Herpes Simplex virus associated erythema multiforme (HAEM) is mechanistically distinct from drug-induced erythema multiforme: interferon-gamma is expressed in HAEM lesions and tumor necrosis factor-alpha 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.

Gastrointestinal cancer and herpes zoster in adults.

BACKGROUND/AIMS: Herpes zoster is associated with immunosuppression, and also has an increased risk of malignancy. The aim of this study is to determine whether patients with Herpes zoster are at a higher risk of occult malignancy and gastrointestinal diseases. METHODOLOGY: We examined 131 of 201 Japanese patients who showed evidence of Herpes zoster in the gastrointestinal tract including the large intestine using gastrointestinal endoscopy, total colonoscopy and CT scanning. RESULTS: Six of 131 patients (4.6%) with Herpes zoster, who had undergone all three examinations, had malignancies. This rate is significantly higher than the predicted rate (P < 0.05). Five of six patients had gastrointestinal or colon cancer. Previously, 17 of the 201 patients has been surgically treated for cancers (17/201 = 8.5%, predictable rate = 8.9%), eleven of these 17 patients had surgery for gastric cancer, or for colon cancer etc. We also diagnosed three patients to have cancers after an episode of Herpes zoster, out of the 140 patients who we examined as study prospects (3/140 = 2.1%, relative risks = 1.75). No significant increases in the malignant rates were observed before or after the onset of Herpes zoster. CONCLUSIONS: These findings are considered to support the policy to investigate patients with Herpes zoster for the presence of occult malignancies, though the rate of malignancy in such patients before or after episodes of Herpes zoster was not significantly different from that of the predictable rate.

In vitro and in vivo effects of polyhexamethylene biguanide against herpes simplex virus infection.

PURPOSE: The differential diagnosis of Acanthamoeba keratitis frequently includes herpes simplex viral keratitis. Previous in vitro studies with chlorhexidine, a drug with antiacanthamoebic action, have suggested concomitant antiviral activity against herpes simplex virus. We tested another related antiacanthamoebic compound, polyhexamethylene biguanide (PHMB), to determine its activity against herpes simplex virus (HSV) in vitro and herpes simplex viral keratitis in vivo. METHODS: Equal aliquots of HSV-1 (McKrae) strain were incubated in a medium with no PHMB or with PHMB at 0.01, 0.02, or 0.05 for 5 min at 35 degrees C and the inoculum was then titered on a monolayer of E-2 cells (human corneal fibroblasts). Monolayers were examined on consecutive days and the percentage of plaque reduction was calculated. Eighteen rabbits (36 eyes) were inoculated with HSV-1 McKrae strain (10(5) pfu [plaque-forming units]/per eye). Rabbits were divided into three groups and treatment was initiated on day 3 postinfection. Group I received trifluorothymidine, group II received PHMB, and group III received artificial tears, each given five times daily in both eyes until day 10. Daily corneal swabbing to detect viral shedding and slit-lamp examination every 3 days were performed during this period. RESULTS: In vitro studies showed 62.5, 100, and 100% plaque reduction with 0.01, 0.02, and 0.05% PHMB, respectively. Slit-lamp examination of the rabbit corneas revealed faster resolution of dendrites in animals in group I treated with trifluorothymidine. Virus was not recoverable from corneal swabs in nine of 10 rabbits in group I by day 5, but all animals in groups II and III were still shedding HSV through day 8. CONCLUSION: Although PHMB has potent in vitro activity against HSV, it was not an effective treatment in the in vivo rabbit model of primary HSV keratitis at the concentration commonly used for treatment of Acanthamoeba infection. This suggests that 0.02% PHMB will not provide adequate antiherpetic coverage with treatment of keratitis of undetermined etiology in which the clinical differential diagnosis includes both herpes simplex and Acanthamoeba.

Secretion and dynamics of herpes simplex virus in tears and saliva of patients with Bell's palsy.

OBJECTIVE: For clarification of the direct relationship between the reactivation of herpes simplex virus and the development of Bell's Palsy, a detection of the virus genome by deoxyribonucleic acid diagnostics and a quantitative analysis of its time-course change are both needed. The authors detected the HSV genome in specimens from patients with Bell's Palsy, quantified its number of copies, and examined time-course changes. SUBJECTS AND METHODS: The subjects were 16 patients with Bell's Palsy. The tear fluid and saliva from the submandibular gland and the parotid gland were separately collected from the affected and unaffected sides twice or more. A total of 244 specimens were subjected to extraction of deoxyribonucleic acid, polymerase chain reaction, and microplate hybridization. RESULTS: Herpes Simplex virus-1 deoxyribonucleic acid was detected in 38 specimens (11.8%) from 5 patients (31%). The high detection (28.5%) was obtained within 2 weeks after onset. Detection at 3 weeks and later (2.8%) was significantly lower ( < 0.05). In three cases, deoxyribonucleic acid was also found on the unaffected side in the initial phase of the disease, but detection on that side (18.9%) was significantly lower than on the affected side (83.8%) ( < 0.01). The number of copies of the herpes simplex virus-1 genome was large on the affected side and early after the onset of the disease. CONCLUSIONS: The reactivation of herpes simplex virus-1 on the affected side is involved as a pathogenic factor of Bell's Palsy. A reactivation of herpes simplex virus-1 may be generated even on the unaffected side in the early phase of the disease. Herpes Simplex virus deoxyribonucleic acid was not detected in any of the examined specimens collected from the remaining 11 cases. The need for constant study to clarify other causative factors of Bell's Palsy remains.

Genotypic analysis of sequential genital herpes simplex virus type 1 (HSV-1) isolates of patients with recurrent HSV-1 associated Genital Herpes.

Clinical recurrences of Herpes Simplex virus type 1 (HSV-1)-associated genital herpes simplex are thought to be caused by reactivation of latent endogenous HSV-1. However, the possibility of reinfection with exogenous HSV-1 cannot be excluded. This study aimed to determine the incidence of genital HSV-1 superinfection in patients by investigating the genotype of sequential HSV-1 isolates obtained from the same anatomical site of patients with clinical recurrences of genital HSV-1 recurrent Genital Herpes. Sequential genital HSV-1 isolates were genotyped by PCR amplification of the hypervariable regions located within the HSV-1 genes US1 and US12. Whereas the sequential HSV-1 isolates in 11 of the 13 patients studied had the same genotypes, the sequential isolates of 2 patients showed a different genotype. The data suggest that HSV-1-induced recurrent genital herpes simplex can be associated with genital reinfection with an exogenous HSV-1 strain. Copyright 2004 Wiley-Liss, Inc.

Incidence of herpes zoster in pediatricians and history of reexposure to varicella-zoster virus in patients with herpes zoster

We found that pediatricians have enhanced specific cellular immunity to varicella-zoster virus (VZV) compared with the general population, which may be due to reexposure to VZV from children with chickenpox. There have been some reported that the varicella vaccine enhance the specific cellular immunity. To estimate the efficacy of varicella vaccine for protection against herpes zoster in the elderly, we investigated the incidence of herpes zoster in 500 pediatricians and family practitioners with their fifties and sixties, and history of reexposure to VZV in 61 patients with herpes zoster by questionnaires retrospectively. Thirty-four of 352 pediatricians had a past history of herpes zoster. The incidence per 100,000 person-years of herpes zoster was 65.2 in those in their fifties and 158.2 in those in their sixties, which are 1/2 to 1/8 of other reports regarding the general population. Among 61 immunocompetent patients with herpes zoster, only 4 patients (6.6%) had the chance for reexpose to VZV before their herpes zoster. Only 7 (17.5%) of the 40 patients older than 50 years of age lived with their children less than 14 years of age. Twenty-three (57.5%) of them lived without their children and grandchildren. They are thought to be less chance to reexpose to VZV through children. We may think that the booster effect by reexposure to VZV plays an important role to prevent herpes zoster. Therefore, we can speculate that the varicella vaccine may protect against herpes zoster in the elderly by the enhanced specific cellular immunity due to the booster effect.

Expectant management of preterm premature rupture of membranes complicated by active recurrent Genital Herpes.

OBJECTIVE: The study objective was to examine the neonatal outcome in pregnancies with early preterm premature rupture of the membranes (PPROM) who were managed expectantly despite the development of recurrent active Genital Herpes. STUDY DESIGN: Pregnancies complicated by PPROM at < or =14;31 weeks' gestation that developed an active recurrent genital herpes simplex lesion were collected. The latency time from herpes simplex lesion development to delivery and the neonatal outcome were analyzed. A control group of patients with PPROM at < or =14;31 weeks' gestation with no herpes simplex infection was also obtained. RESULTS: A total of 29 patients were identified during the study period. The mean gestational age at herpes simplex lesion development after PPROM was 28.7 weeks (range 24.6-31.0 weeks). The mean latency period from herpes simplex development to delivery was 13.2 days (range 1-35 days). No cases of neonatal herpes simplex developed in the delivered newborn infants and all neonatal cultures were negative (0 of 29 cases, 95% CI 0%-10.4%). Twelve newborn infants (41%) had major morbidity caused by prematurity and 3 of these (10.3%) died. There were no differences seen between the study cases and the control group. In the study, 15 of the 29 pregnancies were delivered beyond 30 weeks' gestation. If delivery had occurred on the day the herpes simplex lesion developed, only 5 pregnancies would have been delivered beyond 30 weeks' gestation. CONCLUSION: On the basis of the 95% CI of these data, the maximum risk for development of a neonatal herpes simplex infection in the face of PPROM and active recurrent genital herpes simplex was 10.4%. This was equal to the mortality rate and was 75% lower than the major morbidity rate caused by prematurity. If delivery had occurred on the day the herpes simplex lesions developed, on average, the neonates would have been nearly 2 weeks more premature, thereby potentially increasing the morbidity and mortality related to prematurity. These data concur with the American College of Obstetricians and Gynecologists consensus and expert opinion and would suggest that expectant management of PPROM at </=14;31 weeks' gestation with active recurrent genital herpes simplex is warranted.

Gender-specific predictors of genital herpes simplex vaccine acceptance in a college population.

Vaccines represent one promising method for reducing the sexually transmitted disease (STD) epidemic. This study evaluated whether influences on the decision to accept a genital herpes simplex vaccine differed by gender. In all, 518 college students completed a questionnaire on sexual history, health beliefs, and acceptance of a potential genital herpes simplex vaccine. Each predictor variable plus a gender interaction term were analysed in separate logistic regression models. Follow-up analyses were performed by gender for outcomes that displayed significant interactions. Results indicated that a prior history of an STD and increased perception of risk for acquiring genital herpes simplex were significant predictors of vaccine acceptance for men, while younger age and concerns about vaccine safety were significant predictors for women. Endorsement of a vaccine strategy targeting sexually experienced people was an influential factor for both genders, but was a much stronger one for women. Results suggest that gender-specific strategies may be crucial to genital herpes simplex vaccine acceptance.

Identification and DNA sequence analysis of the Marek's disease virus serotype 2 genes homologous to the thymidine kinase and UL24 genes of herpes simplex virus type 1.

The thymidine kinase (TK) gene has been used as a safe and convenient locus for expression of heterologous proteins in some alphaherpes viruses including herpes simplex virus of turkeys (HVT) antigenically related to Marek's disease virus (MDV) serotypes 1 (MDV1) and 2 (MDV2). In MDV2 strain HPRS 24 genome, genes equivalent to the TK and UL24 homologues of herpes simplex virus type 1 were identified and sequenced. The MDV2 UL24 gene overlaps the 5' end of the TK gene in a head-to-head orientation. The predicted region encoding for the MDV2 TK gene is 1,056 nucleotides, corresponding to a polypeptide of 352 amino acids in length. Putative nucleotide- and thymidine-binding sites were identified within the predicted amino acid sequence. The predicted region encoding for the UL24 gene is 948 nucleotides, corresponding to a polypeptide of 316 amino acids in length. By northern blot analyses using MDV2 TK- and UL24-specific DNA probes, four transcripts of approximately 7.8, 5.0, 3.5, and 1.1 kb for the TK gene, and a transcript of 3.8 kb for the UL24 gene were detected in MDV2-infected cells. Alignment of the amino acid sequence of MDV2 TK homologue with those published for TK homologues of other MDV serotypes showed 73.9% (MDV1 vs. MDV2), 58.2% (MDV1 vs. HVT), and 56.8% (MDV2 vs. HVT) identities. Comparison to other alphaherpes virus TK homologues revealed amino acid sequence homologies varying from 34.5% to 27.8%. The putative MDV2 UL24 homologous protein had identity with the well conserved five motifs among alphaherpes viruses.

Bystander effect of purine nucleoside analogues in HSV-1 tk suicide gene therapy is superior to that of pyrimidine nucleoside analogues.

Introduction of the herpes simplex virus type 1 thymidine kinase gene into tumor cells, followed by the administration of the antiherpes nucleoside analogue ganciclovir has been demonstrated to be effective in eliminating solid tumors in animals. The success of this combination treatment largely depends on the bystander effect, i.e. the killing of nontransfected tumor cells by activated drug carried over from the nearby herpes simplex thymidine kinase (tk) gene-transfected cells. We evaluated the in vitro bystander effect of several antiherpes purine and pyrimidine nucleoside analogues, using a colorimetric assay. All pyrimidine nucleoside analogues, including (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), showed low, if any, bystander killing effect. In contrast, purine nucleoside analogues, such as ganciclovir, were endowed with a pronounced bystander killer effect. Lobucavir (Cyclobut-G), a ganciclovir analogue, displayed a two- to three-fold more pronounced bystander killer effect than ganciclovir, eliminating, at a concentration of 10 microM, 75% and 90% of a cell population that contained 5% and 10% tk gene-transfected cells, respectively. These findings were corroborated by autoradiographic analysis that showed that 2'-3H-BVDU metabolites formed in the herpes simplex tk gene-transfected tumor cells were much less efficiently incorporated in the DNA of bystander cells than 8-3H-GCV. This indicates that, under the same experimental conditions, BVDU metabolites are less prone to pass the gap junctions than GCV metabolites.