American Journal of Clinical Dermatology

, Volume 4, Issue 8, pp 561–572 | Cite as

Differential Diagnosis of Severe Cutaneous Drug Eruptions

  • Nicolas Bachot
  • Jean-Claude Roujeau
Review Article


Adverse cutaneous reactions to drugs are frequent, mostly secondary to antibacterials, however, serious adverse cutaneous reactions are infrequent. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are a spectrum of the same disease. They are the more severe drug eruptions, with a mortality around 30% for TEN. The confusion between erythema multiforme major and SJS means that erythema multiforme major is the main differential diagnosis. Skin disorders involving desquamation, in particular after pustulosis, are also common differential diagnoses. Mechanical or autoimmune blistering are also potential misdiagnoses of TEN/SJS.

Hypersensitivity Syndrome (HSS) or Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) is a severe cutaneous drug reaction with often a long duration of eruption and serious other organ involvement. Exfoliative dermatitis, whether caused by psoriasis, dermatitis or lymphoma, can be thought of as a differential diagnosis of DRESS/HSS. Angio-immunoblastic lymphadenopathy, viral eruption and vasculitis are other differential diagnoses of DRESS/HSS.

Prompt recognition of a severe drug reaction and withdrawal of the culprit drug is often the most important therapeutic action. Alternatively, a delay in starting a specific treatment for a disease misdiagnosed as a drug eruption could be deleterious.


Toxic Epidermal Necrolysis Bullous Pemphigoid Drug Eruption Erythema Multiforme Pustular Psoriasis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors have provided no information on sources of funding or on conflicts of interest directly relevant to the content of this review.


  1. 1.
    Bigby M, Jick S, Jick H, et al. Drug-induced cutaneous reactions: a report from the Boston Collaborative Drug Surveillance Program on 15 438 consecutive inpatients, 1975 to 1982. JAMA 1986; 256: 3358–63PubMedCrossRefGoogle Scholar
  2. 2.
    Bigby M. Rates of cutaneous reactions to drugs. Arch Dermatol 2001; 137: 765–70PubMedGoogle Scholar
  3. 3.
    Hunziker T, Kunzi UP, Braunschweig S, et al. Comprehensive hospital drug monitoring: adverse skin reactions, a 20-year survey. Allergy 1997; 52: 388–93PubMedCrossRefGoogle Scholar
  4. 4.
    Swanbeck G, Dahlberg E. Cutaneous drug reactions: an attempt to quantitative estimation. Arch Dermatol Res 1992; 284: 215–8PubMedCrossRefGoogle Scholar
  5. 5.
    Ewards IR, Aronson JK. Adverse drug reaction: definition, diagnosis, and management. Lancet 2000; 356: 1255–9CrossRefGoogle Scholar
  6. 6.
    Naldi L, Conforti A, Venegoni M, et al. Cutaneous reactions to drugs: an analysis of spontaneous reports in four Italians regions. Br J Clin Pharmacol 1999; 48: 839–46PubMedCrossRefGoogle Scholar
  7. 7.
    Roujeau JC, Stern RS. Severe cutaneous reactions to drugs. N Engl J Med 1994; 331: 1272–85PubMedCrossRefGoogle Scholar
  8. 8.
    Garcia-Doval I, LeCleach L, Bocquet H, et al. Toxic epidermal necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative drugs decrease the risk of death? Arch Dermatol 2000; 136: 323–7PubMedCrossRefGoogle Scholar
  9. 9.
    Bastuji-Garin S, Rzany B, Stern RS, et al. A clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme. Arch Dermatol 1993; 129: 92–6PubMedCrossRefGoogle Scholar
  10. 10.
    Stevens AM, Johnson FC. A new eruptive fever associated with stomatitis and ophtalmia: report of two cases in children. Am J Dis Child 1922; 24: 526–33Google Scholar
  11. 11.
    Lyell A. Toxic epidermal necrolysis: an eruption resembling scalding of the skin. Br J Dermatol 1956; 68: 355–61PubMedCrossRefGoogle Scholar
  12. 12.
    Bastuji-Garin S, Zahedi M, Guillaume JC, et al. Toxic epidermal necrolysis (Lyell syndrome) in 77 elderly patients. Age Ageing 1993; 22: 450–6PubMedCrossRefGoogle Scholar
  13. 13.
    Auquier-Dunant A, Mockenhaupt M, Naldi L, et al. Erythema Multiforme Majus, Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: correlations between clinical patterns and causes. Results of an international prospective study. Arch Dermatol 2002; 138: 1019–24PubMedCrossRefGoogle Scholar
  14. 14.
    Roujeau JC, Kelly JP, Naldi L, et al. Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 1995; 333: 1600–7PubMedCrossRefGoogle Scholar
  15. 15.
    Fagot JP, Mockenhaupt M, Bouwes-Bavinck JN, et al. Nevirapine and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. AIDS 2001; 28: 1843–8CrossRefGoogle Scholar
  16. 16.
    Rasmussen JE. Update to the Stevens-Johnson syndrome. Cleve Clin J Med 1988; 55: 412–4PubMedGoogle Scholar
  17. 17.
    Roujeau JC, Guillaume JC, Febre JP, et al. Toxic epidermal necrolysis (Lyell syndrome): incidence and drug etiology in France, 1981–1985. Arch Dermatol 1990; 126: 37–42PubMedCrossRefGoogle Scholar
  18. 18.
    Schöpf E, Stühmer A, Rzany B, et al. Toxic epidermal necrolysis and Stevens-Johnson syndrome: an epidemiologic study from West Germany. Arch Dermatol 1991; 127 (6): 839–42PubMedCrossRefGoogle Scholar
  19. 19.
    Fournier S, Bastuji-Garin S, Mentec H, et al. Toxic epidermal necrolysis associated with mycoplasma pneumoniae infection [letter]. Eur J Clin Microbiol Infect Dis 1995; 14: 558–9PubMedCrossRefGoogle Scholar
  20. 20.
    Tay YK, Huff JC, Weston WL. Mycoplasma pneumoniae infection is associated with Stevens-John syndrome, not erythema multiforme (von Hebra). J Am Acad Dermatol 1996; 35: 757–60PubMedCrossRefGoogle Scholar
  21. 21.
    de Groot R, Oranje AP, Vuzevski VD, et al. Toxic epidermal necrolysis probably due to Klebsiella pneumoniae sepsis. Dermatologica 1984; 169: 88–9PubMedCrossRefGoogle Scholar
  22. 22.
    Picard E, Gillis D, Klapholz L, et al. Toxic epidermal necrolysis associated with Klebsiella pneumoniae sepsis. Pediatr Dermatol 1994; 11: 331–4PubMedCrossRefGoogle Scholar
  23. 23.
    Bachot N, Roujeau JC. Physiopathology and treatment of severe drug eruptions. Curr Opin Allergy Clin Immunol 2001; 1: 293–8PubMedGoogle Scholar
  24. 24.
    Becker DS. Toxic epidermal necrolysis. Lancet 1998; 351: 1417–20PubMedCrossRefGoogle Scholar
  25. 25.
    Avakian R, Flowers FP, Araujo OE, et al. Toxic epidermal necrolysis: a review. J Am Acad Dermatol 1991; 25: 69–79PubMedCrossRefGoogle Scholar
  26. 26.
    Revuz J. New advances in severe adverse drug reactions. Dermatol Clin 2001; 19: 697–709PubMedGoogle Scholar
  27. 27.
    Bastuji-Garin S, Fouchard N, Bertocchi M, et al. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol 2000; 115: 149–53PubMedCrossRefGoogle Scholar
  28. 28.
    Prins C, Kerdel FA, Padilla RS, et al. Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins: multicenter retrospective analysis of 48 consecutive cases. Arch Dermatol 2003; 139: 26–32PubMedCrossRefGoogle Scholar
  29. 29.
    Trent JT, Kirsner RS, Romanelli P, et al. Analysis of intravenous immunoglobulin for the treatment of toxic epidermal necrolysis using SCORTEN: The University of Miami Experience. Arch Dermatol 2003; 139: 39–43PubMedCrossRefGoogle Scholar
  30. 30.
    Bachot N, Revuz J, Roujeau JC. Intravenous immunoglobulin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis: a prospective noncomparative study showing no benefit on mortality or progression. Arch Dermatol 2003; 139: 33–6PubMedCrossRefGoogle Scholar
  31. 31.
    Assier H, Bastuji-Garin, S, et al. Erythema multiforme with mucous membrane involvement and Stevens-Johnson syndrome are clinically different disorders with distinct causes. Arch Dermatol 1995; 131: 539–43PubMedCrossRefGoogle Scholar
  32. 32.
    Leauté-Labreze C, Lamireay T, Chawki D, et al. Diagnosis, classification and management of erythema multiforme and Stevens-Johnson syndrome. Arch Dis Child 2000; 83: 347–52PubMedCrossRefGoogle Scholar
  33. 33.
    Machet L, Martin L, Vaillant L. Pustulose exanthématique aiguë généralisée. Ann Dermatol Venereol 2001; 128: 73–9PubMedGoogle Scholar
  34. 34.
    Beylot C, Bioulac P, Doutre MS. Pustuloses exanthématiques aiguës généralisées. A propos de 4 cas. Ann Dermatol Venereol 1980; 107: 37–48PubMedGoogle Scholar
  35. 35.
    Roujeau JC, Bioulac-Sage P, Bourseau C, et al. Acute generalized exanthematous pustulosis. Arch Dermatol 1991; 127: 1333–8PubMedCrossRefGoogle Scholar
  36. 36.
    Sidoroff A, Halevy S, Bavinck JN, et al. Acute generalized exanthematous pustulosis (AGEP): a clinical reaction pattern. J Cutan Pathol 2001; 28: 113–9PubMedCrossRefGoogle Scholar
  37. 37.
    Cohen AD, Cagnano E, Halevy S. Acute generalized exanthematous pustulosis mimicking toxic epidermal necrolysis. Int J Dermatol 2001; 40: 458–61PubMedCrossRefGoogle Scholar
  38. 38.
    De Coninck AL, Van Strubarq AS, Pipeleers-Marichal MA, et al. Acute generalized exanthematous pustulosis induced by paracetamol: a case with severe hemodynamic disturbances. Dermatology 1996; 193: 338–41PubMedCrossRefGoogle Scholar
  39. 39.
    Plano LR, Adkins B, Woischnik M, et al. Toxin levels in serum correlate with the development of staphylococcal scalded skin syndrome in a murine model. Infect Immun 2001; 69: 5193–7PubMedCrossRefGoogle Scholar
  40. 40.
    Kuechle MK, Stegemeir E, Maynard B, et al. Drug-induced linear IgA bullous dermatosis: report of six cases and review of the literature. J Am Acad Dermatol 1994; 30: 187–92PubMedCrossRefGoogle Scholar
  41. 41.
    Nousari HC, Kimyai-Asadi A, Caeiro JP, et al. Clinical, demographic, and immunohistologic features of Vancomycin-Induced Linear Bullous Disease of the skin. Medicine 1999; 78: 1–8PubMedCrossRefGoogle Scholar
  42. 42.
    Schneck B, Termeer C, Mockenhaupt M, et al. Linear IgA dermatosis in an adult with clinical signs of Stevens-Johnson syndrome. Hautarzt 1999; 50: 288–91PubMedCrossRefGoogle Scholar
  43. 43.
    Kaur S, Thami GP, Mohan H, et al. Kikuchi disease with facial rash and erythema multiforme. Pediatr Dermatol 2001; 18: 403–5PubMedCrossRefGoogle Scholar
  44. 44.
    Roustan G, Salas C, Barbadillo C, et al. Lupus erythematosus with an erythema multiforme-like eruption. Eur J Dermatol 2000; 10: 459–62PubMedGoogle Scholar
  45. 45.
    Marzano AV, Berti E, Gasparini G, et al. Lupus erythematosus with antiphospholipid syndrome and erythema multiforme-like lesions. Br J Dermatol 1999; 141: 720–4PubMedCrossRefGoogle Scholar
  46. 46.
    Robinson ND, Hashimoto T, Amagai M, et al. The new pemphigus variants. J Am Acad Dermatol 1999; 40: 649–71PubMedCrossRefGoogle Scholar
  47. 47.
    Nguyen VT, Ndoye A, Bassler KD, et al. Classification, clinical manifestations, and immunopathological mechanisms of the epithelial variant of paraneoplastic autoimmune multiorgane syndrome. Arch Dermatol 2001; 137: 193–206PubMedGoogle Scholar
  48. 48.
    Speron S, Gamelli R. Toxic epidermal necrolysis syndrome versus mycosis fungoides. J Burn Care Rehabil 1997; 18: 421–3PubMedCrossRefGoogle Scholar
  49. 49.
    Saltzstein S, Ackerman L. Lymphadenopathy induced by anticonvulsivant drugs and mimicking clinically and pathologically malignant lymphomas. Cancer 1959; 12: 164–82PubMedCrossRefGoogle Scholar
  50. 50.
    Shear N, Spielberg S. Anticonvulsivant hypersensitivity syndrome: in vitro assessment of risk. J Clin Invest 1988; 82: 1826–32PubMedCrossRefGoogle Scholar
  51. 51.
    Bocquet H, Bagot M, Roujeau JC. Drug induced pseudolymphoma and drug hypersensitivity syndrome (drug rash with eosinopholia and systemic symptoms-DRESS). Semin Cutan Med Surg 1996; 15: 250–7PubMedCrossRefGoogle Scholar
  52. 52.
    Sullivan JR, Shear NH. The drug hypersensitivity syndrome: what is the pathogenesis? Arch Dermatol 2001; 137: 357–64PubMedGoogle Scholar
  53. 53.
    Descamp V, Valence A, Edlinger C, et al. Association of human herpes virus 6 infection with drug reaction with eosiniphilia and systemic symptoms. Arch Dermatol 2001; 137: 301–4Google Scholar
  54. 54.
    Martel P, Laroche L, Courville P, et al. Cutaneous involvement in patients with angioimmunoblastic lymphadenopathy with dysproteinemia. Arch Dermatol 2000; 136: 881–6PubMedCrossRefGoogle Scholar
  55. 55.
    Sigurdsson V, Toonstra J, Hezemans-Boer M, et al. A clinical and follow-up study of 102 patients, with special emphasis on survival. J Am Acad Dermatol 1996; 35: 53–7PubMedCrossRefGoogle Scholar
  56. 56.
    Asai T, Horiuchi Y. Senile erythroderma with serum hyper-IgE. Int J Dermatol 1989; 28: 225–8CrossRefGoogle Scholar
  57. 57.
    Abel EA. Diagnosis of drug-induced psoriasis. Semin Dermatol 1992; 11: 269–74PubMedGoogle Scholar
  58. 58.
    Wilson NJ, Evans S. Severe pustular psoriasis provoked by oral terbinafine. Br J Dermatol 1998; 139: 168PubMedCrossRefGoogle Scholar
  59. 59.
    Papa CA, Miller OF. Pustular psoriasiform eruption with leukocytosis associated with terbinafine. J Am Acad Dermatol 1998; 39: 115–7PubMedCrossRefGoogle Scholar
  60. 60.
    Gupta AK, Lynde CW, Lauzon GJ, et al. Cutaneous adverse effects associated with terbinafine therapy: 10 case reports and a review of the literature. Br J Dermatol 1998; 138: 529–32PubMedCrossRefGoogle Scholar
  61. 61.
    De Silva BD, Benton EC, Tidman MJ. Generalized pustular psoriasis following withdrawal of oral cyclosporin treatment for palmo-plantar pustulosis. Clin Exp Dermatol 1999; 24: 10–3PubMedCrossRefGoogle Scholar
  62. 62.
    Davis MDP, Daoud MS, McEvoy MT, et al. Cutaneous mainfestations of Churg-Strauss syndrome: a clinicopathologic correlation. J Am Acad Dermatol 1997; 37: 199–203PubMedCrossRefGoogle Scholar
  63. 63.
    Guillevin L, Le THD, Godeau P, et al. Clinical findings and prognosis of polyarteritis nodosa and Churg and Strauss angiitis: a study in 165 patients. Br J Rheumatol 1988; 27: 258–64PubMedCrossRefGoogle Scholar
  64. 64.
    Pinching AJ, Lockwood CM, Pussel BA, et al. Wegener’s granulomatosis: observations on 18 patients with severe renal disease. Q J Med 1983; 208: 435–60Google Scholar
  65. 65.
    Cardinali C, Giomi B, Caproni M, et al. Maculopapular lupus rash in a young woman with systemic involvement. Lupus 2000; 9: 713–6PubMedCrossRefGoogle Scholar
  66. 66.
    Schacker T, Collier AC, Hughes J, et al. Clinical and epidemiologic features of primary HIV infection. Ann Intern Med 1996; 125: 257–64PubMedGoogle Scholar
  67. 67.
    Stoeckle MY. The spectrum of human herpesvirus 6 infection: from roseola infantum to adult disease. Annu Rev Med 2000; 51: 423–30PubMedCrossRefGoogle Scholar
  68. 68.
    Renn CN, Straff W, Dorfmüller A, et al. Amoxicillin-induced exanthema in young adults with infectious mononucleosis: demonstration of drug-specific lymphocyte reactivity. Br J Dermatol 2002; 147: 1166–70PubMedCrossRefGoogle Scholar
  69. 69.
    Barbaud A, Goncalo M, Bruynzeel D, et al. Guidelines for performing skin tests with drugs in the investigation of cutaneous adverse drug reactions. Contact Dermatitis 2001; 45: 321–8PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2003

Authors and Affiliations

  1. 1.Department of Dermatology, Hôpital Henri MondorUniversité Paris XIICréteilFrance

Personalised recommendations