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A Complex Interaction Between Drug Allergy and Viral Infection

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Abstract

A relationship between viral infections and the simultaneous or subsequent development of drug rashes has been observed in a number of clinical situations. We have recently provided evidence to indicate an intimate relationship between reactivation of human herpesvirus 6 (HHV-6) and the development of a severe systemic hypersensitivity reaction referred to as drug-induced hypersensitivity syndrome (DIHS). This syndrome has several unique features that cannot be explained by a drug etiology; they include its delayed onset, paradoxical worsening of clinical symptoms after discontinuation of the causative drugs, and a step-wise development of several organ system failures long after clinical resolution. Many aspects of this syndrome suggest close similarities between DIHS and graft-versus-host disease (GVHD). Indeed, a wide variety of complications frequently occurring in GVHD, such as autoimmune diseases, is often observed during the course of this syndrome and even long after clinical resolution. Our recent studies have shown that in DIHS sequential reactivations of several herpesviruses (HHV-6, HHV-7, Epstein-Barr virus, and cytomegalovirus) can be detected coincident with various clinical symptoms in the same order as demonstrated in GVHD. Thus, not only the timing but also the order in which these herpesviruses can be reactivated in the host would be crucial determinant of outcomes of the disease. Our results indicate the importance of recognizing DIHS and other drug rashes associated with viral infections at risk of eventually developing autoimmune diseases.

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References

  1. Dahl M, Dabbagh K, Liggitt D, Kim S, Lewis DB (2004) Viral-induced T helper type 1 responses enhance allergic disease by effects on lung dendritic cells. Nat Immunol 5:337–343

    Article  PubMed  CAS  Google Scholar 

  2. Levy M (1984) The combined effect of viruses and drugs in drug-induced diseases. Med Hypotheses 14:293–296

    Article  PubMed  CAS  Google Scholar 

  3. Pullen H, Wright N, Murdoch JM (1967) Hypersensitivity reactions to antibacterial drugs in infectious mononucleosis. Lancet 2:1176–1178

    Article  PubMed  CAS  Google Scholar 

  4. Coopman SA, Johnson RA, Platt R, Stern RS (1993) Cutaneous disease and drug reactions in HIV. N Engl J Med 328:1670–1674

    Article  PubMed  CAS  Google Scholar 

  5. Suzuki Y, Inagi R, Aono T, Yamanishi K, Shiohara T (1998) Human herpesvirus 6 infection as a risk factor for the development of severe drug-induced hypersensitivity syndrome. Arch Dermatol 134:1108–1112

    Article  PubMed  CAS  Google Scholar 

  6. Tohyama H, Yahata Y, Yasukawa M, Inagi R, Urano Y, Yamanishi K, Hashimoto K (1998) Severe hypersensitivity syndrome due to sulfasalazine associated with reactivation of human herpesvirus 6. Arch Dermatol 134:1113–1117

    Article  PubMed  CAS  Google Scholar 

  7. Kieff E, Rickinson A (2001) EBV and its replication. In: Knipe D, Howley P (eds) Field’s virology, 4th edn, Vol 2. Lippincott, Wilkins & Williams, Philadelphia, pp 2511–2574

    Google Scholar 

  8. Cowdrey SC (1969) Acute urticaria in infectious mononucleosis. Ann Allergy 27:182–187

    PubMed  CAS  Google Scholar 

  9. Nazareth I, Mortimer P, McKendrick GD (1972) Ampicillin sensitivity in infectious mononucleosis temporary or permanent? Scand J Infect Dis 4:229–230

    PubMed  CAS  Google Scholar 

  10. Vetsika EK, Callan M (2004) Infectious mononucleosis and Epstein-Barr virus. Expert Rev Mol Med 6:1–6

    Article  PubMed  Google Scholar 

  11. Callan MF, Steven N, Krausa P, Wilson JD, Moss PA, Gillespie GM, Bell JI, Rickinson AB, McMichael AJ (1996) Large clonal expansions of CD8+ T cells in acute infectious mononucleosis. Nat Med 2:906–911

    Article  PubMed  CAS  Google Scholar 

  12. Silins SL, Sherritt MA, Silleri JM, Cross SM, Elliott SL, Bharadwaj M, Le TT, Morrison LE, Khanna R, Moss DJ, Suhrbier A, Misko IS (2001) Asymptomatic primary Epstein-Barr virus infection occurs in the absence of blood T-cell repertoire perturbations despite high levels of systemic viral load. Blood 98:3739–3744

    Article  PubMed  CAS  Google Scholar 

  13. Callan MF, Tan L, Annels N, Ogg GS, Wilson JD, O’Callaghan CA, Steven N, McMichael AJ, Rickinson AB (1998) Direct visualization of antigen-specific CD8+ T cells during the primary immune response to Epstein-Barr virus in vivo. J Exp Med 187:1395–1402

    Article  PubMed  CAS  Google Scholar 

  14. Williams H, Crawford DH (2006) Epstein-Barr virus: the impact of scientific advances on clinical practice. Blood 107:862–869

    Article  PubMed  CAS  Google Scholar 

  15. Massa M, Mazzoll F, Plgnattl P, De Benedetti F, Passalla M, Viola S, Samodal R, La Cava A, Gianoni F, Ollier W, Martini A, Aibani (2002) Proinflammatory responses to self HLA epitopes are triggered by molecular mimicry to Epstein-Barr virus proteins in oligoarticular juvenile idiopathic arthritis. Arthritis Rheum 46:2721–2729

    Article  PubMed  CAS  Google Scholar 

  16. Burrows SR, Khanna R, Silins SL, Moss DJ (1999) The influence of antiviral T-cell responses on the alloreactive repertoire. Immunol Today 20:203–207

    Article  PubMed  CAS  Google Scholar 

  17. Coopman SA, Johnson RA, Platt R, Stern RS (1993) Cutaneous disease and drug reactions in HIV infection. N Engl J Med 328:1670–1674

    Article  PubMed  CAS  Google Scholar 

  18. Rzany B, Mockenhaupt M, Stocker U, Hamouda O, Schöpf E (1993) Incidence of Stevens-Johnson syndrome and toxic epidermal necrolysis in patients with the acquired immunodeficiency syndrome in Germany. Arch Dermatol 129:1059

    Article  PubMed  CAS  Google Scholar 

  19. Eliaszewicz M, Flahault A, Roujeau JC, Fillet AM, Challine D, Mansouri S, et al. (2002) Prospective evaluation of risk factors of cutaneous drug reactions to sulfonamides in patients with AIDS. J Am Acad Dermatol 47:40–46

    Article  PubMed  Google Scholar 

  20. Shiohara T, Inaoka M, Kano Y (2006) Drug-induced hypersensitivity syndrome (DIHS): A reaction induced by a complex interplay among herpesviruses and antiviral and antidrug immune responses. Allergol Int 55:1–8

    Article  PubMed  Google Scholar 

  21. Chan HL, Stern RS, Arndt KA, Langlois J, Jick SS, Jick H, Walker AM (1990) The incidence of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. A population-based study with particular reference to reaction caused by drugs among outpatients. Arch Dermatol 126:43–47

    Article  PubMed  CAS  Google Scholar 

  22. Vittorio CC, Muglia JJ (1995) Anticonvulsant hypersensitivity syndrome. Arch Intern Med 155:2285–2290

    Article  PubMed  CAS  Google Scholar 

  23. Kano Y, Inaoka M, Shiohara T (2004) Association between anticonvulsant hypersensitivity syndrome and human herpesvirus 6 reactivation and hypogammaglobulinemia. Arch Dermatol 140:183–188

    Article  PubMed  Google Scholar 

  24. Taliercio CP, Olney BA, Lie JT (1986) Myocarditis related to drug hypersensitivity. Mayo Clin Proc 60:463–468

    Google Scholar 

  25. Engel JN, Mellul VG, Goodman OB (1986) Phenytoin hypersensitivity: a case of severe acute rhabdomyolysis. Am J Med 81:928–930

    Article  PubMed  CAS  Google Scholar 

  26. Fujino Y, Nakajima M, Inoue H, Kusuhara T, Yamada T (2002) Human herpesvirus 6 encephalitis associated with hypersensitivity syndrome. Ann Neurol 51:771–774

    Article  PubMed  Google Scholar 

  27. Sekine N, Motokura T, Oki T, Umeda Y, Sasaki N, Hayashi M, Sato H, Fujita T, Kaneko T, Asano Y, Kikuchi K (2001) Rapid loss of insulin secretion in a patient with fulminant type 1 diabetes mellitus and carbamazepine hypersensitivity syndrome. JAMA 285:1153–1154

    Article  PubMed  CAS  Google Scholar 

  28. Chiou CC, Chung WH, Hung SI, Yang LC, Hong HS (2006) Fulminant type1 diabetes mellitus caused by drug hypersensitivity syndrome with human herpesvirus 6 infection. J Am Acad Dermatol 54:S14–S17

    Article  PubMed  Google Scholar 

  29. Sakuma K, Kano Y, Fukuhara M, Shiohara T (2007) Syndrome of inappropriate secretion of antidiuretic hormone associated with limbic encephalitis in a patient with drug-induced hypersensitivity syndrome. Clin Exp Dermatol (in press)

  30. Descamps V, Mahe E, Houhou N, Abramowitz L, Rozenberg F, Rnager-Rogez S, Crickx B (2003) Drug-induced hypersensitivity syndrome associated with Epstein-Barr virus infection. Br J Dermatol 148:1032–1034

    Article  PubMed  CAS  Google Scholar 

  31. Aihara M, Sugita Y, Takahashi S, Nagatani T, Arata S, Takeuchi K, Ikezawa Z (2001) Anticonvulsant hypersensitivity syndrome associated with reactivation of cytomegalovirus. Br J Dermatol 144:1231–1234

    Article  PubMed  CAS  Google Scholar 

  32. Kano Y, Hirahara K, Sakuma K, Shiohara T (2006) Several herpesviruses can reactivate in a severe drug-induced multi-organ reaction in the same sequential order as in graft-versus-host disease. Br J Dermatol 155:301–306

    Article  PubMed  CAS  Google Scholar 

  33. Maeda Y, Teshima T, Yamada M, Shinagwa K, Nakao S, Ohno Y, et al. (1999) Monitoring of human herpesviruses after allogeneic peripheral blood stem cell transplantation and bone marrow transplantation. Br J Heamatol 105:295–302

    Article  CAS  Google Scholar 

  34. Maeda Y, Teshima T, Yamada M, Harada M (2000) Reactivation of human herpesviruses after allogenic peripheral blood stem cell transplantation and bone marrow transplantation. Leuk Lymphoma 29:229–239

    Google Scholar 

  35. Cone RW, Husng MLW, Corey L, Zeh J, Ashley R, Bowden R (1999) Human herpesvirus 6 infections after bone marrow transplantation: clinical and virologic manifestations. J Infect Dis 179:311–318

    Article  PubMed  CAS  Google Scholar 

  36. Karthaus M, Gabrysiak T, Brabant G, Prahst A, Link H, Soudah B, Geissler RG, Dietrich H, Ganser A, Hertenstein B (1997) Immune thyroiditis after transplantation of allogeneric CD34+ selected peripheral blood cells. Bone Marrow Transplant 20:697–699

    Article  PubMed  CAS  Google Scholar 

  37. Yoshikawa T, Asano Y, Ihira M, Suzuki K, Ohashi M, Suga S, et al. (2002) Human herpesvirus 6 viremia in bone marrow transplant recipients: clinical features and risk factors. J Infect Dis 185:847–853

    Article  PubMed  Google Scholar 

  38. Wainwright MS, Martin PL, Morse RP, Lacaze M, Provenzale JM, Coleman RE, et al. (2001) Human herpesvirus 6 limbic encephalitis after stem cell transplantation. Ann Neurol 50:612–619

    Article  PubMed  CAS  Google Scholar 

  39. Szabo F, Horvath N, Semon S, Hughes T (2000) Inappropriate antidiuretic hormone secretion, abdominal pain and disseminated varicella-zoster virus infection: an unusual triad in a patient 6 months post mini-allogeneic peripheral stem cell transplant for chronic myeloid leukemia. Bone Marrow Transplant 26:231–233

    Article  PubMed  CAS  Google Scholar 

  40. Kobayashi R, Iguchi A, Nakajima M, Sato T, Yoshida M, Kaneda M, Suzuki Y, Mino E, Kuroki F, Kobayashi K (2004) Hyponatremia and syndrome of inappropriate antidiuratic hormone secretion complicating stem cell transplantation. Bone Marrow Transplant 34:975–979

    Article  PubMed  CAS  Google Scholar 

  41. Sato H, Kamoi K, Saeki T, Yamazaki H, Koike T, Miyamura S, Gejyo F (2004) Syndrome of inappropriate secretion of antidiuretic hormone and thrombocytopenia caused by cytomegalovirus infection in a young immunocompetent woman. Intern Med 43:1177–1182

    Article  PubMed  Google Scholar 

  42. Levin MC, Lee SM, Kalume F, Morcos Y, Dohan Jr FC, Hasty KA, et al. (2002) Autoimmunity due to molecular mimicry as a cause of neurological disease. Nat Med 8:509–513

    Article  PubMed  CAS  Google Scholar 

  43. Christen U, Edeimann KH, McGavern DB, Wolfe T, Coon B, Teague MK, et al. (2004) A viral epitope that mimics a self antigen can accelerate but not initiate autoimmune diabetes. J Clin Invest 114:1290–1298

    Article  PubMed  CAS  Google Scholar 

  44. Derman AM, Rager-Zisman B (2004) Viruses and autoimmune disease adapting Koch’s postulates. Autoimm Rev 3:355–361

    Article  Google Scholar 

  45. Kano Y, Sakuma K, Shiohara T (2007) Sclerodermoid graft-versus-host disease-like lesions occuring after drug-induced hypersensitivity syndrome. Br J Dermatol 156:1061–1063

    Google Scholar 

  46. Caballero J, Herrera FA, Guijarro CO, Tello DE, Diez G (1998) Sclerodermatous graft-versus-host disease after donor leucocyte infusion. Br J Dermatol 139:889–892

    Article  Google Scholar 

  47. Sever JL, South MA, Shaver KA (1985) Delayed manifestations of congenital rubella. Rev Infect Dis 1:S164–169

    Google Scholar 

  48. Christen U, Edelmann KH, McGavern DB, Wolfe T, Coon B, Teague MK, et al. (2004) A viral epitope that mimics a self antigen can accelerate but not initiate autoimmune diabetes. J Cliln Invest 114:1290–0298

    Article  CAS  Google Scholar 

  49. Baum H, Davies H, Piekman M (1996) Molecular mimicry in the MHC: hidden clues to autoimmunity. Immunol Today 17:64–71

    Article  PubMed  CAS  Google Scholar 

  50. Wucherpfenning KW (2001) Mechanism for the induction of autoimmunity by infectious agents. J Clin Invest 108:1097–1104

    Article  Google Scholar 

  51. Olsen JK, Croxfourd JL, Calenoff MA, Dal Carto MC, Miller SD (2001) A virus-induced molecular mimicry model of multiple sclerosis. J Clin Invest 108:311–318

    Article  Google Scholar 

  52. Panoutsakopoulou V, Sanchirico ME, Huster KM, Jansson M, Granucci F, Shim DJ, et al. (2001) Analysis of the relationship between viral infection and autoimmune disease. Immunity 15:137–147

    Article  PubMed  CAS  Google Scholar 

  53. Hemmer B, Jacobsen M, Sommer N (2000) Degeneracy in T-cell antigen recognition: implications for the pathogenesis of autoimmune diseases. J Neuroimmunol 107:148–153

    Article  PubMed  CAS  Google Scholar 

  54. Mason D (1998) A very high level of crossreactivity is an essential feature of the T-cell receptor. Immunol Today 19:395–404

    Article  PubMed  CAS  Google Scholar 

  55. Kissler S, Anderton SM, Wraith DC (2001) Antigen-presenting cell activation: a link between infection and autoimmunity. J Autoimmun 16:303–308

    Article  PubMed  CAS  Google Scholar 

  56. Selin LK, Welsh RM (2004) Plasticity of T cell memory responses to viruses. Immunity 20:5–16

    Article  PubMed  CAS  Google Scholar 

  57. Kim S-K, Cornberg M, Wang XZ, Chen HD, Selin LK, Welsh RM (2005) Private specificities of CD8 T cell responses control patterns of heterologous immunity. J Exp Med 201:523–533

    Article  PubMed  CAS  Google Scholar 

  58. Rehermann B, Shin E-C (2005) Private aspects of heterologous immunity. J Exp Med 201:667–670

    Article  PubMed  CAS  Google Scholar 

  59. Yoshikawa T, Suga S, Asano Y, Nakashima Y, Yazaki T, Sobue R, Hirono M, Fududa M, Kojima S, Matsuyama T (1991) Human herpesvirus-6 infection in bone marrow transplantation. Blood 78:1381–1384

    PubMed  CAS  Google Scholar 

  60. Singh N, Carrigan DR (1996) Human herpesvirus-6 in transplantation: An emerging pathogen. Ann Int Med 124:1065–1071

    PubMed  CAS  Google Scholar 

  61. Sharrock CE, Kaminski E, Man S (1990) Limiting dilution analysis of human T cells: a useful clinical tool. Immunol Today 11:281–286

    Article  PubMed  CAS  Google Scholar 

  62. Burrows SR, Silins SL, MossDJ, Khanna R, Misko IS, Argaet VP (1995) T cell receptor repertoire for a viral epitope in humans is diversified by tolerance to a background major histocompatibility complex antigen. J Exp Med 182:1703–1715

    Article  PubMed  CAS  Google Scholar 

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Acknowledgement

This work was supported in part by grants from Ministry of Education, Sports, Science and Culture of Japan (to T. S. and Y.K.), and Ministry of Health, Labor, and Welfare of Japan (to T. S.).

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  1. Department of Dermatology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan

    Tetsuo Shiohara & Yoko Kano

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  1. Tetsuo Shiohara
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  2. Yoko Kano
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Correspondence to Tetsuo Shiohara.

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Shiohara, T., Kano, Y. A Complex Interaction Between Drug Allergy and Viral Infection. Clinic Rev Allerg Immunol 33, 124–133 (2007). https://doi.org/10.1007/s12016-007-8010-9

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