Sequential genital infections with herpes simplex virus types 1 and 2.

Herpes simplex virus (HSV) types 1 and 2, typed by an enzyme linked immunosorbent assay (ELISA), were isolated at different clinical episodes from five people with genital herpes. This finding has important implications for assessing resistance to antiviral drugs in therapeutic studies.     

Epidemiology of recurrent genital herpes simplex virus types 1 and 2

OBJECTIVES: To describe the epidemiology of type specific recurrent genital herpes, and to compare the duration of recurrent genital lesions caused by herpes simplex virus (HSV) types 1 and 2. METHODS: Participants were enrolled at clinics across the United States. Adults suspected of having active genital herpes were eligible. Lesions were cultured for HSV and typed. Data from 940 participants with recurrent culture positive HSV lesions were analysed. Pearson's chi(2) and Fisher's exact tests, multivariate logistic regression models, and a stratified Cox proportional hazards model were used to compare epidemiological characteristics and lesion duration of HSV-1 and HSV-2. RESULTS: HSV-1 was present in 4.2% of the recurrent HSV culture positive lesions. HSV-1 was most prevalent among whites (6.5%) and individuals with 0-2 recurrences in the previous year (9.1%) and, among men, in those with rectal/perirectal lesions (13.2%). Longer lesion duration was not significantly associated with virus type (hazard ratio (HR) 0.95, 95% confidence interval (CI) 0.65 to 1.38, p = 0.79), but was associated with male sex (HR 0.85, 95% CI 0.74 to 0.99, p = 0.04), and HIV seropositivity (HR 0.62, 95% CI 0.48 to 0.81, p<0.01). CONCLUSIONS: The authors found that, in the United States, recurrent genital HSV-1 is relatively rare in the STD and HIV clinic setting, especially among black people. Among men, rectal/perirectal recurrent lesions are more likely to be caused by HSV-1 than are penile lesions. In addition, lesion duration depends on sex and HIV status but not virus type. These findings shed new light on the type specific epidemiology of recurrent genital HSV, and suggest that type specific testing can inform the prognosis and management of genital herpes.     

Analysis of DNA from recurrent genital herpes simplex virus isolates by restriction endonuclease digestion

In a blind study, DNA from 40 clinical isolates of herpes simplex viruses was analyzed by restriction endonucleases to determine whether serial isolates from an individual patient could be identified and whether exogenous reinfection occurred within this population. Five of the 40 isolates served as controls. Based on restriction patterns obtained following Bam H1 cleavage of DNA, 35 isolates were assigned to 15 patients. Isolates from two patients displayed variation in the electrophoretic mobility of certain Bam H1 fragments. However, the isolates from one patient were identical when digested with four additional enzymes. One of three sequential isolates from a patient, when cleaved with Eco R1 and Hind III, showed variable fragments in the terminal and joint regions of the S segment of the genome. The appearance of the fragments was not due to the addition of a known restriction site. We conclude that exogenous reinfection with a genetically distinct strain of herpes simplex virus type 2 (HSV-2) did not occur among these 15 patients with recurrent genital HSV infections.     

Long-term suppression of severe recurrent genital herpes simplex infections with oral acyclovir: a dose-titration study.

Twenty immunocompetent patients, four females and 16 males, with severe recurrent genital herpes (median number of recurrences the previous year 16, range (8-24] entered an open continuous long-term suppressive treatment with oral acyclovir (ACV) for 12 months. The study included a dose-titration schedule: (ACV, 200 mg x 4/1-3 months, ACV, 400 mg x 2/4-6 months, ACV, 200 mg x 2/7-9 months, and ACV, 400 mg x 1/10-12 months). Patients with recurrences on steps two and three received an alternative dose of ACV, 200 mg x 3. Otherwise patients entered the previous dose-step. Five (20%) of patients were completely free of symptoms (recurrences and abortive lesions) during the four dose-reduction periods. A further nine patients (50%) could be dose-reduced to 200 mg x 3 without symptoms. Isolates from three patients showed a decrease in virus sensitivity after ceasing treatment. In conclusion, 14/20 of treated patients could be dose reduced to 200 mg x 2-3 without selection of HSV strains showing clinically important decreases in sensitivity towards ACV.     

Lack of evidence for intertypic recombinants in the pathogenesis of recurrent genital infections with herpes simplex virus type 1

Clinical observations indicate that herpes simplex virus type 1 (HSV-1) is significantly less likely than herpes simplex virus type 2 (HSV-2) to establish latency in (or reactivate from) sacral ganglionic tissue. In an effort to identify viral functions associated with latency, we analyzed HSV-1 isolates from three patients with established recurrent genital herpes and sought evidence of DNA sequences and proteins similar to those found in HSV-2. By restriction endonuclease cleavage patterns and by DNA hybridization analysis using either whole HSV-2 DNA or several cloned segments of HSV-2 DNA as probes, we found that the three HSV-1 isolates from patients with recurrent genital herpes showed no unusual homology to HSV-2 as compared with other HSV-1 isolates. Similarly, the proteins of these isolates could not be distinguished from those of other HSV-1 isolates and were distinct from those of HSV-2. At this level of resolution, there was no evidence to suggest that these recurrent genital HSV-1 isolates were intertypic recombinants, nor did they show any other unusual similarity to HSV-2.     

Psychosocial implications of recurrent genital herpes simplex virus infection.

Fifty seven patients experiencing first attacks of genital herpes simplex virus infection (HSVI) were compared with 50 patients who were concerned about frequently recurring attacks despite routine counselling and reassurance. Using the general health questionnaire this latter group was found to be more psychologically distressed and more socially naive than the first attack group, as measured by socioeconomic class and the lie score of the Eysenck personality questionnaire; otherwise the two groups were similar. Patients presenting to clinics with frequently recurring genital HSVI may therefore be especially psychologically distressed, socially naive, and disadvantaged. Managing these patients needs to include understanding these problems as well as giving advice and using antiviral agents.     

Reliable identification of herpes simplex viruses by DNA restriction endonuclease analysis with EcoRI

A simple procedure that permits the rapid identification of clinical isolates of herpes simplex virus (HSV, type 1 or type 2) on the basis of stable and type-specific differences in the EcoRI restriction endonuclease patterns of the HSV-1 and HSV-2 genomes was tested for reliability. Complete concordance was first obtained for 298 HSV isolates typed by standard laboratory procedures and by analysis of the DNA profiles. Two other HSV isolates showing intermediate biologic, immunologic, and/or biochemical properties were unambiguously identified by restriction endonuclease analysis of their genomes. Identical diagnostic results were also obtained by independent laboratories for another series of 150 HSV isolates after analysis of the EcoRI digestion products. As compared with other restriction enzymes, little intratypic variation in the DNA fragments selected for immediate identification of the isolates was found with EcoRI. The procedure used here, which does not require the purification and/or the radiolabeling of viral DNA, thus appears as most appropriate for the unambiguous typing of large numbers of HSV clinical isolates.     

Relation between herpes simplex viruses and human immunodeficiency virus infections

The rates of herpes simplex virus (HSV) infection are rising, the highest prevalence being in the group infected with the human immunodeficiency virus (HIV). We review the relation between these 2 infections. The presence of genital ulcers increases the transmission of HIV, and the presence of HIV adversely affects the natural history of HSV infection. The detection and treatment of sexually transmitted diseases such as genital herpes actually decrease the rates of HIV infection in groups studied. The treatment of HSV in persons with HIV is challenging because the incidence of immunosuppression increases. Acyclovir resistance is more common in this group, but acyclovir use may prolong survival in some HIV-seropositive patients. Further studies are needed to determine whether persons with HIV disease should routinely be given HSV-specific therapy.     

Treatment of recurrent herpes simplex infections with L-lysine monohydrochloride

In a prospective, randomized, double-blind, placebo-controlled, cross-over study of forty-one patients we found that oral ingestion of 1,248 mg a day of L-Lysine monohydrochloride shows evidence of decreasing the recurrence rate of herpes simplex attacks in nonimmunocompromised hosts. A dose of 624 mg a day was not effective. L-Lysine may also be capable of decreasing the severity of symptoms associated with recurrences. Neither dosage showed any evidence of shortening the healing time compared to placebo.     

One-day regimen of valacyclovir for treatment of recurrent genital herpes simplex virus 2 infection

OBJECTIVES: To evaluate the efficacy of a 1-day course of valacyclovir in reducing the duration and severity of genital herpes recurrences and to measure the frequency of viral shedding episodes subsequent to antiviral therapy. STUDY DESIGN: In an open-label pilot study, patients with recurrent genital herpes simplex virus 2 (HSV-2) infection were given a 1-day course of valacyclovir (2000 mg given by mouth twice daily) to be taken at the first sign of recurrence or prodrome. Participants maintained diaries of signs and symptoms and collected genital swabs for viral culture while lesions persisted and HSV DNA PCR for 14 days after initiating treatment. RESULTS: Ninety (78%; 41 men, 49 women) of the 115 enrolled persons experienced either a lesional recurrence or prodrome. Seventy-seven (86%) participants developed lesions; 4 (5%) participants experienced a second lesional recurrence during the 14-day study period. The median lesion duration was 5 days, episode duration was 5 days, and pain duration was 3 days. Viral shedding was detected in 60 persons by PCR and 31 persons by culture. Shedding detected by culture lasted for a median of 2 days, and shedding detected by PCR lasted for a median of 3 days. Of 60 participants with viral shedding, 14 (23%) had an additional shedding episode after their initial lesion healed, lasting for a median of 2 days. CONCLUSIONS: A 1-day course of valacyclovir may be a convenient treatment for recurrent genital herpes and comparative trials are warranted.     

Apolipoprotein E-epsilon 4 and recurrent genital herpes in individuals co-infected with herpes simplex virus type 2 and HIV

Apolipoprotein E (APOE) alleles have been associated with the severity of, or susceptibility to, infection by various microbes. We investigated the potential association between the APOE-epsilon 4 allele and the rate of recurrence of genital herpes in patients who were HIV positive and herpes simplex virus type 2 (HSV-2) seropositive. The APOE-epsilon 4 allele was significantly associated with recurrent genital ulceration independent of ethnicity, antiretroviral therapy and CD4 count (OR 8.3; 95% CI 2.4 to 28.5). To our knowledge, this is the first published study to demonstrate this association and suggests that APOE-epsilon 4 may represent a future prognostic marker for symptomatic recurrence of genital herpes in individuals with HIV.     

单纯疱疹病毒1型致原发性生殖器疱疹一例

患者女,23岁。因外阴红肿、刺痛4 d入院。4 d前出现会阴瘙痒、分泌物增多,查念珠菌阳性,拟诊念珠菌性阴道炎,给予氟康唑胶囊150 mg顿服,复方明矾散、双唑泰栓及联苯苄唑乳膏外用,3 d前瘙痒加重,出现轻微疼痛,予聚维酮碘溶液阴道冲洗,制霉菌素阴道泡腾片及硝酸咪康唑栓治疗,症状无改善,2 d前外阴明显肿胀,大量水疱及脓疱,渗出,行走时疼痛明显,外院拟急性女阴溃疡给予头孢曲松、泼尼松治疗,效果不佳,疼痛加剧,呈反复持续发作的刺痛,加用盐酸曲马多注射液肌内注射,疼痛未能改善……     

Confirmation of herpes simplex virus type 2 infections in herpes-like genital lesions by a simple complement-fixation test

The presence of complement-fixing antibody to an early herpes simplex virus type 2 (HSV-2) antigen (the AG-4 antigen) was correlated with HSV-2 infection in the sera of patients with genital herpes. Eighty-eight per cent of sera taken two weeks after clinical diagnosis of a primary or recurrent herpes infection in patients, confirmed to have HSV-2 by virus isolation and typing, contained the anti-AG-4 complement-fixing antibody. None of the patients with genital HSV-1 had the antibody, and only 9% of controls or patients with facial HSV-1 infection had positive results for the antibody. This correlation was used to identify genital HSV-2 infections when either no virus sample had been taken or when virus isolations had been unsuccessful. Thus, a simple complement-fixation test can confirm an HSV-2 virus infection without isolation of the virus from the herpetic lesion.     

The epidemiology of herpes simplex types 1 and 2 infection of the genital tract in Edinburgh 1978-1991.

INTRODUCTION--The changing epidemiology of genital herpes in Edinburgh is described in relation to herpes simplex virus (HSV) Type 1 and herpes simplex virus Type 2 infection over a period of 14 years. METHODS--2018 episodes of genital herpes in 1794 patients over a 14 year period were assessed. Data on age, sex, sexual orientation, geographical origin and herpes antibodies were also analysed. RESULTS--The proportion of cases that were HSV Type 1 increased over the period from approximately 20% to over 40%. Type 1 infection is more common in the young, in women and as a primary infection. CONCLUSIONS--HSV Type 1 is of increasing importance as a cause of genital herpes in our population. This may reflect changes in sexual attitudes and practises over the past decade.     

The epidemiology of genital infection with herpes simplex virus types 1 and 2 in genitourinary medicine attendees in inner London

OBJECTIVE: To characterise the epidemiological and clinical features of genital herpes and the diagnostic role of HSV-2 specific serology in an ethnically diverse cohort of genitourinary medicine (GUM) attendees in inner London. METHODS: Genital swabs (n = 186) were tested by real time polymerase chain reaction (PCR) and serum samples (n = 70) by HSV-2 specific enzyme linked immunoassay (ELISA). RESULTS: Among 186 patients (median age 29 years), 104/186 (56%) were male and 176/186 (95%) heterosexual; ethnicity was predominantly black Caribbean (76/186, 41%), white (65/186, 35%), or black-African (41/186, 22%). The most common lesion sites were penis (85/104 men, 82%) and vulva (63/82 women, 77%); 114/186 (61%) patients were diagnosed clinically with first episode disease. Women were more likely to present <5 days of onset (p = 0.008). Black Caribbean patients were more likely to present > or = 5 days (p = 0.04) and decline HIV testing (p = 0.03). By PCR, 108/186 (58%) swabs tested positive for HSV-1 (7/108, 6.5%) or HSV-2 (101/108, 93.5%). Independent predictors of a positive PCR were heterosexual group, <5 days of onset, and visible genital ulceration on examination. HSV-2 was associated with black Caribbean and black African ethnicity; HSV-1 with white ethnicity (p = 0.006). By HSV-2 specific serology, 16/42 (38%) first episodes caused by HSV-2 were recurrent infections, and 7/19 (37%) patients with recurrent genital disease but negative PCR had genital herpes. CONCLUSIONS: Epidemiological trends in genital HSV-1 and HSV-2 infection appear to vary between ethnic groups in the United Kingdom. HSV-2 specific serology improves diagnostic accuracy in GUM populations where most genital infections are caused by HSV-2.     

Confirmation of herpes simplex virus type 2 infections in herpes-like genital lesions by a simple complement-fixation test.

The presence of complement-fixing antibody to an early herpes simplex virus type 2 (HSV-2) antigen (the AG-4 antigen) was correlated with HSV-2 infection in the sera of patients with genital herpes. Eighty-eight per cent of sera taken two weeks after clinical diagnosis of a primary or recurrent herpes infection in patients, confirmed to have HSV-2 by virus isolation and typing, contained the anti-AG-4 complement-fixing antibody. None of the patients with genital HSV-1 had the antibody, and only 9% of controls or patients with facial HSV-1 infection had positive results for the antibody. This correlation was used to identify genital HSV-2 infections when either no virus sample had been taken or when virus isolations had been unsuccessful. Thus, a simple complement-fixation test can confirm an HSV-2 virus infection without isolation of the virus from the herpetic lesion.     

Failure of oral inosiplex treatment of recurrent herpes simplex virus infections

A compound, a mixture of acedoben, dimepranol, and inosine (inosiplex) was used to treat recurrent local herpes simplex virus (HSV) infections in a double-blind placebo-controlled crossover study. Altogether, 58 patients with a history of frequently recurrent HSV infections were examined. Eighteen selected patients participated in the drug trial. Ten patients received both inosiplex and placebo, three received only inosiplex, and five received only the placebo. Three patients received both placebo and inosiplex twice. No substantial differences between the treatments with inosiplex or placebo could be seen in the frequency of occurrence or healing of the local lesions, nor in the results of these patients' immunologic studies. An evident placebo effect was observed, since only 15 (26%) of the 58 subjects examined continued to have an often relapsing form of the disease when followed up regularly.     

The prophylactic use of cyclooxygenase inhibitors in recurrent herpes simplex infections

In an open study, continuous oral therapy with cyclooxygenase inhibitors (ibuprofen or indomethacin) reduced the incidence and frequency of recurrent eruptions in nine of 16 patients with herpes simplex virus infection. Retrospective analysis of seven cases indicated that natural killer cell enhancement assays might allow us to predict the clinical outcome of such treatment.     

Laboratory diagnosis of herpes simplex virus type 1 and type 2 infections

Herpes simplex virus (HSV) is known to infect several body sites. Most commonly HSV infection results in lesions around the mouth or in the genital area. Infection at these sites may also be subclinical. Over the past decade HSV has been increasingly recognized as an important cause of both mild and severe diseases in a wide range of patients. Two distinct types of HSV are known, HSV-1 and HSV-2, and many antigens are shared between the two. Infection with either type of virus can occur early in life, although infection with HSV-2 becomes common only after puberty. The most common manifestation of HSV-1 infection is the orofacial “fever blister,” while HSV-2 is most often responsible for genital lesions.^1,2 Either virus type can, however, cause disease in almost any site of the body and can recur frequently. This recurrence of disease from an inapparent or latent state makes HSV infection unique among the common viral infections.Mistakes in diagnosis of HSV infections based on clinical findings alone are not uncommon. Herpetic lesions have been confused with allergic reactions, drug reactions, and lesions due to other infectious agents. Besides the medical importance of HSV in special situations, the social impact of having “herpes” is of considerable concern is almost everyone. Therefore, precise diagnosis of HSV infection is of paramount importance, particularly since effective antiviral therapy is available for many forms of the disease.Morphologically, all herpesviruses are alike (Fig. 1); therefore, it is not possible to differentiate members of the group by their structure alone. Although rapid techniques for diagnosis of HSV infection are constantly being refined and improved, virus isolation in tissue culture is still the most definitive method of detecting HSV, and it is the most widely used. In this chapter detailed procedures for HSV isolation and typing are described, with brief reviews on methods that have been used in conjunction with virus isolation when cell culture facilities are not available.