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Allergen-specific IgE serologic assays define sensitization, not disease (January 2016)

Robert G. Hamilton, PhD, DABMLI, FAAAA
Cleveland Clinic Journal of Medicine May 2016, 83 (5) 326-327; DOI: https://doi.org/10.3949/ccjm.83c.05001
Robert G. Hamilton
Johns Hopkins University School of Medicine, Baltimore, MD
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TO THE EDITOR: I read with great interest the commentary by Lau and Naugler1 regarding how much allergen-specific immunoglobulin E (IgE) testing is too much. The authors made a number of important conclusions that directly contradict the international consensus statement on IgE antibody test performance published by the Clinical Laboratory Standards Institute (CLSI) in 2009 (2nd edition)2 and updated in 2016 (3rd edition) in the I/LA-20 guidance document.3

The most important conclusion of the CLSI I/LA-20 panel was to reaffirm the golden rule of diagnostic allergy testing, which states that allergen-specific IgE antibody detectedby either skin testing or serology methods is simply a marker for sensitization and thus only one of many risk factors for allergic disease. IgE positivity is not synonymous with the presence of allergic disease without a positive clinical history.4 Clinicians, since the time that IgE was discovered as the reagin in 1967, have tried to use the presence of IgE antibody as detected either by skin testing or serology as the definitive indicator of allergic disease. This is simply inappropriate. Both skin testing and serology are diagnostic tests that indicate sensitization (the presence of IgE antibody) and not disease. The clinician using a positive clinical history of allergic symptoms, objectively collected, must make the link between sensitization (IgE antibody positivity) and allergic disease.

Lau and Naugler make this same mistake and conclude from their Figure 1 data that “serum antigen-specific IgE testing is not a reliable diagnostic tool.” They use the Wians criterion5 of the summed diagnostic sensitivity and specificity of 170 to indicate if a test is clinically useful. They determined the sums of the diagnostic sensitivity and specificity for 89 allergen specificities, most of which they report as below 170. Among the specificities they cover are select aeroallergens, food allergens, venoms, and drugs. Importantly, they use a positive threshold of 0.35 kU/L for only some of their specificities, and they consider a sum of the diagnostic sensitivity and specificity equal to or greater than 170 as clinically relevant.

While Wians’ analysis may have been appropriate for laboratory tests like glucose and even prostate-specific antigen that associate closely with defining a disease state, this criterion is inappropriate for IgE antibody tests that do not directly identify allergic disease. There is peer-reviewed literature on nonreactors based on their clinical history with a validated positive IgE skin test, IgE antibody serology, or food challenge tests.6,7 Thus, the data in their Figure 1 have no value in defining the performance of IgE antibody tests of sensitization.

Moreover, their report is vague on the actual IgE antibody assay method that was used. This information is important because we know that different IgE assay methods measure different populations of IgE antibody.2,3 Also, the report does not define whether the participants who provided sera for testing actually had physician-defined allergic disease based on an objective clinical history.

The act of determining optimal cutoff values to maximize the “diagnostic” sensitivity and specificity is appropriate for many laboratory tests, but for allergen-specific IgE antibody analyses, it should be considered inappropriate. These are tests of sensitization, not disease. The IgE antibody result should be reported down to the regulatory-cleared and manufacturer-defined analytical sensitivity, which for the principal IgE antibody auto-analyzers used worldwide is 0.1 kU/L.8 These concerns essentially invalidate the conclusions of their report. Unfortunately, they leave the reader with misleading negative impressions about the utility of IgE antibody analyses that are extensively validated methods.

Finally, contrary to the assertions of the authors, current commentaries on the topic of relative diagnostic performance of skin testing and autoanalyzer-based IgE serology tests support the conclusion that, especially for aeroallergens, both the in vivo skin test and the current autoanalyzer-based in vitro serology tests provide overlapping, indistinguishable, and thus comparable diagnostic sensitivity and specificity results.9,10 Unfortunately, the authors refer to the 2008 Bernstein practice parameter that is out of date in relation to autoanalyzer technology, which has advanced by 2016.

Thus, contrary to the assertions of Lau and Naugler, IgE antibody serology has a clear, well-defined, and positive role in defining sensitization as a key part of the diagnostic workup of a patient who is suspected of having allergic disease. As with any laboratory test, IgE antibody measurements need to be judiciously ordered and used by the clinician only when there is a strong pretest likelihood, based on the patient’s clinical history, of allergic disease.

  • Copyright © 2016 The Cleveland Clinic Foundation. All Rights Reserved.

REFERENCES

  1. ↵
    1. Lau CK,
    2. Naugler C
    . Serum allergen-specific IgE testing: how much is too much? Cleve Clin J Med 2016; 83;21–24.
    OpenUrlFREE Full Text
  2. ↵
    1. Matsson P,
    2. Hamilton RG,
    3. Esch RE,
    4. et al
    . Analytical Performance Characteristics and Clinical Utility of Immunological Assays for Human Immunoglobulin E (IgE) Antibodies of Defi ned Allergen Specifi cities; Approved Guideline-Second Edition. CLSI document I/LA20-A2. Clinical and Laboratory Standards Institute, Wayne, Pennsylvania USA, 2009
  3. ↵
    1. Hamilton RG,
    2. Matsson P,
    3. Chan S,
    4. et al
    . Analytical Performance Characteristics, Quality Assurance and Clinical Utility of Immunological Assays for Human Immunoglobulin E (IgE) Antibodies of Defi ned Allergen Specifi cities; Approved Guideline-Third Edition. CLSI document I/LA20-A3. Clinical and Laboratory Standards Institute, Wayne, Pennsylvania, USA, 2016.
  4. ↵
    1. Hamilton RG
    . Allergic sensitization is a key risk factor for but not synonymous with allergic disease. J Allergy Clin Immunol 2014; 134:360–361.
    OpenUrl
  5. ↵
    1. Wians FH Jr.
    Clinical laboratory tests: which, why and what do the results mean? Lab Medicine 2009; 40:105–113.
    OpenUrlCrossRef
  6. ↵
    1. Chokshi NY,
    2. Sicherer SH
    . Interpreting IgE sensitization tests in food allergy. Expert Rev Clin Immunol 2015; 15:1–15.
    OpenUrl
  7. ↵
    1. Sicherer SH,
    2. Wood RA,
    3. Vickery BP,
    4. et al
    . Impact of allergic reactions on food-specific IgE concentrations and skin test results. J Allergy Clin Immunol Pract. 2015 Dec 21. pii: S2213-2198(15)00658-3. doi:10.1016/j.jaip.2015.11.015. [Epub ahead of print]
    OpenUrlCrossRef
  8. ↵
    1. Hamilton RG
    . Clinical laboratories worldwide need to report IgE antibody results on clinical specimens as analytical results and not use differential positive thresholds (letter). J Allergy Clin Immunol 2015; 136:811–812.
    OpenUrl
  9. ↵
    1. Adkinson NF Jr.,
    2. Hamilton RG
    . Clinical history-driven diagnosis of allergic diseases: utilizing in vitro IgE testing. Allergy Clin Immunol Pract 2015; 3:871–876.
    OpenUrl
  10. ↵
    1. Kleine-Tebbe J,
    2. Matricardi PM,
    3. Hamilton RG
    . Allergy work-up including component-resolved diagnosis: how to make allergen-specific immunotherapy more specific. Immunol Allergy Clin North Am 2016; 36:191–203.
    OpenUrl
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Cleveland Clinic Journal of Medicine: 83 (5)
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Allergen-specific IgE serologic assays define sensitization, not disease (January 2016)
Robert G. Hamilton
Cleveland Clinic Journal of Medicine May 2016, 83 (5) 326-327; DOI: 10.3949/ccjm.83c.05001

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Allergen-specific IgE serologic assays define sensitization, not disease (January 2016)
Robert G. Hamilton
Cleveland Clinic Journal of Medicine May 2016, 83 (5) 326-327; DOI: 10.3949/ccjm.83c.05001
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