SEVERE BULLOUS HYPERSENSITIVITY REACTIONS AFTER EXPOSURE TO CARBAMAZEPINE IN A HAN-CHINESE CHILD WITH A POSITIVE HLAB* 1502 AND NEGATIVE IN VITRO TOXICITY ASSAYS: EVIDENCE FOR DIFFERENT PATHOPHYSIOLOGICAL MECHANISMS
Main Article Content
Keywords
Adverse drug reactions, drug hypersensitivity syndrome, in vitro diagnosis, drug-induced Stevens-Johnson Syndrome, in vitro toxicity assay
Abstract
Background
Drug hypersensitivity syndrome (DHS) can present in several clinical forms ranging from simple maculopapular skin rash to severe bullous reactions and multi-system dysfunction. Genetic analysis of DHS patients has revealed a striking association between carbamazepine (CBZ)-induced severe bullous reactions, such as Steven-Johnson Syndrome, and toxic epidermal necrolysis in individuals from Southeast Asia who carry a specific HLA allele (HLA-B*1502). This ethnic-specific relationship with a disease phenotype has raised the question of the commonality of the pathogenesis mechanisms of these diseases. The aim of this study was to investigate the genetic and metabolic bases of DHS development to help predict patient susceptibility.
Method
A case of carbamazepine-induced Steven-Johnson Syndrome reaction in a HLA-B*1502 positive child of Han Chinese origin, a carbamazepine-induced DHS case in a Caucasian patient and 3 healthy controls were investigated. We performed two types of in vitro toxicity assay, the lymphocyte toxicity assay (LTA) and the novel in vitro platelet toxicity assay (iPTA) on cells taken from the Chinese child 3 and 9 months after recovery from the reaction and from two healthy volunteers. We also tested the Caucasian patient, who developed CBZ-induced DHS, 3 months after the reaction.
Results
Both LTA and iPTA tests were negative 3 and 9 months after the reaction on samples from the Chinese child whereas the tests were positive in the Caucasian patient.
Conclusion
These results strongly suggest more than one mechanistic pathway for different CBZ-induced hypersensitivity reactions in patients with different ethnic backgrounds.
References
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26. Wu Y, Farrell J, Pirmohamed M, Park BK, Naisbitt DJ. Generation and characterization of antigen-specific CD4+, CD8+, and CD4+CD8+ T-cell clones from patients with carbamazepine hypersensitivity. J Allergy Clin Immunol 2007;119:973-81.
27. Chung WH, Hung SI, Chen YT. Genetic predisposition of life-threatening antiepilepticinduced skin reactions. Expert Opin Drug Saf 2010;9:15-21.
28. Pirmohamed M. Genetic factors in the predisposition to drug-induced hypersensitivity reactions. AAPS J 2006;8:E20-6.
29. Phillips EJ, Mallal SA. HLA and drug-induced toxicity. Curr Opin Mol Ther 2009; 11:231-42.
30. Harr T, French LE. Severe cutaneous adverse reactions: acute generalized exanthematous pustulosis, toxic epidermal necrolysis and Stevens-Johnson syndrome. Med Clin North Am; 2010 Jul;94 (4):727-42, x.
31. Knowles SR, Shear NH. Recognition and management of severe cutaneous drug reactions. Dermatol Clin 2007;25:245-53, viii.
32. Landsteiner K, Jacobs J. Studies on the Sensitization of Animals with Simple Chemical Compounds. J Exp Med 1935;61:643-56.
33. Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol 1994; 12:991-1045.
34. Pichler WJ. Pharmacological interaction of drugs with antigen-specific immune receptors: the p-i concept. Curr Opin Allergy Clin Immunol 2002;2:301-5.
35. Ju C, Uetrecht JP. Mechanism of idiosyncratic drug reactions: reactive metabolite formation, protein binding and the regulation of the immune system. Curr Drug Metab 2002;3:367- 77.
36. Rieder MJ, Uetrecht J, Shear NH, Cannon M, Miller M, Spielberg SP. Diagnosis of sulfonamide hypersensitivity reactions by invitro "rechallenge" with hydroxylamine metabolites. Ann Intern Med 1989;110:286-9.
37. Elzagallaai AA, Rieder MJ, Koren G. The In vitro Platelet Toxicity Assay (iPTA): a novel approach for assessment of drug hypersensitivity syndrome. J Clin Pharm 2010; in press.
38. Wang G, Konig R, Ansari GA, Khan MF. Lipid peroxidation-derived aldehyde-protein adducts contribute to trichloroethene-mediated autoimmunity via activation of CD4+ T cells. Free Radic Biol Med 2008;44:1475-82.
39. Rieder MJ. Immune mediation of hypersensitivity adverse drug reactions: implications for therapy. Expert Opin Drug Saf 2009;8:331-43.
40. Naisbitt DJ, Pirmohamed M, Park BK. Immunological principles of T-cell-mediated adverse drug reactions in skin. Expert Opin Drug Saf 2007;6:109-24.
41. Pichler WJ, Adam J, Daubner B, Gentinetta T, Keller M, Yerly D. Drug hypersensitivity reactions: pathomechanism and clinical symptoms. Med Clin North Am;94:645-64, xv.
42. Posadas SJ, Padial A, Torres MJ, et al. Delayed reactions to drugs show levels of perforin, granzyme B, and Fas-L to be related to disease severity. J Allergy Clin Immunol 2002;109:155- 61.
43. Hausmann O, Schnyder B, Pichler WJ. Drug hypersensitivity reactions involving skin. In: Uetrecht J, editor. Adverse Drug Reactions, Hand book of Experimental Pharmacology. Berlin: Springer-Verlag; 2010. p. 30-52.
44. Uetrecht J. Immune-mediated adverse drug reactions. Chem Res Toxicol 2009;22:24-34.
45. Commbs P, Gell P. Classification of allergic reactions responsible for clinical hypersensitivity and disease. In: RR G, editor. Clinical aspects of immunology. Oxford: Oxford University Press; 1968. p. 575-96.
46. Rodriguez-Pena R, Antunez C, Martin E, Blanca-Lopez N, Mayorga C, Torres MJ. Allergic reactions to beta-lactams. Expert Opin Drug Saf 2006;5:31-48.
47. Pichler WJ. Delayed drug hypersensitivity reactions. Ann Intern Med 2003;139:683-93.
48. Elzagallaai AA, Knowles SR, Rieder MJ, Bend JR, Shear NH, Koren G. In vitro testing for the diagnosis of anticonvulsant hypersensitivity syndrome: a systematic review. Mol Diagn Ther 2009;13: 313-30.
49. Shiohara T, Inaoka M, Kano Y. Drug-induced hypersensitivity syndrome (DIHS): a reaction induced by a complex interplay among herpes viruses and antiviral and antidrug immune responses. Allergol Int 2006;55:1-8.
50. Shiohara T, Iijima M, Ikezawa Z, Hashimoto K. The diagnosis of a DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivations. Br J Dermatol 2007;156:1083-4.
51. Gerber BO, Pichler WJ. The p-i concept: Evidence and implications. In: Pichler WJ, editor. Drug Hypersensitivity. Basel: Karger; 2007. p. 66-73.
2. Uetrecht J. Idiosyncratic drug reactions: current understanding. Annu Rev Pharmacol Toxicol 2007; 47:513-39.
3. Demoly P, Viola M, Rebelo Gomes E, Romano A. Epidemiology and Causes of Drug Hypersensitivity. In: Pichler W, editor. Drug Hypersensitivity. Basel: Karger; 2007. p. 2-17.
4. Hunziker T, Bruppacher R, Kuenzi UP, et al. Classification of ADRs: a proposal for harmonization and differentiation based on the experience of the Comprehensive Hospital Drug Monitoring Bern/St. Gallen, 1974-1993. Pharmacoepidemiol Drug Saf 2002;11:159-63.
5. Zaccara G, Franciotta D, Perucca E. Idiosyncratic adverse reactions to antiepileptic drugs. Epilepsia 2007;48:1223-44.
6. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med 1994; 331:1272-85.
7. Teraki Y, Shibuya M, Izaki S. Stevens-Johnson syndrome and toxic epidermal necrolysis due to anticonvulsants share certain clinical and laboratory features with drug-induced hypersensitivity syndrome, despite differences in cutaneous presentations. Clin Exp Dermatol 2010;35(7):723-8.
8. Wolf R, Matz H, Marcos B, Orion E. Drug rash with eosinophilia and systemic symptoms vs. toxic epidermal necrolysis: the dilemma of classification. Clin Dermatol 2005;23:311-4.
9. Shear NH, Spielberg SP. Anticonvulsant hypersensitivity syndrome. In vitro assessment of risk. J Clin Invest 1988;82:1826-32.
10. Knowles SR, Uetrecht J, Shear NH. Idiosyncratic drug reactions: the reactive metabolite syndromes. Lancet 2000;356:1587-91.
11. Spielberg SP, Gordon GB, Blake DA, Goldstein DA, Herlong HF. Predisposition to phenytoin hepatotoxicity assessed in vitro. N Engl J Med 1981;305:722-7.
12. Gennis MA, Vemuri R, Burns EA, Hill JV, Miller MA, Spielberg SP. Familial occurrence of hypersensitivity to phenytoin. Am J Med 1991;91:631-4.
13. Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature 2004;428:486.
14. Mallal S, Nolan D, Witt C, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 2002;359: 727-32.
15. Hung SI, Chung WH, Jee SH, et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics 2006;16:297-306.
16. Ferrell PB, Jr., McLeod HL. Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations. Pharmacogenomics 2008;9:1543-6.
17. Franciotta D, Kwan P, Perucca E. Genetic basis for idiosyncratic reactions to antiepileptic drugs. Curr Opin Neurol 2009;22:144-9.
18. Alfirevic A, Jorgensen AL, Williamson PR, Chadwick DW, Park BK, Pirmohamed M. HLA-B locus in Caucasian patients with carbamazepine hypersensitivity. Pharmacogenomics 2006;7:813- 8.
19. Kano Y, Hirahara K, Asano Y, Shiohara T. HLA-B allele associations with certain drugs are not confirmed in Japanese patients with severe cutaneous drug reactions. Acta Derm Venereol 2008;88: 616-8.
20. Lonjou C, Thomas L, Borot N, et al. A marker for Stevens-Johnson syndrome: ethnicity matters. Pharmacogenomics J 2006;6:265-8.
21. Leeder JS. Mechanisms of idiosyncratic hypersensitivity reactions to antiepileptic drugs. Epilepsia 1998;39 Suppl 7:S8-16.
22. Wu Y, Sanderson JP, Farrell J, et al. Activation of T cells by carbamazepine and carbamazepine metabolites. J Allergy Clin Immunol 2006; 118:233-41.
23. Naisbitt DJ, Britschgi M, Wong G, et al. Hypersensitivity reactions to carbamazepine: characterization of the specificity, phenotype, and cytokine profile of drug-specific T cell clones. Mol Pharmacol 2003; 63:732-41.
24. Elzagallaai AA, Knowles SR, Rieder MJ, Bend JR, Shear NH, Koren G. Patch testing for the diagnosis of anticonvulsant hypersensitivity syndrome: a systematic review. Drug Saf 2009;32:391-408.
25. Lee AY, Choi J, Chey WY. Patch testing with carbamazepine and its main metabolite carbamazepine epoxide in cutaneous adverse drug reactions to carbamazepine. Contact Dermatitis 2003;48: 137-9.
26. Wu Y, Farrell J, Pirmohamed M, Park BK, Naisbitt DJ. Generation and characterization of antigen-specific CD4+, CD8+, and CD4+CD8+ T-cell clones from patients with carbamazepine hypersensitivity. J Allergy Clin Immunol 2007;119:973-81.
27. Chung WH, Hung SI, Chen YT. Genetic predisposition of life-threatening antiepilepticinduced skin reactions. Expert Opin Drug Saf 2010;9:15-21.
28. Pirmohamed M. Genetic factors in the predisposition to drug-induced hypersensitivity reactions. AAPS J 2006;8:E20-6.
29. Phillips EJ, Mallal SA. HLA and drug-induced toxicity. Curr Opin Mol Ther 2009; 11:231-42.
30. Harr T, French LE. Severe cutaneous adverse reactions: acute generalized exanthematous pustulosis, toxic epidermal necrolysis and Stevens-Johnson syndrome. Med Clin North Am; 2010 Jul;94 (4):727-42, x.
31. Knowles SR, Shear NH. Recognition and management of severe cutaneous drug reactions. Dermatol Clin 2007;25:245-53, viii.
32. Landsteiner K, Jacobs J. Studies on the Sensitization of Animals with Simple Chemical Compounds. J Exp Med 1935;61:643-56.
33. Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol 1994; 12:991-1045.
34. Pichler WJ. Pharmacological interaction of drugs with antigen-specific immune receptors: the p-i concept. Curr Opin Allergy Clin Immunol 2002;2:301-5.
35. Ju C, Uetrecht JP. Mechanism of idiosyncratic drug reactions: reactive metabolite formation, protein binding and the regulation of the immune system. Curr Drug Metab 2002;3:367- 77.
36. Rieder MJ, Uetrecht J, Shear NH, Cannon M, Miller M, Spielberg SP. Diagnosis of sulfonamide hypersensitivity reactions by invitro "rechallenge" with hydroxylamine metabolites. Ann Intern Med 1989;110:286-9.
37. Elzagallaai AA, Rieder MJ, Koren G. The In vitro Platelet Toxicity Assay (iPTA): a novel approach for assessment of drug hypersensitivity syndrome. J Clin Pharm 2010; in press.
38. Wang G, Konig R, Ansari GA, Khan MF. Lipid peroxidation-derived aldehyde-protein adducts contribute to trichloroethene-mediated autoimmunity via activation of CD4+ T cells. Free Radic Biol Med 2008;44:1475-82.
39. Rieder MJ. Immune mediation of hypersensitivity adverse drug reactions: implications for therapy. Expert Opin Drug Saf 2009;8:331-43.
40. Naisbitt DJ, Pirmohamed M, Park BK. Immunological principles of T-cell-mediated adverse drug reactions in skin. Expert Opin Drug Saf 2007;6:109-24.
41. Pichler WJ, Adam J, Daubner B, Gentinetta T, Keller M, Yerly D. Drug hypersensitivity reactions: pathomechanism and clinical symptoms. Med Clin North Am;94:645-64, xv.
42. Posadas SJ, Padial A, Torres MJ, et al. Delayed reactions to drugs show levels of perforin, granzyme B, and Fas-L to be related to disease severity. J Allergy Clin Immunol 2002;109:155- 61.
43. Hausmann O, Schnyder B, Pichler WJ. Drug hypersensitivity reactions involving skin. In: Uetrecht J, editor. Adverse Drug Reactions, Hand book of Experimental Pharmacology. Berlin: Springer-Verlag; 2010. p. 30-52.
44. Uetrecht J. Immune-mediated adverse drug reactions. Chem Res Toxicol 2009;22:24-34.
45. Commbs P, Gell P. Classification of allergic reactions responsible for clinical hypersensitivity and disease. In: RR G, editor. Clinical aspects of immunology. Oxford: Oxford University Press; 1968. p. 575-96.
46. Rodriguez-Pena R, Antunez C, Martin E, Blanca-Lopez N, Mayorga C, Torres MJ. Allergic reactions to beta-lactams. Expert Opin Drug Saf 2006;5:31-48.
47. Pichler WJ. Delayed drug hypersensitivity reactions. Ann Intern Med 2003;139:683-93.
48. Elzagallaai AA, Knowles SR, Rieder MJ, Bend JR, Shear NH, Koren G. In vitro testing for the diagnosis of anticonvulsant hypersensitivity syndrome: a systematic review. Mol Diagn Ther 2009;13: 313-30.
49. Shiohara T, Inaoka M, Kano Y. Drug-induced hypersensitivity syndrome (DIHS): a reaction induced by a complex interplay among herpes viruses and antiviral and antidrug immune responses. Allergol Int 2006;55:1-8.
50. Shiohara T, Iijima M, Ikezawa Z, Hashimoto K. The diagnosis of a DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivations. Br J Dermatol 2007;156:1083-4.
51. Gerber BO, Pichler WJ. The p-i concept: Evidence and implications. In: Pichler WJ, editor. Drug Hypersensitivity. Basel: Karger; 2007. p. 66-73.