Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Insulin allergy

2,489 views

Published on

Insulin allergy

Presented by Wat Mitthamsiri, MD.

June28, 2013

Published in: Health & Medicine
  • Be the first to comment

Insulin allergy

  1. 1. A pregnant woman with insulin allergy Wat Mitthamsiri, M.D. Allergy and Clinical Immunology Unit Department of Medicine King Chulalongkorn Memorial Hospital
  2. 2. A 28-years old Thai female U/D diabetes mellitus > 2 years, most likely T1DM Now she is pregnant, G2P0A1 (criminal abortion), GA about 6 months
  3. 3. Consultation O She used to use oral hypoglycemic agent before becoming pregnant but eventually changed to insulin by endocrinologist O After pregnancy, her endocrinologist adjust her DM Rx using multiple insulin injection as timeline in the next slide
  4. 4. Her DM Rx after pregnancy Insulin used Feb Mar Apr May Jun rapid-acting Humulin-R® 28/2/13 11/3/13 Actrapid® 11/3/13 17/6/13 NovoRapid® 17/6/13 Apidra® 19/6/13 Long-acting Humulin-N® 28/2/13 Insulatard® ??/4/13 17/6/13 Levemir® 17/6/13 3/6/13 Early rash 17/6/13 Large area of rash
  5. 5. Related Hx O Dosage of insulin was gradually increased due to her GA O She took a brand of combined vitamins pill received from ANC clinic O She denied any other concurrent medicine O She denied previous Hx of drug and food allergy
  6. 6. Related Hx O Injection sites O Humulin-R® and Actrapid® to Rt.side of her belly O Humulin-N® and Insulatard® to Lt.side of her belly O The reaction started about 3-4 hr after injection
  7. 7. 17/6/2013 O Due to her rash, she consulted her endocrinologist. O Actrapid® was changed to NovoRapid® O Insulatard® was changed to Levemir®
  8. 8. 19/6/2013 O 2 days of new insulin usage O She got some rash on her thighs at injection sites
  9. 9. 19/6/2013 O Due to rash on her thighs, her endocrinologist planned to try using 2 other insulin: Apidra® and Levemir® O But before trying new insulin brands, she was sent to consult allergist about ―insulin allergy”
  10. 10. Insulin allergy Review of Literatures
  11. 11. History O 1922: 1st use of insulin extracted from animal islet cells -> Bovine insulin caused a 7.5-cm callus at the injection site. Bliss M. The discovery of insulin. Chicago: University of Chicago,Press; 1982. p. 155. O 1936: 1st use of protamine + zinc to develop slow-release insulin O 1950: Introduction of NPH Jersild M. Insulin zinc suspension; four years’ experience. Lancet 1956; 271:1009-13
  12. 12. History O 1970s: Highly purified animal insulin was introduced and dramatically decrease allergic reactions Schernthaner G. Immunogenicity and allergenic potential of animal and human insulins. Diabetes Care 1993;16(suppl 3):155-65. O 1975: Fully synthetic insulin was produced O 1978: Human insulin was produced from genetically-engineered E.coli plasmids. Katsoyannis PG, Tometsko A, Zalut C, Insulin peptides XII. Human insulin generation by combination of synthetic A and B chains. J Am Chem Soc 1966;88:186.
  13. 13. Prevalence O The current prevalence of reactions during insulin treatment: about 2% O Less than 1% have been considered to be related to the insulin therapy. Schernthaner G. Immunogenicity and allergenic potential of animal and human insulins. Diabetes Care 1993;16(suppl 3):155-65. Matheu V. Et al. Insulin allergy and resistance successfully treated by desensitisation with Aspart insulin. Clin Molec Allergy 2005;3:16.
  14. 14. Possible causal components O Insulin O Local disinfectants O Nickel O Zinc O Protamine Plantin P, Sassolas B, Guillet MH. Accident cutanes allergiques aux insulines. Ann Dermatol Venereol 1988; 115:813-7. O Preservatives and solvents O Metacresol O Glycerol O Phenol O Sodium phosphate
  15. 15. Insulin David RO, New horizons — alternative routes for insulin therapy, Nature Reviews Drug Discovery.2002;1:529-540
  16. 16. Protamine O A low-molecular-weight polycationic protein O Purified from the sperm of salmon or related fish O Used for prolong insulin’s pharmacologic effect by decreased absorption
  17. 17. Protamine O No certainly known secondary and tertiary structure but there were several proposals Martins RP, Ostermeier GC, Krawetz SA. Nuclear matrix interactions at the human protamine domain: a working model of potentiation. J. Biol. Chem. 2004; 279 (50): 51862–8. Vilfan ID, Conwell CC, Hud NV. Formation of native-like mammalian sperm cell chromatin with folded bull protamine. J. Biol. Chem. 2004; 279 (19): 20088–95. Biegeleisen K. The probable structure of the protamine-DNA complex. J. Theor. Biol. 2006;241 (3): 533–40. O Binding mode of the insulin–protamine complex is not known Mathias N, Frantisek H, Gerd S, Structural characterization of insulin NPH formulations, European Journal of Pharmaceutical Sciences, 2007; 30(5); 414-423
  18. 18. Protamine O An anaphylactic reaction to protamine sulfate during cardiac surgery was reported Mishra DK, Sathyamurthy I, Subramanyan K, Girinath MR. Life threatening protamine reaction during bypass surgery—a case report. Indian Heart J 2009;61:216-7. O Patient with antiprotamine Ab, were high risk for Ig-mediated protamine reactions Chang LC, Liang JF, Lee HF, Lee LM, Yang VC. Low molecular weight protamine (LMWP) as nontoxic heparin/low molecular weight heparin antidote (II): in vitro evaluation of efficacy and toxicity. AAPS PharmSci 2001;3 article 18
  19. 19. Protamine O Non-immunologic mechanism might also cause the reaction O Heparin-protamine complexes could activate the classical complement pathway O -> Sequestration of neutrophils in the lungs O -> Formation of thromboxane A2 and release of histamine Chang LC, Liang JF, Lee HF, Lee LM, Yang VC. Low molecular weight protamine (LMWP) as nontoxic heparin/low molecular weight heparin antidote (II): in vitro evaluation of efficacy and toxicity. AAPS PharmSci 2001;3 article 18
  20. 20. Zinc O Alter immunogenicity of insulin by changing the structure of the β chain O Immediate type of localized nodular reaction at the injection sites was reported to be caused by zinc Simpson K, Clements M, Ogilvie A, et al. A case of insulin allergy: something to zinc about. Endocrine Abstracts 2008;18:36
  21. 21. Insulin-Zinc complex Chang X, Jorgensen AM, Bardrum P, Led JJ. Solution structures of the R6 human insulin hexamer,. Biochemistry, 1997;36 (31): 9409–22.
  22. 22. Cresol O C7H8O O A group of aromatic organic compounds called ―Phenolics‖ O Use as preservative in some insulin preparations
  23. 23. Cresol O 3 forms Todd H. http://chemistry.about.com/od/factsstructures/ig/Chemical-Structures---C/Cresol- Isomers.htm, online article, accessed June 2013.
  24. 24. Cresol O DTH reactions to meta-cresol in insulin was reported: O Erythematous burning lesions at the injection sites on the day after SC use O Mild headache + gastric pain + erythematous burning lesions at the injection sites on the day after SC use Clerx V, Keybus VD, Kochuyt A, Goossens A. Drug intolerance reaction to insulin therapy caused by metacresol. Contact Dermatitis 2003;48:162-3 Kim D, Baraniuk J. Delayed-type hypersensitivity reaction to the metacresol component of insulin. Ann Allergy Asthma Immunol 2007;99:194-5.
  25. 25. Glycerol O A simple polyol compound
  26. 26. Glycerol O Increased insulin stability by decreasing precipitation A.M. Gualandi-Signorini, G. Giorgi, Insulin formulations – a review, Eur Rev Med Pharmacol Sci. 2001; 5: 73-83. Blackshear PJ, Rohde TD, Palmer JL. Glycerol prevents insulin precipitation and interruption of flow in an implantable insulin infusion pump. Diabetes Care 1983; 6: 387- 392. O Numerous of contact allergic reactions from glycerol were reported O No report of reaction to glycerol in insulin preparations from PubMed
  27. 27. Phenol O C6H6O O No reported reaction to phenol in insulin preparations found on PubMed
  28. 28. Reported reactions O Type I: IgE-mediated reactions (most common) with rare anaphylaxis case O Type III: immune complex-type (Arthus reaction-localized or serum sickness- generalized) O Type IV: delayed-type hypersensitivity (no report of occurrence due to insulin, but occur due to added components) Heinzerling L, Raile K, Rochlitz H, Zuberbier T, Worm M. Insulin allergy. Allergy 2008;63:148-55.
  29. 29. Diagnostic tests O Type I: IgE-mediated reactions O Skin tests: O Prick test O Intradermal test O Specific IgE titer O Drug provocation test
  30. 30. Diagnostic tests O Type III: immune complex-type O Clinical Dx O Immune complex titer O Skin Biopsy O Type IV: delayed-type hypersensitivity O Skin patch test
  31. 31. Mohammad KG, Graham AJ. Insulin allergy. Clinics in Dermatology 2011; 29:300–305
  32. 32. Let’s go back to our patient Searching for causative agent
  33. 33. Diagnostic tests done O Type I: IgE-mediated reactions O Skin prick test O Intradermal skin test O Type IV: delayed-type hypersensitivity O Skin patch test
  34. 34. Skin prick test O rapid-acting insulin tested (All 1:10) O Actrapid® -> Actra O Apidra® -> Apid O NovoRapid® -> Nov O Long-acting insulin tested (All 1:10) O Insulatard® -> Ins O Levemir® -> Lev O Lantus® -> Lan
  35. 35. All Negative
  36. 36. Intradermal skin test O rapid-acting insulin tested (All 1:10) O Actrapid® -> Ac O Apidra® -> Ap O Long-acting insulin tested (All 1:10) O Insulatard® -> In O Lantus® -> La
  37. 37. Intradermal skin test results O rapid-acting insulin tested (All 1:10) O Actrapid® 7x7 mm -> 28x10 mm O Apidra® 7x7 mm -> 9x7mm O Long-acting insulin tested(All 1:10) O Insulatard® 9x9 mm -> 11x8 mm O Lantus® 10x10 mm -> 16x11 mm
  38. 38. Skin patch test O rapid-acting insulin tested (All 1:10) O Actrapid® -> Ac O Apidra® -> Ap O NovoRapid® -> No O Long-acting insulin tested (All 1:10) O Insulatard® -> In O Levemir® -> Le O Lantus® -> La
  39. 39. Properties of involved agents O Actrapid® Novo Nordisk O Apidra® Sanofi-Aventis O NovoRapid® Novo Nordisk O Insulatard® Novo Nordisk O Levemir® Novo Nordisk O Lantus® Sanofi-Aventis
  40. 40. Actrapid® O Insulin human O Produced by recombinant DNA technology in Saccharomyces cerevisiae O No restriction in pregnancy Novo Nordisk A/S, Actrapid® Prescribing information leaflet, 2011.
  41. 41. Actrapid® O List of excipients O Zinc chloride O Glycerol O Metacresol O Sodium hydroxide (for pH adjustment) O Hydrochloric acid (for pH adjustment) O Water for injections Novo Nordisk A/S, Actrapid® prescribing information leaflet, 2011.
  42. 42. Actrapid® O Immune-related undesirable effects O Uncommon - Urticaria, rash O Very rare - Anaphylactic reactions O Generalized hypersensitivity O Generalized skin rash O Itching O Sweating O gastrointestinal upset Novo Nordisk A/S, Actrapid® prescribing information leaflet, 2011.
  43. 43. Actrapid® O Immune-related undesirable effects O Generalized hypersensitivity O Angioneurotic edema O Difficulties in breathing O Palpitation O Reduction in blood pressure O Fainting/loss of consciousness Novo Nordisk A/S, Actrapid® prescribing information leaflet, 2011.
  44. 44. Apidra® O Insulin glulisine (rapid-acting) O Recombinant insulin analogue O Produced from non-pathological laboratory strain E.coli (K12) O Pregnancy category C Sanofi-Aventis, Apidra® prescribing information leaflet, 2009.
  45. 45. Apidra® Sanofi-Aventis, Apidra® prescribing information leaflet, 2009.
  46. 46. Apidra® O List of excipients O Tromethamine O Metacresol O Sodium chloride O Polysorbate O Water for injections Sanofi-Aventis, Apidra® prescribing information leaflet, 2009.
  47. 47. Apidra® O Allergic reactions O Local O Redness, swelling and itching at injection site O Systemic (4.3% in 12-mo controlled trial) O Anaphylaxis O Whole body rash O Dyspnea Sanofi-Aventis, Apidra® prescribing information leaflet, 2009.
  48. 48. Apidra® O Allergic reactions O Systemic (4.3% in 12-mo controlled trial) O Wheezing O Hypotension O Tachycardia O Diaphoresis Sanofi-Aventis, Apidra® prescribing information leaflet, 2009.
  49. 49. NovoRapid® O Insulin aspart O Biosynthetically modified human insulin analog (rapid-acting) O Produced using a modified strain of the yeast Saccharomyces cerevisiae O Well-tolerated and may benefit the fetus in pregnant women Novo Nordisk A/S, NovoRapid® product monograph, 2001.
  50. 50. NovoRapid® Novo Nordisk A/S, NovoRapid® product monograph, 2001.
  51. 51. NovoRapid® O List of excipients O Glycerol O Phenol O Metacresol O Zinc chloride O Disodium phosphate dihydrate O Sodium chloride O Hydrochloric acid/Sodium hydroxide O Water for injections Novo Nordisk A/S, NovoRapid® product monograph, 2001.
  52. 52. NovoRapid® O Allergic reactions O Few potentially allergic events O No anaphylactic reactions O Incidence of potentially allergic events was no greater than soluble human insulin O No increase the risk of injection site reactions compared with soluble human insulin Novo Nordisk A/S, NovoRapid® product monograph, 2001.
  53. 53. Insulatard® O Isophane NPH insulin O Insulin human, produced by recombinant DNA technology in Saccharomyces cerevisiae O No restriction of use in pregnancy Novo Nordisk A/S, Insulatard® prescribing information leaflet, 2007.
  54. 54. Insulatard® O List of excipients O Zinc chloride O Glycerol O Metacresol O Phenol O Disodium phosphate dihydrate . O Sodium hydroxide or/and hydrochloric acid O Protamine sulphate O Water for injections Novo Nordisk A/S, Insulatard® prescribing information leaflet, 2007.
  55. 55. Insulatard® O Undesirable effects (immune system) O Uncommon – Urticaria, rash O Very rare- Anaphylatic reactions O Generalized skin rash O Itching O Sweating O Gastrointestinal upset Novo Nordisk A/S, Insulatard® prescribing information leaflet, 2007.
  56. 56. Insulatard® O Undesirable effects (immune system) O Angioneurotic edema O Difficulties in breathing O Palpitation O reduction in blood pressure O Fainting/loss of consciousness O Generalized hypersensitivity reactions are potentially life threatening. Novo Nordisk A/S, Insulatard® prescribing information leaflet, 2007.
  57. 57. Levemir® O Insulin determir O Long-acting insulin analog O Produced from recombinant DNA in Saccharomyces cerevisiae followed by chemical modification O Pregnancy Category B Novo Nordisk A/S, Levemir® prescribing information leaflet, 2013.
  58. 58. Levemir® Novo Nordisk A/S, Levemir® prescribing information leaflet, 2013.
  59. 59. Levemir® O List of excipients: O Zinc O Metacresol O Glycerol O Phenol O Disodium phosphate dihydrate O Sodium chloride O water for injection O Hydrochloric acid and/or sodium hydroxide Novo Nordisk A/S, Levemir® prescribing information leaflet, 2013.
  60. 60. Levemir® O Hypersensitivity and allergic reactions O Local reactions: O Localized erythema O Pain O Pruritus O Urticaria O Edema O Inflammation. Novo Nordisk A/S, Levemir® prescribing information leaflet, 2013.
  61. 61. Levemir® O Hypersensitivity and allergic reactions O Systemic reactions: O Generalized skin reactions O Angioedema O Bronchospasm O Hypotension O Shock O Anaphylaxis Novo Nordisk A/S, Levemir® prescribing information leaflet, 2013.
  62. 62. Lantus® O Insulin glargine O Long-acting recombinant human insulin analog O Produced by utilizing a nonpathogenic laboratory strain of Escherichia coli (K12) O Pregnancy Category C Sanofi-Aventis, Lantus® Product information leaflet, 2007
  63. 63. Lantus® O Molecular structure Sanofi-Aventis, Lantus® Product information leaflet, 2007
  64. 64. Lantus® O List of excipients: O Meta-cresol O Glycerol O Zinc chloride O Hydrochloric acid O Sodium hydroxide O Water for injections Sanofi-Aventis, Lantus® Product information leaflet, 2007
  65. 65. Lantus® O Allergic reactions O Redness O Pain O Itching O Hives (urticarial rash) O Swelling O Inflammation Sanofi-Aventis, Lantus® Product information leaflet, 2007
  66. 66. Lantus® O Allergic reactions O Immediate-type allergic reactions are rare O Generalized skin reactions O Angioedema O Bronchospasm O Hypotension O Shock O Sanofi-Aventis, Lantus® Product information leaflet, 2007
  67. 67. Insulin brands Type Source Zinc Prot- amine Creso l Gly- cerol Other s Rapid-acting Actrapid® Human S.cerevisiae    Apidra® Analog (Glulisine ) E.coli  Tromet h- amine NovoRapid ® Analog (Aspart) S.cerevisiae    Phenol Long-acting Insulatard® Human S.cerevisiae     Phenol Levemir® Analog (Determir ) S.cerevisiae    Phenol Analog Comparison of involved agents
  68. 68. Next Rx by endocrinologist O Rapid-acting insulin O Apidra® O Long-acting insulin tested O Levemir® (intradermal test was not done) O Rx was started on 19/6/2013
  69. 69. Next Rx by allergist O Antihistamine O Cetirizine 10 mg b.i.d. (Pregnancy cat.B) O Topical steroid O 0.1% TA cream O Elomet lotion O Vitamins-> Continue as usual O Rx was started on 19/6/2013
  70. 70. 24/6/2013 O Patient reported that more rash occurred since 20/6/2013 and spread more on all limbs O Rash on her abdominal wall was darker with some greenish-bluish area. O She injected both types of insulin to her lateral aspect of both thighs, without local rash at injection sites.
  71. 71. Right thigh Left thigh
  72. 72. Skin patch test results
  73. 73. Current Rx since 24/6/2013 O Levemir® = suspected cause -> Stopped O Try using only rapid-acting insulin: O Apidra® 14-12-12 U + 4 U sc at 23.00, 3.00 O Maintain cetirizine at 10 mg b.i.d. +advice to add more dose prn (max 40 mg/d) O Continue TA cream and Elomet lotion O Stop all other medications (vitamin, etc)
  74. 74. What to do next? Management of insulin reactions
  75. 75. Possible useful management O If specific causal agent can be identified O Changing the preparation is obviously useful O If not, O Desensitization O Changes in the route or the rate of administration O Immunotherapy Mohammad KG, Graham AJ. Insulin allergy. Clinics in Dermatology 2011; 29:300–305
  76. 76. In this patient O She is pregnant O From current data, Apidra® and Insulatard® is the most likely usable agent O But when she has stress (e.g. in-labor), short/rapid-acting, dose-adjustable insulin infusion is needed O So we try only Apidra® first
  77. 77. In this patient O If Apidra® can be tolerated, it will be used until she give birth to her child O After that, we can retest any insulin preparation again without limitation from her pregnancy O We will know that on next Monday…
  78. 78. But if Apidra® cause the reaction again… What should we do next? Please help me…. (^_^!)

×