Elevated IgE Levels

Evaluating elevated Immunoglobulin E (IgE) levels involves a comprehensive approach to determine the underlying cause. The following steps are considered:

• Measurement of IgE, IgG, IgA, IgM, and IgG subclasses in blood samples to confirm elevated IgE levels 3
• Assessment of clinical diagnosis, comorbidities, and laboratory parameters to identify potential causes such as atopic diseases, parasitic diseases, malignancy, or hyper-IgE syndrome (HIES) 4
• Consideration of demographic characteristics, such as sex, area/environment, and age, and their effect on IgE serum levels 5
• Genetic testing to identify specific genetic abnormalities, such as mutations in STAT3, DOCK8, TYK2, or PGM3 molecules, which can provide important insight into the immunopathogenesis of the disease and accurate determination of optimal therapy 6, 7

Potential Underlying Causes

Potential underlying causes of elevated IgE levels include:

• Allergic diseases, such as atopic dermatitis and bronchial asthma 3, 5
• Infectious diseases, such as recurrent skin abscesses and pneumonias 4
• Inborn errors of immunity, such as hyper-IgE syndrome (HIES) 3, 4, 6, 7
• Monogenic atopic conditions or primary immunodeficiencies (PIDs) with elevated IgE levels 3, 7

Diagnostic Approach

A genomics-based diagnostic approach is becoming increasingly important in evaluating elevated IgE levels, particularly in cases with severe atopy and recurrent infections 6. This approach involves:

• Genomic testing to identify specific genetic defects, such as mutations in FLG, DOCK8, SPINK5, or CARD11 6
• Consideration of the spectrum of atopy and immunodeficiency seen in patients with underlying mutations 6
• Synergism of multiple variants of unknown significance, which can contribute to the disease phenotype 6