Skip to main content

Advertisement

SpringerLink
Log in

Crucial Role of Viral Reactivation in the Development of Severe Drug Eruptions: a Comprehensive Review

  • Published:
Clinical Reviews in Allergy & Immunology Aims and scope Submit manuscript

Abstract

A growing number of cells, mediators, and pathways have been implicated in severe drug eruptions. Fifteen years ago, we published landmark studies that sparked the current advances in our understanding of the role of viral reactivations in severe drug eruptions. Viral reactivations then became critically important as diagnostic tools, but how precisely they participated in the pathogenesis remained less well-defined. The question of whether viral reactivations are pathogenic or are instead as epiphenomenon of severe tissue damage has plagued the field of drug allergy for some decades. Recent evidence points to a crucial role for tissue-resident memory T (TRM) cells in immune protection against viral infections. Yet immune protection against viral infections is but one side of a coin, the other side of which comprises effector cells capable of mediating severe immunopathology: Once drug antigen is cross-recognized by these T cells, they could be activated to kill surrounding epidermal cells, resulting in drug-induced tissue damage. Such TRM cells could persistently reside in the skin lesions of fixed drug eruptions (FDE) and are most likely a major cell type responsible for the development of FDE. We also discuss the role of regulatory T (Treg) cells in the setting of drug allergy, in which herpesviruses are reactivated in sequence. Although many details of the complicated interactions among viruses, anti-viral immune responses, TRM cells, and Treg cells remain to be elucidated, we review the current status of this rapidly advancing field.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Shiohara T, Kano Y (2007) A complex interaction between drug allergy and viral infection. Clin Rev Allergy Immunol 33:124–133

    Article  CAS  PubMed  Google Scholar 

  5. Aota N, Hirahara K, Kano Y, Fukuoka T, Yamada A, Shiohara T (2009) Systemic lupus erythematosus presenting with Kikuchi–Fujimoto’s disease as a long-term sequela of drug-induced hypersensitivity syndrome. A possible role of Epstein–Barr virus reactivation. Dermatology 218:275–277

    Article  CAS  PubMed  Google Scholar 

  6. Hirahara K, Kano Y, Mitsuyama Y, Takahashi R, Kimishima M, Shiohara T (2010) Differences in immunological alterations and underlying viral infections in two well-defined severe drug eruptions. Clin Exp Dermatol 35:863–868

    Article  CAS  PubMed  Google Scholar 

  7. 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  CAS  PubMed  Google Scholar 

  8. Tohyama H, Yahata Y, Hashimoto K et al (1998) Severe hypersensitivity syndrome due to sulfasalazine associated with reactivation of human herpesvirus 6. Arch Dermatol 134:1113–1117

    Article  CAS  PubMed  Google Scholar 

  9. Gebhardt T, Wakim LM, Eidsmo L, Reading PC, Heath WR, Carbone FR (2009) Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat Immunol 10:524–530

    Article  CAS  PubMed  Google Scholar 

  10. Gebhardt T, Whitney PG, Mueller SN et al (2011) Different patterns of peripheral migration by memory CD4+ and CD8+ T cells. Nature 477:216–219

    Article  CAS  PubMed  Google Scholar 

  11. Ariotti S, Beltman JB, Schumacher TN et al (2012) Tissue-resident memory CD8+ T cells continuously patrol skin epithelia to quickly recognize local antigen. Proc Natl Acad Sci U S A 109:19739–19744

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Jiang X, Clark PA, Liu L, Wagers AJ, Fuhlbrigge RC, Kupper TS (2012) Skin infection generates non-migratory memory CD8+ T(RM) cells providing global skin immunity. Nature 483:227–231

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Hofmann M, Pircher H (2011) E-cadherin promotes accumulation of a unique memory CD8 T-cell population in murine salivary glands. Proc Natl Acad Sci U S A 108:16741–16746

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Mackay LK, Stock AT, Ma JZ et al (2012) Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation. Proc Natl Acad Sci U S A 109:7037–7042

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Shiohara T, Mizukawa Y (2012) Fixed drug eruption: the dark side of activation of intraepidermal CD8+ T cells uniquely specialized to mediate protective immunity. Chem Immunol Allergy 97:106–121

    Article  CAS  PubMed  Google Scholar 

  16. Shiohara T (2009) Fixed drug eruption: pathogenesis and diagnostic tests. Curr Opin Allergy Clin Immunol 9:316–321

    Article  PubMed  Google Scholar 

  17. Mizukawa Y, Shiohara T (2002) Trauma-localized fixed drug eruption: involvement of burn scars, insect bites and venipuncture sites. Dermatology 205:159–161

    Article  PubMed  Google Scholar 

  18. Sigal-Nahum M, Konqui A, Gaulier A, Sigal S (1988) Linear fixed drug eruption. Br J Dermatol 118:849–851

    Article  CAS  PubMed  Google Scholar 

  19. Senturk N, Yanik F, Yildiz L, Aydin F, Canturk T, Turanli AY (2002) Topotecan-induced cellulitis-like fixed drug eruption. J Eur Acad Dermatol Venereol 16:414–416

    Article  CAS  PubMed  Google Scholar 

  20. Komatsu T, Moriya N, Shiohara T (1996) T cell receptor (TCR) repertoire and function of human epidermal T cells: restricted TCR Vα–Vβ genes are utilized by T cells residing in the lesional epidermis in fixed drug eruption. Clin Exp Immunol 104:343–350

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Mizukawa Y, Yamazaki Y, Shiohara T et al (2002) Direct evidence for IFN-γ production by effector-memory-type intraepidermal T cells residing at an effector site of immunopathology in fixed drug eruption. Am J Pathol 161:1337–1347

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Cornberg M, Chen AT, Selin LK et al (2006) Narrowed TCR repertoire and viral escape as a consequence of heterologous immunity. J Clin Invest 116:1443–1456

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Burrows SR, Khanna R, Burrows JM, Moss DJ (1994) An alloresponse in humans is dominated by cytotoxic T lymphocytes (CTL) cross-reactive with a single Epstein–Barr virus CTL epitope: implications for graft-versus-host disease. J Exp Med 179:1155–1161

    Article  CAS  PubMed  Google Scholar 

  24. Burrows SR, Silins SL, Moss DJ, 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  CAS  PubMed  Google Scholar 

  25. Burrows SR, Silins SL, Moss DJ (1997) Cross-reactive memory T cells for Epstein–Barr virus augment the alloresponse to common human leukocyte antigens: degenerate recognition of major histocompatibility complex-bound peptide by T cells and its role in alloreactivity. Eur J Immunol 27:1726–1736

    Article  CAS  PubMed  Google Scholar 

  26. Koehn B, Gangappa S, Miller JD, Ahmed R, Larsen CP (2006) Patients, pathogens, and protective immunity: the relevance of virus-induced alloreactivity in transplantation. J Immunol 176:26912696

    Article  Google Scholar 

  27. Archbold JK, Macdonald WA, Rossjohn J et al (2009) Natural micropolymorphism in human leukocyte antigens provides a basis for genetic control of antigen recognition. J Exp Med 206:209–219

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Mizukawa Y, Yamazaki Y, Shiohara T (2008) In vivo dynamics of intraepidermal CD8+ T cells and CD4+ T cells during the evolution of fixed drug eruption. Br J Dermatol 158:1230–1238

    Article  CAS  PubMed  Google Scholar 

  29. Takahashi R, Kano Y, Yamazaki Y, Kimishima M, Mizukawa Y, Shiohara T (2009) Defective regulatory T cells in patients with severe drug eruptions: timing of the dysfunction is associated with the pathological phenotype and outcome. J Immunol 182:8071–8079

    Article  CAS  PubMed  Google Scholar 

  30. Peng G, Guo Z, Wang R-F et al (2005) Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science 309:1380–1384

    Article  CAS  PubMed  Google Scholar 

  31. Pasare C, Medzhitov R (2003) Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299:1033–1036

    Article  CAS  PubMed  Google Scholar 

  32. Lühn K, Simmons CP, Rowland-Jones S et al (2007) Increased frequencies of CD45+CD25 (high) regulatory T cells in acute dengue infection. J Exp Med 204:979–985

    Article  PubMed Central  PubMed  Google Scholar 

  33. Yu XL, Cheng YM, Ghildyal R et al (2008) Measles virus infection in adults induces production of IL-10 and is associated with increased CD4+CD25+ regulatory T cells. J Immunol 181:7356–7366

    Article  CAS  PubMed  Google Scholar 

  34. Kubota Y, Nakaura J, Nakayama J (2005) Stevens–Johnson syndrome due to allopurinol with positive DLST to several other drugs. Jpn J Dermatol 116:927–934 (in Japanese)

    Google Scholar 

  35. Shiohara T, Kano Y (2012) Drug-induced hypersensitivity syndrome: recent advances in drug allergy. Expert Rev Dermatol 7:539–547

    Article  CAS  Google Scholar 

  36. Shiohara T (2007) Drug-induced hypersensitivity syndrome and viral reactivation. In: Pichler WJ (ed) Drug hypersensitivity. Karger, Basel, pp 251–266

    Chapter  Google Scholar 

  37. Tohyama M, Hashimoto K, Shear NH et al (2007) Association of human herpesvirus 6 reactivation with the flaring and severity of drug-induced hypersensitivity syndrome. Br J Dermatol 157:934–940

    Article  CAS  PubMed  Google Scholar 

  38. Shiohara T, Iijima M, Ikezawa Z, Hashimoto K (2007) The diagnosis of a DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivations. Br J Dermatol 156:1083–1084

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  40. Agut H (1993) Puzzles concerning the pathogenicity of human herpesvirus 6. N Engl J Med 329:203–204

    Article  CAS  PubMed  Google Scholar 

  41. Asano Y, Kagawa H, Kano Y, Shiohara T (2009) Cytomegalovirus disease during severe drug eruption: report of 2 cases and retrospective study of 18 patients with drug-induced hypersensitivity syndrome. Arch Dermatol 145:1030–1036

    Article  PubMed  Google Scholar 

  42. Picard D, Janela B, Musette P et al (2010) Drug reaction with eosinophilia and systemic symptoms (DRESS): a multiorgan antiviral T cell response. Sci Transl Med 2:46–62

    Article  Google Scholar 

  43. Takahashi R, Kano Y, Yamazaki Y, Kimishima M, Mizukawa Y, Shiohara T (2009) Defective regulatory T cells in patients with severe drug eruptions: timing of the dysfunction is associated with the pathological phenotype and outcome. J Immunol 182:8071–8079

    Article  CAS  PubMed  Google Scholar 

  44. Korn T, Mitsdoerffer M, Oukka M et al (2008) IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells. Proc Natl Acad Sci U S A 105:18460–18465

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Hall BM, Verma ND, Tran GT, Hodgkinson SJ (2011) Distinct regulatory CD4+ T cell subsets: differences between naïve and antigen specific T regulatory cells. Curr Opin Immunol 23:641–647

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  47. Aota N, Shiohara T (2009) Viral connection between drug rashes and autoimmune diseases: how autoimmune responses are generated after resolution of drug rashes. Autoimmun Rev 8:488–494

    Article  CAS  PubMed  Google Scholar 

  48. Ishida T, Kano Y, Mizukawa Y, Shiohara T (2014) The dynamics of herpesvirus reactivations during and after severe drug eruptions: their relation to the clinical phenotype and therapeutic outcome. Allergy (in press)

  49. Hirahara K, Kano Y, Mitsuyama Y, Takahashi R, Kimishima M, Shiohara T (2010) Differences in immunological alterations and underlying viral infections in two well-defined severe drug eruptions. Clin Exp Dermatol 35:863–868

    Article  CAS  PubMed  Google Scholar 

  50. Ushigome Y, Kano Y, Ishida T, Hirahara K, Shiohara T (2013) Short- and long-term outcomes of 34 patients with drug-induced hypersensitivity syndrome in a single institution. J Am Acad Dermatol 68:721–728

    Article  PubMed  Google Scholar 

  51. Miceli MH, Maertens J, Anaissie EJ et al (2007) Immune reconstitution inflammatory syndrome in cancer patients with pulmonary aspergillosis recovering from neutropenia: proof of principle, description, and clinical and research implications. Cancer 110:112–120

    Article  PubMed  Google Scholar 

  52. Legrand F, Lecuit M, Lortholary O et al (2008) Adjuvant corticosteroid therapy for chronic disseminated candidiasis. Clin Infect Dis 46:696–702

    Article  CAS  PubMed  Google Scholar 

  53. Shiohara T, Kurata M, Mizukawa Y, Kano Y (2010) Recognition of immune reconstitution syndrome necessary for better management of patients with severe drug eruptions and those under immunosuppressive therapy. Allergol Int 59:333–343

    Article  CAS  PubMed  Google Scholar 

  54. Smith KJ, Skelton HG, Yeager J, Ledsky R, Ng TH, Wagner KF (1997) Increased drug reactions in HIV-1 positive patients: a possible explanation based on patterns of immune dysregulation seen in HIV-1 disease. The Military Medical Consortium for the Advancement of Retroviral Research (MMCARR). Clin Exp Dermatol 22:118–123

    Article  CAS  PubMed  Google Scholar 

  55. Garcia Vidal C, Rodriguez Femandez S, Garau J et al (2005) Paradoxical response to antituberculous therapy in infliximab-treated patients with disseminated tuberculosis. Clin Infect Dis 40:756–759

    Article  PubMed  Google Scholar 

  56. Arend SM, Leyten EM, Franken WP, Huisman EM, van Dissel JT (2007) A patient with de novo tuberculosis during anti-tumor necrosis factor-α therapy illustrating diagnostic pitfalls and paradoxical response to treatment. Clin Infect Dis 45:1470–1475

    Article  CAS  PubMed  Google Scholar 

  57. Belknap R, Reves R, Burman W (2005) Immune reconstitution to Mycobacterium tuberculosis after discontinuing infliximab. Int J Tuberc Lung Dis 9:1057–1058

    PubMed  Google Scholar 

  58. Marais S, Wilkinson RJ, Pepper DJ, Meintjes G (2009) Management of patients with the immune reconstitution inflammatory syndrome. Curr HIV/AIDS Rep 6:162–171

    Article  PubMed  Google Scholar 

  59. Shelburne SA 3rd, Hamill RJ, Rodriguez-Barradas MC, Greenberg SB, Atmar RL, Musher DW, Gathe JC Jr, Visnegarwala F, Trautner BW (2002) Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy. Medicine 81:213–227

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology (to T.S.) and the Health and Labour Sciences Research Grants (Research on Intractable Diseases) from the Ministry of Health, Labour and Welfare of Japan (to T.S.).

Author information

Authors and Affiliations

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

    Tetsuo Shiohara, Yukiko Ushigome & Yoko Kano

  2. Division of Flow Cytometry, School of Medicine, Kyorin University, Mitaka, Tokyo, 181-8611, Japan

    Tetsuo Shiohara & Ryo Takahashi

Authors
  1. Tetsuo Shiohara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yukiko Ushigome
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yoko Kano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ryo Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ryo Takahashi.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shiohara, T., Ushigome, Y., Kano, Y. et al. Crucial Role of Viral Reactivation in the Development of Severe Drug Eruptions: a Comprehensive Review. Clinic Rev Allerg Immunol 49, 192–202 (2015). https://doi.org/10.1007/s12016-014-8421-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12016-014-8421-3

Keywords

Search

Navigation