Herpes Simplex Virus-associated Erythema Multiforme Research Articles

Clonal expansion of CD4+CD8+ T cells in an adult patient with Mycoplasma pneumoniae-associated Erythema multiforme majus

BackgroundErythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease, most often preceded by herpes simplex virus (HSV) infection or reactivation. Mycoplasma pneumoniae (Mp) is considered the second major trigger of EM and is often associated with an atypical and more severe presentation of disease, characterized by prominent mucosal involvement. However, contrary to HSV-associated Erythema multiforme (HAEM), immunological mechanisms of Mp-associated EM remain unclear.Case presentationWe present the case of a 50-year-old male patient presenting with community-acquired pneumonia (CAP) and erythema multiforme majus (EMM). Acute Mp infection was diagnosed by seroconversion, with no evidence of HSV infection as a cause of EMM. We performed immune phenotyping of blister fluid (BF) and peripheral blood (PB) T cells and detected a clonally expanded TCRVβ2+ T cell population that was double positive for CD4 and CD8, and expressed the cytotoxic markers granulysin and perforin. This CD4+CD8+ population comprised up to 50.7% of BF T cells and 24.9% of PB T cells. Two years prior to the onset of disease, the frequency of PB CD4+CD8+T cells had been within normal range and it gradually returned to baseline levels with the resolution of symptoms, suggesting an involvement of this population in EMM disease pathophysiology.ConclusionsThis report is the first to provide a phenotypic description of lesional T cells in Mp-associated EMM. Characterizing the local immune response might help to address pathophysiological questions and warrants further systematic research.

Current Perspectives on Erythema Multiforme.

Recognition and timely adequate treatment of erythema multiforme remain a major challenge. In this review, current diagnostic guidelines, potential pitfalls, and modern/novel treatment options are summarized with the aim to help clinicians with diagnostic and therapeutic decision-making. The diagnosis of erythema multiforme, that has an acute, self-limiting course, is based on its typical clinical picture of targetoid erythematous lesions with predominant acral localization as well as histological findings. Clinically, erythema multiforme can be differentiated into isolated cutaneous and combined mucocutaneous forms. Atypical erythema multiforme manifestations include lichenoid or granulomatous lesions as well as lesional infiltrates of T cell lymphoma and histiocytes. Herpes simplex virus infection being the most common cause, other infectious agents like-especially in children-Mycoplasma pneumoniae, hepatitis C virus, Coxsackie virus, and Epstein Barr virus may also trigger erythema multiforme. The second most frequently identified cause of erythema multiforme is drugs. In different studies, e.g., allopurinol, phenobarbital, phenytoin, valproic acid, antibacterial sulfonamides, penicillins, erythromycin, nitrofurantoin, tetracyclines, chlormezanone, acetylsalicylic acid, statins, as well as different TNF-α inhibitors such as adalimumab, infliximab, and etanercept were reported as possible implicated drugs. Recently, cases of erythema multiforme associated with vaccination, immunotherapy for melanoma, and even with topical drugs like imiquimod have been described. In patients with recurrent herpes simplex virus-associated erythema multiforme, the topical prophylactic treatment with acyclovir does not seem to prevent further episodes of erythema multiforme. In case of resistance to one virostatic drug, the switch to an alternative drug, and in patients non-responsive to virostatic agents, the use of dapsone as well as new treatment options, e.g., JAK-inhibitors or apremilast, might be considered.

Erythema multiforme syndrome associated with acute acquired cytomegalovirus infection.

A 7-year-old boy was admitted to the pediatric ward (University of Chieti) for the onset of multiple erythematous target lesions, some with vesicles in the middle, located on the ears, face (Figure 1 A), in the oral cavity (Figure 1 B), on both hands, feet and lower limbs. Four days prior to admission the patient presented prodromal symptoms, such as fever (maximum temperature 38°C), sore throat and asthenia. All these features supported a diagnosis of erythema multiforme (EM) secondary to an infection. Blood examination revealed lymphopenia (1.28 × 10,000/µl), neutrophilia (6.10 × 10,000/µl), erythrocyte sedimentation rate of 15 mm/h (normal range: 1–12 mm/h) and alanine aminotransferase of 80 U/l (normal range: 11–66). Serum antibodies against Mycoplasma pneumoniae, Adenovirus, Varicella Zoster, Epstein-Barr virus and Herpes Simplex Virus (HSV) 1 and 2 were negative. In contrast, cytomegalovirus (CMV) IgM antibody titers were positive (23.6 U/ml; normal range: 0 to 18), whereas IgG antibody values were normal (< 5 U/ml; normal range: 0 to 12). Four weeks later, the levels of anti-CMV IgG antibodies rose (190 U/ml) with normalization of anti-CMV IgM levels. During hospitalization, management included intravenous fluids and electrolyte infusion for skin and mucosae dehydration and for the poor oral intake due to an intense oral burning sensation; methylprednisolone (0.8 mg/kg/day); intravenous antibiotic therapy (ceftriaxone) to prevent skin bacterial infection, because the patient (unable to take oral drugs for the several lesions in the oral cavity) presented fever and neutrophilia (6.10 × 10,000/µl) and mild elevation of erythrocyte sedimentation rate (15 mm/h).

Long-term valacyclovir treatment and immune modulation for Herpes-associated erythema multiforme.

ObjectiveErythema multiforme (EM) is an immune-mediated condition characterized by the appearance of target-like lesions on the skin and often accompanied by erosions or bullae involving the oral, genital, and/or ocular mucosae. 70% of recurrent EM cases are associated with HSV reactivation and it is labelled as herpes-associated erythema multiforme (HAE M). Recurrences are seen in approximately 20-25% of EM cases and managing these conditions are challenging for both the patient and the doctor. The effectiveness of antiviral drugs is proven for Herpes simplex infection, however most patients use a multiplicity of alternative and complementary therapies.Clinical presentationWe present clinical data of 3 patients with recurrent HAE M managed by long-term valacyclovir therapy and immunostimulation with Echinacea or replacement immunoglobulin therapy in the case of IgG1 subclass deficiency. The presented cases have demonstrated that immune mechanisms are relevant for HAEM recurrences.ConclusionsThe immune abnormalities, such as antibody deficiency, in the patients with HSV-associated EM can lead to frequent relapses of disease and should be evaluated. Long-term antiviral therapy with immunomodulation can control the relapses of HAEM.

Herpes simplex virus–associated erythema multiforme as a potential paraneoplastic marker in cholangiocarinoma treated with yttrium-90 microsphere ablation

Herpes simplex virus–associated erythema multiforme as a potential paraneoplastic marker in cholangiocarinoma treated with yttrium-90 microsphere ablation

Frequent Detection of Herpes Simplex Virus Antigen in Skin and Peripheral Blood CD34+ Mononuclear Cells from Patients with Graft-versus-Host Disease

Viruses are implicated in the initiation or flare of graft-versus-host disease (GVHD) by virtue of their ability to activate antigen-presenting dendritic cells (DC). Herpes simplex virus (HSV) infects circulating CD34+ stem cell progenitors, favoring their differentiation into skin homing DC (CD1a+ Langerhans cells) that contribute to the development of an inflammatory skin rash known as HSV-associated erythema multiforme (HAEM). Following on these findings, we conducted a prospective study to examine whether HSV is also associated with GVHD. Skin biopsies and peripheral blood mononuclear cells (PBMC) were collected from 37 consecutive patients on admission before and after allogeneic hematopoietic stem cell transplantation (HSCT) and examined for HSV antigen (Pol) expression and the presence of Pol+CD34+ and Pol+CD1a+ cells. Sixteen patients developed a skin rash that was histopathologically consistent with GVHD (group I), 3 patients had a rash that was not GVHD (group II, EM-like) and 18 patients did not develop any rash after HSCT (group III). Skin biopsies from the group I patients were Pol negative pre-HSCT (baseline) but became Pol+ after the diagnosis of GVHD. The GVHD biopsies also contained Pol+CD34+ and Pol+CD1a+ cells, and these patients had a significant percentage of circulating Pol+CD34+ and Pol+CD1a+ PBMC. By contrast, the group II patients had Pol+ skin cells and Pol+CD34+ circulating PBMC at baseline that decreased post-HSCT. The group III patients had Pol negative skin and very few circulating Pol+CD34+ and Pol+CD1a+ PBMC at baseline that were not significantly changed post-HSCT. The data associate skin GVHD with HSV reactivation during conditioning and its propensity for nonreplicative infection of CD34+ PBMC that induces DC activation. Further studies are needed to better elucidate this association.

Gastrointestinal: Herpes simplex virus‐associated erythema multiforme (HAEM) during infliximab treatment for ulcerative colitis

Anti-TNF-α antibodies are effective in the treatment of inflammatory bowel diseases. These biologic drugs, however, may result in adverse effects that include opportunistic infections. Viral infections may also reactivate following immunosuppression. Molecular and immunologic evidence demonstrate that herpes simplex virus (HSV) can cause erythema multiforme (EM), which may appear as a polymorphous eruption with symmetrically distributed macules, papules, bullae, and typical target lesions with a central vesicle or bulla. EM caused by HSV, also known as HSV-associated EM (HAEM), is dissimilar to drug-induced EM (DIEM). IFN-γ and TNF-α are pro-inflammatory cytokines produced by different cell types: T cells accumulating in HAEM lesions are primarily CD4+ (Vβ2+) cells that are activated by HSV antigen while non-T and CD8+ T cells are predominant in DIEM lesions. There is a strong correlation between IFN-γ and HSV-protein expression in the skin tissues. HAEM lesions are positive for IFN-γ, a product of HSV antigen-triggered CD4+ cells; DIEM, in contrast, is a distinct condition in which keratinocytes are positive for TNF-α, a sign of toxic injury, primarily produced by monocytes/macrophage. This finding indicates that HAEM and DIEM are mechanistically distinct syndromes. A 19-year-old girl with UC on oral prednisone and mesalamine, presented with an active pancolitis. Clinical picture did not improve after intravenous corticosteroids, so infliximab (5 mg/kg at week 0,2,6 then every 8 weeks) was commenced. She clinically improved. However, at the time of the third drug infusion, she reported 2 days' history of a diffuse, mildly pruritic cutaneous rash. She denied constitutional symptoms such as fever or chills. A symmetric erythematous, annular macular rash was seen on the acral extremities, including palms and soles, and on the face (Figure 1). Herpes-like vesicles were also evident on her lips (Figure 2). Some lesions were edematous and slightly raised from scratching, whereas others were target lesions with central vesicles. The herpes lesions on the lips had appeared 5 days after the first infliximab infusion. Vesicle fluid polymerase chain reaction was positive for HSV type I. The skin lesion was positive for HSV-DNA and IFN-γ on immunohistochemistry. The diagnosis was HAEM due to infliximab-related immunosuppression reactivating a latent HSV infection. Infliximab was suspended to avoid HSV-related complications, and the cutaneous rash gradually vanished and she was treated with valaciclovir. The patient subsequently underwent restorative proctocolectomy with J-pouch construction, and a loop-ileostomy. Symmetric erythematous rash on acral extremities and on the face. Some lesions were edematous and slightly raised due to scratching; some target lesion were observed. Lesions on patient's face. Note herpes signs on her lips. At our knowledge, this is the first case of HAEM associated with infliximab administration causing reactivation of HSV infection. Infliximab does not cause DIEM as it suppresses TNF-α. Contributed by

Current understanding of herpes simplex virus-associated erythema multiforme

In this article evidence summarizing our present understanding of herpes simplex virus (HSV)-associated erythema multiforme (HAEM) is reviewed. The numbers of circulating bone marrowderived CD34+ stem cells, including the subset that differentiates into skin antigen-presenting cells, known as Langerhans’ cells (LCs), are increased in patients with HAEM. During their circulation through a HSV-infected site, these cells become infected and sustain viral DNA fragmentation. The DNA fragments are subsequently deposited at distant skin sites where the HSV genes are expressed. Viral DNA polymerase (Pol) is the major gene product expressed in most (70–75%) HAEM lesions. Viral gene expression triggers the recruitment of HSV-specifi c CD4+ Th1 cells that respond to viral antigens by producing IFN-γ. Pol also induces a skin infl ammatory response that is based on molecular mimicry and upregulation/activation of the transcription factor SP-1 and its target genes TGF-β and Hsp27. This response is amplifi ed by IFN-γ a...

Acute Skin Eruptions That Are Positive for Herpes Simplex Virus DNA Polymerase in Patients With Stem Cell Transplantation

Patients with stem cell transplantation (SCT) develop erythematous eruptions (SCTE) that are often misdiagnosed and poorly treated. Latent herpes simplex virus (HSV) is likely to be reactivated by SCT-associated immunosuppression. Therefore, one of the differential diagnostic possibilities for SCTE is HSV-associated erythema multiforme (HAEM) in which HSV genetic fragments localize in stem cells that deliver them to the skin on differentiation. Lesional skin from patients with SCTE, HAEM, HSV, or drug-induced erythema (DIEM) was stained with antibodies to the HSV antigen DNA polymerase (Pol) and the major capsid protein, virion protein 5 (VP5). The HSV DNA polymerase Pol was expressed in 79% of patients with SCTE and 75% of those with HAEM. The protein VP5 was not expressed in these patients, indicative of the absence of virus replication. Findings in patients with DIEM were negative for both antigens, and those with HSV lesions were positive for both antigens. There is a growing problem with SCTE, related to the increasing numbers of performed SCT. The greater frequency of SCT-generated circulating stem cells in patients with hematological malignant neoplasms (who have latent HSV infection) may result in a widespread SCTE characterized by skin deposition of HSV DNA fragments, notably those expressing Pol antigen. This HAEM-like presentation should be considered in the differential diagnosis of SCTE. Prolonged high-dosage antiviral chemotherapy during and after hospitalization may be warranted.

The Herpes Simplex Virus Gene Pol Expressed in Herpes-Associated Erythema Multiforme Lesions Upregulates/Activates SP1 and Inflammatory Cytokines

Background/Aims: Herpes-simplex-virus-associated erythema multiforme (HAEM) is characterized by lesional skin expression of the viral protein Pol and localized inflammation. The objective of this study is to examine the mechanism whereby Pol induces localized inflammation. Methods: A431 cells transfected with Pol or an empty vector and lesional skin from HAEM or drug-induced erythema multiforme patients were examined for expression of the transcription factor SP1 and SP1-regulated genes by immunoblotting, immunohistochemistry and immunofluorescence. Results: SP1, TGF-β, p21^waf1 and Hsp27 were upregulated in A431 cells transfected with Pol but not the empty vector. Expression was further increased by exposure to IFN-γ. Pol+ HAEM lesional skin expressed SP1, Hsp27, TGF-β and p21^waf1. Normal skin and drug-induced erythema multiforme lesional skin were negative. Conclusion: The data indicate that Pol activates SP1, causing upregulation of SP1 target genes (notably TGF-β) involved in localized inflammation. Upregulation is potentiated by IFN-γ.

CD34+ Cells in the Peripheral Blood Transport Herpes Simplex Virus DNA Fragments to the Skin of Patients with Erythema Multiforme (HAEM)

Herpes simplex virus (HSV)-associated erythema multiforme (HAEM) is a recurrent disease characterized by the presence and expression of HSV DNA fragments in lesional skin. Our studies examined the mechanism of viral DNA transport to the skin of HAEM patients. CD34+ cells were isolated from the blood of normal subjects and HSV and HAEM patients during acute lesions and at quiescence. They were cultured with cytokines that favor their differentiation into Langerhans cells (LC) precursors (CD1a+/CD14-) and examined for HSV replication, HSV-induced cellular alterations, viral DNA fragmentation, and clearance. CD34+ cells from all study groups were non-permissive for HSV replication but infection favored their differentiation into CD1a+/CD14- LC precursors and upregulated E-cadherin expression, thereby assisting LC targeting to the skin. Only HAEM patients had CD34+ cells that retained viral DNA fragments, notably polymerase DNA, for at least 7 d of in vitro culture. The percentages of circulating CD34+ (and CD34+/CLA+) cells were significantly higher in HAEM patients at the time of acute lesions. A similar increase was not seen for HSV patients. The data are the first report implicating CD34+ cells in HAEM pathogenesis, likely by transporting HSV DNA fragments to lesional skin.

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.

Treatment of mucocutaneous presentations of herpes simplex virus infections.

Infections by herpes simplex virus (HSV) types I and II are diverse and quite frequent. After primary infection, the virus establishes a life-long latency in the sensory ganglia and recrudescences may occur at an unpredictable rate. Recurrent labial and genital herpes infections represent the majority of clinical manifestations of HSV infections. Their management is currently well established using evidence-based medicine data. Primary labial herpes is generally not treated with antivirals in otherwise healthy children, although intravenous aciclovir may be offered in severe primary infections, particularly in the immunocompromised patient. The decision whether or not to treat recurrent labial herpes should be evaluated individually and depends on the frequency and severity of relapses, the impairment of the quality of life, and the cost of therapy. Patients with mild disease may benefit from topical therapy, and those with severe and frequent recurrences may be considered for intermittent or long-term oral antiviral therapy. Primary genital herpes is treated with oral or intravenous antivirals, depending on the severity of the infection and associated symptoms. Recurrent genital herpes can be managed with episodic short courses of oral antivirals in patients whose recurrences are moderate to severe and rare, and have a clear prodrome. Patients with >5 episodes/year, severe recurrences or unrecognisable prodromes may be best managed with long-term suppressive antiviral prophylaxis. HSV is also responsible for a variety of other clinical manifestations, including herpetic whitlow, neonatal infection, disseminated and atypical cutaneous infections, traumatic herpes, eczema herpeticum, and HSV-associated erythema multiforme. HSV infection may also represent a complication following cosmetic procedures of the oro-facial region, surgical and dental interventions, sun exposure and burns. Precise treatment guidelines for these HSV infections are not firmly established.

Herpes Simplex Virus Associated Erythema Multiforme (HAEM) is Mechanistically Distinct from Drug-Induced Erythema Multiforme: Interferon-γ is Expressed in HAEM Lesions and Tumor Necrosis Factor-α in Drug-Induced Erythema Multiforme Lesions

Erythema multiforme follows administration of several drugs or infection with various agents, including herpes simplex virus, a syndrome designated herpes 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 transcriptase-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 of 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 correlation coefficient). Interferon-gamma signals were in infiltrating mononuclear cells and in intercellular spaces within inflammatory sites in the epidermis and at the epidermis/dermis junction. Herpes simplex virus lesional skin was also positive for DNA polymerase [five of five (100%)] and interferon-gamma [four of five (80%)], but lesional skin from drug-induced erythema multiforme patients was negative. Lesional herpes simplex virus associated erythema multiforme keratinocytes also stained with antibody to transforming growth factor-beta [14 of 23 (61%)] and cyclin-dependent kinase inhibitor waf [12 of 18 (67%)]. Staining was also seen in keratinocytes from herpes simplex virus lesions [five of five (100%)], but not in normal skin. By contrast, staining with antibody to tumor necrosis factor-alpha, another pro-inflammatory cytokine, was seen in seven of 11 (64%) drug-induced erythema multiforme patients, but not in herpes simplex virus or herpes simplex virus associated erythema multiforme patients, and lesional keratinocytes from 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 multiforme pathology includes a delayed-type hypersensitivity component and is mechanistically distinct from drug-induced erythema multiforme.

Target lesions on the lips: Childhood herpes simplex associated with erythema multiforme mimics Stevens-Johnson syndrome

Erythema multiforme and Stevens-Johnson syndrome are both characterized by areas of epithelial necrosis. An important clinical feature that distinguishes the two is the extensive mucosal necrosis in Steven-Johnson syndrome but not in erythema multiforme. Because significant and serious complications may develop with Stevens-Johnson syndrome and not with erythema mutiforme, it is important to differentiate between the conditions. We describe three boys with herpes simplex virus–associated erythema multiforme who had severe necrosis of the lips develop and were initially diagnosed with Stevens-Johnson syndrome. The lip lesions were large target lesions of erythema multiforme rather than the extensive necrosis seen in Stevens-Johnson syndrome and all three had a benign course. (J Am Acad Dermatol 1997;37:848-50.)

Expression of Herpes Simplex Virus DNA Fragments Located in Epidermal Keratinocytes and Germinative Cells Is Associated with the Development of Erythema Multiforme Lesions

Skin from acute and healed herpes simplex virus or herpes simplex virus-associated erythema multiforme (HAEM) lesions was examined by polymerase chain reaction with primers for DNA polymerase, ICP8, thymidine kinase (5' end of herpes simplex virus genome), and ICP27 (3' end of herpes simplex virus genome). The primers were herpes simplex virus specific and equally sensitive. The four herpes simplex virus genes were seen in acute herpes simplex virus lesions, but except for one patient, only polymerase (or polymerase and ICP8) were seen in 7-d healed lesional skin. Herpes simplex virus DNA was not seen 1-1.5 mo after healing. HAEM skins from 18 of 24 patients (75%) were positive for polymerase DNA and four of 24 (17%) were also positive for ICP8 or thymidine kinase DNA. Only one tissue (4%) was positive for polymerase, ICP8, and ICP27 DNA. Skin from healed HAEM lesions was still polymerase DNA positive 1-3 mo after lesion resolution. The polymerase DNA signal was in the basal and spinous cell layers of the epidermis and in the outer root sheath of the hair follicle. Polymerase RNA was identified by reverse transcriptase polymerase chain reaction in skin from acute, but not healed polymerase DNA positive HAEM lesions, suggesting that polymerase expression is associated with HAEM lesion development.

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.