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Insulin allergy can be successfully managed by a systematic approach

Insulin allergy can be successfully managed by a systematic approach Background: Type I insulin allergy can be a challenging condition, and there is no international consensus on how to establish the diagnosis. Measurement of specific IgE and skin testing have been cornerstones in the diagnostic work‑ up. However, these tests have limitations, mainly lack of correlation between test results and clinical findings. At the Allergy Centre, Odense University Hospital, patients with suspected insulin allergy have been evaluated since 2003. The aim of this study was to establish a systematic approach to diagnose and treat patients with insulin allergy. Methods: The study was conducted retrospectively by retrieving data from the Allergy Centre database on patients with suspected insulin allergy evaluated from 2003 to 2017. The examination comprised a comprehensive medical history, specific IgE against insulin and intracutaneous tests (ICT ) with different insulins. Results: A total of 144 patients were examined on suspicion of insulin allergy of which 110 had negative specific IgE in serum. Of the remaining 34 patients, 33 had ICT performed; 2 had negative ICTs, while 31 had one or more posi‑ tive ICT. All 34 patients had mild symptoms, and 4 could obtain symptom relief with antihistamines or local steroids, 9 could be managed with oral antidiabetics, and 7 were switched to other insulins. The final 14 patients were offered an insulin pump because of reactions to many different insulins, many positive ICTs, unmanageable diabetes, young age and compliance, or convenience. Conclusion: Insulin allergy can be managed by a systematic approach, and symptom relief is obtainable in most patients. Keywords: Insulin, Allergy, IgE, Intracutaneous test Background questionable for a number of reasons including false-neg- Insulin allergy affects 0.1–3% of insulin-treated diabetics ative tests, and non-specific reactions as well as reactions [1, 2] and causes symptoms ranging from localized itch- to additives (e.g. protamine sulfate) [3, 5, 6, 8–10]. Meas- ing and rash to life-threatening anaphylaxis [3–5]. The urement of specific IgE (sIgE) is another cornerstone in IgE-mediated (type I) reaction is by far the most com- the diagnosis, but this method has limitations as well, mon, but type III and type IV reactions have been mainly due to poor correlation between clinical findings reported as well [1, 6–9]. and elevated IgE levels [3, 6]. Consequently, there is no The diagnosis is based on past and present symptoms consensus on the correct method for diagnosing insulin and signs, together with skin tests and specific immu - allergy yet, though one was suggested by Jacquier et  al. noglobulin E (IgE) measurement in serum. Skin prick in 2013 [11], based on three patient cases. The authors test (SPT) and intracutaneous test (ICT) have tradition- suggested the use of measurement of total IgE, insulin- specific IgE, and anti-insulin antibodies (IgG) in addition ally been used in the evaluation of these patients. How- to SPT or ICT. ever, the reliability of the results from skin tests has been The treatment of insulin allergy is often straightfor ward. For many patients it is possible to switch insulin *Correspondence: mhaastrup@health.sdu.dk preparation or to avoid insulin use by managing their dia- Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark betes through diet or oral antidiabetics and/or injections Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Haastrup et al. Clin Transl Allergy (2018) 8:35 Page 2 of 6 with glucagon-like peptide 1 (GLP1) analogue treatment. detemir (Levemir ). Most recently, the following addi- ® ® Some patients, however, are insulin dependent and expe- tions have been made to the panel: T oujeo, Abasaglar rience symptoms during treatment with many different (both insulin glargine), Tresiba (insulin deglucec), insulins. These patients are difficult to treat and require NovoMix (insulin aspart with added protamine), and a more comprehensive approach, sometimes including Apidra (insulin glulisine). desensitization [3, 9, 12]. SPT with insulin was initially a part of the examination At the Allergy Centre at Odense University Hospital but was abandoned due to the poor sensitivity and speci- patients with insulin allergy have been diagnosed and ficity of the test. Basophil histamine release (HR test) was treated since 2003. The aim of the present study was to performed in a few patients but not systematically. Con- summarize the diagnostic findings and to present a sys - sequently, the results of SPT and HR test are omitted. tematic approach for the examination and treatment of The patients—or in the case of children, their parents— these patients. gave informed consent to store their data in the ACbase. All data for this study were collected after approval from the Danish Data Protection Agency (17/11270). Methods This study was conducted retrospectively and included data from the Allergy Centre database, ACbase, on Results patients seen at the Odense Research Center for Ana- A flow chart of the protocol for the examination of sus - phylaxis (ORCA), Allergy Centre at Odense University pected insulin allergy is presented in Fig. 1. Hospital from 2003 through March 2017 with suspi- A total of 144 patients with suspected insulin allergy cion of insulin allergy. Since 2010 the Allergy Centre in were seen at the Allergy Centre, Odense University Hos- Odense has been the only place in Denmark to evaluate pital, from 2003 through March 2017. Of these, 34 had patients suspected of insulin allergy in collaboration with positive sIgE for insulin and were included in the study the Department of Endocrinology, Odense University while 110 had negative sIgE for insulin and were judged Hospital. non-allergic (type I). Among those deemed non-allergic The examination comprised a comprehensive medical 71 had an ICT performed with 12 having one or more history (type of diabetes, duration and severity of symp- positive ICTs. Another 5 were positive to protamine sul- toms, prior treatment etc.), measurement of specific IgE fate but none of the included insulins. ICTs were per- against human, bovine, and porcine insulin and—where formed in these patients before the results of the IgE appropriate—also ICT with different insulins. measurements were available. A positive ICT in a patient Specific IgE measurement (ImmunoCAP) against with a negative IgE may be an unspecific reaction, a reac - human, bovine and porcine insulin was performed by tion to an additive, or a delayed reaction reflecting a type Thermo Fisher, Uppsala Sweden. Values above 0.35 kIU/L IV allergy. were considered positive. The 34 patients with positive sIgE were categorised Intracutaneous tests were performed by injecting according to symptom severity. All 34 patients had local 20–50  µL of the different insulins in the concentration symptoms only (pruritus, nodules, localised dermati- 5  IE/mL, and reactions were considered positive if the tis and infiltration at injection sites). Patients, whose wheal size diameter was 3 mm larger than the initial bleb. symptoms could be alleviated by antihistamines or local ICTs were read after 20 min, according to guidelines from steroids (n = 4), and patients, who could be managed by the European Network on Drug Allergy (ENDA) [13]. As other antidiabetic medications than insulin (n = 9), were controls, skin prick tests were performed with histamine treated accordingly. 10  mg/mL (ALK-Abello, Denmark) as the positive con- In 33 of the 34 patients with positive sIgE, ICT was per- trol and isotonic NaCl as the negative control. formed. One was not tested due to age (12 years). Two of The insulins available for the test varied over time, and the 33 patients exhibited negative ICTs, however one of some of the first patients seen (n = 3) were only tested the two was only tested for one specific insulin prepara - with a selection of the available insulin types, based on tion (Apidra ) due to age (9 years). the clinician’s judgment. The majority, however, were The demographics and test results of the 21 insulin tested with the full panel of insulins, which included dependent patients with positive sIgE are presented in rapid acting human insulin (Humulin Re gular , Insuman ® ® Table  1 (data not shown for the remaining 13 patients Rapid, Actrapid ), rapid acting analogue insulin lispro ® ® because the symptoms of these patients could be man- (Humalog ), and insulin aspart (NovoRapid ), and inter- aged without insulin). Of the 20 patients tested with ICTs mediate acting isophane human insulin (Humulin N PH , 19 were ICT-positive for at least one insulin preparation Insulatard , both containing protamine), and long acting (range 1–9). The ICT-negative patient was the 9-year old analogue insulin: Insulin glargine (L antus ), and insulin Haastrup et al. Clin Transl Allergy (2018) 8:35 Page 3 of 6 Paents suspected of insulin allergy (n = 144) No (n = 110) Posive IgE? Not type I allergy Yes (n = 34) No (n = 4) No change in treatment, Severe symptoms? symptom relief if necessary Yes (n = 30) No (n = 9) Need of insulin? Oral andiabecs Yes (n = 21) Change of insulin Yes (n = 7) possible? No (n = 14) Insulin pump Change of insulin • ≥7 positive ICTs • Changed prior to examination, well (n = 7) tolerated (n = 4) • History of reactions to many • Changed based on insulins(n = 3) ICT results (n = 2) • Unmanageable • Changed despite diabetes (n = 1) positive ICT, well tolerated (n = 1) • Young age, compliance (n = 2) • Convenience (n = None had other atopic 1) manifestations/drug allergy. Eight of 14 had other atopic manifestations/drug allergy. Fig. 1 Flow chart of the procotol for examination of suspected insulin allergy girl, who was only tested for one insulin preparation by Where possible (n = 7), a switch was made to another ICT. insulin preparation. Of these 7 patients, a well-toler- In the 21 insulin dependent patients a change in treat- ated switch had already been made prior to evaluation ment regimen was necessary due to symptom severity. at the Allergy Centre in 4, and consequently, no further Haastrup et al. Clin Transl Allergy (2018) 8:35 Page 4 of 6 Table 1 Demographics and test results ID Sex Age DM type sIgE ICT Porcine Bovine Human A B C D E F G H I J 1 F 60 II 2.1 1.3 1.6 – + – – – – – – – N/D 2 F 55 II 0.6 0.4 0.5 + N/A N/A N/A N/A N/A N/A + + N/D 3 F 14 I 2.6 2.0 1.9 + + – – + + N/D + + N/D 4 F 59 II 7.1 5.9 6.2 + + + + + + + N/D N/D N/D 5 F 41 II 1.5 1.1 1.8 + + + + + + + + + N/D 6 M 55 II 22.8 18.5 22.8 + + + + + + + + + N/D 7 M 67 II 0.6 0.4 0.5 + + + + + + + + – N/D 8 F 47 II 8.9 7.9 7.7 + + + + + + + N/D – N/D 9 M 37 II 0.4 < 0.35 0.4 – + – – – – – – + N/D 10 F 36 I 1.3 1.0 1.0 – – – – – – + – – N/D 11 F 37 II 1.7 1.3 1.6 + + + + + + + + + N/D 12 F 12 I 0.4 < 0.35 < 0.35 N/D N/D N/D N/D N/D N/D N/D N/D N/D N/D 13 F 9 I 0.5 < 0.35 0.4 N/D N/D N/D N/D N/D N/D N/D N/D N/D – 14 F 54 I 0.1 < 0.35 0.4 – – N/D – – – – + – N/D 15 F 64 I 2.9 2.4 2.7 + + + N/A N/A N/A N/A + + N/D 16 F 46 II 2.5 2.2 2.2 + + + N/D N/D N/D N/D + N/D N/D 17 M 56 II 2.4 2.1 1.8 + + + + + + + + + N/D 18 M 55 I 0.4 < 0.35 0.4 – – – – – – + – – N/D 19 M 30 I 3.4 2.5 2.2 + + + – – + + – + N/D 20 M 57 I 0.6 0.6 0.7 + – + – + – – – – N/D 21 M 79 II 15.0 15.2 13.2 N/D + – + + + + + + N/D Patients 1–14 were given an insulin pump, 15–21 changed insulin preparation. All symptoms were local. N/A result not available in the database, N/D not done. IgE > 0.35 was considered positive A humulin regular, B insuman rapid, C actrapid, D humulin NPH, E insulatard, F lantus, G levemir, H novorapid, I humalog, J apidra treatment adjustment was needed. Two were success- Table 2 Comparison of  patient characteristics and  test fully switched to a different insulin, based on negative results between the two groups ICT. The last patient in this group was switched to an Insulin pump (n = 14) Other insulin (n = 7) insulin despite a positive ICT for this particular insulin. The switch, however, was well-tolerated. Sex (M:F) 3:11 5:2 The final group of patients (n = 14) was offered treat - Age (years) 41.6 (9–67) 55.3 (30–79) ment with an insulin pump in collaboration with the Diabetes type (I:II) 4:10 4:3 Department of Endocrinology, Odense University Hos- Other atopic manifesta‑ 8:6 0:7 pital. Seven of these patients exhibited ≥ 7 positive tions/drug allergy (Y:N) ICTs. Three additional patients had histories of reac - No. of positive ICTs 5.9 (0–9) 5 (1–9) tions to many different insulins. One patient’s diabetes IgE (kIU/L) 4.07 (0.4–22.8) 3.31 (0.4–13.2) was unmanageable, two were offered an insulin pump human IgE (kIU/L) 4.76 (0.4–18.5) 4.17 (0.6–15.2) because of young age and compliance and one due to bovine IgE (kIU/L) 3.64 (0.4–22.8) 3.89 (0.4–15.0) convenience. porcine Of the 14 patients given an insulin pump, eight had Overview of sex distribution and type I/type II diabetes ratio, average age, sIgE (human, bovine and porcine) and number of positive ICTs (range). Other atopic other atopic manifestations or drug allergy (challenge- manifestations/drug allergy: Two patients had challenge-proven penicillin verified penicillin allergy, atopic dermatitis, asthma, allergy, 2 asthma, 2 hay fever, 1 urticaria and 1 atopic dermatitis and contact allergy. Only positive sIgE values are included hay fever, contact allergy, and urticaria). None of the 7 patients, whose insulins were changed, had other atopic manifestations/other drug allergies. The groups did not Discussion differ with regards to age, sex, diabetes type, sIgE levels The majority of the published literature concerning insu - or number of positive ICTs, see Table 2. lin allergy has been case reports or small case series. This study is the largest of its kind so far. Haastrup et al. Clin Transl Allergy (2018) 8:35 Page 5 of 6 Abbreviations Of a total of 144 patients suspected of insulin allergy ENDA: European Network on Drug Allergy; ICT: intracutaneous test; IgE: immu‑ only 34 (24%) had positive sIgE, which is comparable to a noglobulin E; ORCA : Odense Research Center for Anaphylaxis; sIgE: specific study by Bodtger and Wittrup from 2005 [14], where the IgE; SPT: skin prick test. diagnosis was established in 9 of 22 patients (41%). The Authors’ contributions diagnostic work-up in this study consisted, however, only MBH analysed the patient data. MBH, CGM, and CBJ interpreted the patient of intracutaneous testing. data. All authors were major contributors in writing the manuscript. All authors read and approved the final manuscript. We focused mainly on specific IgE measurement for the diagnosis of insulin allergy, because this in  vitro test Author details has a high negative predictive value [10, 15], whereas ele- Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark. Steno Diabetes Center Odense, Odense Uni‑ vated levels are not necessarily indicative of allergy and versity Hospital, Odense, Denmark. Odense Research Center for Anaphylaxis are thus of limited value without a thorough medical his- (ORCA), Department of Dermatology and Allergy Centre, Odense University tory and supplementary skin testing [9, 16]. Hospital, Odense, Denmark. Skin tests, particularly SPT, have poor sensitivity but Acknowledgements high specificity, and the negative predictive value of ICT The authors would like to thank Ulla Johannessen and Esben Eller for assis‑ is high [5, 9, 15]. These tests can be helpful in distinguish - tance in retrieving data from the database. ing between insulins with and without the capability of Competing interests causing clinical reactions when choosing future treat- The authors declare that they have no competing interests. ment for a given patient. Availability of data and materials A total of 13 of the 34 patients (38%) with an insulin The datasets used during the current study are available from the correspond‑ allergy diagnosis in our study could be managed without ing author on reasonable request. a change in treatment or with oral antidiabetics. Another Consent for publication 7 were switched to a different insulin preparation, and The patients—or in the case of children, their parents—gave informed the final 14 were desensitised with continuous subcuta - consent to store their data in the ACbase for use in future research in allergic neous infusions through an insulin pump. This has been diseases after approval of the Danish Data Protection Agency. described in several reports as an option for patients Ethics approval and content to participate with an indispensable need for insulin who cannot be The patients—or in the case of children, their parents—gave informed managed by switching to another insulin preparation [8, consent to store their data in the ACbase (License No. 2008‑58‑0035). All data for this study were collected after approval from the Danish Data Protection 17–22]. Agency (17/11270). The most recent addition to the treatment options for these patients is omalizumab. This has been successful Funding No funding was supplied for this study. in two of three case reports so far and may represent an interesting alternative for patients whose symptoms can- Publisher’s Note not otherwise be managed [23–25]. Springer Nature remains neutral with regard to jurisdictional claims in pub‑ None of the patients in the present study had a history lished maps and institutional affiliations. of systemic reactions to insulin. Therefore, other treat - Received: 13 June 2018 Accepted: 22 August 2018 ment options than desensitization were chosen whenever possible. An insulin desensitization was mainly per- formed in those with many positive ICTs and a history of reactions to many different insulin preparations. In case References of a history of anaphylaxis in insulin dependent patients, 1. Radermecker RP, Scheen AJ. Allergy reactions to insulin: effects of con‑ desensitization should always be performed. tinuous subcutaneous insulin infusion and insulin analogues. Diabetes Metab Res Rev. 2007;23(5):348–55. Type 2 diabetics potentially represent a twofold chal- 2. Fineberg SE, Huang J, Brunelle R, Gulliya KS, Anderson JH Jr. Eec ff t of lenge given that their endogenous insulin production long‑term exposure to insulin lispro on the induction of antibody decreases with time which most likely will cause a return response in patients with type 1 or type 2 diabetes. Diabetes Care. 2003;26(1):89–96. of the symptoms of insulin allergy, when the patients can 3. Heinzerling L, Raile K, Rochlitz H, Zuberbier T, Worm M. Insulin no longer be managed with oral antidiabetics. allergy: clinical manifestations and management strategies. Allergy. 2008;63(2):148–55. 4. Borch JE, Andersen KE, Bindslev‑ Jensen C. Cutaneous adverse drug reactions seen at a university hospital department of dermatology. Acta Conclusion Derm Venereol. 2006;86(6):523–7. Insulin allergy is a challenging condition, but can most 5. Lee AY, Chey WY, Choi J, Jeon JS. Insulin‑induced drug eruptions and reli‑ ability of skin tests. Acta Derm Venereol. 2002;82(2):114–7. often be managed by a systematic approach, and symp- 6. deShazo RD, Mather P, Grant W, Carrington D, Frentz JM, Lueg M, Lauri‑ tom relief is obtainable in most if not all patients. tano AA, Falholt K. Evaluation of patients with local reactions to insulin with skin tests and in vitro techniques. Diabetes Care. 1987;10(3):330–6. Haastrup et al. Clin Transl Allergy (2018) 8:35 Page 6 of 6 7. Wittrup M, Pildal J, Rasmussen AK, Skov BG, Petersen J, Mandrup‑ 18. Pratt EJ, Miles P, Kerr D. Localized insulin allergy treated with continuous Poulsen TR. Systemic and local allergy to human insulin. Ugeskr Laeger. subcutaneous insulin. Diabet Med. 2001;18(6):515–6. 2003;165(21):2207–8. 19. Sola‑ Gazagnes A, Pecquet C, Radermecker R, Piétri L, Elgrably F, Slama 8. Ghazavi MK, Johnston GA. Insulin allergy. Clin Dermatol. 2011;29(3):300–5. G, Sélam JL. Successful treatment of insulin allergy in a type 1 diabetic 9. Akinci B, Yener S, Bayraktar F, Yesil S. Allergic reactions to human insulin: patient by means of constant subcutaneous pump infusion of insulin. a review of current knowledge and treatment options. Endocrine. Diabetes Care. 2003;26(10):2961–2. 2010;37(1):33–9. 20. Matheu V, Perez E, Hernández M, Díaz E, Darias R, González A, García JC, 10. Brockow K, et al. Skin test concentrations for systemically administered Sánchez I, Feliciano L, Caballero A, de la Torre F. Insulin allergy and resist‑ drugs—an ENDA/EAACI Drug Allergy Interest Group position paper. ance successfully treated by desensitisation with Aspart insulin. Clin Mol Allergy. 2013;68(6):702–12. Allergy. 2005;23(3):16. 11. Jacquier J, Chik CL, Senior PA. A practical, clinical approach to the 21. Zhang L, Zhang M, Liu YY, Hu M, Zhou X, Luo Y. Successful treatment with assessment and management of suspected insulin allergy. Diabet Med. continuous subcutaneous insulin infusion for allergy to human insulin 2013;30(8):977–85. and its analogs. Diabetes Res Clin Pract. 2011;94(1):e1–2. 12. Heinzerling L. Insulin allergy. Diabet Med. 2013;30(8):891–2. 22. Fujikawa T, Imbe H, Date M, Go Y, Kitaoka H. Severe insulin allergy suc‑ 13. Brockow K, et al. General considerations for skin test procedures in the cessfully treated with continuous subcutaneous insulin infusion. Diabetes diagnosis of drug hypersensitivity. Allergy. 2002;57(1):45–51. Res Clin Pract. 2012;97(2):e31–3. 14. Bodtger U, Wittrup M. A rational clinical approach to suspected insulin 23. Yong PF, Malik R, Arif S, Peakman M, Amiel S, Ibrahim MA, Gough A. Rituxi‑ allergy: status after five years and 22 cases. Diabet Med. 2005;22(1):102–6. mab and omalizumab in severe, refractory insulin allergy. N Engl J Med. 15. Joint Task Force on Practice Parameters, American Academy of Allergy, 2009;360(10):1045–7. Asthma and Immunology, American College of Allergy, Asthma and 24. Cavelti‑ Weder C, Muggli B, Keller C, Babians‑Brunner A, Biason‑Lauber A, Immunology, Joint Council of Allergy, Asthma and Immunology. Drug Donath MY, Schmid‑ Grendelmeier P. Successful use of omalizumab in allergy: an updated practice parameter. Ann Allergy Asthma Immunol. an inadequately controlled type 2 diabetic patient with severe insulin 2010;105(4):259–73. allergy. Diabetes Care. 2012;35(6):e41. 16. Demoly P, Adkinson NF, Brockow K, Castells M, Chiriac AM, Green‑ 25. Koroscil T, Kagzi Y, Zacharias D. Failure of multiple therapies in the berger PA, Khan DA, Lang DM, Park HS, Pichler W, Sanchez‑Borges M, treatment of a type 1 diabetic patient with insulin allergy: a case report. Shiohara T, Thong BY. International consensus on drug allergy. Allergy. Endocr Pract. 2011;17(1):91–4. 2014;69(4):420–37. 17. Valentini U, Cimino A, Rocca L, Pelizzari R, Rotondi A, Tosoni C. CSII in management of insulin allergy. 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Insulin allergy can be successfully managed by a systematic approach

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Springer Journals
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Copyright © 2018 by The Author(s)
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Medicine & Public Health; Allergology; Immunology; Pneumology/Respiratory System
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Abstract

Background: Type I insulin allergy can be a challenging condition, and there is no international consensus on how to establish the diagnosis. Measurement of specific IgE and skin testing have been cornerstones in the diagnostic work‑ up. However, these tests have limitations, mainly lack of correlation between test results and clinical findings. At the Allergy Centre, Odense University Hospital, patients with suspected insulin allergy have been evaluated since 2003. The aim of this study was to establish a systematic approach to diagnose and treat patients with insulin allergy. Methods: The study was conducted retrospectively by retrieving data from the Allergy Centre database on patients with suspected insulin allergy evaluated from 2003 to 2017. The examination comprised a comprehensive medical history, specific IgE against insulin and intracutaneous tests (ICT ) with different insulins. Results: A total of 144 patients were examined on suspicion of insulin allergy of which 110 had negative specific IgE in serum. Of the remaining 34 patients, 33 had ICT performed; 2 had negative ICTs, while 31 had one or more posi‑ tive ICT. All 34 patients had mild symptoms, and 4 could obtain symptom relief with antihistamines or local steroids, 9 could be managed with oral antidiabetics, and 7 were switched to other insulins. The final 14 patients were offered an insulin pump because of reactions to many different insulins, many positive ICTs, unmanageable diabetes, young age and compliance, or convenience. Conclusion: Insulin allergy can be managed by a systematic approach, and symptom relief is obtainable in most patients. Keywords: Insulin, Allergy, IgE, Intracutaneous test Background questionable for a number of reasons including false-neg- Insulin allergy affects 0.1–3% of insulin-treated diabetics ative tests, and non-specific reactions as well as reactions [1, 2] and causes symptoms ranging from localized itch- to additives (e.g. protamine sulfate) [3, 5, 6, 8–10]. Meas- ing and rash to life-threatening anaphylaxis [3–5]. The urement of specific IgE (sIgE) is another cornerstone in IgE-mediated (type I) reaction is by far the most com- the diagnosis, but this method has limitations as well, mon, but type III and type IV reactions have been mainly due to poor correlation between clinical findings reported as well [1, 6–9]. and elevated IgE levels [3, 6]. Consequently, there is no The diagnosis is based on past and present symptoms consensus on the correct method for diagnosing insulin and signs, together with skin tests and specific immu - allergy yet, though one was suggested by Jacquier et  al. noglobulin E (IgE) measurement in serum. Skin prick in 2013 [11], based on three patient cases. The authors test (SPT) and intracutaneous test (ICT) have tradition- suggested the use of measurement of total IgE, insulin- specific IgE, and anti-insulin antibodies (IgG) in addition ally been used in the evaluation of these patients. How- to SPT or ICT. ever, the reliability of the results from skin tests has been The treatment of insulin allergy is often straightfor ward. For many patients it is possible to switch insulin *Correspondence: mhaastrup@health.sdu.dk preparation or to avoid insulin use by managing their dia- Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark betes through diet or oral antidiabetics and/or injections Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Haastrup et al. Clin Transl Allergy (2018) 8:35 Page 2 of 6 with glucagon-like peptide 1 (GLP1) analogue treatment. detemir (Levemir ). Most recently, the following addi- ® ® Some patients, however, are insulin dependent and expe- tions have been made to the panel: T oujeo, Abasaglar rience symptoms during treatment with many different (both insulin glargine), Tresiba (insulin deglucec), insulins. These patients are difficult to treat and require NovoMix (insulin aspart with added protamine), and a more comprehensive approach, sometimes including Apidra (insulin glulisine). desensitization [3, 9, 12]. SPT with insulin was initially a part of the examination At the Allergy Centre at Odense University Hospital but was abandoned due to the poor sensitivity and speci- patients with insulin allergy have been diagnosed and ficity of the test. Basophil histamine release (HR test) was treated since 2003. The aim of the present study was to performed in a few patients but not systematically. Con- summarize the diagnostic findings and to present a sys - sequently, the results of SPT and HR test are omitted. tematic approach for the examination and treatment of The patients—or in the case of children, their parents— these patients. gave informed consent to store their data in the ACbase. All data for this study were collected after approval from the Danish Data Protection Agency (17/11270). Methods This study was conducted retrospectively and included data from the Allergy Centre database, ACbase, on Results patients seen at the Odense Research Center for Ana- A flow chart of the protocol for the examination of sus - phylaxis (ORCA), Allergy Centre at Odense University pected insulin allergy is presented in Fig. 1. Hospital from 2003 through March 2017 with suspi- A total of 144 patients with suspected insulin allergy cion of insulin allergy. Since 2010 the Allergy Centre in were seen at the Allergy Centre, Odense University Hos- Odense has been the only place in Denmark to evaluate pital, from 2003 through March 2017. Of these, 34 had patients suspected of insulin allergy in collaboration with positive sIgE for insulin and were included in the study the Department of Endocrinology, Odense University while 110 had negative sIgE for insulin and were judged Hospital. non-allergic (type I). Among those deemed non-allergic The examination comprised a comprehensive medical 71 had an ICT performed with 12 having one or more history (type of diabetes, duration and severity of symp- positive ICTs. Another 5 were positive to protamine sul- toms, prior treatment etc.), measurement of specific IgE fate but none of the included insulins. ICTs were per- against human, bovine, and porcine insulin and—where formed in these patients before the results of the IgE appropriate—also ICT with different insulins. measurements were available. A positive ICT in a patient Specific IgE measurement (ImmunoCAP) against with a negative IgE may be an unspecific reaction, a reac - human, bovine and porcine insulin was performed by tion to an additive, or a delayed reaction reflecting a type Thermo Fisher, Uppsala Sweden. Values above 0.35 kIU/L IV allergy. were considered positive. The 34 patients with positive sIgE were categorised Intracutaneous tests were performed by injecting according to symptom severity. All 34 patients had local 20–50  µL of the different insulins in the concentration symptoms only (pruritus, nodules, localised dermati- 5  IE/mL, and reactions were considered positive if the tis and infiltration at injection sites). Patients, whose wheal size diameter was 3 mm larger than the initial bleb. symptoms could be alleviated by antihistamines or local ICTs were read after 20 min, according to guidelines from steroids (n = 4), and patients, who could be managed by the European Network on Drug Allergy (ENDA) [13]. As other antidiabetic medications than insulin (n = 9), were controls, skin prick tests were performed with histamine treated accordingly. 10  mg/mL (ALK-Abello, Denmark) as the positive con- In 33 of the 34 patients with positive sIgE, ICT was per- trol and isotonic NaCl as the negative control. formed. One was not tested due to age (12 years). Two of The insulins available for the test varied over time, and the 33 patients exhibited negative ICTs, however one of some of the first patients seen (n = 3) were only tested the two was only tested for one specific insulin prepara - with a selection of the available insulin types, based on tion (Apidra ) due to age (9 years). the clinician’s judgment. The majority, however, were The demographics and test results of the 21 insulin tested with the full panel of insulins, which included dependent patients with positive sIgE are presented in rapid acting human insulin (Humulin Re gular , Insuman ® ® Table  1 (data not shown for the remaining 13 patients Rapid, Actrapid ), rapid acting analogue insulin lispro ® ® because the symptoms of these patients could be man- (Humalog ), and insulin aspart (NovoRapid ), and inter- aged without insulin). Of the 20 patients tested with ICTs mediate acting isophane human insulin (Humulin N PH , 19 were ICT-positive for at least one insulin preparation Insulatard , both containing protamine), and long acting (range 1–9). The ICT-negative patient was the 9-year old analogue insulin: Insulin glargine (L antus ), and insulin Haastrup et al. Clin Transl Allergy (2018) 8:35 Page 3 of 6 Paents suspected of insulin allergy (n = 144) No (n = 110) Posive IgE? Not type I allergy Yes (n = 34) No (n = 4) No change in treatment, Severe symptoms? symptom relief if necessary Yes (n = 30) No (n = 9) Need of insulin? Oral andiabecs Yes (n = 21) Change of insulin Yes (n = 7) possible? No (n = 14) Insulin pump Change of insulin • ≥7 positive ICTs • Changed prior to examination, well (n = 7) tolerated (n = 4) • History of reactions to many • Changed based on insulins(n = 3) ICT results (n = 2) • Unmanageable • Changed despite diabetes (n = 1) positive ICT, well tolerated (n = 1) • Young age, compliance (n = 2) • Convenience (n = None had other atopic 1) manifestations/drug allergy. Eight of 14 had other atopic manifestations/drug allergy. Fig. 1 Flow chart of the procotol for examination of suspected insulin allergy girl, who was only tested for one insulin preparation by Where possible (n = 7), a switch was made to another ICT. insulin preparation. Of these 7 patients, a well-toler- In the 21 insulin dependent patients a change in treat- ated switch had already been made prior to evaluation ment regimen was necessary due to symptom severity. at the Allergy Centre in 4, and consequently, no further Haastrup et al. Clin Transl Allergy (2018) 8:35 Page 4 of 6 Table 1 Demographics and test results ID Sex Age DM type sIgE ICT Porcine Bovine Human A B C D E F G H I J 1 F 60 II 2.1 1.3 1.6 – + – – – – – – – N/D 2 F 55 II 0.6 0.4 0.5 + N/A N/A N/A N/A N/A N/A + + N/D 3 F 14 I 2.6 2.0 1.9 + + – – + + N/D + + N/D 4 F 59 II 7.1 5.9 6.2 + + + + + + + N/D N/D N/D 5 F 41 II 1.5 1.1 1.8 + + + + + + + + + N/D 6 M 55 II 22.8 18.5 22.8 + + + + + + + + + N/D 7 M 67 II 0.6 0.4 0.5 + + + + + + + + – N/D 8 F 47 II 8.9 7.9 7.7 + + + + + + + N/D – N/D 9 M 37 II 0.4 < 0.35 0.4 – + – – – – – – + N/D 10 F 36 I 1.3 1.0 1.0 – – – – – – + – – N/D 11 F 37 II 1.7 1.3 1.6 + + + + + + + + + N/D 12 F 12 I 0.4 < 0.35 < 0.35 N/D N/D N/D N/D N/D N/D N/D N/D N/D N/D 13 F 9 I 0.5 < 0.35 0.4 N/D N/D N/D N/D N/D N/D N/D N/D N/D – 14 F 54 I 0.1 < 0.35 0.4 – – N/D – – – – + – N/D 15 F 64 I 2.9 2.4 2.7 + + + N/A N/A N/A N/A + + N/D 16 F 46 II 2.5 2.2 2.2 + + + N/D N/D N/D N/D + N/D N/D 17 M 56 II 2.4 2.1 1.8 + + + + + + + + + N/D 18 M 55 I 0.4 < 0.35 0.4 – – – – – – + – – N/D 19 M 30 I 3.4 2.5 2.2 + + + – – + + – + N/D 20 M 57 I 0.6 0.6 0.7 + – + – + – – – – N/D 21 M 79 II 15.0 15.2 13.2 N/D + – + + + + + + N/D Patients 1–14 were given an insulin pump, 15–21 changed insulin preparation. All symptoms were local. N/A result not available in the database, N/D not done. IgE > 0.35 was considered positive A humulin regular, B insuman rapid, C actrapid, D humulin NPH, E insulatard, F lantus, G levemir, H novorapid, I humalog, J apidra treatment adjustment was needed. Two were success- Table 2 Comparison of  patient characteristics and  test fully switched to a different insulin, based on negative results between the two groups ICT. The last patient in this group was switched to an Insulin pump (n = 14) Other insulin (n = 7) insulin despite a positive ICT for this particular insulin. The switch, however, was well-tolerated. Sex (M:F) 3:11 5:2 The final group of patients (n = 14) was offered treat - Age (years) 41.6 (9–67) 55.3 (30–79) ment with an insulin pump in collaboration with the Diabetes type (I:II) 4:10 4:3 Department of Endocrinology, Odense University Hos- Other atopic manifesta‑ 8:6 0:7 pital. Seven of these patients exhibited ≥ 7 positive tions/drug allergy (Y:N) ICTs. Three additional patients had histories of reac - No. of positive ICTs 5.9 (0–9) 5 (1–9) tions to many different insulins. One patient’s diabetes IgE (kIU/L) 4.07 (0.4–22.8) 3.31 (0.4–13.2) was unmanageable, two were offered an insulin pump human IgE (kIU/L) 4.76 (0.4–18.5) 4.17 (0.6–15.2) because of young age and compliance and one due to bovine IgE (kIU/L) 3.64 (0.4–22.8) 3.89 (0.4–15.0) convenience. porcine Of the 14 patients given an insulin pump, eight had Overview of sex distribution and type I/type II diabetes ratio, average age, sIgE (human, bovine and porcine) and number of positive ICTs (range). Other atopic other atopic manifestations or drug allergy (challenge- manifestations/drug allergy: Two patients had challenge-proven penicillin verified penicillin allergy, atopic dermatitis, asthma, allergy, 2 asthma, 2 hay fever, 1 urticaria and 1 atopic dermatitis and contact allergy. Only positive sIgE values are included hay fever, contact allergy, and urticaria). None of the 7 patients, whose insulins were changed, had other atopic manifestations/other drug allergies. The groups did not Discussion differ with regards to age, sex, diabetes type, sIgE levels The majority of the published literature concerning insu - or number of positive ICTs, see Table 2. lin allergy has been case reports or small case series. This study is the largest of its kind so far. Haastrup et al. Clin Transl Allergy (2018) 8:35 Page 5 of 6 Abbreviations Of a total of 144 patients suspected of insulin allergy ENDA: European Network on Drug Allergy; ICT: intracutaneous test; IgE: immu‑ only 34 (24%) had positive sIgE, which is comparable to a noglobulin E; ORCA : Odense Research Center for Anaphylaxis; sIgE: specific study by Bodtger and Wittrup from 2005 [14], where the IgE; SPT: skin prick test. diagnosis was established in 9 of 22 patients (41%). The Authors’ contributions diagnostic work-up in this study consisted, however, only MBH analysed the patient data. MBH, CGM, and CBJ interpreted the patient of intracutaneous testing. data. All authors were major contributors in writing the manuscript. All authors read and approved the final manuscript. We focused mainly on specific IgE measurement for the diagnosis of insulin allergy, because this in  vitro test Author details has a high negative predictive value [10, 15], whereas ele- Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark. Steno Diabetes Center Odense, Odense Uni‑ vated levels are not necessarily indicative of allergy and versity Hospital, Odense, Denmark. Odense Research Center for Anaphylaxis are thus of limited value without a thorough medical his- (ORCA), Department of Dermatology and Allergy Centre, Odense University tory and supplementary skin testing [9, 16]. Hospital, Odense, Denmark. Skin tests, particularly SPT, have poor sensitivity but Acknowledgements high specificity, and the negative predictive value of ICT The authors would like to thank Ulla Johannessen and Esben Eller for assis‑ is high [5, 9, 15]. These tests can be helpful in distinguish - tance in retrieving data from the database. ing between insulins with and without the capability of Competing interests causing clinical reactions when choosing future treat- The authors declare that they have no competing interests. ment for a given patient. Availability of data and materials A total of 13 of the 34 patients (38%) with an insulin The datasets used during the current study are available from the correspond‑ allergy diagnosis in our study could be managed without ing author on reasonable request. a change in treatment or with oral antidiabetics. Another Consent for publication 7 were switched to a different insulin preparation, and The patients—or in the case of children, their parents—gave informed the final 14 were desensitised with continuous subcuta - consent to store their data in the ACbase for use in future research in allergic neous infusions through an insulin pump. This has been diseases after approval of the Danish Data Protection Agency. described in several reports as an option for patients Ethics approval and content to participate with an indispensable need for insulin who cannot be The patients—or in the case of children, their parents—gave informed managed by switching to another insulin preparation [8, consent to store their data in the ACbase (License No. 2008‑58‑0035). All data for this study were collected after approval from the Danish Data Protection 17–22]. Agency (17/11270). The most recent addition to the treatment options for these patients is omalizumab. This has been successful Funding No funding was supplied for this study. in two of three case reports so far and may represent an interesting alternative for patients whose symptoms can- Publisher’s Note not otherwise be managed [23–25]. Springer Nature remains neutral with regard to jurisdictional claims in pub‑ None of the patients in the present study had a history lished maps and institutional affiliations. of systemic reactions to insulin. Therefore, other treat - Received: 13 June 2018 Accepted: 22 August 2018 ment options than desensitization were chosen whenever possible. An insulin desensitization was mainly per- formed in those with many positive ICTs and a history of reactions to many different insulin preparations. In case References of a history of anaphylaxis in insulin dependent patients, 1. Radermecker RP, Scheen AJ. Allergy reactions to insulin: effects of con‑ desensitization should always be performed. tinuous subcutaneous insulin infusion and insulin analogues. 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Clinical and Translational Allergy – Springer Journals

Published: Sep 25, 2018

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