Identification of herpes simplex virus DNA in lesions of erythema multiforme by the polymerase chain reaction.

An association between erythema multiforme and herpes simplex virus infection has been supported by clinical studies and by the detection by immunofluorescence of herpes viral antigen in sera and skin biopsy specimens of patients with erythema multiforme. In rare cases, the virus has also been isolated in cultures of skin biopsy specimens of erythema multiforme. To investigate further the association between erythema multiforme and herpes simplex virus, we used the polymerase chain reaction for herpes simplex virus to examine skin lesions from patients with erythema multiforme. In this study herpes simplex virus DNA was detected in 11 of 31 biopsy specimens of erythema multiforme; six additional cases showed equivocal amplification results, which is suggestive of low amounts of viral DNA. Seven skin and mucosal biopsy specimens with the histologic changes of herpes virus infection served as positive controls: all were positive for herpes simplex virus DNA. Viral DNA was not detected in control biopsy specimens from skin excised for unrelated conditions. These studies support the association of herpes simplex virus in the pathogenesis of some cases of erythema multiforme. The polymerase chain reaction provides a quick and effective method of detecting herpes simplex virus in lesions of herpes-associated erythema multiforme. Furthermore, the polymerase chain reaction may delineate those cases of erythema multiforme that are etiologically related to herpes virus infection and therefore might be treated with acyclovir to prevent recurrence.     

Erythema multiforme: a case with unusual histopathological features

A 14-year-old boy presented with widespread cutaneous and mucosal lesions clinically consistent with erythema multiforme. He gave a history of previous episodes of a similar eruption. Histological examination of a representative lesion showed changes consistent with erythema multiforme. It also, however, contained large numbers of eosinophils, forming a dermal interstitial infiltrate and epidermal microabscesses. The full blood examination showed a persistent eosinophilia. The appearances initially confused two experienced dermatopathologists.     

Erythema-multiforme-like eruption due to topical contactants: expression of adhesion molecules and their ligands and characterization of the infiltrate

Erythema-multiforme-like reactions are a rare manifestation of allergic contact sensitivity, the pathomechanisms of which and their possible relationship to erythema multiform: remain unclear. We present our histopathological and immunohistochemical findings regarding the expression of several adhesion molecules and inmumophenotypic markers of the infiltrate in skin biopsy specimens from 2 cases of erythema-multiforme-like reactions due to contact sensitizers and 3 -cases of typical post-herpetic erythema multiforme. The histopathological pattern of erythema multiforme-like reactions was characterized by an upper-dermal perivascular tymphoid infiltrate with exocyiosis and keratinocyte necrosis: in 1 of the cases, there were foci of spongiosis and an admixture of eosinophils in the infiltrate. In comparison with biopsy specimens from cases of typical erythema multiforme, in both cases of erythema-multiforme-like reactions, the epidermal expression of ICAM-I was more prominent, the % of CD4⁺ cells in the infiltrate was higher and the % of CD69⁺ cells was lower. There were no other significant differences in the cell phenotype of the infiltrate or in adhesion molecule expression in biopsy samples from both disorders.     

Histopathological spectrum of erythema multiforme

Lesions of erythema multiforme from seventy-five patients have been studied histologically. In addition to peculiar intercellular epidermal oedema, subepidermal separation and a Lymphohistiocytic inflammatory infiltrate in the papillary dermis, epidermal cell necrosis was observed in a variable percentage of the lesions. While dermal disturbance was a predominant finding in the macular lesions, focal or generalized keratinocytic necrosis was seen in the macular, papular, bullous and iris lesions in that order of frequency. Significant numbers of eosinophils were present in the inflammatory infiltrate in 60% of the bullous and 28% of the macular lesions. Our findings suggest that erythema multiforme represents a tissue reaction with spectral expression, one end presenting as a predominantly dermal disturbance and the other merging into the adult type of toxic epidermal necrolysis. Yet, the histological features remain sufficiently characteristic for differentiation from other erythematous and vesiculobullous eruptions.     

Erythema multiforme in a patient with T cell chronic lymphocytic leukemia

A patient with T4+ (helper-inducer) T cell chronic lymphocytic leukemia developed an erythema multiforme-like eruption, the diagnosis of which was supported by routine light microscopic findings. Immunopathologic studies using monoclonal antibodies demonstrate that despite an overwhelming majority of leukemic T4+ cells in the peripheral blood and dermal infiltrate, the predominant cells in the epidermal infiltrate are T8+ (cytotoxic-suppressor) cells. These findings are different from those seen in epidermotropic T cell leukemic infiltrates and are similar to those previously reported in erythema multiforme. Thus it is likely that the leukemic T4+ cells are participating in this cutaneous hypersensitivity reaction along with residual, normal T8+ cells.     

Persistent Erythema Multiforme Treated with Thalidomide

Erythema multiforme is a common self-limited disorder that predominantly affects younger individuals. It is characterized by typical iris or target lesions on the skin and mucous membranes. Three clinical subgroups of erythema multiforme have been identified: classical erythema multiforme, recurrent erythema multiforme, and persistent erythema multiforme. By definition, persistent erythema multiforme is characterized by the occurrence of continuous typical and atypical lesions without interruption. We report a 15-year-old boy who developed persistent erythema multiforme for 6 months and responded to treatment with thalidomide.     

Linear IgA Bullous Dermatosis Mimicking Erythema Multiforme in Adult

This report describes a 49-year-old woman with an erythema multiforme--like rash and direct immunofluorescence showing linear IgA deposits at the dermoepidermal junction. Light microscopy revealed features of bullous pemphigoid, dermatitis herpetiformis, and erythema multiforme; immunoelectron microscopy demonstrated IgA deposition beneath the lamina densa about anchoring fibrils. These data provide additional information about the variable clinical and histologic manifestations of the adult linear IgA bullous dermatosis and emphasize the diagnostic dilemmas of light microscopy, which are resolved by immunohistochemical methods.     

Intermittent oral cyclosporin for recurrent herpes simplex-associated erythema multiforme

Recurrent erythema multiforme is one of three distinct clinical subtypes of erythema multiforme. We present a 42-year-old man with a 10-year history of recurrent herpes simplex virus-induced erythema multiforme. Our patient was debilitated by the frequency of his attacks and the associated pain, for which he often required leave from work. The frequency, duration and morbidity of the attacks were poorly controlled using oral prednisone and oral aciclovir. Three episodes of his recurrent herpes simplex virus-induced erythema multiforme were treated with intermittent oral cyclosporin. Oral cyclosporin rapidly reduced his symptoms and led to rapid resolution of his erythema multiforme, provided the cyclosporin was commenced on day 1 or 2 of the erythema multiforme episode. Consequently, his quality of life has dramatically improved. We recommend the use of intermittent oral cyclosporin for recurrent, debilitating episodes of erythema multiforme.     

Erythema multiforme due to Mycoplasma pneumoniae infection in two children

Mycoplasma pneumoniae is an important and highly relevant cause of bullous erythema multiforme, isolated mucositis, and Stevens-Johnson syndrome in children. In this article, we present two children with respiratory Mycoplasma pneumoniae infection and associated cutaneous findings within the spectrum of erythema multiforme. We review the literature associating these three entities with Mycoplasma pneumoniae infection and discuss controversies regarding the classification of erythema multiforme, as well as update reported infectious causes of the bullous form. Many understand the erythema multiforme spectrum to include bullous erythema multiforme, mucositis, and Stevens-Johnson syndrome in the order of increasing severity. We feel that this relationship should be reconsidered to help better understand the prognosis and outcomes. It is our opinion that bullous erythema multiforme is a separate, yet related condition that can occur in the context of Mycoplasma pneumoniae infection. With many similarities to mucositis and Stevens-Johnson syndrome, bullous erythema multiforme can be considered part of a spectrum of disease that includes Stevens-Johnson syndrome. Unlike mucositis and Stevens-Johnson syndrome, bullous erythema multiforme caused by Mycoplasma pneumoniae infection has low morbidity for the child. Mycoplasma pneumoniae-associated mucositis and Stevens-Johnson syndrome seem to occur along a spectrum with separate prognosis and potential pathogenesis compared with bullous erythema multiforme. Making the distinction between these conditions is valuable for predicting the child's prognosis. Patients who develop symptoms consistent with these conditions should be appropriately evaluated for Mycoplasma pneumoniae infection and closely monitored.     

Histopathologic pattern analysis of human intracutaneous tuberculin reaction

The involvement of cellular immune reactions in the pathogenesis of many inflammatory dermatoses can be postulated from their histopathologic features, e.g., those dermatoses that show a perivascular lymphohistiocytic infiltration in the dermis in addition to their own characteristic epidermal changes. Several granulomatous dermatoses further show an additional infiltration of epithelioid cells. However, experimental production of similar changes is usually not feasible in animals. A human model is needed of delayed-hypersensitivity skin reaction induced by a definite antigen. After closely observing the histopathologic changes of the skin reactions to the purified protein derivative (PPD) of tuberculin, we noted that all patients did not show uniform histologic patterns at intradermal PPD injection sites. Therefore, we have tentatively analyzed histopathologically the pattern of tuberculin skin reactions at injection sites 48 h to 1 year after injection in eight healthy volunteers and 63 patients with various dermatoses. We classified the reactions at 48 h into three types, based on the extent of the tissue damage (i.e., their resemblance to features noted in corresponding inflammatory dermatoses): (a) the perivascular dermatitis type, (b) the basal spongiotic dermatitis type, and (c) the erythema multiforme type. There was a clear correlation between the magnitude of macroscopic skin reactions and these histopathologic patterns. Even those with clinically negative reactions showed a reaction pattern of perivascular dermatitis, whereas those who clinically developed prominent inflammatory reactions with blister formation always showed a erythema multiforme-like histologic pattern. Interestingly, in more than half of the cases, the dermal cellular infiltrate had a mixture of various numbers of neutrophils in addition to mononuclear cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lymphocyte subsets and Langerhans cells/indeterminate cells in erythema multiforme

A peroxidase-antiperoxidase study using monoclonal antibodies directed against T and B lymphocytes and Langerhans cells/indeterminate cells (LC/IC) was undertaken in order to understand more clearly the changes observed in erythema multiforme. At the various stages of development, from normal skin to target lesions, the quantity of inflammatory cells differed, but in each case the number of T8+ (cytotoxic/suppressor) cells was greater than the number of T4+ (helper/inducer) cells in the epidermis, whereas the latter exceeded the former in the dermis. Concomitant with the initial epidermis changes, there was an increase in the number of T6+ (LC/IC) cells in the upper and lower epidermis. With slight to moderate basal unit destruction, the number of LC/IC in the upper epidermis exceeded those in the lower epidermis. With severe basal unit destruction, there was a loss of LC/IC in the lower epidermis as detected by T6 reactivity. In fully formed blisters, the LC/IC in the upper half of the epidermis were decreased in parallel with the degree of epidermal necrosis. The character of the lymphocytic inflammatory infiltrate and redistribution in LC/IC are similar to those findings described in allergic contact dermatitis. The clinical, histologic, and immunopathologic changes in erythema multiforme appear to be due in part to cellular immune mechanisms with the lymphocyte as the predominant effector cell, and our data suggest a possible role for LC/IC in this disorder.     

Recurrent and continuous erythema multiforme– a clinical and immunological study

A series of 26 patients with recurrent erythema multiforme was studied. A distinct clinical and immunological subgroup was found called ‘continuous erythema multiforme’ characterized by the presence of atypical lesions in addition to typical lesions, both of which occur continuously and a high level of circulating immune complexes with low levels of haemolytic complement. Herpes labialis preceded erythema multiforme in 17 of the 26 patients (65%) but in no cases could live virus be isolated from the lesions of erythema multiforme. Circulating immune complexes were found in 50 of 129 sera, being found in only 18 % sera between attacks and more commonly in the first 24 h of erythema multiforme lesions (58%). Immunological studies failed to provide conclusive evidence that erythema multiforme is solely immune complex mediated.     

Cutaneous immunofluorescence study of erythema multiforme: correlation with light microscopic patterns and etiologic agents

Direct immunofluorescence microscopy was positive in 88% of forty-one skin biopsy specimens from thirty-four patients with the clinical diagnosis of erythema multiforme. The most common finding, present in 67% of positive specimens, was the cytoid body, or fluorescent keratinocyte, which stained most often with IgM (homogeneously) or with C3 (speckled). Other findings included basement membrane zone (BMZ) fluorescence, primarily with fibrinogen and C3, and vascular fluorescence, most commonly C3 in a granular pattern. Correlation of direct immunofluorescent and light microscopic findings revealed that (1) the fluorescent keratinocyte was prevalent only in epidermal and mixed patterns, correlating with the eosinophilic necrotic keratinocyte by light microscopy, and (2) vascular fluorescence was most prominent in dermal forms. Herpes simplex-associated erythema multiforme showed exclusively a mixed histologic pattern, whereas the drug-related form was primarily epidermal.     

Oral acyclovir for the prevention of herpes-associated erythema multiforme

Herpes simplex virus is the single most common precipitator of erythema multiforme. Typically, erythema multiforme lesions appear 10 to 14 days after a recurrent herpes simplex virus infection and attacks can be disabling when they occur at frequent intervals. Prior to the introduction of acyclovir (Zovirax), there was no effective therapy to prevent herpes-associated erythema multiforme. Four patients were treated with a maintenance dose of acyclovir for periods ranging from 10 to 26 months; there were no significant side effects from the drug and only one recurrence of erythema multiforme. Oral acyclovir may become the treatment of choice for herpes-associated erythema multiforme.     

Erythema multiforme

In summary, the diagnosis of erythema multiforme is appropriate for a self-limiting or episodic cutaneous or mucocutaneous illness with skin lesions morphologically and histologically compatible. With typical erythema multiforme minor, characterized by classic skin lesions with or without oral erosions, most patients' disease is associated with recurrent herpes simplex infections. This is particularly true with recurrent erythema multiforme. Symptomatic conservative care, antibiotic treatment for purulent secondarily infected oral lesions, and avoidance of systemic steroids are appropriate therapeutic guidelines. The more serious syndrome, erythema multiforme major, or Stevens-Johnson syndrome, is characterized by skin lesions that are somewhat atypical and different from those of erythema multiforme minor in association with erosions on multiple mucosal surfaces. Drugs and mycoplasmal infections are important precipitating factors for erythema multiforme major. Hospitalization and laboratory tests are often required because of the severity of the illness and the occasional damage to other organ systems. Conservative, symptomatic care, withdrawal of any drug that may have caused the illness, treatment of any mycoplasmal infection, and antibiotic therapy for purulent secondarily infected lesions are worthwhile therapeutic measures. Early treatment with systemic steroids may be helpful in preventing further damage, and the risks and potential benefits of such therapy must be evaluated on an individual basis.     

Erythema multiforme following polymorphic light eruption: a report of two cases

We report two patients in whom episodes of polymorphic light eruption were followed by recurrent erythema multiforme on exposed and nonexposed sites. Treating the polymorphic light eruption with prophylactic PUVA and/or oral prednisolone or cyclosporin prevented the development of erythema multiforme, suggesting that the two events are related. It is possible that erythema multiforme develops as a response to the same causative antigen as polymorphic light eruption.     

A Case of Herpetic Whitlow Associated with Erythema Multiforme

Abstract: We report a 6-month-old girl with erythema multiforme minor occurring during the course of a herpetic whitlow. Erythema multiforme minor is unusual in infants, and in this population herpes simplex virus has not been reported as a significant etiologic factor. The clinical coexistence of erythema multiforme minor and the herpetic lesion is also atypical. To our knowledge, this is the first report of erythema multiforme minor associated with a concomitant HSV infection in an infant.     

Urticarial Papular and Plaque Eruptions A Noneczematous Manifestation of Allergic Contact Dermatitis

A noneczematous eruption associated with allergic contact dermatitis is described. Five patients had disseminated erythematous urticarial papular and plaque eruptions secondary to contact allergy to two substances (four to proflavine and one to a permanent waving lotion). The eruption appeared to be similar to the previously described "erythema multiforme-like eruption" associated with allergic contact dermatitis. A review of the previous report indicated that the eruptions currently being reported do not have the typical clinical and histologic features of erythema multiforme. The term "urticarial papular and plaque eruption of contact allergy" is suggested to describe the eruption. The exact mechanism of the eruption remained speculative.     

Isomorphic phenomenon in erythema multiforme

The cutaneous lesions of erythema multiforme have a propensity to localize at previously inflamed or traumatized skin sites. Evidence of the isomorphic phenomenon may be demonstrated in most cases of erythema multiforme by a careful history and physical examination. We present three cases of erythema multiforme which illustrate localization of skin lesions around scratches, recent surgical scars, lacerations, traumatized nail folds and folliculitis. The isomorphic phenomenon may serve as an important clue in understanding the clinical features and possibly, the pathogenesis of erythema multiforme.