Herpes simplex virus infections of women and their offspring: implications for a developed society.

Herpes simplex virus infections of humans have been known since ancient times. Contemporary society has witnessed a series of devastating manifestations of herpes simplex virus infections--namely, genital herpes simplex virus infection and neonatal herpes simplex virus infection. With the evolution of society, particularly advances in birth control and increasing promiscuity, the seroprevalence of herpes simplex virus type 2 infections has increased worldwide, however, more so in developed societies. As a consequence, individuals of child-bearing age are at risk for either reactivation of herpes simplex virus at termination of gestation or acquisition of a new primary infection at that time. The consequences of vertical transmission of herpes simplex virus from mother to child, resulting in neonatal herpes simplex virus infection, can be devastating. Current efforts, which are directed toward the treatment of neonatal herpes, have established the value of drugs such as vidarabine and acyclovir. However, the real emphasis for future programs is the prevention of herpes simplex virus infections to avoid person-to-person transmission either horizontally or vertically. The development of vaccines directed against herpes simplex virus may be of value toward this end.     

Antiviral agents for the prevention of the sexual transmission of herpes simplex in discordant couples

PURPOSE OF REVIEW: The aim of this review is to summarize recent developments in our understanding of the modifiable behavioural and biological factors contributing to the transmission of genital herpes simplex infection, and the limited data on the use of antiviral agents for reducing transmission risk in serodiscordant couples. RECENT FINDINGS: With the developing herpes simplex virus epidemic, the significance of biological and behavioural factors for the acquisition and transmission of genital herpes infection are increasingly recognized as important. Studies looking at the modification of behavioural factors indicate that knowledge of disease status, disease recognition and the promotion of condoms appears to modify transmission risk. However, these effects are disputed and their value is likely to be limited. In the absence of effective prophylactic vaccines, the reduction of clinical and subclinal herpes simplex virus shedding with the use of antiviral agents is an attractive option. A large study recently reported on the value of once daily valaciclovir for the prevention of transmission of genital herpes infection in serodiscordant couples. The study showed that continuous suppressive therapy not only controls symptomatic disease in the source partner, but reduces the likelihood of disease in the susceptible partner by between 48 and 75%. These findings will have a major impact on clinical practice. Questions remain, however, on whether these results can be extended to non-heterosexual populations and to drugs other then valaciclovir.     

Herpes simplex virus infections

There are two serological types of herpes simplex virus, HSV-1 and HSV-2. The types can be differentiated by different methods. After a primary infection HSV reaches the sensory ganglions by the way of peripheral nervous tracts. The virus remains for life in the ganglion as virus genome. After activation and return movement a new infection can appear. A lot of various diseases are caused by primary infection, reactivation or reinfection. The diagnosis in herpes virus diseases includes the detection of virus or viral antigens and the demonstration of specific antibodies against HSV. Effective antiviral drugs are available for chemotherapy of HSV-infection. Acyclovir is a beneficial drug without toxic secondary effects. The prevalence of HSV-antibodies in the population is very high.     

Detection of herpes virus DNA in post-operative thyroid tissue specimens of patients with autoimmune thyroid disease.

AIM: To demonstrate any differences in the detection of herpes simplex virus type 1 and 2, cytomegalovirus, human herpes virus type 6 and 7 DNA from thyroid tissue blocks of patients with autoimmune thyroid disease and multi-nodular goiter and to propose few mechanisms, which could explain the possible role of herpesvirus infection in the development of thyroid autoimmune responses. MATERIAL-METHODS: Thyroid tissue specimens were obtained postoperatively from 4 patients with multinodular goiter and 18 patients with autoimmune thyroid disease (Graves' disease and Hashimoto thyroiditis). Herpes virus DNA was detected using polymerase chain reaction based assays. RESULTS: No statistically significant differences were observed between autoimmune thyroid disease and multinodular goiter tissue specimens concerning herpes simplex virus type 1, 2 DNA isolation (44.4% vs 0%, P=0.094), human herpes virus type 6 DNA isolation (11.1% vs 0%, P=0.48), human herpes virus type 7 DNA isolation (33.3% vs 25%, P=0.75). No CMV DNA was isolated from any tissue specimen. At least one kind of herpes virus DNA was detected in 13 out of 18 (72.22%) AITD tissue specimens and in 1 out of 4 (25%) MNG tissue specimens (P=0.01). CONCLUSIONS: Although no data are available relating the direct effect of herpes infection on thyroid epithelial cells, a better understanding of how an aberrant immune response against the thyroid gland is initiated and propagated through herpes virus infection is required. Elucidation of the underlying mechanisms may allow the development of new etiologically based therapeutic modalities.     

Consequences of herpes simplex virus in pregnancy and their prevention

PURPOSE OF REVIEW: New findings reveal that first-time infection of the mother is the most important factor for the transmission of genital herpes from mother to fetus/newborn. Interventions based on these findings will lead to new management of the pregnant patient with genital herpes prior to pregnancy and measures to prevent the acquisition of herpes during pregnancy. RECENT FINDINGS: Risk factors for the transmission of herpes from mother to newborn have been detailed. It is the pregnant woman who acquires genital herpes as a primary infection in the latter half of pregnancy, rather than prior to pregnancy, who is at greatest risk of transmitting this virus to her newborn. This is true for both herpes simplex virus type-1 and herpes simplex virus type-2. Additional risk factors for neonatal herpes simplex virus infection include the use of a fetal-scalp electrode and maternal age of less than 21 years. SUMMARY: Risk factors for the transmission of herpes from mother to newborn are detailed. Antiviral suppressive therapy initiated in the late third trimester has been shown to decrease viral shedding and the need for cesarean section.     

Inability of enzyme immunoassays to discriminate between infections with herpes simplex virus types 1 and 2.

OBJECTIVE: To determine the accuracy of three commercial enzyme immunoassays in detecting and subtyping antibodies to herpes simplex virus type 1 or 2. DESIGN: Cross-sectional. SETTING: Referral medical center. PATIENTS: Ninety patients with culture-positive lesions caused by infection with herpes simplex virus type 1 or 2. The results of Western blot and glycoprotein G immunodot enzyme assays showed that an additional 53 patients had subclinical herpes simplex virus 2 infection, that another 20 patients had subclinical herpes simplex virus type 1 infection, and that 23 patients were seronegative. MEASUREMENTS: Three commercial enzyme immunoassays were used to determine herpes simplex virus antibody subtypes. MAIN RESULTS: All three commercial assays performed poorly in all patient groups (except in patients who were seronegative for herpes simplex virus). Among the 40 patients with a first episode of genital herpes, seroconversion to the appropriate viral type was shown by the three assays in only 33%, 55%, and 75% of cases. Among patients with recurrent genital herpes, the three commercial assays identified more than 90% of patients with only herpes simplex virus type 2 antibodies but failed to identify herpes simplex virus type 2 infections in 58% to 76% of patients with antibodies to both virus subtypes. The three assays correctly identified only 55%, 75%, and 85% of the 53 "silent carriers" of herpes simplex virus type 2. Overall, the three enzyme immunoassays detected herpes simplex virus type 2 antibodies in 60%, 62%, and 93% of patients with subtype 2 infections and falsely detected type 2 antibodies in 8%, 27%, and 49% of patients with type 1 infections. CONCLUSION: Currently licensed enzyme immunoassays give inaccurate or misleading results about the correct herpes simplex virus infecting subtype.     

Nosocomial herpes simplex virus infection associated with oral endotracheal intubation

Background: To determine by culture the frequency of herpes simplex virus reactivation complicating oral endotracheal intubation. Additionally, clinical appearance and recognition of patient infection by attendant health care workers were studied. Last, evidence of any occupational acquisition of herpes simplex virus infection was sought.Methods: In a prospective, non-randomized study, three serial viral cultures were taken of oro-facial or mucosal sites on the day of oral endotracheal intubation and in the subsequent 3rd and 5th or 7th days from 51 consecutive adults undergoing oral endotracheal intubation in a suburban community hospital. Clinical variables including appearances of lesions and therapeutic interventions were noted during serial assessments by study authors. Employee health records were reviewed for evidence of health care worker occupational herpes simplex virus infection associated with these cases.Results: Of 51 patients, 4 were culture positive on the day of oral endotracheal intubation. Of the remaining 47 patients, serial cultures during the first week post intubation revealed herpes simplex virus in 25 (53.2%) patients. Of cohort variables studied, a history of prior oral herpes simplex virus was significantly associated with a subsequent positive viral culture for herpes simplex virus (relative risk, 2.29; 95% confidence interval, 1.48 to 3.56). Typical or atypical lesions were visible in only 52% of the herpes simplex virus culture-positive cases. No occupational transmission of herpes simplex virus was detected. Tape-securing practices appeared to contribute to the morbidity of herpes simplex virus eruptions.Conclusions: Nosocomial reactivation of herpes simplex virus infection complicated oral endotracheal intubation in our patient population in approximately one half of the patients who were intubated for more than 48 hours during the first week after the procedure. Clinically, the infection was recognizable in only one half of the virus culture-positive cases. Increased awareness of this infection is needed by health care workers, patients, and families. More information is needed on optimal therapy and prevention.     

Immunization against genital herpes with a vaccine virus that has defects in productive and latent infection

An effective vaccine for genital herpes has been difficult to achieve because of the limited efficacy of subunit vaccines and the safety concerns about live viruses. As an alternative approach, mutant herpes simplex virus strains that are replication-defective can induce protective immunity. To increase the level of safety and to prove that replication was not needed for immunization, we constructed a mutant herpes simplex virus 2 strain containing two deletion mutations, each of which eliminated viral replication. The double-mutant virus induces protective immunity that can reduce acute viral shedding and latent infection in a mouse genital model, but importantly, the double-mutant virus shows a phenotypic defect in latent infection. This herpes vaccine strain, which is immunogenic but has defects in both productive and latent infection, provides a paradigm for the design of vaccines and vaccine vectors for other sexually transmitted diseases, such as AIDS.     

Prospects and current data in antiviral chemotherapy

The advances achieved in our knowledge on the virus multiplication cycle and the challenge created by the advent of AIDS have resulted in a rational development of new antiviral agents. However, antiviral chemotherapy is hindered by several obstacles: (1) most antiviral drugs are cytotoxic, with the exception of acyclovir which owes its remarkable safety to its activation by the thymidine kinase of the herpes simplex viruses and of the varicella-zoster virus; (2) the risk of selecting resistant strains by mutation of viral enzymes is the unavoidable price to pay for the specificity of new antiviral agents which interfere with these enzymes; so far, this risk seems to apply only to immunocompromised patients; (3) latent viral infection, defined as the lack of active multiplication of the virus, cannot be eradicated by the antiviral drugs available at present since these drugs are inhibitors of viral multiplication. However, anti-sens oligonucleotides could, at least in theory, be used to treat this type of infection which is not limited to the Retroviridae or Herpesviridae families. Finally, antiviral drugs active against life-threatening infections that are as common as rabies and the severe forms of measles or viral hepatitis remain to be discovered.     

Replication-incompetent herpesvirus vector delivery of an interferon alpha gene inhibits human immunodeficiency virus replication in human monocytes.

Human monocytes and macrophages are nondividing cells that serve as a major reservoir for human immunodeficiency virus (HIV) at all stages of infection. To investigate viral-mediated gene delivery as a means of inhibiting HIV replication in human monocytes, a replication-incompetent herpes simplex virus vector was developed that expressed human interferon alpha. Monocytes infected with this herpes simplex virus vector and then challenged with HIV showed dramatically reduced cytopathic effects and HIV replication compared to control treated monocytes. Similar effects on HIV replication were observed if monocytes were first infected with HIV and then treated with the recombinant vectors. These results demonstrate that replication-incompetent herpes simplex virus gene delivery of interferon alpha directly to human monocytes can greatly decrease HIV replication and suggest that such a vector might deliver therapeutically important genes directly to sites of HIV infection.     

Baseline IgG antibody titers to Chlamydia pneumoniae, Helicobacter pylori, herpes simplex virus, and cytomegalovirus and the risk for cardiovascular disease in women.

BACKGROUND: Results of cross-sectional and retrospective studies have suggested that chronic infection may be a risk factor for cardiovascular disease. However, prospective data evaluating the relation between baseline antibody titers against various plausible agents and risk for cardiovascular disease are sparse, particularly among women. OBJECTIVE: To determine whether previous exposure to Chlamydia pneumoniae, Helicobacter pylori, herpes simplex virus, or cytomegalovirus is associated with increased risk for cardiovascular events. DESIGN: Prospective, nested, case-control study. SETTING: Women's Health Study. PARTICIPANTS: Apparently healthy postmenopausal women. MEASUREMENTS: IgG antibody titers against C. pneumoniae, H. pylori, herpes simplex virus, and cytomegalovirus were measured in baseline blood samples obtained from 122 study participants who subsequently reported a first cardiovascular event (case-patients) and 244 participants matched for age and smoking status who did not report a cardiovascular event (controls) during 3 years of follow-up. RESULTS: Little evidence was found of an association between risk for cardiovascular events and baseline IgG seropositivity for antibodies against C. pneumoniae (rate ratio, 1.1 [95% CI, 0.7 to 1.8]), H. pylori (rate ratio, 0.90 [CI, 0.6 to 1.4]), herpes simplex virus (rate ratio, 1.2 [CI, 0.6 to 2.1]), and cytomegalovirus (rate ratio, 0.9 [CI, 0.6 to 1.5]). In addition, there was little evidence of an association between a participant's total number of infections and subsequent cardiovascular risk (P > 0.2). CONCLUSION: In apparently healthy postmenopausal women, little evidence was found that previous infection, as measured by IgG antibody titers to C. pneumoniae, H. pylori, herpes simplex virus, and cytomegalovirus, is associated with subsequent risk for cardiovascular disease.     

Herpes zoster and recurrent herpes simplex.

87 patients with the clinical diagnosis of herpes zoster were seen during a one-year period in 8 general practices in Glasgow, the rate per 1 000 practice population being approximately 2.4. Of these, 78 (90%) had serological evidence of active infection with herpes zoster. A history of recurrent herpes simplex was obtained in 25 (32%) of the 78 patients with confirmed herpes zoster; 63 (81%) of these 78 had complement-fixing (CF) antibodies to herpes simplex. Thus, latent herpes simplex infection did not prevent herpes zoster nor modify the severity of herpes zoster. In most of the patients CF antibodt to varicella-zoster was not detected within 5 days from appearance of the rash. After the acute phase of the illness CF antibody titres fell fairly rapidly, the geometric mean titre being 189 at 2-4 weeks after the rash, 27 from 3-6 months, and 8 from 12-18 months. The rapid rise and decline in CF antibody after herpes zoster infection compared with the unchanging CF titres associated with recurrent herpes simplex infection suggest that varicella-zoster and herpes simplex virus differ in their mechanism of latency.     

Parvovirus and herpes simplex association with unexplained anemia in pregnancy: a prospective study

Anemia in pregnancy is a health problem in developing countries. Unexplained anemia constitutes about one-third of anemia. The purpose of the present study is to evaluate the association of parvovirus B19 and herpes simplex virus in pregnant females with unexplained anemia. The study included 100 pregnant patients with anaemia. Nutritional and hemolytic anemia were excluded. In addition, 24 healthy pregnant control were included. Virological markers for parvovirus B19 and herpes simplex were evaluated by PCR and specific IgM. Eighty-four patients had parvovirus infection as determined by positive PCR or/and positive IgM. While 40 patients had positive herpes simplex infection by positive PCR or/and IgM. Patients with parvovirus and herpes simplex infections either separately or had combined infections had significantly lower level of hemoglobin compared to patients negative for viruses infections (p=0.03, p=0.034, p<0.005 respectively). It can be concluded that both parvovirus B19 and herpes simplex are common among pregnant patients. Screening for parvovirus B19 and herpes simplex may help to reach for the diagnosis of unexplained anemia during first trimester of pregnancy and allow appropriate treatment to be offered.     

Neonatal herpes simplex virus infection

PURPOSE OF REVIEW: In spite of the availability of antiviral therapy for the treatment of neonatal herpes simplex virus infections, the outcome remains poor, particularly for babies with disseminated multi-organ infection or central nervous system disease. This review considers recent advances that impact on disease management. RECENT FINDINGS: Two areas of investigation have impacted on our understanding of neonatal herpes simplex virus infection. First, the transmission of infection from mother to baby has been clarified by extensive epidemiological investigations of genital herpes in pregnant women at term. Risk factors for neonatal herpes simplex virus disease include first-episode maternal infection in the third trimester, invasive monitoring, delivery before 38 weeks, and maternal age of less than 21 years. Regarding the management of neonatal herpes simplex virus disease, the utilization of high-dose acyclovir (20 mg/kg every 8 h) for 21 days significantly reduces mortality for babies with either encephalitis or disseminated disease. SUMMARY: Recent findings from epidemiological studies have identified women at risk of delivering a child who develops neonatal herpes simplex virus infection, and suggest methods to decrease maternal-fetal transmission. If infection is identified in the pregnant woman, cesarean delivery decreases the frequency of neonatal disease. With neonatal disease, acyclovir should be administered promptly at higher dosages and for longer periods than previously reported.     

Viral pneumonia in recipients of solid organ transplants

Viral pulmonary infections are a major cause of morbidity and mortality in solid organ transplant recipients. The herpes viruses-cytomegalovirus, herpes simplex virus, varicella zoster virus, and Epstein-Barr virus--cause most of the viral infections in this population. Respiratory syncytial virus, adenovirus, and human immunodeficiency virus also cause pneumonitis in the transplant recipient. Differences in the clinical and laboratory presentation of pneumonitis due to the various viral agents can provide clues to the etiology. However, definitive diagnosis requires laboratory identification of the virus or appropriate serologic changes. With cytomegalovirus, herpes simplex virus, Epstein-Barr virus, and adenovirus, one must take care to distinguish between asymptomatic shedding of the virus and disease produced by the virus. Advances in diagnostic techniques such as rapid antigen detection, nucleic acid hybridization, and gene amplification may allow an earlier diagnosis of viral pneumonia. Advances in risk reduction with appropriate pairing of donors and recipients, improved immunosuppressive regimens, vaccination, and prophylactic administration of antiviral agents may reduce the incidence of viral infection. Finally, advances in anti-viral therapy have made possible the successful treatment of pneumonia due to some of the viral agents.     

The diagnosis and management of oral herpes simplex infection

Acute herpetic gingivostomatitis and recurrent herpes labialis are the most common manifestations of infection with herpes simplex virus type 1 (HSV-1). In primary and recrudescent HSV-associated disease, the symptoms may range from subclinical to debilitating and life-threatening, depending on the host’s immune responses or competence level. In this paper, the typical and atypical manifestations, and the current diagnostic and treatment options for localized, non-complicated oro-labial HSV infection are reviewed, with attention to cumulative evidence for the ef.cacy and safety of systemic antiviral agents. Some recent data on HSV-1 seroprevalence, viremia, and viral shedding are discussed in relation to disease transmission and global importance of herpesvirus disease.     

INHIBITION OF HERPES SIMPLEX VIRUS BY SYNTHETIC DOUBLE-STRANDED RNA (POLYRIBOADENYLIC AND POLYRIBOURIDYLIC ACIDS AND POLYRIBOINOSINIC AND POLYRIBOCYTIDYLIC ACIDS)

Two-stranded polyriboadenylic and polyribouridylic acids and polyriboinosinic and polyribocytidylic acids protect against herpes simplex virus-induced cytopathogenicity in HEp 2 cultures, systemic herpes simplex virus infection in mice, and herpes simplex virus-induced keratoconjunctivitis in rabbits.     

Viruses in the etiology of atherosclerosis.

To examine the possible role of viruses in the etiology of atherosclerosis, we searched for the presence of viral genomes in arterial tissues by in situ hybridization. Because chickens infected with Marek disease virus, a herpesvirus, develop atherosclerotic lesions after infection, we looked for the presence of herpesvirus or parts thereof in human artery wall tissue, particularly in individuals with evidence of atherosclerosis. Herpesvirus probes were used on specimens of aortic wall removed from patients undergoing coronary bypass surgery. Evidence for the presence of herpes simplex viral mRNA was obtained in 13 specimens. Some of the specimens positive for herpes simplex virus appear to represent early stages in atherogenesis. Evidence for the presence of cytomegalovirus or Epstein-Barr viral genome was not observed in any of the specimens examined. We have also shown that herpes simplex virus can infect human fetal smooth muscle cells in culture. There are several ways in which viruses could operate in the pathogenesis of atherosclerosis: They could induce proliferation of artery wall intimal smooth muscle cells via injury or by genomic alterations leading to clonal expansion of intimal smooth muscle cell populations. We suggest that expression of at least a part of the herpesvirus genome in arterial smooth muscle cells may in some cases be instrumental in initiating or maintaining this enhanced cell proliferation. Furthermore, viral agents could explain other puzzling features in the occurrence of atherosclerosis and the attendant heart disease and strokes.     

Varicella zoster and herpes simplex virus infections.

There are six herpes viruses, three of which, the varicella-zoster virus and the herpes simplex viruses types 1 and 2, are of particular concern to patients and staff in critical care units. These viruses, especially in their reactivated states, may present atypically in critically ill and immune-suppressed patients, and, by the time the diagnosis is made, exposures of other patients and clinicians may have occurred. Pregnancy and immunosuppressed states can result in severe, even life-threatening varicella-zoster virus infections in susceptible adults. Similarly, nosocomial herpes simplex virus infections can have serious consequences for exposed patients and staff. An additional problem after herpes simplex virus infection is the potential of lifelong and possibly frequent recurrences. In this article, the manifestations, modes of transmission, and treatment will be discussed. Special emphasis will be placed on describing the types of patients who are at high risk of presenting with varicella-zoster virus or herpes simplex virus infection so that physicians and nurses can use appropriate preventive measures to avert nosocomial infections in patients and staff.