Allergic sensitization is a key risk factor for but not synonymous with allergic disease

Allergic sensitization is a key risk factor for but not synonymous with allergic disease

Editorial Allergic sensitization is a key risk factor for but not synonymous with allergic disease Robert G. Hamilton, PhD, DABMLI, FAAAAI Baltimore...

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Editorial

Allergic sensitization is a key risk factor for but not synonymous with allergic disease Robert G. Hamilton, PhD, DABMLI, FAAAAI

Baltimore, Md

Key words: IgE, prevalence, sensitization, atopy, National Health and Nutrition Examination Survey

The impressive team of investigators involved in the detailed analysis of the National Health and Nutrition Examination Survey (NHANES) 2005-2006 data are to be highly commended for their careful analyses and meticulous dissection of IgE antibody data, as they have chronicled in the report by Salo et al1 and a previous 2011 report2 using a similar data set. With support from the National Institutes of Health and the National Institute of Environmental Health Sciences, the authors of the current report have analyzed trends in IgE antibody positivity in sera from 856 children 1 to 5 years old for 9 allergen specificities and 7268 subjects greater than 6 years of age for 19 allergen specificities using 0.35 kUA/L as the positive ImmunoCAP threshold criterion. While reviewing this excellent article for sociodemographic and US regional patterns, the reader is encouraged to remember the golden rule of allergic disease diagnosis. The authors nicely placed this rule in evidence in the second-to-last paragraph of their article. The golden rule, as stated in the current American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma & Immunology diagnostic practice parameter,3 is that IgE antibody positivity strictly indicates allergic sensitization. Although it is a key risk factor for allergic disease, allergic sensitization is not synonymous with allergic disease without the presence of a positive clinical history. Although a questionnairebased history was collected from subjects participating in the NHANES 2005-2006 study,2 no clinical history data were considered in the current report. Thus the authors correctly make no attempt to translate their reported ‘‘IgE sensitization prevalence rates’’ into regional trends of ‘‘allergic disease’’ among the American population. The reader is encouraged do the same and not make this leap between IgE sensitization and allergic disease. Thus the 36.2% of 1- to 5-year-olds and 44.6% of subjects greater than 6 years of age who are identified as sensitized by having circulating IgE antibodies to at least 1 allergen specificity will most certainly be an overestimate of the actual prevalence of actual allergic disease in the United States. Balancing this is the From Medicine–Allergy and Clinical Immunology, Johns Hopkins University School of Medicine. Disclosure of potential conflict of interest: R. G. Hamilton declares that he has no relevant conflicts of interest. Received for publication February 13, 2014; accepted for publication February 14, 2014. Corresponding author: Robert G. Hamilton, PhD, DABMLI, FAAAAI, Medicine– Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD 21224. E-mail: [email protected]. J Allergy Clin Immunol 2014;nnn:nnn-nnn. 0091-6749/$36.00 Ó 2014 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaci.2014.02.022

possibility that some sensitized subjects in the study cohort were not identified because of the practical necessity of limiting the number of allergen specificities tested with the available blood. In 2008, the principal clinical laboratory autoanalyzers that are used in North America to quantify IgE antibody levels in human serum were permitted by the US Food and Drug Administration to reduce their analytic sensitivity based on objective empiric data from 0.35 to 0.1 kUA/L.4 Technically, these modern autoanalyzers from their conception have been able to measure down to 0.1 kUA/L of IgE, as interpolated from a total IgE ‘‘heterologous’’ calibration curve. Historically, 0.35 kUA/L was selected for use with the original RAST produced by Pharmacia (Uppsala, Sweden) because IgE antibody levels of greater than 0.35 kUA/L tended to correlate best with the presence of allergic disease symptoms. The 0.35 kUA/L positive cut point was thus initially adopted for use by the modern autoanalyzers. Because of studies, such as that by Linden et al,5 that provide empiric evidence for the utility of lower levels, 0.1 kUA/L was adopted for use in current IgE antibody autoanalyzers. The study by Linden et al showed, using receiver operating characteristic curves and Youden plots, that IgE antibody levels of 0.12 and 0.20 kUA/L specific for cat and dog epidermal allergens, respectively, provide the highest predictive value for allergic disease involving pet allergen exposure in young US adults. However, because the clinical relevance of human IgE antibody results between 0.1 and 0.35 kUA/L has in general remained undetermined for the majority of allergen specificities, use of 0.35 kUA/L as the positive threshold by Salo et al1 in the current study provides an appropriate conservative estimate of allergic sensitization for subjects across the United States. In any future NHANES studies, however, determination of IgE antibody positivity should be based on the current technology involving a 0.1 kUA/L analytic sensitivity criterion. Then a subset analysis can be performed with the 0.35 kUA/L cut point to permit a comparison for temporal trends with data in the current report by Salo et al. As a reader examines the prevalence data based on IgE antibody levels of greater than 0.35 kUA/L, it is appropriate to assume that these are ‘‘quantitative’’ estimates of IgE antibody circulating in the blood. Direct comparison with estimates of allergic sensitization based on skin test results from previous NHANES studies is not ideal because skin test and serologic measures of IgE antibodies are not interchangeable. Thus Salo et al1 can rightly claim that their report is among the first to report sensitization patterns across Americans older than 1 year of age using a more quantitative measure of IgE antibody. IgE antibody serology has moved into the age of componentresolved diagnostics using recombinant or native allergens on allergosorbents and multiplexing chip technology. Despite these advances in methodology, future NHANES studies that examine the prevalence of allergic sensitization in the American 1

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population should be encouraged to continue using ‘‘extract’’based IgE antibody assay reagents. Use of quality-controlled and validated extract-based allergosorbents provides future investigators with the highest probability of detecting IgE antibodies to all the principal allergenic components for any given specificity using a single allergosorbent. This approach should maximize the detection of IgE with the least number of required individual analyses and possibly permit a broader number of specificities to be evaluated in future studies with the same limited financial resources. REFERENCES 1. Salo PM, Arbes SJ, Jarameillo R, Calatroni A, Weir CH, Sever ML, et al. Prevalence of allergic sensitization in the United States: results from the National Health

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and Nutrition Examination Survey (NHANES) 2005-2006. J Allergy Clin Immunol 2014;133:XXX-XXX. Salo PM, Calatroni A, Gergen PJ, Hoppin JA, Sever ML, Jaramillo R, et al. Allergy-related outcomes in relation to serum IgE: results from the National Health and Nutrition Examination Survey 2005-2006. J Allergy Clin Immunol 2011;127: 1226-35. Bernstein IL, Li JT, Bernstein DI, Hamilton RG, Spector SL, Tan R, et al. Allergy diagnostic testing: an updated practice parameter. Ann Allergy Asthma Immunol 2008;100(suppl):S1-148. Hamilton RG. Laboratory tests for allergic and immunodeficiency diseases. In: Adkinson NF Jr, Bochner B, Burks W, Busse WW, Holgate ST, Lemanske RF Jr, editors. Middleton’s allergy: principles and practice. 8th ed. St Louis (MO): Elsevier; 2013. Linden CC, Misiak RT, Wegienka G, Havstad S, Ownby DR, Johnson CC, et al. Analysis of allergen specific IgE cut points to cat and dog in the Childhood Allergy Study. Ann Allergy Asthma Immunol 2011;106:153-8.