Endotyping Non–IgE-mediated Immunoreactivity to Polyethylene Glycol: Implications for Allergic Patients

Celso Eduardo Olivier *

Instituto Alergoimuno de Americana, Brazil.

Daiana Guedes Pinto

Instituto Alergoimuno de Americana, Brazil.

Ana Paula Monezzi Teixeira

Instituto Alergoimuno de Americana, Brazil.

Jhéssica Letícia Santos Santana

Instituto Alergoimuno de Americana, Brazil.

Raquel Acácia Pereira Gonçalves Santos

Instituto Alergoimuno de Americana, Brazil.

Regiane Patussi Santos Lima

Lavoisier’s Laboratories, Sao Paulo, Brazil.

*Author to whom correspondence should be addressed.


Abstract

Background: Several publications report polyethylene glycols (PEGs) and PEGylated therapeutics as responsible for non–IgE-mediated allergic reactions. There is no standardized lab exam that can endotype (quantify the participation of these mechanisms inside each patient’s pattern of symptoms) besides in vivo provocation tests.

Objective and Aim: To evaluate the Tube Titration of Precipitins (TTP) and the Leukocyte Adherence Inhibition Test (LAIT) to discriminate and endotype non–IgE-mediated immunoreactivity against a PEGs solution in patients with non–IgE-mediated allergic phenotypes.

Research Design and Research Protocol: To retrospectively examine the medical charts of two cohorts (with 100 patients each) diagnosed with non–IgE-mediated allergic rhinitis, allergic bronchitis, asthma, allergic sinus headache, atopic dermatitis, and/or urticaria who were investigated with the help of TTP or ex vivo challenge tests monitored by LAIT against PEGs.

Methodology: We identified the registered results of the semi-quantitative serum TTP against 1 mg/mL PEGs 4000 solution, which were distributed in ranges through a cascade distribution chart to outline the variability of the results inside the first cohort. The LAI done with the ex vivo challenges with 1 mg/mL PEGs 4000 solution were distributed in ranges through a cascade distribution chart The statistical characteristics of the two cohorts were calculated.

Results: The TTP showed a wide distribution range of results. The mean was estimated at 1:246; the median at 1:192; the standard deviation at 1:188. The LAIT showed a wide distribution range of results. The LAI ranged from 0% to 98%. The mean was 41.9%; the median was 45%; the standard deviation was 28.5%. The cascade distribution demonstrates a wide range of LAI results.

Conclusion: Some patients showed any or low immunoreactivity during the ex vivo challenge test, while most displayed moderate or strong immunoreactivity, which could reflect the participation of PEGs antibodies in a non–IgE-mediated hypersensitivity condition.

Keywords: Allergy, asthma, atopic dermatitis, bronchitis, COVID-19 vaccination, diagnosis, exposome-wide association study, endotype, hypersensitivity, leukocyte adherence inhibition test, macrogol, Non–IgE-mediated immunoreactivity, precision medicine, polyethylene glycol, E1521, rhinitis, sinus headache, urticaria


How to Cite

Olivier, Celso Eduardo, Daiana Guedes Pinto, Ana Paula Monezzi Teixeira, Jhéssica Letícia Santos Santana, Raquel Acácia Pereira Gonçalves Santos, and Regiane Patussi Santos Lima. 2024. “Endotyping Non–IgE-Mediated Immunoreactivity to Polyethylene Glycol: Implications for Allergic Patients”. Asian Journal of Immunology 7 (1):100-111. https://journalaji.com/index.php/AJI/article/view/135.


References

Ravve A. Principles of polymer chemistry - Third edition. Springer, New York. 2012;1.

Jang HJ, Shin CY, Kim KB. Safety Evaluation of polyethylene glycol (PEG) compounds for cosmetic use. Toxicol Res. 2015;31(2):105-36.

Expert Committee on Food Additives. Evaluation of certain food additives. Twenty-third Report of the Joint FAO/WHO In World Health Organization technical report series. Geneve. 1980; 648:17-18.

Younes M, Aggett P, Aguilar F, Crebelli R, Dusemund B, Filipič M, et al. Refined exposure assessment of polyethylene glycol (E 1521) from its use as a food additive. EFSA Journal. European Food Safety Authority. 2018;16(6):e05293.

Cox S, Sandall A, Smith L, Rossi M, Whelan K. Food additive emulsifiers: A review of their role in foods, legislation and classifications, presence in food supply, dietary exposure, and safety assessment. Nutr Rev. 2021:79(6):726-741.

Bancil AS, Sandall AM, Rossi M, Chassaing B, Lindsay JO, Whelan K. Food additive emulsifiers and their impact on gut microbiome, permeability, and inflammation: Mechanistic insights in inflammatory bowel disease. Journal of Crohn's & Colitis. 2021;15(6):1068-1079.

Olivier CE. Considering intestinal permeability and immune metabolism in the treatment of food allergies. Eur J Clin Med. 2022;3(3):13-18.

Castellanos IJ, Crespo R, Griebenow K. Poly(ethylene glycol) as stabilizer and emulsifying agent: A novel stabilization approach preventing aggregation and inactivation of proteins upon encapsulation in bioerodible polyester microspheres. J Controlled Release. 2003;88(1):135-45.

Jokerst JV, Lobovkina T, Zare RN, Gambhir SS. Nanoparticle PEGylation for imaging and therapy. Nanomedicine (London, England). 2011; 6(4):715-28.

Veronese FM, Mero A. The impact of PEGylation on biological therapies. BioDrugs. 2008;22(5):315-29.

Tenchov R, Sasso JM, Zhou QA. PEGylated lipid nanoparticle formulations: Immunological safety and efficiency perspective. Bioconjugate Chemistry. 2023;34(6):941-960.

Klibanov AL, Maruyama K, Torchilin VP, Huang L. Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes. FEBS Lett. 1990;268(1) :235-7.

Ibrahim M, Ramadan E, Elsadek NE, Emam SE, Shimizu T, Ando H, et al. Polyethylene glycol (PEG): The nature, immunogenicity, and role in the hypersensitivity of PEGylated products. J Controlled Release. 2022;351:215-230.

Koppen IJN, Broekaert IJ, Wilschanski M, Papadopoulou A, Ribes-Koninckx C, Thapar N, et al. Role of polyethylene glycol in the treatment of functional constipation in children. J Ped Gastroenterol Nutr. 2017;65(4):361-363.

Corazziari E, Badiali D, Bazzocchi G, Bassotti G, Roselli P, Mastropaolo G, et al. Long term efficacy, safety, and tolerability of low daily doses of isosmotic polyethylene glycol electrolyte balanced solution (PMF-100) in the treatment of functional chronic constipation. Gut. 2000; 46(4):522-6.

Expert Panel Cosmetic Ingredient Review. PEGs.

https://www.cir-safety.org/sites/default/files/115_final_pegs.pdf (accessed April 06, 2024).

Fruijtier-Pölloth C. Safety assessment on polyethylene glycols (PEGs) and their derivatives as used in cosmetic products. Toxicol. 2005;214(1-2):1-38.

Bruns DE, Herold DA, Rodeheaver GT, Edlich RF. Polyethylene glycol intoxication in burn patients. Burns Incl Therm Inj. 1982;9(1):49-52.

Inoue H, Yoshikawa H, Haraura H, Eguchi T, Kawano Y. Polyethylene glycol allergy caused by a diazepam suppository. Pediatr Int. 2023;65(1):e15402.

Caballero ML, Krantz MS, Quirce S, Phillips EJ, Stone-Jr CA. Hidden dangers: Recognizing excipients as potential causes of drug and vaccine hypersensitivity reactions. J Allergy Clin Immunol Pract. 2021;9(8):2968-2982.

Habran M, Vandebotermet M, Schrijvers R. Polyethylene glycol allergy and immediate-type hypersensitivity reaction to COVID-19 vaccination: Case report. J Investig Allergol Clin Immunol. 2022;32(3):234-235.

Cabanillas B, Akdis CA, Novak N. Allergic reactions to the first COVID- 19 vaccine: A potential role of polyethylene glycol? Allergy. 2021;76(6): 1617-1618.

Ieven T, Coorevits L, Vandebotermet M, Tuyls S, Vanneste H, Santy L, et al. Endotyping of IgE-mediated polyethylene glycol and/or polysorbate 80 allergy. J Allergy Clin Immunol Pract. 2023;11(10):3146-3160.

Shi D, Beasock D, Fessler A, Szebeni J, Ljubimova JY, Afonin KA, Dobrovolskaia MA. To PEGylate or not to PEGylate: Immunological properties of nanomedicine’s most popular component, polyethylene glycol and its alternatives. Advanced drug delivery reviews. 2022;180:114079.

Giavina-Bianchi P, Kalil J. Polyethylene glycol Is a cause of IgE-Mediated anaphylaxis. J Allergy Clin Immunol Pract. 2019:7(6):1874-1875.

Kelso JM. IgE-mediated allergy to polyethylene glycol (PEG) as a cause of anaphylaxis to mRNA COVID-19 vaccines. Clin Exp Allergy. 2022;52(1):10-11.

Brockow K, Mathes S, Fischer J, Volc S, Darsow U, Eberlein B. et al. Experience with polyethylene glycol allergy-guided risk management for COVID-19 vaccine anaphylaxis. Allergy. 2022:77(7):2200-2210.

Chiang V, Kan A, Yeung H, Au E, Lau CS, Li PH. Polyethylene glycol allergy: Risks of skin testing and complement-mediated anaphylaxis. J Investig Allergol Clin Immunol. 2023;33(1):71-73.

Olivier CE, Argentão DGP, Santos RAPG, Silva MD, Lima RPS, Zollner RL. Skin scrape test: an inexpensive and painless skin test for recognition of immediate hypersensitivity in children and adults. The Open Allergy Journal. 2013;6:9-17.

Zhou ZH, Stone-Jr CA, Jakubovic B, Phillips EJ, Sussman G, Park J, et al. Anti-PEG IgE in anaphylaxis associated with polyethylene glycol. J Allergy Clin Immunol Pract. 2021;9(4):1731-1733.e3.

Klimek L, Novak N, Cabanillas B, Jutel M, Bousquet J, Akdis CA. Allergenic components of the mRNA-1273 vaccine for COVID-19: Possible involvement of polyethylene glycol and IgG-mediated complement activation. Allergy. 2021;76(11):3307-3313.

Freire-Haddad H, Burke JA, Scott EA, Ameer GA. Clinical relevance of pre-existing and treatment-induced anti-poly (Ethylene Glycol) antibodies. Regener Engineer Transl Med. 2022; 8(1):32-42.

Gaballa SA, Shimizu T, Takata H, Ando H, Ibrahim M, Emam SE, et al. Impact of Anti-PEG IgM induced via the topical application of a cosmetic product containing PEG derivatives on the antitumor effects of pegylated liposomal antitumor drug formulations in mice. Mol Pharm. 2024; 21(2):622-632.

Ju Y, Lee WS, Pilkington EH, Kelly HG, Li S, Selva KJ, et al. Anti-PEG antibodies boosted in humans by SARS-CoV-2 lipid nanoparticle mRNA vaccine. ACS Nano. 2022;16(8):11769-11780.

Rogozina O, Ruiz-Fernández C, Martín-López S, Akatbach-Bousaid I, González-Muñoz M, Ramírez E. Organ-specific immune-mediated reactions to polyethylene glycol and polysorbate excipients: three case reports. Front Pharmacol. 2023;14:1293294.

Kuratsuji T. Studies on leukocyte adherence inhibition test. Part II. Clinical applications of LAI test to detect delayed type hypersensitivity in infants and children. Keio J Med. 1981;30(2):65-9.

Olivier CE, Pinto DG, Teixeira APM, Santana JLS, Santos RAPGS, Lima RPS, et al. Evaluating non-IgE-mediated allergens’ immunoreactivity in patients with “intrinsic” persistent rhinitis with help of the leukocyte adherence inhibition test. Eur J Med Health Sci. 2023;5(1):17-22.

Olivier CE, Pinto DG, Teixeira APM, Santana JLS, Santos RAPGS, Lima RPS, et al. Evaluating non-IgE-mediated allergens’ immunoreactivity in patients formerly classified as “intrinsic” asthmatics with help of the leukocyte adherence inhibition Test. Eur J Clin Med. 2023; 4(2):1-7.

Olivier CE, Pinto DG, Teixeira APM, Santana JLS, Santos RAPGS, Lima RPS, et al. Contribution of the leukocyte adherence inhibition test to the diagnosis of innate Non–IgE-mediated Immunoreactivity against Alternaria alternata. Asian J Immunol 2023;6(1):243-251.

Olivier CE, Pinto DG, Teixeira APM, Santana JLS, Santos RAPGS, Lima RPS. Contribution of the leukocyte adherence inhibition test to the diagnosis of innate non–IgE-mediated immunoreactivity against saccharomyces cerevisiae. Asian J Immunol. 2023;6(1):234-241.

Olivier CE, Pinto DG, Teixeira APM, Santana JLS, Santos RAPGS, Lima RPS, et al. Contribution of the leukocyte adherence inhibition test to the diagnosis of non–IgE-mediated Immunoreactivity against Candida albicans in Patients with Atopic Dermatitis. Asian J Immunol. 2023;6(1):268-276.

Olivier CE, Pinto DG, Teixeira APM, Santana JLS, Santos RAPGS, Lima RPS, et al. Contribution of the leukocyte adherence inhibition test in diagnosing non–IgE-mediated immunoreactivity against Aspergillus fumigatus in patients with allergic rhinitis and asthma. Asian J Immunol. 2024;7(1):12-20.

Olivier CE, Lima RPS, Pinto DG, Santos RAPG, Silva GKM, Lorena SLS, et al. In search of a tolerance-induction strategy for cow’s milk allergies: significant reduction of beta-lactoglobulin allergenicity via transglutaminase/cysteine polymerization. Clinics. 2012;67(10):1171-1179.

Olivier CE, Santos RAPG, Lima RPS, Argentão DGP, Silva GKM, Silva MD. A novel utility for an old method: The leukocyte adherence inhibition test Is an easy way to detect the immunoreactive interference of the collection tube anticoagulant on cellular immunoassays. Journal of Cell Adhesion; 2014; Article ID 860427 (http://dx.doi.org/10.1155/2014/860427):1-6.

Olivier CE, Pinto DG, Lima RPS, Silva MD, Santos RAPG, Teixeira APM, et al. Assessment of immunoreactivity against therapeutic options employing the leukocyte adherence inhibition test as a tool for precision medicine. Eur J Clin Med. 2021;2(3):40-45.

Olivier CE, Pinto DG, Santos RAPG, Lima RPS. Dextran’s interference over the leukocyte adherence inhibition test. Academia Letter. 2021; article number 3792.

Olivier CE, Pinto DG, Teixeira APM, Santana JLS, Santos RAPGS, Lima RPS. Immunoreactivity against dermatophagoides pteronyssinus assessed by the leukocyte adherence inhibition test in patients with intrinsic atopic dermatitis and correlated “Intrinsic” Non–IgE-mediated allergic conditions. Eur J Clin Med. 2021;2(6):45-50.

Olivier CE, Pinto DG, Teixeira APM, Santana JLS, Santos RAPGS, Lima RPS. Contribution of the leukocyte adherence inhibition test to the evaluation of cellular immunoreactivity against latex extracts for Non—IgE-Mediated Latex-Fruit-Pollen syndrome in allergic candidates to exclusion diets and allergic desensitization. Eur J Clin Med. 2022; 3(1):11-17.

Olivier CE, Pinto DG, Teixeira APM, Santana JLS, Santos RAPGS, Lima RPS. Contribution of the leukocyte adherence inhibition test for the evaluation of immunoreactivity against gluten extracts in non—IgE-mediated / non-autoimmune Gluten-Related Disorders. Eur J Clin Med. 2022;3(2):1-7.

Olivier CE, Pinto DG, Teixeira APM, Santana JLS, Santos RAPGS, Lima RPS. Leukocyte adherence inhibition test to the assessment of immunoreactivity against cow’s milk proteins in Non—IgE-mediated gastrointestinal food allergy. Eur J Clin Med. 2022;3(2):38-43.

Olivier CE, Pinto DG, Teixeira APM, Santana JLS, Santos RAPGS, Lima RPS. Contribution of the leukocyte adherence inhibition test to the diagnosis of immunoreactivity against cobalt. Asian J Immunol. 2023;6(1):174-184.

Olivier CE, Pinto DG, Teixeira APM, Santana JLS, Santos RAPGS, Lima RPS. Intrinsic atopic dermatitis: Titration of precipitins in the screening of food allergens for prescription of elimination diets and desensitization strategies. Eur J Clin Med. 2021.2(6):1-9.

Williams CA, Chase MW. CHAPTER 13 - Precipitation reactions. In reactions of antibodies with soluble antigens, Academic Press. 1971;3:1-102.

Bruusgaard-Mouritsen MA, Johansen JD, Garvey LH. Clinical manifestations and impact on daily life of allergy to polyethylene glycol (PEG) in ten patients. Clin Exp Allergy. 2021;51(3):463-470.

Hicks ED, Hall G, Hershfield MS, Tarrant TK, Bali P, Sleasman JW, et al. Treatment with elapegademase restores immunity in infants with adenosine deaminase deficient severe combined immunodeficiency. J Clin Immunol. 2024; 44(5):107.

Bento C, Katz M, Santos MMM, Afonso CAM. Striving for uniformity: A review on advances and challenges To achieve uniform polyethylene glycol. Org Process Res Develop. 2024;28(4):860-890.

Kayode OS, Nakonechna A, Siew LQC, Dziadzio M, Kennard L, Rutkowski K, et al. Polyethylene glycol hypersensitivity, patient outcomes in a 7-year retrospective study. Ann Allergy Asthma Immunol. Published online March 30, 2024.

DOI: 10.1016/j.anai.2024.03.022.

Perkins G, Troelnikov A, Hissaria P. Reply. J Allergy Clin Immunol. 2021; 148(3):902-903.

Lisiecka MZ. Polyethylene glycol and immunology: Aspects of allergic reactions and their mechanisms, as well as ways to prevent them in clinical practice. Immunol Res. Published online March 19, 2024.

DOI: 10.1007/s12026-024-09473-w

Eberlein B, Mathes S, Darsow U, Biedermann T, Brockow K. Allergy to PEG (polyethylene glycol) - sensitivity of basophil activation test with COVID-19 mRNA-vaccine BNT162B2. Hum Vaccin Immunother. 2024;20(1):2312600.

Perkins GB, Tunbridge MJ, Hurtado PR, Zuiani J, Mhatre S, Yip KH, et al. PEGylated liposomes for diagnosis of polyethylene glycol allergy. J Allergy Clin Immunol. Published online May 6, 2024.

DOI: 10.1016/j.jaci.2024.03.030

Tuttle KL, Lynch DM, Marquis K, Besz KM, Matulonis UA, Castells MC. Phenotypes of hypersensitivity reactions to pegylated liposomal doxorubicin: Safety and efficacy of 128 rapid desensitizations. J Allergy Clin Immunol Pract. 2024;12(5):1348-1350.e2.

Wells HG. Studies on the chemistry of anaphylaxis (III). Experiments with isolated proteins, especially those of the hen’s egg. J Infec Diseases. 1911;9:147-171.

Gell PGH, Harington CR, Rivers RP. The antigenic function of simple chemical compounds; production of precipitins in rabbits. Briti J Exp Pathol. 1946;27(5):267-286.

Olivier CE, Lima RPS, Pinto DG, Santos RAPG. The Plasma preincubation with papain before the assay suggests that a gell and coombs type II reaction is been demonstrated by the leukocyte adherence inhibition test. Biomed J Sci Techn Res. 2021;36(3):28647-28655.

Thomson DMP. Assessment of immune status by the leukocyte adherence inhibition test. Academic Press: New York, 1982;17,380 p.

Tong AW, Burger DR, Finke P, Barney C, Vandenbark AA, Vetto RM. Assessment of the mechanism of the leukocyte adherence inhibition test. Cancer Res. 1979;39(2 Pt 2):597-603.

Fink A, Heller L, Eliraz A, Weisman Z, Miskin A, Schlezinger M, et al. Allergen-specific leukocyte adherence inhibition (LAI) assay: Sensitivity, specificity and mechanism. Immunol Lett. 1987;16(1):65-70.

Halliday WJ, Maluish A, Miller S. Blocking and unblocking of cell-mediated anti-tumor immunity in mice, as detected by the leucocyte adherence inhibition test. Cell Immunol. 1974;10(3):467-475.

Chung MK, House JS, Akhtari FS, Makris KC, Langston MA, Islam KT, et al. Decoding the exposome: Data science methodologies and implications in exposome-wide association studies (ExWASs). Exposome. 2024;4(1): osae001.

Olivier CE, Pinto DG, Teixeira APM, Santana JLS, Santos RAPG, Lima RPS. Exploring the role of leukocyte adherence inhibition test in assessing Non-IgE mediated immunoreactivity to benzoic acid in allergic patients. Asian J Immunol; 2024;7(1):63-70.

Anouar S, Hazim R, Brahim A. Interferences in immunological assays: Causes, detection, and prevention. Asian J Immunol. 2024;7(1):71-78.

Chiarentin L, Gonçalves C, Augusto C, Miranda M, Cardoso C, Vitorino C. Drilling into “quality by design” approach for analytical methods. Crit Rev Analytical Chem. 2023;1-42.

World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects. JAMA. 2013;310(20): 2191-4.