Erythema multiforme: Differences between HSV‐1 and HSV‐2 and management of the disease—A case report and mini review

Erythema multiforme (EM) is an immune‐mediated reaction characterized by target lesions and with possible mucosal involvement. Its most frequent cause is HSV, with HSV‐1 more common than ?2. It is usually self‐limited but it can show recurrences. We report a peculiar case of recurrent herpes‐associated erythema multiforme (HAEM) in a 35‐year‐old man. The patient was affected by both herpes labialis and genitalis, but the typical target lesions were only associated with recurrent herpes labialis. Here, we hypothesize about the pathogenic differences between HSV‐1 and HSV‐2, and discuss the therapeutic management of HAEM.     

Detection of herpes simplex virus genomic DNA in various subsets of Erythema multiforme by polymerase chain reaction

BACKGROUND: The wide variation in the detection of herpes simplex virus (HSV) DNA (36-75%) by polymerase chain reaction (PCR) in erythema multiforme (EM) may be partly attributed to differences in case selection in terms of subsets of EM studied. OBJECTIVE: To determine the frequencies of detection of HSV DNA in specific subsets of EM. METHODS: Nested PCR was used to detect HSV DNA in skin biopsies with histologically proven EM. RESULTS: PCR was performed on skin biopsies from 63 patients with EM. HSV DNA was detected in 3/11 (27.2%) of single-episode HSV-associated EM (HAEM), 6/10 (60%) of recurrent HAEM, 1/4 (25%) of single-episode idiopathic EM and 6/12 (50%) of recurrent idiopathic EM. HSV DNA was not detected in atypical EM (0/11), suspected drug-induced EM (0/9) or Stevens-Johnson syndrome (0/6). CONCLUSION: The overall PCR positive rates of HAEM (42.9%) and idiopathic EM (43.8%) were comparable suggesting that idiopathic EM is likely to be related to a subclinical HSV infection.     

Case of autoimmune progesterone dermatitis presenting as necrotic migratory erythema successfully controlled by danazol

Autoimmune progesterone dermatitis (APD) is a rare cutaneous disorder with cyclic skin eruptions during the luteal phase of the menstrual cycle. Patients can present with various clinical manifestations, including urticaria and angioedema, erythema multiforme, eczema, fixed drug eruption and centrifugal erythema annulare. In our case, however, the patient’s skin lesions mimic necrotic migratory erythema (NME) which is most commonly associated with glucagonoma and rarely with liver disease, inflammatory bowel disease, malnutrition and other tumors. To our knowledge, this is the first case of NME-like APD and is successfully controlled by danazol. This also sheds lights on the etiologic diversity of NME.     

The herpes-specific immune response of individuals with herpes-associated erythema multiforme compared with that of individuals with recurrent herpes labialis

Infection with herpes simplex virus (HSV) is the most common precipitating factor in the development of erythema multiforme (EM). It is not known why only a few of the many individuals who experience recurrent HSV infection also develop herpes-associated EM (HAEM), although a difference in the HSV-specific immune response has been postulated. The purpose of this study was to compare the HSV-specific immune response of individuals with HSV infection alone with that of individuals with HAEM. There were 21 patients in each of the two groups. Four parameters of the HSV-specific immune response were examined: (1) anti-HSV IgG titers were measured by ELISA; (2) antibody neutralization was assessed using a plaque assay; and (3) antibody-dependent complement-mediated cytotoxicity, and (4) antibody-dependent cellular cytotoxicity were investigated using a previously described in vitro HSV-specific cytotoxicity assay. No statistically significant differences were detected between the two patient groups. Thus, a difference in these HSV-specific immune mechanisms does not explain the development of HAEM in some individuals with recurrent HSV infection.Grant support: AI 16637 from the National Institutes of Allergy and Infectious Disease     

Detection of HSV-specific DNA in biopsy tissue of patients with erythema multiforme by polymerase chain reaction

Formalin-fixed paraffin-embedded skin biopsies of lesions of erythema multiforme (EM) from 32 patients and 13 controls were examined for the presence of herpes simplex virus (HSV) by polymerase chain reaction (PCR) and for histological findings by direct immunofluorescence and staining with haematoxylin and eosin. HSV-specific DNA was detected in 23 (72%) patients. A history of recurrent skin rash was present in 59% of the PCR-positive cases, while 55% had had suspected HSV infections. Only two PCR-positive specimens were found in patients without a history of recurrent rash and/or previous oral lesions. One biopsy was positive for HSV by conventional cell cultures. There was no significant difference in histology between HSV-related and HSV-negative cases of EM. In the 13 control specimens [bullous pemphigoid (3), dermatitis herpetiformis (2), lichen planus (1), aphthous ulcer (1), fixed-drug eruption (1), varicella-zoster (1), hypereosinophilic syndrome (1), photocontact dermatitis (1), contact dermatitis (1), and cellulitis (1)], no HSV-DNA was detected.     

Erythema multiforme after orf virus infection

The case of a 6‐year‐old boy with multiple, target‐shaped lesions and a crusted nodule on his right index finger is presented. Based on clinical findings and the patient's recent contact with sheep and goats, a diagnosis of orf disease associated with erythema multiforme was suspected. Microscopy studies confirmed the presence of parapoxvirus in the primary lesion. Orf‐induced erythema multiforme is a rare complication of orf in children, possibly related to the presence of orf virus DNA in erythema multiforme lesions.     

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.     

Postherpetic erythema exsudativum multiforme with concomitant exacerbation of psoriasis vulgaris

Herpes simplex virus (HSV) infection is a well-known trigger mechanism for both erythema multiforme (EM) and psoriasis. While HSV-related EM and psoriasis are not uncommon, simultaneous development of both disorders following HSV infection is relatively rare. We report on a patient who simultaneously developed both EM and a guttate psoriasis within 16 days of an HSV infection. The major differences in the pathophysiological mechanisms by which these dermatoses are triggered are discussed.     

Histiocytic erythema multiforme

Erythema multiforme is histologically characterized by liquefactive degeneration along the dermal-epidermal junction, necrotic keratinocytes and a lymphocytic infiltrate. We report a 10-year-old boy with recurrent erythema multiforme major of undetermined etiology with unusual histologic findings. A skin biopsy taken at day 2 of his eruption revealed histologic features otherwise characteristic of erythema multiforme, but mediated instead by a CD68-positive infiltrate, resembling cutaneous Kikuchi's disease. To the best of our knowledge this is the first reported case of 'histiocytic' erythema multiforme.     

Successful differentiation of herpes zoster‐associated erythema multiforme from generalized extension of herpes by rapid polymerase chain reaction analysis

The polymerase chain reaction (PCR) assay for varicella zoster virus (VZV), herpes simplex virus (HSV)‐1 and HSV‐2 is available for use. Sometimes the differential diagnosis of the generalized herpes zoster (HZ), HSV1/2, and drug eruption is difficult. We report a case of HZ followed by the vesicular erythema multiforme (EM)‐like lesion. In this case the use of PCR was of great assistance. A 78‐year‐old Japanese man without any significant previous history of disease was admitted to our hospital complaining of zosteriform vesicle on an erythematous base from his right shoulder to the upper arm. We diagnosed him with HZ at the level of right Th2. In spite of the prompt start of antiviral therapy, a secondary new vesiculous erythema developed on his trunk. Clinically, it was quite difficult to differentiate the lesion from the generalized HZ. Rapid PCR assay of effusion and crust for VZV was performed. A PCR assay of VZV was positive for the crust taken from the primary lesion, while it was negative for the effusion and crust of the secondary widespread lesion. We diagnosed the secondary widespread lesion as an EM‐type drug eruption induced by acyclovir, or an EM associated with herpes zoster. We then stopped the use of acyclovir and applied steroid ointment of a very strong class for the secondary lesions, which improved after a few days. A PCR assay for VZV was useful for ruling out the generalized HZ in our case with secondary developed vesiculous lesions.     

Progesterone sensitive Interferon-gamma producing cells detected by ELISpot assay in autoimmune progesterone dermatitis

Autoimmune progesterone dermatitis (APD) is a rare cutaneous disorder, characterized by recurrent polymorphous cutaneous and mucosal manifestations. It is considered to be caused by a hypersensitive reaction to endogenous progesterone. However, in vitro T-cell activity to this hormone has been described in few patients. Here we report the case of a 30-year-old woman with recurrent pruritic erythematous, and erythema multiforme-like eruptions localized to the genital area. Positive cutaneous reaction to intradermal progesterone injection suggested the diagnosis of APD. The analysis of cellular immune response to progesterone, investigated by the ELISpot assay, showed a significantly higher level of Interferon-gamma (IFN-gamma) producing cells in this patient compared with a control group comprising five asymptomatic women in the luteal phase of the menstrual cycle. Our results suggest that the ELISpot technique, together with clinical evaluations and assessment of allergies, could be useful in the diagnosis of APD.     

Recurrent erythema multiforme: tissue typing in a large series of patients

Previous reports have shown an increased frequency of certain HLA antigens in association with erythema multiforme, including HLA-B15(B62), HLA-B35, HLA-A33, HLA-DR53 and, more recently, HLA-DQB1*0301. A strong association with HLA-DQ3 has been documented in patients with recurrent erythema multiforme. We have performed HLA typing in 39 patients with recurrent erythema multiforme, of whom 33 were associated with herpes simplex virus infection. The results were compared with 309 controls. In the recurrent erythema multiforme patients there was a statistically significant increase in HLA-B62 and HLA-B35. An increase in HLA-DR53 was also found, although this did not reach statistical significance. There was no increase in HLA-A33. The presence of HLA-DQ3 in the study population approached that in the controls. Finally, the study population demonstrated a trend towards a reduction in the HLA antigens A1, B8, and DR3. The study confirms the previously reported associations with HLA-B62 (B15), HLA-B35 and HLA-DR53. We have been unable to confirm an association of HLA-A33 or HLA-DQ3 with erythema multiforme. The HLA antigens A1, B8, and DR3 are associated with autoimmune disease, reflecting an increased host response to tissue self antigens. Their absence in patients with recurrent erythema multiforme (REM) may be an indicator of a poor host response to an antigen, which in the case of REM is the herpes simplex virus.     

用聚合酶链反应检测多形红斑皮损中单纯疱疹病毒的DNA

用聚合酶链反应检测２３例多形红斑石蜡组织切块中ＨＳＶ－ＤＮＡ，１６例为阳性（６９．５６％），其中ＨＳＶ－Ⅰ型１３例（８１．２５％），ＨＳＶ－Ⅱ型３例（１８．７５％）。对照组为银屑病３例，大疱性类天疱疮５例，扁平苔藓３例均为阴性。对于探讨ＨＳＶ在多形红斑发病机理中的作用有重要意义。     

Herpes simplex virus type 1 as a cause of widespread intracorneal blistering of the lower limbs

Herpes simplex virus (HSV) infections often manifest as acute self-limiting eruptions of grouped vesicles, which have a tendency to recur. Common manifestations include that of gingivostomatitis, vulvovaginitis, recurrent erythema multiforme, herpetic whitlow, and eczema herpeticum. We report a case of HSV-1 presenting as a symmetrical intracorneal blistering eruption involving the lower limbs in a patient with no previous history of herpes simplex infection.     

阿达木单抗联合丙种球蛋白治疗HSV相关性慢性复发性多形红斑一例

本文报道种球蛋白联合阿达木单抗治疗单纯疱疹病毒(HSV)相关的复发性多形红斑1例并复习相关文献。患儿,男,9岁。口唇反复糜烂、渗出15个月,全身反复红斑8个月。皮肤科查体:口唇糜烂,背部、四肢散在暗红色斑片,局部周边可见松弛水疱。病理检查符合多形红斑,单纯疱疹病毒I型IgG滴度444.72 RU/mL。诊断为单纯疱疹病毒感染相关多形红斑,给予伐昔洛韦抗病毒治疗的同时,给予阿达木单抗联合人免疫球蛋白治疗,2周后皮损消退,单纯疱疹病毒I型IgG滴度明显下降。     

ERYTHEMA MULTIFORME: EPIDEMIOLOGY, CLINICAL CHARACTERISTICS AND NATURAL HISTORY IN FIFTY-NINE PATIENTS

In this paper we report fifty-nine patients with erythema multiforme. Thirty-four of the patients were classified as erythema multiforme major (EM major) or Stevens- Johnson syndrome and the other twenty-five erythema multiforme minor (EM minor). The overall features of this group of fifty-nine patients are discussed and the significant differences between the two sub-groups (EM major and EM minor) highlighted.     

Clinical features, diagnosis, and treatment of erythema multiforme: a review for the practicing dermatologist

Erythema multiforme (EM) is an uncommon, immune-mediated disorder that presents with cutaneous or mucosal lesions or both. In herpes simplex virus (HSV)-associated EM, the findings are thought to result from cell-mediated immune reaction against viral antigen-positive cells that contain the HSV DNA polymerase gene (pol). The target lesion, with concentric zones of color change, represents the characteristic cutaneous finding seen in this disorder. Although EM can be induced by various factors, HSV infection continues to be the most common inciting factor. Histopathologic testing and other laboratory investigations may be used to confirm the diagnosis of EM and to differentiate it from other clinical imitators. Imitators of EM include urticaria, Stevens-Johnson syndrome, fixed drug eruption, bullous pemphigoid, paraneoplastic pemphigus, Sweet's syndrome, Rowell's syndrome, polymorphus light eruption, and cutaneous small-vessel vasculitis. Because disease severity and mucosal involvement differ among patients, treatment should be tailored to each patient, with careful consideration of treatment risk vs benefit. Mild cutaneous involvement of EM can be managed primarily with a goal of achieving symptomatic improvement; however, patients with HSV-associated recurrent EM and idiopathic recurrent EM require treatment with antiviral prophylaxis. Inpatient hospitalization may be required for patients with severe mucosal involvement that causes poor oral intake and subsequent fluid and electrolyte imbalance. With this review, we strive to provide guidance to the practicing dermatologist in the evaluation and treatment of a patient with EM.     

Interventions for erythema multiforme: a systematic review

Treatment of erythema multiforme (EM) is not codified. We performed a systematic review of the effect of any topical or systemic treatment on time to healing and frequency of episodes with acute and chronic forms of EM in adults. Four databases (MEDLINE, CENTRAL, EMBASE and LILACS) and other sources were searched for articles published up to 20 March 2018. Randomized control trials (RCTs), observational studies and case series (n ≥ 10) were considered. From 1558 references, we included one RCT and six case series. The RCT (n = 20) showed a significant difference in complete remission of EM with continuous acyclovir vs. placebo over 6 months. One case series found a mean reduction in flare duration with thalidomide for recurrent EM (5.1 vs. 16.2 days; n = 20). Adverse events were poorly or not reported in included studies. Quality of life was never assessed. One limitation of our study is that we excluded the cases of isolated mucosal EM in order to prevent inclusion of Stevens‐Johnson syndrome cases. In conclusion, there is low‐level evidence for continuous acyclovir treatment for recurrent EM (one RCT). Evidence for other treatments is only based on retrospective case series. Results for thalidomide, in particular, encourage further research. Data concerning safety are insufficient. PROSPERO registration no. CRD42016053175.     

Detection of herpes simplex virus DNA in cutaneous lesions of erythema multiforme

The association between erythema multiforme (EM) and herpes simplex virus (HSV) infection has long been appreciated, although the exact role which HSV may play in the pathogenesis of this herpes-associated EM (HAEM), is unknown. Previous studies have suggested, but not definitively demonstrated, the presence of HSV in lesions of HAEM. The presence of HSV would support the hypothesis that an immune-mediated response directed against HSV-specific antigens in the skin is central to lesion development in HAEM. The purpose of this study was to examine lesions of EM for the presence of HSV DNA by using the polymerase chain reaction (PCR). In addition, in situ hybridization using an HSV-specific RNA probe was performed to further localize the HSV nucleic acids within the skin. DNA was extracted from formalin-fixed, paraffin-embedded specimens of cutaneous lesions of HAEM and also from EM for which no precipitating factor could be documented, otherwise known as idiopathic EM (IPEM). DNA from lesions of bullous pemphigoid served as a negative control. Using PCR to specifically amplify HSV sequences which might be present, and then performing Southern analysis, we demonstrated HSV DNA in 9/13 HAEM and 6/9 IPEM biopsies. No HSV was detected in six lesions of bullous pemphigoid. In situ hybridization of three cutaneous HAEM lesions using an 35S-labeled HSV-specific RNA probe localized the HSV nucleic acids predominantly to the epidermis. Three biopsies of chronic dermatitis, used as negative controls, did not demonstrate this specific hybridization. These findings confirm the presence of HSV in lesions of HAEM and are consistent with the concept of an HSV-specific immune-mediated pathogenesis for this disease. In addition, most cases of IPEM appear to be herpes associated despite the absence of clinically apparent HSV infection.