Biagio Napoli

Plastic Surgery and Burns Therapy, Civic Hospital, Palermo, Italy

Dear Sir,

The article by Cabral et al., published in Annals, vol. 17 (2), 2004, reports every other treatment of Lyell’s syndrome (corticosteroids, plasmapheresis, N-acetylcisteine, Pentoxifylline, cyclophosphamide, cyclosporin A, granulocyte colony-stimulating factor, hyperbaric oxygen therapy) but makes no mention of a therapy that in recent years has considerably enriched the literature on the subject.

We are referring to the use of elevated doses of IVIG in the immediate days after the onset of the disease, the rationale of which is the blockade, by the antibodies contained in the preparations of IVIG, of the apoptosis receptor (FAS or CD 95) present on the cell membrane of the keratinocytes and therefore in the competition with its ligand (FAS-L). This is, if not the only mechanism (a perforin-mediated way has been reported), the main pathogenetic mechanism that leads to the death of epithelial cells.

It may therefore be useful to recall some recent case history reports regarding the use of IVIG in Lyell’s syndrome, even if only to demonstrate that a lively debate rotates around this type of therapy (Table I).

As can be seen, not all results show an effective benefit induced by the therapy with IVIG. In the collected cases of Bachot et al. - one of the most numerous - actual mortality (32%) was higher than that expected (24%). Even if the majority of deaths occurred among elderly patients and with kidney failure, the conflicting results led some researchers to suggest that in the absence of any proven effectiveness of IVIG, the only valid therapy (Lyell’s syndrome is a self-limiting disease) is one of support.

It is probably more reasonable to consider a non-routine use of IVIG, also in view of the serious side effects that it is capable of causing, namely:

1. aseptic meningitis, with severe headache, especially in patients with a positive history of hemicranial attacks;
2. serious anaphylactic reactions in patients with IgA deficit in the presence of anti-IgA antibodies that form immunocomplexes with activation of the complement with the IgA contained in IVIG preparations;
3. syndrome caused by haematic hyperviscosity with cerebral ictus, myocardial infarctus, and jugular thrombosis especially in elderly patients or those with extensive vascular disease due to increased risk of thromboembolic episodes;
4. acute kidney failure due to osmotic suffering of the proximal tubule following the use of IVIG containing saccharose.12

High doses of IVIG are widely indicated in addition to its use in Lyell’s syndrome.13 However, the serious side effects (and also the particularly high costs) have induced some researchers to use low doses.

Kofler et al. (1997) successfully treated a case of acquired bullous epidermolysis resistant to therapy with low doses of IVIG.14 Toth et al. (1999) successfully treated a case of penicillin-induced pemphigus foliaceus resistant to low-dose IVIG therapy.

Recently we successfully used low doses of IVIG (gamma venin P 2.5 g 2 per day), in association with frozen fresh plasma (4 units per day) as an adjuvant function to reduce the dosage of corticosteroids and immunosuppressors in a case of very extensive pemphigus vulgaris. We treated the last cases of SJS-Lyell that we have seen with low-dosage IVIC associated with frozen fresh plasma. The administration of frozen fresh plasma has three functions:

1. to provide fluids for reanimation due to the increase of volaemia caused by the increased protein content;
2. to provide a specific treatment for the elevated presence of immunoglobulins;
3. to reduce the dosage of IVIG or to replace its action after suspansion.16

1. Klein P.A., Stevens-Johnson syndrome and Toxic Epidermal Necrolysis, www.emedicine.com/DERM/topic 405.htm.
2. Viard I., Wehrli Ph., Bullani R., Schneider P., Holler N., Salomon D., Hunziker Th., Saurat J.M., Tschopp J., French L.E., Inhibition of toxic epidermal necrolysis by blockade of CD 95 with human intravenous immunoglobulin. Science 1998, 282: 490-493.
3. Morici M.V., Galen W.K., Shetty A.K., Lebouef R.P., Gouri T.P., Cowan G., Gedalia A., Intravenous immunoglobulin therapy for children with Stevens-Johnson syndrome. J. Rheumatol. 2000 Oct. 27 (10): 2494-2497.
4. Paquet P., Jacob E., Damas P., Pierard G.E., treatment of drug-induced toxic epidermal necrolysis (Lyell’s syndrome) with intravenous human immunoglobulins. Burns 2001, 6: 652-655.
5. Stella M., Cassano P., Bollero D., Clemente A., Giorio G., Toxic epidermal necrolysis treated with intravenous high dose immunoglobulins: our experience. Dermatology 2001, 203: 45-49.
6. Tristani-Firouzi P., Petersen M.J., Saffle J.R., Morris S.E., Zone J.J., Treatment of Toxic epidermal necrolysis with intravenous immunoglobulin in children. J. Am. Acad. Dermatol. 2002 Oct., 47 (4): 548-552.
7. Trent J.T., Kirsner R.S., Romanelli P., Kerdel F.A., Analysis of intravenous immunoglobulin for the treatment of toxic epidermal necrolysis using SCORTEN: the University of Miami experience. Arch. Dermatol. 2003 Jan, 139 (1): 39-43.
8. Prins C., Kerdel F.A., Padilla S., Hunziker Th., Chimenti S., Viard I., Mauri D.N., Flynn K., Trent J.T., Margolis D.I., Saurat J.H., French L.E., Treatment of Toxic epidermal necrolysis with high-dose intravenous immunoglobulins. Arch. Dermatol. 2003 Jan., 139 (1):26-32.
9. Bachot N., Revuz J., Roujeau J.C., 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 Jan., 139 (1): 33-36.
10. Al-Mutairi N., Arun J., Osama N-E, Amr Z., Mazen A-S, Ibtesam El-A, Nazeha E-B., Prospective, non comparative open study from Kuwait of the role of intravenous immunoglobulin in the treatment of toxic epidermal necrolysis International Journal of Dermatology Online Early, doi:10.1111/J.1365-4632.2004.02048.x.
11. Bachot N., Roujeau J.C., Intravenous immunoglobulins in the treatment of severe drug eruptions: Curr. Opin. Allergy Clin. Immunol. 2003, 3 (4): 269-274.
12. Laghi Pasini F., Capecchi P.L., Bellisai F., Lazzerini P.E., Galeazzi M., Le indicazioni al trattamento con immunoglobuline endovena nelle malattie reumatiche. Reumatismo 2003, 55 (4): 209-219.
13. Mydlarski P.R., Mittmann N., Shear N.H., Intravenous immunoglobulin: use dermatology, Skin therapy lett. 2004, 9 (5): 1-6.
14. Kofler H., Wambacher-Gasser B., Topar G., Weinlich G., Schuler G., Hintner H., Romani N., Fritsch P., Intravenous immunoglobulin treatment in therapy-resistant epidermolysis bullosa acquisita. J. Am. Acad., Dermatol. 1997 Feb, 36: 331-335.
15. Toth G.G., Jonkman M.F., Successful treatment of recalcitrant Penicillamine-induced Pemphigus Foliaceus by low-dose intravenous immunoglobulins (letter) Br. J. Dermatol. 1999, 141: 583-585.
16. Napoli B., D’Arpa N., Iaia A., Masellis M., Resuscitation treatment in Lyell’s syndrome. Annals of Burns and Fire Disasters, Vol. XVI, n. 3, September 2003, 126-130.