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.     

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.     

寻常型银屑病与单纯疱疹病毒1型相关性的研究

目的 探讨寻常型银屑病与单纯疱疹病毒1型(HSV-1)的可能相关性。方法 应用PCR法检测患者皮损、外周血单一核细胞(PBMCs)和咽拭子中HSV-1DNA,ELISA法检测患者血清中抗HSV-1的IgM、IgG抗体,并与正常人对照做比较。结果 患者皮损、PBMCs和咽拭子中HSV-1DNA检出率分别为37.5%、18.6%和18.8%,血清中抗HSV-1的IgM、IgG抗体检出率分别为37.2%和53.5%.经χ²检验,患者皮损、PBMCs中HSV-1DNA和血清中IgM抗体检出率显着高于正常人对照,点滴状患者的皮损、PBMCs和咽拭子中HSV-1DNA以及血清中抗HSV-1IgM抗体检出率显着高于斑块状患者。结论 寻常型银屑病尤其是皮损呈点滴状者与HSV-1显着相关,患者可能存在HSV-1的近期感染。     

Mast cells in oral erythema multiforme.

We compared the number of mast cells in erythema multiforme lesions, in clinically healthy mucosa between the EM attacks and in healthy mucosa from healthy volunteers. The mast cell count in patients with erythema multiforme was numerically higher than in healthy controls, but the differences were not statistically significant. In erythema multiforme lesions the mast cell count was low in the intensely inflamed superficial lamina propria, but high in normal appearing mucosa between the attacks suggesting local mast cell degranulation in the most intensely inflamed areas.     

Herpes folliculitis: clinical, histopathological, and molecular pathologic observations

BACKGROUND: Herpes folliculitis is a rare manifestation of herpes virus infection and it is often misdiagnosed. Diagnostic criteria are not well established, only 24 patients being reported in the literature. Recently it has been suggested that herpetic folliculitis is more common in infections with varicella zoster (VZV) than in those with herpes simplex viruses (HSV-1 and -2). OBJECTIVES: To refine diagnostic criteria for folliculitis caused by VZV, HSV-1 and HSV-2, and to study whether follicular involvement enables morphological differentiation between VZV and HSV infections. PATIENTS AND METHODS: Twenty-one patients with herpetic infection of follicular epithelium were assessed clinically and histopathologically. Polymerase chain reaction (PCR) studies for specific DNA of herpes viruses were performed on paraffin-embedded biopsy specimens. RESULTS: In 17 of our cases PCR was positive for VZV, four were positive for HSV-1, none for HSV-2. The clinical presentation of herpes folliculitis often lacked vesicles or pustules (14/21). Histopathological features were often devoid of ballooning (12/21), multinucleated giant cells (12/21) and keratinocytes with steel grey nuclei (15/21). The most consistent findings were lymphocytic folliculitis and perifolliculitis (20/21) and necrotic keratinocytes in follicular epithelium (12/21). In zoster, but not in varicella eruption or HSV infections, follicular involvement was unaccompanied by marked changes in the epidermal surface. CONCLUSIONS: In biopsy specimens taken from herpes virus infections, involvement of follicular units is more commonly encountered in VZV infections compared with HSV infections. Early in the course, herpes folliculitis presents as lymphocytic folliculitis devoid of epithelial changes considered to be diagnostic of herpes virus infections. Exclusive involvement of follicles is rather typical of zoster.     

Herpes simplex virus (HSV)-associated erythema multiforme (HAEM): a viral disease with an autoimmune component

Erythema multiforme (EM) is a clinical conundrum the name of which reflects the broad morphological spectrum of the lesions. Molecular and immunologic evidence that herpes simplex virus (HSV) causes a subset of EM lesions [herpes-associated EM (HAEM)] is reviewed, and new data are presented which suggest that autoreactive T-cells triggered by virus infection play an important role in HAEM pathogenesis. Disease development begins with viral DNA fragmentation and the transport of the DNA fragments to distant skin sites by peripheral blood mononuclear cells (PBMCs). HSV genes within DNA fragments deposited on the skin [notably DNA polymerase (Pol)] are expressed, leading to recruitment of HSV-specific CD4+ Th1 cells that respond to viral antigens with production of interferon-gamma (IFN-gamma). This step initiates an inflammatory cascade that includes expression of IFN-gamma induced genes, increased sequestration of circulating leukocytes, monocytes and natural killer (NK) cells, and the recruitment of autoreactive T-cells generated by molecular mimicry or the release of cellular antigens from lysed cells. The PBMCs that pick up the HSV DNA [viz. macrophages or CD34+ Langerhans cells (LC) precursors], their ability to process it, the viral proteins expressed in the skin and the presence of epitopes shared with cellular proteins may determine whether a specific HSV episode is followed by HAEM development. Drug-associated EM (DIEM) is a mechanistically distinct EM subset that involves expression of tumor necrosis factor alpha (TNF-alpha) in lesional skin. It is our thesis that the polymerase chain reaction (PCR) assay for HSV DNA detection in lesional skin and staining with antibodies to IFN-gamma and TNF-alpha, are important criteria for the diagnosis of skin eruptions and improved patient management.     

Expression of cytokines and chemokine receptors in the cutaneous lesions of erythema multiforme and Stevens-Johnson syndrome/toxic epidermal necrolysis

BACKGROUND: Erythema multiforme (EM) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are caused by a dysregulation of cellular immunity. OBJECTIVES: To evaluate further the potential role of certain cytokines and chemokine receptors in cutaneous lesions of patients affected by EM and SJS/TEN and to establish whether such diseases are polarized preferentially towards a T-helper (Th) 1 or Th2 pattern. METHODS: Biopsy specimens from eight patients with EM, six with SJS/TEN and three healthy controls were stained for immunohistochemical examination using the alkaline phosphatase-antialkaline phosphatase method. The monoclonal antibodies used included those to tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-2, IL-5, IL-13, receptor 3 for C-C chemokines (CCR3), receptor 3 for C-x-C chemokines (CXCR3) and CXCR4. RESULTS: The SJS/TEN specimens showed significantly higher expression of all the cytokines and chemokine receptors (except CXCR3) tested than the EM specimens. Both lesional series showed significantly higher expression of all the receptors tested than the healthy control specimens, with the sole exception of a lower expression of CCR3 in EM specimens. Comparison between molecules associated with a Th1 or Th2 response revealed a predominance of Th1 response in EM and no significant imbalance between Th1 and Th2 in SJS/TEN. CONCLUSIONS: We have provided further evidence that TNF-alpha is strongly expressed in SJS/TEN lesions and therefore it may be involved in the epidermal necrosis featured in such diseases. IFN-gamma may play an important role both in EM and SJS/TEN. IL-2, IL-5 and IL-13 may contribute to the cutaneous immunoinflammation in these diseases. Chemokine receptors may be involved strongly in the recruitment of inflammatory cells in lesional skin. In our cases we found a sharp polarization towards a Th1 pattern in EM, while the SJS/TEN lesions showed a mixed Th1/Th2 pattern.     

Investigation of herpes simplex virus DNA in pityriasis rosea by polymerase chain reaction

BACKGROUND: Pityriasis rosea (PR) is an acute, inflammatory disease of unknown cause. Clinical and experimental findings indicate an infectious etiology of PR. Our purpose is to examine the skin lesions and blood samples of PR patients by polymerase chain reaction (PCR) for the presence of HSV type 1 and 2 DNA. METHODS: The lesional skin biopsies from 10 patients and blood samples from two randomized patients with clinically and histologically confirmed pityriasis rosea were examined by PCR. RESULTS: No HSV 1 and HSV 2 DNA was detected in the lesional biopsy and blood samples. CONCLUSIONS: We could not identify a relationship between HSV 1, HSV 2 and PR.     

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.     

Progressive macular hypomelanosis in Singapore: a clinico-pathological study

INTRODUCTION: Progressive macular hypomelanosis (PMH), a condition of uncertain etiology, is characterized by asymptomatic hypopigmented macules predominantly located on the trunk. To date, there are no reports from South-East Asia concerning this condition. We sought to record the clinical features of PMH in Asian patients, identify etiologic factors, and study the structural and ultrastructural features of melanocytes in this disorder. METHODS: Patients who presented to the National Skin Center with acquired, hypopigmented macules on the trunk, without a history of inflammation or infection, were recruited. Erythrocyte sedimentation rate (ESR), complete blood count, fasting blood glucose, liver function tests, skin scrapings for fungi, and skin biopsy specimens (from lesional and normal skin) were obtained. Biopsies were stained with hematoxylin and eosin (H&E), Fontana Masson, an immunohistochemical panel for identification of melanocyte differentiation antibodies (HMB 45, Melan A, and S100) and CD 68. Electron microscopy (EM) was also performed. The patients were evaluated every 3 months. RESULTS: During a 9 month period, eight patients (all Chinese) presented with hypopigmented, ill-defined, confluent macules involving the lower aspect of the trunk. There were four men and four women, and the mean age was 25.9 years (range 19-45 years). Skin scrapings were negative for fungi and laboratory tests were normal. Microscopic evaluation of skin biopsy specimens showed reduced pigmentation of lesional as compared with normal appearing skin, but H&E-stained sections revealed only minimal histologic differences between lesional and normal skin. EM demonstrated a statistically significant (P = 0.047, Wilcoxon Signed Rank Test, Wilcoxon 95% CI 0.02-0.62) higher ratio of stage IV and late stage III (dark) melanosomes in normal vs. lesional skin. CONCLUSIONS: PMH may occur among young adults in Singapore. Its etiology is uncertain. The melanin content of lesional skin appears to be less than that in normal sites. EM shows a higher ratio of immature melanosomes in lesional vs. normal skin.     

Detection of herpes simplex virus DNA in serum and oral secretions during acute recurrent herpes labialis

Although herpes simplex virus (HSV) has been detected in the peripheral blood of immunocompromised patients and in neonates with disseminated disease, the extent to which the virus may be present in the blood during a localized infection in otherwise healthy patients is still unknown. Literature on patterns of HSV shedding into the oral cavity at the prodromal stage of the disease, during recurrences, and also during asymptomatic periods is still lacking. The present study aims at the detection of HSV DNA in the serum and oral secretions during acute herpes labialis using a highly sensitive technique, the polymerase chain reaction (PCR). The study included 10 patients with acute herpes labialis and five healthy controls. Using PCR, herpes simplex virus DNA was detected in the serum of seven patients (70%) and in the saliva of nine patients (90%). One of the control cases showed positive HSV DNA in the saliva (20%). There was good statistical agreement between the presence of HSV DNA in the serum and saliva. Frequency of attacks, patient's age, and gender had no statistically significant effect on the presence of the virus in serum or in saliva. It is concluded that HSV viremia during attacks of recurrent herpes simplex is more frequent than previously appreciated.     

CD36(OKM5)+ dendritic cells in the oral mucosa of HIV- and HIV+ subjects.

In this study, we have investigated by light and electron microscopy the presence, distribution, and inner structure of CD36(OKM5)+ dendritic cells (DC) in the lamina propria and epithelium of the oral mucosa of HIV- and HIV+ subjects; in the latter, both clinically healthy areas and areas of hairy leukoplakia (HL) were studied. Perivascular CD36+ DC were present in the lamina propria of all the specimens studied. They were also found in small numbers in the epithelium of clinically healthy mucosa of HIV- and HIV+ subjects, but were practically absent from the epithelium of HL. CD36+ DC seemed to be regularly HLA-DR+ in HIV-subjects; this positivity was recognized only in some cells in the clinically healthy mucosa of HIV+ subjects, and practically never in HL. Because the only perivascular cells observed in the clinically healthy areas of HIV+ subjects were CD36+, we investigated the ultrastructure of perivascular DC in these same areas. These cells were characterized by the presence of a prominent Golgi apparatus, many lysosomes, and focal adhesions to the extracellular matrix. It may be concluded that 1) CD36+ DC are physiologic components of the oral mucosa, 2) they share some ultrastructural features with macrophages, 3) no differences in numbers were found between HIV+ and HIV- subjects, and 4) these cells are affected in their expression of HLA-DR antigens during HIV infection, particularly in areas of HL. This may be a hint that the antigen-presenting function of these cells in the oral mucosa is negatively affected during HIV infection.     

Chronic herpes simplex virus type I glossitis in an immunocompromised man

Herpes simplex virus (HSV) type 1 (HSV-1) infection of the tongue commonly accompanies acute primary herpetic gingivostomatitis. However, recurrent infection of the tongue is exceptional and is restricted to immunocompromised individuals. A 57-year-old man with corticosteroid-dependent chronic obstructive pulmonary disease and sciatica presented with a chronic median glossitis due to HSV-1. The main clinical and histological feature was massive necrosis of the entire mucosa. Immunohistochemistry demonstrated a considerable amount of HSV gB, gC and gD envelope glycoproteins dispersed in the chorion. In contrast, HSV-1 DNA was detected only in a limited number of epithelial cells using in situ hybridization. The extent of necrosis and the pattern of viral DNA and envelope protein distribution represent unique features of median herpetic glossitis, which are not found in more common types of HSV infection.     

Herpes simplex virus infection of the hand

The first episode of herpes simplex virus (HSV) infection of the hand can occur in association with infection at another site, such as primary HSV-1 gingivostomatitis. Autoinoculation is the likely route of transmission. The attacks are usually solitary and last about 14 days. A first episode that results from exogenous inoculation may be severely inflammatory and may last up to 28 days. The majority of cases are recurrent infections and most often occur in adults with HSV-2 infection.     

Herpes simplex virus infection and genital ulcer disease among patients with sexually transmitted infections in Dar es Salaam, Tanzania

The relative importance of Haemophilus ducreyi and Treponema pallidum in genital ulcer disease in Africa has decreased recently, whereas that of herpes simplex virus (HSV) type 2 has increased. We analysed 301 lesional specimens from Tanzanian patients with genital ulcer disease for the presence of H. ducreyi, T. pallidum and HSV-1/HSV-2 by performing a separate PCR for each pathogen. Infectious agents were detected in 211 (70%) of the cases. A single pathogen was found in 191 samples and two or more pathogens in the remaining 20. HSV-2 represented 83% of all identified pathogens, HSV-1 8%, T. pallidum 4% and H. ducreyi 5%. HSV-1 was identified as a single pathogen in four samples, in combination with others in an additional 14 samples. Thus, HSV-1 can also be the cause of genital ulcer disease in Africa. Regular surveillance of genital ulcer disease aetiology is important in programs for management of genital ulcer disease and HIV in Africa.     

Recurrent erythema multiforme triggered by progesterone sensitivity

Determining the underlying etiology of recurrent erythema multiforme (EM) can be a difficult endeavor. Although infection with herpes simplex virus (HSV) has been implicated in some cases, the precise trigger of a given patient's recurrent EM often remains elusive. We discuss the case of a woman with a recurrent blistering eruption that was clinically and histopathologically consistent with EM. An investigation into the etiology of the patient's EM suggested that HSV was not the causative factor but instead pointed toward a hormonal influence that we interpret as autoimmune progesterone dermatitis (APD). This case is presented to highlight the importance of considering hormonal triggers in women with recurrent EM that consistently flares during the luteal phase of the menstrual cycle, the point at which serum progesterone levels peak. A brief review of the literature regarding the diagnosis, histopathology, etiology and treatment of APD is further provided. Nasabzadeh TJ, Stefanato CM, Doole JE, Radfar A, Bhawan J, Venna S. Recurrent erythema multiforme triggered by progesterone sensitivity.     

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。     

天疱疮或大疱性类天疱疮合并单纯疱疹病毒感染8例临床特征及治疗分析

目的回顾分析天疱疮/大疱性类天疱疮(BP)合并单纯疱疹病毒(HSV)感染的临床特征及治疗方法。方法回顾分析2016—2021年在武汉市第一医院住院治疗的天疱疮/BP合并HSV感染病例的临床特征及治疗和随访情况。结果 8例天疱疮/BP合并HSV感染患者中, 男2例, 女6例, 年龄(50.6 ± 8.3)岁, 包括5例寻常型天疱疮, 1例落叶型天疱疮, 2例BP。7例合并HSV-1感染, 1例合并HSV-2感染。8例均因天疱疮或BP接受系统糖皮质激素及免疫抑制剂治疗, 并对治疗抵抗入院, 其中7例表现为原发病灶加重或复发, 1例表现为全身皮损增加。HSV感染位于躯干4例, 口腔4例, 头皮3例, 面部2例。皮疹表现为不规则的糜烂面, 伴血痂, 部分为中央有脐凹的脓疱, 7例伴有皮疹处明显疼痛。发生HSV感染时, 6例天疱疮患者抗Dsg1抗体均下降, 5例寻常型天疱疮中4例抗Dsg3抗体下降;2例BP患者中1例抗BP180抗体降低, 1例升高。予足量足疗程抗病毒治疗(伐昔洛韦或更昔洛韦治疗7 ～ 14 d), 所有患者HSV感染均被控制, 自身免疫性大疱性皮肤病严重程度评分较抗病毒治疗前均...     

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.     

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.