Reference values of serum total IgE in Uppsala – comparison over four decades
Abstract
Background: Total immunoglobulin E (IgE) analysis is a common tool in allergy diagnosis. Suggested reference values for IgE are divergent and sometimes based on outdated assay methods. We aimed to validate the published reference values (geometric mean [GM]: 13.2 kU/L, upper limit of normal [ULN], 114 kU/L) shown in an Uppsala cohort from 1974 using Phadebas IgE PRIST, and the suggested clinical threshold of 100 kU/L (Zetterström and Johansson 1981).
Methods: Immunoglobulin E was measured in two Uppsala cohorts from 1997 (Blood bank) and 2011 to 2013 (the European community respiratory health survey part III [ECRHS III]) using ImmunoCAP™ Total IgE. For the reference value calculations, exclusion criteria were atopy (both cohorts), doctor’s diagnosis of asthma and self-reported allergy (hay fever, rhinitis, rash) (only ECRHS III). Upper limit of normal was defined as mean + 2 standard deviations (SD) calculated using log-transformed values and back-transformation of the ULN prior to presentation. Common imputation methods for results below the assay range were evaluated.
Results: The average GM was 14.2 kU/L (Blood bank, n = 63; imputation method range: 16.9–17.4 kU/L; ECRHS III, n = 113: 10.7–11.6 kU/L) and the overall mean ULN was 118 kU/L (Blood bank: 113–130 kU/L; ECRHS III: 104–128 kU/L). The clinical sensitivity and specificity of the 100 kU/L IgE threshold were 37.8 and 94.3% for atopy, 34.9 and 89.5% for doctor’s diagnosis of asthma, and 24.5 and 97.3% for any self-reported allergy (ECRHS III).
Conclusion: The calculated ULN values were similar between the cohorts. We conclude that the total IgE reference values shown for Uppsala subjects from 1974 are still valid and suitable also for the ImmunoCAP Total IgE assay. The 100 kU/L threshold for total IgE had a low sensitivity but high specificity for atopy, asthma, and allergy.
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References
2. Gergen PJ, Arbes SJ Jr, Calatroni A, Mitchell HE, Zeldin DC. Total IgE levels and asthma prevalence in the US population: results from the National Health and Nutrition Examination Survey 2005–2006. J Allergy Clin Immunol 2009;124:447–53. doi: 10.1016/j.jaci.2009.06.011
3. 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 e7. doi: 10.1016/j.jaci.2010.12.1106
4. Kerkhof M, Dubois AE, Postma DS, Schouten JP, de Monchy JG. Role and interpretation of total serum IgE measurements in the diagnosis of allergic airway disease in adults. Allergy 2003;58:905–11. doi: 10.1034/j.1398-9995.2003.00230.x
5. Carosso A, Bugiani M, Migliore E, Anto JM, DeMarco R. Reference values of total serum IgE and their significance in the diagnosis of allergy in young European adults. Int Arch Allergy Immunol 2007;142:230–8. doi: 10.1159/000097025
6. Eriksson NE. Allergy screening with Phadiatop and CAP Phadiatop in combination with a questionnaire in adults with asthma and rhinitis. Allergy 1990;45:285–92. doi: 10.1111/j.1398-9995.1990.tb00497.x
7. Erb KJ. Helminths, allergic disorders and IgE-mediated immune responses: where do we stand? Eur J Immunol 2007;37:1170–3. doi: 10.1002/eji.200737314
8. Mulu A, Anagaw B, Gelaw A, Ota F, Kassu A, Yifru S. Effect of deworming on Th2 immune response during HIV-helminths co-infection. J Transl Med 2015;13:236. doi: 10.1186/s12967-015-0600-3
9. Mogensen TH. STAT3 and the Hyper-IgE syndrome: clinical presentation, genetic origin, pathogenesis, novel findings and remaining uncertainties. JAKSTAT 2013;2:e23435. doi: 10.4161/jkst.23435
10. Kjellman NM, Johansson SG, Roth A. Serum IgE levels in healthy children quantified by a sandwich technique (PRIST). Clin Allergy 1976;6:51–59. doi: 10.1111/j.1365-2222.1976.tb01411.x
11. Alcocer M, Yman L. Allergy. In: Wild D, ed. The immunoassay handbook. 4th ed. Oxford: Elsevier; 2013, pp. 857–67.
12. Martins TB, Bandhauer ME, Bunker AM, Roberts WL, Hill HR. New childhood and adult reference intervals for total IgE. J Allergy Clin Immunol 2014;133:589–91. doi: 10.1016/j.jaci.2013.08.037
13. Patelis A, Gunnbjornsdottir M, Alving K, Borres MP, Hogman M, Janson C, et al. Allergen extract vs. component sensitization and airway inflammation, responsiveness and new-onset respiratory disease. Clin Exp Allergy 2016;46:730–40. doi: 10.1111/cea.12607
14. Hornung RW, Reed LD. Estimation of average concentration in the presence of nondetectable values. Appl Occup Environ Hyg 1990;5:46–51. doi: 10.1080/1047322X.1990.10389587
15. Richardson DB, Ciampi A. Effects of exposure measurement error when an exposure variable is constrained by a lower limit. Am J Epidemiol 2003;157:355–63. doi: 10.1093/aje/kwf217
16. Vinnes EW, Skarbo B, Wentzel-Larsen T, Sylte MS, Apelseth TO. Updated total IgE reference intervals in Norwegian adults. Immun Inflamm Dis 2023;11:e751. doi: 10.1002/iid3.751
17. Ansotegui IJ, Melioli G, Canonica GW, Caraballo L, Villa E, Ebisawa M, et al. IgE allergy diagnostics and other relevant tests in allergy, a World Allergy Organization position paper. World Allergy Organ J 2020; 13:100080. doi: 10.1016/j.waojou.2019.100080
18. Rowe DS, Tackett L, Bennich H, Ishizaka K, Johansson SG, Anderson SG. A research standard for human serum immunoglobulin E. Bull World Health Organ 1970;43:609–11.
19. Seagroatt V, Anderson SG. The second international reference preparation for human serum immunoglobulin E and the first British standard for human serum immunoglobulin E. J Biol Stand 1981;9:431–7. doi: 10.1016/s0092-1157(81)80034-0
20. Kerkhof M, Droste JH, de Monchy JG, Schouten JP, Rijcken B. Distribution of total serum IgE and specific IgE to common aeroallergens by sex and age, and their relationship to each other in a random sample of the Dutch general population aged 20–70 years. Allergy 1996;51:770–6. doi: 10.1111/j.1398-9995.1996.tb00021.x
21. Amaral AF, Newson RB, Abramson MJ, Anto JM, Bono R, Corsico AG, et al. Changes in IgE sensitization and total IgE levels over 20 years of follow-up. J Allergy Clin Immunol 2016;137:1788–95 e9. doi: 10.1016/j.jaci.2015.09.037
22. Burney P, Malmberg E, Chinn S, Jarvis D, Luczynska C, Lai E. The distribution of total and specific serum IgE in the European Community Respiratory Health Survey. J Allergy Clin Immunol 1997;99:314–22. doi: 10.1016/s0091-6749(97)70048-4
23. CLSI. Defining, establishing, and verifying reference intervals in the clinical laboratory; Approved guideline.– 3rd ed. CLSI document C28-A3c. Wayne, PA: Clinical and Laboratory Standards Institute; 2010.
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