Clinical Features and Treatment Response in Chronic Recurrent Erythema Multiforme: Difference Based on the Etiology Related to Herpes Simplex Virus

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

Herpes simplex virus (HSV)-associated erythema multiforme (HAEM) is an acute and self-limiting mucocutaneous hypersensitivity reaction triggered by herpes virus infections. We reported a patient with HAEM after hematopoietic stem cell transplantation (HSCT). A 55-year-old man received HSCT 7 months ago. He suffered from chronic graft versus host disease 4 months after HSCT and was treated with prednisone and tacrolimus. One week ago, he developed generalized macules with leukopenia. Dermatological examination revealed multiple iris-like erythemas on his trunk and extremities. The skin lesions and leukopenia resolved upon anti-HSV treatment.

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

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).

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

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

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 Snippets

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 and is associated with the autoreactive T-cell recruitment to the skin. Recently, a new variant of HAEM that follows stem cell transplants in patients with hematological malignancies was also described. Use of PCR to measure HSV DNA and immunohistochemistry for a HAEM profi le (antibodies to Pol, IFN-γ, SP-1, TGF-β and Hsp27) provide a differential diagnosis of HAEM and should preferentially be performed early after lesion onset (days 3–10). Prophylactic antiviral chemotherapy, notably with acyclovir or valacyclovir, inhibits HSV reactivation and prevents HAEM development.

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.

A subset of erythema multiforme (erythema multiforme) is associated with herpes simplex virus (HSV) infection; viral cultures of erythema multiforme lesions are, however, usually negative and viral antigens difficult to identify. Polymerase chain reaction (PCR) has been used to demonstrate the association, hence, is currently the only available sensitive diagnostic means for HSV-associated erythema multiforme. A nested PCR, which could simultaneously detect and genotype HSV in erythema multiforme lesions and in clinical swab specimen was developed using the DNA polymerase gene of HSV as target gene because it is the only detectable HSV gene in a high proportion of erythema multiforme lesions. The PCR has demonstrated its robust sensitivity on swab samples by being able to detect further 45.3% HSV cases in comparison with virus isolation with 100% specificity in both detection and genotyping confirmed by virus isolation and DNA sequencing. This study represents the first investigation of typing HSV virus in HSV-associated erythema multiforme patients, and the finding that 66.7% of the patients was attributed to HSV1, 27.8% to HSV2, and 5.6% to HSV1 and 2 co-infection may reflect the distribution of HSV1 and 2 in local general population.

Idiopathic erythema multiforme: Evidence of underlying Janus kinase–signal transducer and activator of transcription activation and successful treatment with tofacitinib

Erythema Multiforme is an acute, self-limited inflammatory cutaneous disorder characterized by distinctive target lesions. Stevens-Johnson syndrome (SJS) is defined as severe erythema multiforme with mucosal involvement, visceral involvement, or both. Both diseases are part of a continuum of immunologically mediated mucocutaneous diseases at various grades of severity. Viral infections are known triggers of these skin disorders. We report the success of a management strategy of acyclovir and prednisone for herpes simplex virus-associated erythema multiforme. In addition we describe the apparent first case of primary varicella infection as a direct cause of SJS. The two cases are presented and a single-case statistical analysis has been employed to evaluate the significance of the management protocol. The method of analysis is presented in the appendix. When a patient with primary varicella infection develops bullous lesions, SJS should be considered in the differential diagnosis, as early and intense corticosteroid therapy may be lifesaving. A regimen of prophylactic acyclovir and therapy for an exacerbation of herpetic lesions with acyclovir and prednisone was effective in inducing significant control of recurrent erythema multiforme secondary to herpes simplex in our patient.

Erythema multiforme (EM) is a polymorphic, often recurring eruption caused by exposure to medication or various infections, notably herpes simplex virus (HSV). Understanding the pathogenesis of HSV-associated EM (HAEM) is essential for patient management. We suggest that HAEM results from the combination of viropathic effects mediated by HSV proteins, notably DNA polymerase (Pol), and an immunological reaction to viral antigens. Presumably, viral DNA and proteins ingested by macrophages at HSV lesion sites undergo fragmentation and processing for presentation to T cells with HSV memory. HSV DNA is deposited on the skin, where it is expressed. Activated T cells are recruited to the skin site of Pol expression, directly or indirectly resulting in the generation of an inflammatory cascade. Factors potentially involved in the incidence of recurrences, lesion severity and anatomical localization include the identity of the deposited HSV genes, cutaneous capillary size, degree of vasoconstriction and ambient temperature. Evidence in support of this interpretation is reviewed.

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