Correspondence

Toxic Epidermal Necrolysis

N Engl J Med 1996; 334:922-923April 4, 1996

Article

To the Editor:

Roujeau et al. (Dec. 14 issue)1 present data showing a morbidity of 1 in 230,000 associated with toxic epidermic necrolysis and the Stevens–Johnson syndrome due to one week of trimethoprim–sulfamethoxazole therapy. If the death rate is assumed to be 15 percent,2 the mortality rate would be 1 in 1,550,000. It would be interesting to know the actual mortality among their index patients.

To put this excess mortality in context, it is similar to the transfusion-associated frequency of human immunodeficiency virus transmission in Germany (1 in 800,000 to 1 in 2,000,000)3,4 and the United States (1 in 450,000 to 1 in 660,000).5 In many countries, including the United States and Germany, as a result of recent court rulings, patients are to be informed about this adverse effect and the therapeutic alternatives, even if blood transfusion is only a remote possibility.

A consistent approach would imply that before prescribing trimethoprim–sulfamethoxazole one should counsel patients about the associated risk of death and obtain informed consent. However, it is difficult for patients to understand the small risk figures. Being told about a singular, exactly quantified adverse effect may impede patients' perception of other, often more important adverse effects. Compliance will probably be reduced. We question whether explicit counseling about a very low mortality risk benefits patients and would like to know the authors' views on this.

The authors conclude with the statement that “prescribing physicians should still consider that alternative therapies have substantially lower excess risks.” What are the rational options for the practitioner? What is the impact of the excess mortality due to toxic epidermic necrolysis on the overall mortality associated with trimethoprim–sulfamethoxazole? Can we conclude with sufficient confidence that alternative therapies, such as amoxicillin or fluoroquinolones for urinary tract infections, are associated with lower overall mortality rates? Since trimethoprim–sulfamethoxazole is inexpensive, how much in additional costs for alternative therapies should be deemed acceptable?

Franz F. Wagner, M.D.
Willy A. Flegel, M.D.
University of Ulm, D-89081 Ulm, Germany

5 References

1
Roujeau J-C, Kelly JP, Naldi L, et al. Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 1995;333:1600-1607
Full Text | Web of Science | Medline

2
Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med 1994;331:1272-1285
Full Text | Web of Science | Medline

3
Gluck D, Elbert G, Dengler T, et al. HIV lookback of the Red Cross blood banks in Germany. Infusionsther Transfusionsmed 1994;21:368-375
Medline

4
Zeiler T, Kretschmer V, Sibrowski W, et al. A retrospective investigation concerning the practice of HIV lookback methods, the incidence of HIV-1/2-positive blood donors and the risk of transfusion-associated HIV infection from blood donations of governmental and communal blood transfusion services in Germany. Infusionsther Transfusionsmed 1994;21:362-367
Medline

5
Lackritz EM, Satten GA, Aberle-Grasse J, et al. Estimated risk of transmission of the human immunodeficiency virus by screened blood in the United States. N Engl J Med 1995;333:1721-1725
Full Text | Web of Science | Medline

To the Editor:

Because in children toxic epidermal necrolysis can be easily confused with staphylococcal scalded skin syndrome, Roujeau and colleagues included children in their study “only if they had mucous-membrane erosions or target-like lesions, or had had a skin biopsy.” For the rapid differentiation of staphylococcal scalded skin syndrome from toxic epidermal necrolysis, a frozen section of peeled skin1 can be analyzed. The level of the skin split in staphylococcal scalded skin syndrome is the epidermal granular-cell layer, whereas in toxic epidermal necrolysis the level is subepidermal, with a full-thickness necrotic epidermis (Figure 1AFigure 1Peeled skin from a Patient with Toxic Epidermal Necrolysis (Panel A) and a Patient with Staphylococcal Scalded Skin Syndrome (Panel B). and Figure 1B). It is interesting to note that in his original 1956 description of toxic epidermal necrolysis, Lyell2 included a case of adult staphylococcal scalded skin syndrome. This led to two decades of confusion because the terminology for staphylococcal scalded skin syndrome and toxic epidermal necrolysis overlapped, with terms such as Lyell's syndrome, staphylococcal-induced toxic epidermal necrolysis, and drug-induced scalded skin syndrome. These last three terms should no longer be used.

Henry M. Feder, Jr., M.D.
Diane M. Hoss, M.D.
University of Connecticut Health Center, Farmington, CT 06030

Robert L. Dimond, M.D.
Dartmouth–Hitchcock Medical Center, Lebanon, NH 03756

2 References

1
Amon RB, Dimond RL. Toxic epidermal necrolysis: rapid differentiation between staphylococcal- and drug-induced disease. JAMA 1975;111:1433-1437

2
Lyell A. Toxic epidermal necrolysis: an eruption resembling scalding of the skin. Br J Dermatol 1956;68:355-361
CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Drs. Wagner and Flegel comment on the excess mortality due to Stevens–Johnson syndrome or toxic epidermal necrolysis in relation to the administration of sulfonamides and question whether other antiinfective drugs are safer.

Our study was designed to quantify the risks of occurrence of these severe skin reactions in relation to medication use. The results demonstrated that the risk of Stevens–Johnson syndrome or toxic epidermal necrolysis was significantly higher with antibacterial sulfonamides than with aminopenicillins or quinolones. Among our 245 patients, the actual death rate was 16 percent (38 deaths among 241 patients with information on vital status). Fortunately, most patients survived the reactions, and our study therefore lacked the statistical power to detect a significant difference in the number of deaths among users of various drugs. A higher risk of developing these reactions clearly indicates not only a higher morbidity but also an increased risk of mortality. We agree that it is difficult to appreciate the clinical relevance of very rare adverse events and to counsel patients on such risks. It is of course necessary to consider an overall estimation of the risk–benefit ratio. In that respect our study provided useful data for quantifying one type of side effect.

Dr. Feder and coworkers advocate the use of histologic examination of a frozen section of peeled skin for the rapid differentiation of staphylococcal scalded skin syndrome from toxic epidermal necrolysis. That technique, used in some of the patients included in our study, has been used in Créteil for years and has proved helpful. However, we now rely on examination of the frozen section of a full-thickness skin biopsy, because it is as easy to do and is less prone to misinterpretation of the level of separation.

Jean-Claude Roujeau, M.D.
Hôpital Henri Mondor, 94010 Créteil, France

David W. Kaufman, Sc.D.
Boston University School of Medicine, Boston, MA 02118

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