Herpes simplex virus associated erythema multiforme (HAEM) is mechanistically distinct from drug-induced erythema multiforme: Interferon-gamma is expressed in HAEM lesions and tumor necrosis factor-alpha in drug-induced erythema multiforme lesions

Erythema multiforme follows administration of several drugs or infection wi th various agents, including herpes simplex virus, a syndrome designated he rpes simplex virus associated erythema multiforme, Lesional skin from 21 of 26 (81%) herpes simplex virus associated erythema multiforme patients was positive for herpes simplex virus gene expression as evidenced by reverse t ranscriptase-polymerase chain reaction with primers for DNA polymerase and/ or immunohistochemistry with DNA polymerase antibody. Reverse transcriptase -polymerase chain reaction and immunohistochemistry studies indicated that herpes simplex virus associated erythema multiforme lesional skin from 16 o f 21 (76%) DNA polymerase positive herpes simplex virus associated erythema multiforme patients was also positive for interferon-gamma, a product of T cells involved in delayed-type hypersensitivity (p < 0.0001 by Pearson cor relation coefficient). Interferon-gamma signals were in infiltrating mononu clear cells and in intercellular spaces within inflammatory sites in the ep idermis and at the epidermis/dermis junction. Herpes simplex virus lesional skin was also positive for DNA polymerase [five of five (100%)] and interf eron-gamma [four of five (80%)], but lesional skin from drug-induced erythe ma multiforme patients was negative. Lesional herpes simplex virus associat ed erythema multiforme keratinocytes also stained with antibody to transfor ming growth factor-beta [14 of 23 (61%)] and cyclin-dependent kinase inhibi tor waf [12 of 18 (67%)]. Staining was also seen in keratinocytes from herp es simplex virus lesions [five of five (100%)], but not in normal skin, By contrast, staining with antibody to tumor necrosis factor-alpha, another pr o-inflammatory cytokine, was seen in seven of 11 (64%) drug-induced erythem a multiforme patients, but not in herpes simplex virus or herpes simplex vi rus associated erythema multiforme patients, and lesional keratinocytes fro m drug-induced erythema multiforme patients were negative for transforming growth factor-beta and cyclin-dependent kinase inhibitor waf. We interpret the data to indicate that herpes simplex virus associated erythema multifor me pathology includes a delayed-type hypersensitivity component and is mech anistically distinct from drug-induced erythema multiforme.