Recurrent Erythema Multiforme Research Articles

Examination of non-involved skin, previously involved skin, and peripheral blood for herpes simplex virus DNA in patients with recurrent herpes-associated erythema multiforme.

The association between infection with HSV and the subsequent development of erythema multiforme is well established, although the role that the virus plays in the pathogenesis of this disorder is not known. HSV DNA has been detected in cutaneous lesions of herpes-associated erythema multiforme (HAEM), and it has been suggested that the tissue damage seen in these lesions is virus-specific. In the current, prospective study, we examined biopsies of lesional, non-involved, and previously involved but healed skin, in addition to specimens of peripheral blood, from patients with HAEM, for HSV DNA by using the polymerase chain reaction. HSV DNA was detected in lesional skin of 10 of 11 patients compared to 2 of 11 non-involved skin biopsies obtained at the same time. HSV was present in 4 of 6 blood specimens obtained during the acute episode. Five patients returned 3 months after the acute episode resolved for biopsies of previously involved skin. HSV was detected in 4 of these 5 biopsies. Thus, the presence of HSV DNA in the skin of patients with HAEM appears to be predominantly in areas of clinical involvement; the virus remains in those cutaneous sites for up to 3 months without evidence of clinical disease; and HSV DNA may be detected in the peripheral blood cells during acute HAEM. Based on these findings, we suggest that the virus plays a role in lesion development, that the skin may function as a site of viral persistence, and that hematogenous spread of viral DNA may be an important factor in the development of HAEM.

Recurrent post-herpetic erythema multiforme mimicking polymorphic light and juvenile spring eruption: report of two cases in young boys

We report two young boys with a variant of recurrent post-herpetic erythema multiforme which clinically mimicked polymorphic light eruption and juvenile spring eruption.

Recurrent erythema multiforme: clinical features and treatment in a large series of patients

Recurrent erythema multiforme is an uncommon disorder. We have reviewed the clinical features and treatment of 65 patients with this condition. The mean number of attacks per year was six (range 2-24), and the mean duration of the disease was 9.5 years (range 2-36) reflecting its chronicity. The majority of patients had oral mucous membrane involvement (69%). In 46 patients (71%) the condition was precipitated by a preceding herpes simplex virus infection. Acyclovir was found to be the most useful first-line treatment, with 55% of patients deriving benefit from either continuous oral acyclovir or a patient-initiated 5-day oral course at the onset of herpes simplex virus infection. Of those failing to respond to acyclovir, a small proportion responded to dapsone. The most resistant patients (11) were treated with azathioprine, with complete disease suppression in all cases.

Natural history, management and complications of herpes labialis.

Infection with herpes simplex virus (HSV) is a common worldwide problem. Primary infection with HSV-1 rarely causes significant problems although widespread involvement in atopic eczema can be life-threatening as may associated encephalitis. Keratoconjunctivitis, pharyngitis and hepatitis can also complicate primary infection. Twenty to 40% of the population at some stage have recurrent orolabial infections with HSV although in only 1% of these cases is this recurrence severe. Recurrent erythema multiforme appears to be associated with HSV-65% of patients are thought to have preceding herpes labialis. Many primary and recurrent infections with HSV-1 require little more than topical antiseptic therapy to control secondary infection. Systemic acyclovir, however, is indicated in various situations including complicated primary infection, infection in neonates, eczema herpeticum, HSV infections in the immunocompromised, and recurrent erythema multiforme. In the latter, prophylactic treatment with 6 months acyclovir appears to be effective.

Recurrent Erythema Multiforme

Recurrent erythema multiforme (EM), an uncommon disorder, becomes disabling in some patients because of frequent recurrences over many years. To better evaluate precipitating events for the disorder and its response to treatment, these authors studied 65 patients with recurrent EM. The mean age of onset was 29 years, the mean number of attacks per year was 6, (range, 2 to 24), and the mean duration of disease was 9 1/2 years (range, 2 to 36). …

Detection of viral DNA within skin of healed recurrent herpes simplex infection and erythema multiforme lesions.

The polymerase chain reaction (PCR) was used to detect HSV DNA in genomic DNA extracted from skin biopsies obtained from healed skin of five patients with hyperpigmented macules following recurrent cutaneous HSV infections and from eight patients with HSV-associated erythema multiforme (EM). A 92-bp HSV-1 DNA fragment was found in all the skin biopsies from the site of recurrent HSV infection and in five of eight (62%) biopsies from the EM patients. Virus DNA was not found in tissues distant from the site of HSV recurrence or from a patient without a history of HSV infection. These findings confirm the presence of HSV in healed skin from the site of recurrent HSV disease and are consistent with the concept that HSV is involved in EM pathogenesis.

Herpes simplex virus antigens and inflammatory cells in oral lesions in recurrent erythema multiforme. Immunoperoxidase and autoradiographic studies.

Herpes simplex virus (HSV) antigens were sought in 15 biopsy specimens from both lesional mucosa and clinically healthy looking oral mucosa between attacks in patients with erythema multiforme (EM). Four of the eight biopsy specimens obtained from lesional EM mucosa stained positively with HSV-1-and/or HSV-2-specific antisera applied in direct immunoperoxidase staining. Of the 16 tissue specimens used as controls, two displayed positive staining with HSV-1 and/or HSV-2. Five of the seven biopsy specimens from macroscopically healthy oral mucosa obtained between attacks from patients with recurrent EM stained positively with HSV-1 and/or HSV-2. Of the six tissue specimens used as controls, three stained positively. Most of the local inflammatory mononuclear cells belonged to the T cell series, mainly to the CD-4 subset. A small proportion of the local T cells were blast transformed as assessed by CD-25 expression and [3H]thymidine incorporation. This, together with the findings showing a lower degree of activation in the biopsy from macroscopically healthy looking mucosa between attacks suggest an active role of the cell-mediated immune response in the genesis of oral lesions in EM. The persistence of HSV antigens, and the well-established role of HSV as a precipitating factor in recurrent EM, suggest that HSV may be involved, but since HSV seems to be present in other mucosal lesions as well as in clinically healthy mucosa, quite frequently an additional, hitherto unknown factor must be present in order that EM may occur.

An electron microscopic study of oral lesions in erythema multiforme.

The ultrastructure of oral lesions in 6 patients with erythema multiforme (EM) and of one apparently clinically healthy oral mucosa in one patient with recurrent EM during remission is described. Alterations were observed in epithelium, basal lamina and lamina propria. Both intercellular and intracellular oedema, intracellular vacuolization, decreased numbers of desmosomes, and also loss of cytoplasmic organelles and occasional nuclei were noted in the epithelium. Inflammatory cells--mainly lymphocytes--were found intra-epithelially. Several discontinuities together with some evidence of duplication of the basal lamina were seen in five of the six lesional mucosa specimens. The inflammatory infiltrate in the lamina propria consisted mainly of lymphocytes, although plasma cells, neutrophilic and eosinophilic leukocytes, macrophages and mast cells were also found. Some of the mast cells were partly degranulated. The apparently clinically healthy oral mucosa in the patient with EM in remission showed mild inflammatory changes. The changes observed in the lesional mucosa in EM are thus according to our study mostly non-specific inflammatory alterations and are not pathognomonic for EM.

An electron microscopic study of oral lesions in erythema multiforme.

The ultrastructure of oral lesions in 6 patients with erythema multiforme (EM) and of one apparently clinically healthy oral mucosa in one patient with recurrent EM during remission is described. Alterations were observed in epithelium, basal lamina and lamina propria. Both intercellular and intracellular oedema, intracellular vacuolization, decreased numbers of desmosomes, and also loss of cytoplasmic organelles and occasional nuclei were noted in the epithelium. Inflammatory cells--mainly lymphocytes--were found intra-epithelially. Several discontinuities together with some evidence of duplication of the basal lamina were seen in five of the six lesional mucosa specimens. The inflammatory infiltrate in the lamina propria consisted mainly of lymphocytes, although plasma cells, neutrophilic and eosinophilic leukocytes, macrophages and mast cells were also found. Some of the mast cells were partly degranulated. The apparently clinically healthy oral mucosa in the patient with EM in remission showed mild inflammatory changes. The changes observed in the lesional mucosa in EM are thus according to our study mostly non-specific inflammatory alterations and are not pathognomonic for EM.

Herpes simplex virus antigens and inflammatory cells in oral lesions in recurrent erythema multiforme. Immunoperoxidase and autoradiographic studies.

Herpes simplex virus (HSV) antigens were sought in 15 biopsy specimens from both lesional mucosa and clinically healthy looking oral mucosa between attacks in patients with erythema multiforme (EM). Four of the eight biopsy specimens obtained from lesional EM mucosa stained positively with HSV-1-and/or HSV-2-specific antisera applied in direct immunoperoxidase staining. Of the 16 tissue specimens used as controls, two displayed positive staining with HSV-1 and/or HSV-2. Five of the seven biopsy specimens from macroscopically healthy oral mucosa obtained between attacks from patients with recurrent EM stained positively with HSV-1 and/or HSV-2. Of the six tissue specimens used as controls, three stained positively. Most of the local inflammatory mononuclear cells belonged to the T cell series, mainly to the CD-4 subset. A small proportion of the local T cells were blast transformed as assessed by CD-25 expression and [3H]thymidine incorporation. This, together with the findings showing a lower degree of activation in the biopsy from macroscopically healthy looking mucosa between attacks suggest an active role of the cell-mediated immune response in the genesis of oral lesions in EM. The persistence of HSV antigens, and the well-established role of HSV as a precipitating factor in recurrent EM, suggest that HSV may be involved, but since HSV seems to be present in other mucosal lesions as well as in clinically healthy mucosa, quite frequently an additional, hitherto unknown factor must be present in order that EM may occur.

Erythema multiforme

Erythema multiforme (EM) is an acute, self-limited cutaneous or mucocutaneous disorder, characterized by the development of symmetrically distributed, fixed, red lesions. Some lesions evolve concentric zones of color to form “targets,” the hallmark of EM. The spectrum of disease known as erythema multiforme includes the more common and familiar form, designated EM minor (von Hebra), and a more serious mucocutaneous process, designated EM major (Stevens-Johnson syndrome). Both forms of EM may follow a number of precipitating factors, primarily infections or drugs. EM minor most frequently follows an infection with herpes simplex virus (HSV), and in those cases, the disease often recurs with subsequent HSV infection. Recently, the presence of HSV specific antigens and nucleic acids were demonstrated within the epidermis of cutaneous lesions of recurrent EM minor. These findings, together with results of immunopathology studies, support the concept that EM lesions may result from an immune-mediated response to HSV present in the skin at those sites. In EM major, drug exposure is more frequently the precipitating factor. There is evidence to suggest that in those cases, a toxic mechanism directed at the skin may be important. Recent studies carefully detailing the usual clinical course and histologic features of EM, together with investigative studies examining potential pathomechanisms, have begun to yield a clearer picture of this disease process such that a more rational approach to therapy is now possible.

Recurrent erythema multiforme: a possible role of foodstuffs.

Seven patients are described, who presented with a history of recurrent episodes of erythema multiforme and who were subsequently found to be sensitive, by patch testing, to benzoic acid. Advice on avoidance of benzoic acid resulted in resolution of attacks in four patients, but three patients who were not able to adhere to an exclusion diet continued to have symptoms. These findings implicate benzoic acid, a food preservative, as an aetiological factor in erythema multiforme. It is proposed that patch testing to food substances should be carried out on patients who present with recurrent erythema multiforme, since avoidance of potential allergens may lead to resolution of symptoms.

Recurrent erythema multiforme.

In a prospective clinical study of erythema multiforme (EM), we identified 22 subjects who experienced more than 1 episode. These subjects were young, with an average age of 29 years. They had an average number of 12 previous episodes, with each episode lasting 3 weeks. The average interval between episodes was 4.9 months. We counted the number and location of each skin lesion and found that patients had an average of 188 EM skin lesions at the time of their evaluation. We found the isomorphic phenomenon, that is, lesions appearing at sites of skin trauma, in 19 of the 22 study subjects; photodistribution of skin lesions in 15 of the 22, grouping of the lesions over the elbow and knees in 7 of the 22, and nailfold involvement in 7 of the 22. In this study there was compelling evidence for herpes simplex virus association with recurrent EM. All 22 patients had histories of herpes simplex virus infections preceding at least 1 of their previous episodes of EM. Sera from all study subjects had antibodies to HSV detectable by enzyme immunoassay. None, however, had HSV isolated from the throat at the time of the EM or from an EM skin lesion. All 11 patients who were subsequently tested had positive viral cultures for HSV taken from the suspected recurrent herpes lesion. When 8 EM skin biopsies were examined by indirect immunofluorescence with a monoclonal antibody to the type common HSV glycoprotein gB, all had positive staining of keratinocytes. Only one-third of patients with a single episode of EM had a history of possible herpes lesions preceding EM.(ABSTRACT TRUNCATED AT 250 WORDS)

Association of herpes simplex virus-induced erythema multiforme with the human leukocyte antigen DQw3.

We studied the genetic markers in human leukocyte antigen (HLA) region HLA-A, -B, -C, -DR, -DQ, C2, Bf, C4A, and C4B of 31 patients with erythema multiforme (EM) and their families. In contrast to the complement allotypes, which showed no deviation from the distribution in the normal population, two HLA class II antigens occurred in much higher frequency in patients with EM. The frequency of HLA-DQw3 (77.4%) increased with high significance compared with normal Caucasian control individuals (41.2%). An even stronger DQw3 association was found in the patient group with postherpetic EM (88.8%; relative risk, 9.41). Interestingly, all patients suffering from frequently recurrent EM were found to have the DQw3 allele (relative risk 44.2). The previously reported association to HLA-B15 was also seen and may be due to a linkage disequilibrium with the HLA-DR4 allele (66.6% in recurrent EM). Our data provide further evidence that classic recurrent EM is related to herpes simplex virus infection and should be regarded as a distinct entity within the enigmatic EM syndrome. DQw3 may serve as a helpful marker for distinguishing this entity from other diseases with EM-like lesions.

Episodic Conjunctival Inflammation after Stevens-Johnson Syndrome

The authors studied the histopathologic, ultrastructural, and immunopathologic characteristics of conjunctiva from patients with Stevens-Johnson syndrome (SJS). A small subset of SJS patients with recurrent conjunctival inflammation unassociated with external factors such as lid margin keratinization, sicca syndrome, trichiasis, or entropion was identified. The ultrastructural and immunopathologic characteristics of the conjunctiva from these patients were distinctly different from those of the conjunctiva from SJS patients without recurrent conjunctivitis, and suggested an active, immunologically mediated inflammation. Vasculitis or perivasculitis, immunoreactant deposition in vessel walls, vascular basement membrane disruption, thickening, and reduplication, and a preponderance of helper T-lymphocytes, macrophages, and Langerhans' cells were the notable distinguishing features in those patients with recurrent conjunctival inflammation. This rare clinical syndrome may represent the ocular counterpart to recurrent dermal or oral mucosal erythema multiforme.

Acyclovir for recurrent erythema multiforme caused by herpes simplex

Herpes-associated erythema multiforme can be controlled by continuous suppressive treatment with oral acyclovir. Erythema multiforme is not prevented if oral acyclovir is administered after a herpes simplex recurrence is evident and it is of no value after erythema multiforme has occurred. There is some question whether continuous topical treatment with acyclovir to sites of recurrent herpes will sometimes prevent erythema multiforme. Erythema multiforme may be precipitated by orolabial and genital recurrences and by recurrences on skin of the buttocks and other sites. Some herpetic recurrences are associated with erythema multiforme and some are not and episodes of erythema multiforme are not always associated with clinical herpetic recurrences.

Diagnosis and Management of Chronic Oral Mucosal Bullous Diseases

Chronic blistering diseases involving the mouth are frequently difficult to diagnose correctly and can present a problem with management. Pemphigus vulgaris, cicatricial pemphigoid, and recurrent oral erythema multiforme may be difficult to separate from each other and from other erosive diseases such as recurrent aphthous stomatitis and erosive lichen planus. Essential to establishing a correct diagnosis is a pertinent history, a physical examination, and histopathologic and direct immunofluorescence studies. Oral pemphigus vulgaris can usually be managed successfully with prednisone alone but occasionally another immunosuppressive medication in concurrence with prednisone is necessary. Dapsone is the most efficacious treatment for oral cicatricial pemphigoid, and brief courses of prednisone usually control individual episodes of severe recurrent oral erythema multiforme. It is important that physicians who undertake treatment of these diseases be fully aware of the untoward effects of the medications that are being utilized.

An immunopathological study of herpes-associated erythema multiforme.

Any pathogenetic mechanism proposed for erythema multiforme (EM) must account for the prominent mononuclear cell infiltrate in the skin lesions. The purpose of this study was to characterize immunopathologically, with monoclonal antibodies to human leukocyte antigens, the inflammatory cells in early target lesions of recurrent herpes-associated EM. Cryostat sections of snap-frozen skin biopsies were studied by the avidin-biotin immunoperoxidase technique with use of the following monoclonal antibodies: anti-HLA-DR, anti-Leu M5, anti-Leu 4 + 5b, anti-Leu 3a + 3b, anti-Leu 2a, anti-Leu 14, and anti-Leu 6. The dermal mononuclear inflammatory infiltrate in the EM biopsies consisted of monocyte-macrophages and T-lymphocytes, with both helper and suppressor T cells present. Both the dermal inflammatory infiltrate and the overlying keratinocytes were strongly HLA-DR positive. No definite alteration of Langerhans cell number or distribution was noted. These findings are consistent with the characteristics seen in cell-mediated immune reactions in the skin and point to this as a likely immune mechanism for the tissue damage of EM.

Recurrent and continuous erythema multiforme--a clinical and immunological study.

Summary 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.

Erythema multiforme: Clinical, histopathologic, and immunologic study

In a prospective study of erythema multiforme, forty-two cases were selected with the use of defined criteria. In thirty-three cases (79%), the erythema multiforme occurred following a lesion of recurrent herpes simplex; in four cases (10%), it was related to administration of a sulfonamide drug. Herpes-associated erythema multiforme (HEM) was largely recurrent erythema multiforme minor and was characterized histopathologically by inflammatory changes, such as spongiosis and exocytosis, and by focal liquefaction degeneration of the basal cell zone of the epidermis. Sulfa-associated erythema multiforme (SEM) was a nonrecurrent illness with widespread cutaneous and mucosal damage associated with prominent histologic necrosis of epidermal cells. The deposition of C3 and fibrin along the dermoepidermal junction and the deposition of IgM, C3, and fibrin around dermal blood vessels by immunofluorescence microscopy were similar in both groups. Although HEM and SEM may have somewhat different clinical and histologic features, there is significant overlap in the pattern of tissue damage.