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Herpes Simplex Virus Type-1 (HSV-1) IgM Enzyme-Linked Immunosorbent Assay (ELISA) Diagnostics Test Kit , Manufacturers from Jei Daniel Biotech Corp. Herpetic gingivostomatitis is common in young children, but primary oral infection has also been described in adults. JavaScript is currently disabled, this site works much better if you enable JavaScript in your browser.
Herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) are two of the eight known viruses which comprise the human herpesvirus family. The DNAs of HSV-1 and HSV-2 are largely colinear, and a great degree of homology exists between the HSV-1 and HSV-2 genomes. Predictors of HSV-2 serologic status include female sex, black race or Mexican-American ethnic background, a greater lifetime number of sexual partners, older age, less formal education, and an income below the poverty line (75,A 100,A 160).
Gingivostomatitis and recurrent herpes labialis represent the most common clinical manifestations of HSV infections, and are caused by HSV-1. Recurrences of herpes labialis may be associated with physical or emotional stress, fever, exposure to ultraviolet light, tissue damage, and immune suppression. As compared with recurrent episodes of genital herpes, first episodes of genital herpes infection may have associated systemic symptoms, involve multiple sites including nongenital sites, and have longer lesion duration and viral shedding (49). Not all people with first clinical episodes of symptomatic genital herpes actually have first episode primary or nonprimary infections: approximately 20% of such persons will have serologic evidence of HSV-2 at presentation, indicative of past asymptomatic acquisition of HSV-2 (62,A 139). Recurrent genital HSV-2 infection is clinically very different from first episode infections. As theA incidence of genital HSV-2 infections have increased over the past two decades (discussed above), so too has there been a dramatic rise in the incidence of genital HSV-1 acquisition.
The vast majority of patients with documented first episode genital HSV-2 infection develop recurrences within 12 months: 90% have at least one recurrence, 38% have at least six recurrences, and 20% have at least 10 recurrences during the first year following diagnosis (20). The importance of asymptomatic (subclinical) viral shedding on the epidemiology and transmission of HSV cannot be overstated (243).
Herpes simplex virus disease of the newborn is acquired in one of three distinct times: intrauterine (in utero), peripartum (perinatal), and postpartum (postnatal). Historically,A disseminated HSV infections have accounted for approximately one-half to two-thirds of all children with neonatal HSV disease.
Herpes simplex virus can invade and replicate in both neurons and glia, resulting in necrotizing encephalitis and widespread hemorrhagic necrosis throughout infected brain parenchyma but particularly the temporal lobe. Characteristic abnormalities of the CSF of patients with HSE include elevated levels of white blood cells (usually mononuclear cells), red blood cells, and protein. In untreatedA patients, mortality exceeds 70% and only 2.5% of survivors return to normal neurologic function.
Among HSE patients with concurrent herpetic lesions on the lip or in the mouth, restriction endonuclease analysis has confirmed that identical isolates are found in approximately 65% of subjects (248). Not unexpectedly, immunocompromised persons can experience frequent mucocutaneous HSV infections, including genital HSV infections, which have a prolonged course (235,A 256).
Genital ulcer disease, including that caused by HSV-2, has been recognized as a risk factor for HIV transmission since the early years of the HIV epidemic (93,A 105). Until recently, the commercially available serologic assays were unable to distinguish between HSV-1 and HSV-2 antibodies, severely limiting their utility. At the current time, the optimal application of these type-specific assays has not been determined. Detection ofA intrathecal antibodies directed against HSV has been studied extensively in the diagnosis of HSE.
In contrastA to other congenital and neonatal infections, serologic diagnosis of neonatal HSV infection is not of great clinical value. Isolation of HSV by culture remains the definitive diagnostic method of documenting an HSV infection, including establishing neonatal HSV disease. The reliability of viral culture, however, is dependent on the stage of the genital herpes episode, with the quantity of virus being higher during the prodromal and vesicular stages than in the crusting stage (157). While isolation of HSVA by culture remains the definitive diagnostic method of establishing HSV disease outside of the CNS, low viral culture yields from CSF cultures in patients with CNS HSV disease significantly limit the value of viral culture in the diagnosis of CNS HSV infections. PCR has had a considerable impact on the understanding of HSV-2 shedding in the genital tract.
PCR has primarily been utilized in research settings to better define the natural history of HSV reactivation from latency. Prior to the development of PCR technology, diagnosis of HSE required viral culture of material obtained by brain biopsy. AA pivotal report of the utility of PCR for the diagnosis of HSE involved assessment of PCR of CSF specimens from a large number of patients with brain biopsy-proven HSE (128).
Recognizing the differences among these reports both in the original case-definition of HSE and in the methodology of PCR employed, it is nevertheless useful to calculate a cumulate sensitivity and specificity of PCR in the diagnosis of HSE, with a relatively recent review of the literature suggesting that overall sensitivity is 96% and overall specificity is 99% (226).
PCRA of blood components from babies with neonatal HSV has been evaluated to a much lesser extent, with only six relatively small studies reported to date in the literature.
Two biologic properties of HSV which directly influence human disease are neurovirulence and latency. Cutaneous HSVA infection causes ballooning of infected epithelial cells, with nuclear degeneration and loss of intact cellular membranes.
Host immuneA responses to HSV infections in children and adults include nonspecific mechanisms such as interferons, neutrophils, complement, macrophages, and natural killer cells, as well as specific mechanisms including humoral (antibody) immunity, TA cell-mediated immunityA (such as cytotoxic T cells and T helper activity), and cytokine release. Lymphocyte blastogenesis responses develop between two weeks and six weeks following infection (51,A 223).
The hostA responses of neonates with HSV disease differ from those of older children and adults. T-lymphocyte proliferative responses are delayed in babies with neonatal HSV disease as compared with older children and adults (223). HSV-infectedA neonates also have decreased alpha-interferon production in response to HSV antigens as compared with adults suffering from primary HSV infection (223). The oral bioavailability of acyclovir is poor, with only 15-30% of the oral formulations being absorbed (173).
In the absence of compromised renal function, the half life of acyclovir is 2 to 3 hours in older children and adults and 2.5 to 5 hours in neonates with normal creatinine clearance. TheA most serious side effect of acyclovir is neurotoxicity, which usually occurs in subjects with compromised renal function who attain high serum concentrations of drug (186).
Although acyclovir is mutagenic at high concentrations in someA in vitroA assays, it is not teratogenic in animals. AsA a prodrug of acyclovir, valaciclovir has the same mechanism of action, antiviral spectrum, and resistance profiles as those of its parent drug, acyclovir. The profiles of adverse effects and potential drug interactions observed with valaciclovir therapy are the same as those observed with acyclovir treatment. InA cells which are infected with HSV, the viral TK phosphorylates penciclovir to its monophosphate derivative, which in turn is converted to the active penciclovir triphosphate by cellular kinases. The bioavailability of penciclovir following oral administration of famciclovir is about 70%. Resistance of HSV toA acyclovirA has become an important clinical problem, especially among immunocompromised patients exposed to long-term therapy (71).
BecauseA penciclovir, like acyclovir, must be activated by the viral encoded TK enzyme, TK deficient viral strains are resistant to both acyclovir and penciclovir. Treatment of primary gingivostomatitis in pediatric patients using oralA acyclovirA decreases time to cessation of symptoms by 30-50%, and time to lesion healing by 20-25% (6).
Oral acyclovir has a more modest effect in the treatment of recurrent herpes labialis (178,A 179), and treatment of these patients should be individualized (Table 7) (114).
TopicalA penciclovirA (Denavir) for the treatment of recurrent herpes labialis reduces time to healing and duration of pain by about half a day (26).
For the treatment of first episode genital herpes, the dose of oralA acyclovirA is 200 mg orally five times per day, or 400 mg orally three times per day (Table 8). For the episodic treatment of recurrent genital herpes, dosing options for acyclovir include 200 mg orally five times per day, or 800 mg orally two times per day, administered for five days (5) (Table 8).
In addition to the treatment of an active genital herpes infection, acyclovir has been effectively used to prevent recurrences of genital herpes.
In the episodic treatment of genital herpes,A famciclovirA reduces time to healing, time to cessation of viral shedding, and durations of lesion edema, vesicles, ulcers, and crusts when compared with placebo (194). A Valaciclovir treatment of first-episode genital HSV is as effective as acyclovir therapy, while at the same time providing a more favorable dosing schedule compared with acyclovir (74).
Topical therapy withA acyclovirA for HSV ocular infections is effective, but probably not superior to trifluridine (Table 7) (94). A AcyclovirA also is indicated for the treatment of disseminated HSV infections in otherwise normal hosts, including pregnant women, and mucocutaneous HSV infections in immunocompromised hosts (114). Acyclovir prophylaxis of HSV infections is of clinical value in severely immunocompromised patients, especially those undergoing induction chemotherapy or transplantation.
Unlike antiviral management of HIV infections, combination antiviral therapy is not employed in the antiviral treatment of HSV infections.
InA contrast to genital disease, the protection against infection and amelioration of disease severity afforded by neutralizing and ADCC antibodies in neonatal HSV may portend a future role for passive immunotherapy in conjunction with antiviral treatment. While antibody therapy offers promise for improving neonatal HSV disease prevention and outcome, studies in humans have yet to be performed.
Despite the advances in our understanding of genital herpes, considerable shame, embarrassment, and stigma remain among infected persons (2).
Persistence of viral DNA in the CSF as detected by PCR occurs in virtually all cases of HSE through the first week following initiation of antiviral therapy (128,A 175,A 187). Quantitative PCR may also have a role in monitoring response to therapy (261), although evaluation for this purpose has been limited to date (57). The available data for neonatal HSV suggest that having HSV DNA detected in CSF at or after completion of intravenous therapy is associated with poor outcomes (111,A 141). Use of images for any purpose including but not limited to research, commercial, personal, or non-commercial use is prohibited without prior written consent. Fluorescence and neutralizing antibodies to herpes simplex virus in the cerebrospinal fluid of patients with central nervous system disease.
Evaluation of a rapid enzyme immunoassay for the detection of herpes simplex virus antigen in children with herpetic gingivostomatitis. As with all herpesviruses, they are large, enveloped virions with an icosahedral nucleocapsid consisting of 162 capsomeres, arranged around a linear, double-stranded DNA core.
These homologous sequences are distributed over the entire genomic map, and most of the polypeptides specified by one viral type are antigenically related to polypeptides of the other viral type.
As discussed below, gingivostomatitis and recurrent herpes labialis represent the most common clinical manifestations of HSV infections. HSV-2 antibodies do not routinely appear prior to adolescence (100,132), and antibody prevalence rates correlate with prior sexual activity. For sexually active Americans with a single lifetime sexual partner, the probability of acquisition of HSV-2 is 10.2%. Recurrent orolabial HSV lesions are frequently preceded by a prodrome of pain, burning, tingling, or itching. When a person with no prior HSV-1 or -2 antibody acquires either virus in the genital tract, a first-episode primary infection results. First episode primary infections are more likely to have systemic symptoms than are first episode nonprimary infections, and have higher rates of complications and a longer duration of disease (Table 1) (103,A 233). Thus, first clinical episode of genital herpes does not necessarily equate with acquisition of HSV in the genital tract, a fact that should be remembered in counseling couples in long-term monogamous relationships in whom one partner has a first clinically recognized case of genital herpes. Genital HSV-2 recurrences can be either symptomatic (recognized by the patient) or asymptomatic (unrecognized throughout the time of recurrence) (181). Patients whose primary HSV-2 infection lasts 35 days or more are more likely to have frequent recurrences than are persons whose primary HSV-2 infection lasts fewer than 35 days. Utilizing polymerase chain reaction (PCR) technology, HSV DNA can be detected fromA genital swab specimens from HSV-2 seropositive women on 28% of days (239). Among infected infants, the time of transmission for the overwhelming majority (~ 85%) of neonates is in the peripartum period.
Clinical manifestations of encephalitis, either alone or in association with disseminated disease, include seizures (both focal and generalized), lethargy, irritability, tremors, poor feeding, temperature instability, and bulging fontanelle. However, this figure has been reduced to about 23% since the development and utilization of antiviral therapy, likely the consequence of recognizing and treating SEM infection before its progression to more severe disease (253). With the introduction of early antiviral therapy, this frequency has increased to 43% (253). The manifestations of herpes simplex encephalitis (HSE) in the older child and adult are indicative of the areas of the brain affected. The electroencephalogram (EEG) generally localizes spike and slow wave activity to the temporal lobe. Even with the utilization of antiviral therapy, substantial mortality and morbidity remain (205), with 19% of patients dying and 62% of survivors having residual neurologic sequelae (251). When the virus was proven to be identical, invariably the patient was experiencing a primary infection, as determined serologically. In a majority of HSV seropositive renal transplant and bone marrow transplant recipients, reactivation of latent virus occurs within the first month post-transplantation. High titers of HIV are found in genital herpes ulcerations (197), and plasma HIV viral load increases when HSV-2 infection reactivates in HIV-infected persons (154). More specific information on the newer, type-specific serologic tests is provided inA Table 5.
In the past few years, several type-specific antibody assays have received FDA approval and are now commercially available (Table 5).
As these standards are being established, though, recommendations from leaders in the field can be found (Table 6).
However, it is of little diagnostic value today due to the delay in the development of intrathecal antibody for a disease that requires rapid diagnosis in order to facilitate therapeutic decisions. With the availability of reliable type-specific assays, one barrier to interpreting serologic results in babies with suspected HSV disease has been removed.
Skin or mucous membrane lesions are scraped and transferred in appropriate viral transport media on ice to a diagnostic virology laboratory (3).
As such, confirmatory diagnosis of genital herpes in a patient presenting with crusting or healed lesions should not include viral culture, since the likelihood of a false-negative result is high. For example, HSV can be cultured from only 4% of CSF specimens from older children and adults with HSE (161). Subclinical shedding of HSV-2 occurs commonly when PCR is utilized, detecting HSV DNA on 20-25% of all days (239). PCR oftentimes is more expensive than viral culture, although price disparities are diminishing. Furthermore, PCR has allowed the detection of perhaps 15-20% of patients identified as having mild or atypical forms of HSE who likely would have been unrecognized in the pre-PCR era (65,A 76,A 119). In the largest series, CSF specimens from 77 neonates in the United States with culture-proven HSV disease were evaluated retrospectively by PCR (111).
Neurovirulence refers to the affinity with which HSV is drawn to and propagated in neuronal tissue. During primary HSV infection, virions are transported by retrograde flow along axons that connect the point of entry into the body to the nuclei of sensory neurons (Figure 4) (219). The relative importance of these various mechanisms is different for initial versus recurrent HSV disease.
Both neutralizing antibodies and antibody-dependent cellular cytotoxic (ADCC) antibodies generally appear between two weeks and six weeks following infection and persist for the lifetime of the host. With viral reactivation from latency and subsequent recurrence of infection, boosts in blastogenic responses can be noted promptly, and subsequently decrease over time. Infected neonates will produce HSV-specific IgM antibodies (as detected by immunofluorescence) within three weeks of acquisition of the viral infection. At two to four weeks following onset of clinical symptoms, most neonates lack detectable T-lymphocyte responses to HSV (180,A 223).


Lymphocytes from infected babies also have diminished HSV antigen-stimulated lymphocyte proliferation and gamma-interferon production in the first three to six weeks after onset of infection (37).
Although Epstein-Barr virus (EBV) has only minimal TK activity, EBV DNA polymerase is susceptible to inhibition by acyclovir triphosphate and thus EBV is moderately susceptible to acyclovirA in vitro.
In addition to HSV, penciclovir has demonstrableA in vitroA activity against VZV, EBV, and hepatitis B virus (HBV). It has been available for clinical use for over 2 decades and has demonstrated remarkable safety and efficacy against mild to severe infections caused by HSV and VZV in both normal and immunocompromised patients.
Neurotoxicity is manifest as lethargy, confusion, hallucinations, tremors, myoclonus, seizures, extrapyramidal signs, and changes in state of consciousness, developing within the first few days of initiating therapy. Limited human data suggest that acyclovir use in pregnant women is not associated with congenital defects or other adverse pregnancy outcomes (220).
Subjects being treated with both zidovudine and acyclovir can develop severe somnolence and lethargy. Licensed in 1995, it has a safety and efficacy profile similar to which of acyclovir but offers potential pharmacokinetic advantages. Following oral administration of valaciclovir, rapid and complete conversion to acyclovir occurs with first pass intestinal and hepatic metabolism.
Neurotoxicity has not been reported in humans to date, although it has been observed in animal models (98). Following oral ingestion and systemic absorption, famciclovir is rapidly deacetylated and oxidized to form the active parent drug penciclovir. Penciclovir triphosphate inhibits viral DNA polymerase by competing with deoxyguanosine triphosphate for incorporation into the growing DNA strand. Complaints of nausea, diarrhea, and headache occurred in clinical trials, but at frequencies similar to those reported by placebo recipients. Viral resistance to acyclovir usually results from mutations in the viral TK gene although mutations in the viral DNA polymerase gene also occur rarely. Strains of HSV whose resistance to acyclovir is conferred by alteration of the TK enzyme or by DNA polymerase mutations may remain sensitive to penciclovir (110).
In general, therapeutic benefit is enhanced if treatment is initiated as soon as possible after onset of symptoms, preferably within 24 to 48 hours of onset of the recurrence.
Topical acyclovir cream also is effective in preventing recurrent herpes labialis in skiers (177) and in persons with a history of frequent recurrences of herpes labialis (82). Topical penciclovir cream decreases the time to lesion healing by approximately one to two days when compared with placebo (26,A 214), and is equally effective as topical acyclovir cream (137).
However, early valaciclovir treatment does not appear to increase the likelihood that a clinical recurrence will be aborted prior to cold sore lesion development (42,A 212). Neither higher doses of oral acyclovir nor the addition of topical acyclovir provide added benefit (237). Topical acyclovir provides no clinical benefit in the episodic management of recurrences and is not recommended (50,A 140). Times to cessation of all symptoms and of moderate to severe lesion tenderness, pain, and burning are also reduced (194). In the treatment of recurrent genital HSV, valaciclovir decreases the duration of lesions, the duration of pain, and the duration of viral shedding when compared to placebo (216). The dosing interval of intravenous acyclovir may need to be increased in premature infants, based upon their creatinine clearance (70). Long-term suppressive therapy reduces the number of recurrences of ocular infection in those with histories of frequent recurrences (90,A 91). Similarly, HSV infections of the lip, mouth, skin, perianal area, or genitals may be much more severe in immunocompromised patients than in normal hosts, with HSV lesions tending to be more invasive, slower to heal, and associated with prolonged viral shedding.
Intravenous or oral administration of acyclovir reduces the incidence of symptomatic HSV infection from about 70% to 5-20% (195). Empiric changes in classes of antiviral agents are sometimes made based upon the clinician’s judgment that a resistant virus could be present. In addition, an HSV hyperimmune globulin preparation does not exist, and the amount of anti-HSV antibodies present in conventional intravenous gammaglobulin (IVIG) preparations is low and variable, such that unacceptable large volumes would need to be injected to potentially confer protective immunity. For many patients, the psychological impact is far more severe than the physical consequences of the disease (39).
During the second week of therapy, HSV DNA is detected in the CSF of approximately half of the patients, and 20% or fewer of patients have a positive PCR result beyond day 15 of antiviral therapy (128,A 187).
While at least one investigation failed to correlate amount of virus present with severity of outcome (187), other studies have found a relation between HSV viral load in the CSF and likelihood of future neurologic impairment (64).
As such, all patients with CNS HSV involvement should have a repeat lumbar puncture at the end of intravenousA acyclovirA therapy to determine that the specimen is PCR-negative in a reliable laboratory, and to document the end-of-therapy CSF indices (113). Four cases of primary herpetic gingivostomatitis are reported in two pediatricians and two pediatric nurses who contracted the infection in their fourth decade of life.
The genome consists of two covalently linked components, designated as L (long) and S (short).
This results in considerable cross-reactivity between the HSV-1 and HSV-2 glycoproteins, although unique antigenic determinants exist for each virus.
Using type-specific serologic assays, the seroprevalence of HSV-1 infections has been redefined utilizing sera obtained from the United States National Health and Nutrition Examination Survey (NHANES). Primary oropharyngeal infection with HSV-1 occurs most commonly in young children between one and three years of age. These symptoms generally last for less than six hours, followed within 24 to 48 hours by the appearance of painful vesicles, typically at the vermillion border of the lip (Figure 2). If a person with preexisting HSV-1 antibody acquires HSV-2 genital infection, a first-episode nonprimary infection ensues. By the mid-1990s, the percentage of primary cases of genital herpes caused by HSV-1 had doubled to 20% (126). Genital HSV-1 infections recur less frequently than do genital HSV-2 infections (46,A 125,A 183), a finding which could explain why recurrent genital herpes infections are caused by HSV-2 in more than 90% of cases (126). Thus, within the course of a year, women who are completely asymptomatic will shed virus on average in excess of 100 days.
An additional 10% of infected neonates acquire the virus postnatally, and the final 5% are infected with HSV in utero. Patients with disseminated or SEM disease generally present to medical attention at 10-12 days of life, while patients with CNS disease on average present somewhat later at 16-19 days of life (113).
Of those infants with CNS disease without visceral dissemination, between 60% and 70% have associated skin vesicles at any point in the disease course (113,A 224). These include primarily focal encephalitis associated with fever, altered consciousness, bizarre behavior, disordered mentation, and localized neurologic findings.
A burst suppression pattern is characteristic of, but not pathognomonic for, HSE (periodic lateralizing epileptiform discharges, or PLEDS).
Patients with a Glasgow coma score of less than 6, those older than 30 years, and those with encephalitis for longer than 4 days have a poorer outcome (251).
Thus, virus excreted from the mouth of patients with HSE may be identical to that of the brain or may be entirely different.
As noted above, women are more likely than men to have meningeal symptoms, with approximately one-third of women with primary HSV-2 genital infection having meningeal symptoms as compared with approximately one in ten men with such symptoms (Table 2).
Administration of prophylactic acyclovir prior to bone marrow transplantation can prevent such reactivation (195,234). It is likely that a substantial proportion of new HIV infections are attributable to underlying genital HSV infection (48). Two of these, the HerpeSelectA® HSV-1 and HSV-2 ELISA and the HSV-1 and HSV-2 Immunoblot tests, are manufactured by Focus Technologies, Inc.
However, the presence of transplacentally acquired maternal IgG still confounds the assessment of the neonatal antibody status during acute infection, especially given the large proportions of the adult American population who are HSV-1- and HSV-2-seropositive. Such specimens are inoculated into cell culture systems, which are then monitored for cytopathic effects characteristic of HSV replication. While HSV can be cultured from the CSF of 40% of infants with neonatal HSV CNS disease (113), it still has been replaced as the gold standard for virologic confirmation of CNS involvement by PCR due to markedly greater sensitivity of the PCR assay, as discussed below. Overall, PCR is three to four times more sensitive for detecting HSV on mucosal surfaces than culture, independent of the presence of lesions or the immune status of the patient (240). As such, it will increasingly be utilized for diagnosis of individual patients in the future. The overall sensitivity and specificity of PCR in this patient cohort was 98% and 94%, respectively, with a positive predictive value of 95% and a negative predictive value of 98% (128).
Results of this analysis both enhanced the understanding of the spectrum of natural history of neonatal HSV disease and validated the utilization of PCR in the management of such infants. This can result in profound disease with severe neurologic sequelae, as is the case with HSE in children and adults, and with neonatal HSV CNS disease. Viral multiplication occurs in a small number of sensory neurons, and the viral genome then remains in a latent state for the life of the host. With cell lysis, clear fluid containing large quantities of virus, cellular debris, and inflammatory cells accumulates between the epidermal and dermal layers. Animal studies suggest that activated macrophages, interferons, and, to a lesser extent, natural killer cells are important in limiting initial HSV infection, whereas humoral immunity and cell-mediated immunity are important in controlling both initial and recurrent infections. The host response to virus-specific infected cell polypeptides and the development of neutralizing antibodies have been defined through immunoblot and immunoprecipitation assays (24,A 68). HSV-specific IgM concentrations increase rapidly during the first two to three months, and in some infants may be detectable for as long as one year following neonatal infection. Acyclovir is a deoxyguanosine analogue with an acyclic side chain that lacks the 3'- hydoxyl group of natural nucleosides (236).
If it extravasates, intravenous acyclovir can cause severe inflammation, phlebitis, and sometimes a vesicular eruption leading to cutaneous necrosis at the injection site.
These signs and symptoms usually resolve spontaneously within several days of discontinuing acyclovir. The likelihood of renal toxicity is increased when acyclovir is administered with nephrotoxic drugs such as cyclosporine and amphotericin B. The bioavailability of valaciclovir exceeds 50%, which is three to five times greater than that of acyclovir (207). Manifestations resembling thrombotic microangiopathy have been described in patients with advanced HIV disease receiving very high doses of valaciclovir (8 grams per day), but the multitude of other medications being administered to such patients makes the establishment of a causal relationship to valaciclovir difficult (19). Acyclovir is removed during hemodialysis, and therefore an extra dose of valaciclovir should be administered following completion of hemodialysis. While penciclovir triphosphate is neither an obligate DNA chain terminator nor an inactivator of the DNA polymerase, once incorporated penciclovir triphosphate does retard the rate of subsequent nucleotide incorporation. No clinically significant drug interactions have been reported to date, although concentrations of famciclovir among volunteers increase by about 20% in patients receiving concomitant cimetidine or theophylline administration.
Although these acyclovir resistant isolates exhibit diminished virulence in animal models, among HIV infected patients they can cause severe, progressive, debilitating mucosal disease and (rarely) visceral dissemination (80).
Among patients who start treatment in the prodrome or erythema lesion stage, acyclovir therapy (400 mg five times a day for five days) reduces the duration of pain by approximately one-third, and the healing time to loss of crust by approximately one-fourth (215). Long-term suppressive therapy reduces the number of recurrences of oral infection in those with histories of frequent recurrences (189).
Valaciclovir administered as a 500 mg dose once daily is effective in suppressing recurrences of herpes labialis, with almost two-thirds of treated patients remaining recurrence-free during four months of suppressive therapy compared with approximately one-third of placebo recipients (14,A 15). A recent study indicates that two days of oral acyclovir therapy (800 mg three times per day) is also efficacious in the episodic treatment of genital HSV recurrences (238). One quarter to one third of patients on suppressive therapy experience no further recurrences while taking acyclovir. For suppression of genital HSV recurrences, famciclovir delays the time to the first recurrence of genital herpes when compared with placebo (63,A 149). Valaciclovir also is as effective as acyclovir for the episodic treatment of recurrent genital HSV, again providing a more favorable dosing schedule compared with acyclovir (230). Duration of therapy is 21 days for patients with disseminated or CNS neonatal HSV disease, and 14 days for patients with HSV infection limited to the SEM (3).
A randomized, controlled trial of long-term suppressive oral valaciclovir therapy following the treatment of the acute HSE disease is currently being conducted by the National Institute of Allergy and Infectious Diseases (NIAID) Collaborative Antiviral Study Group. A sequential regimen of intravenous acyclovir followed by oral acyclovir for 3 to 6 months can virtually eliminate symptomatic HSV infections in organ transplant recipients. Similarly, vaccines have been developed which generate robust humoral responses yet fail to protect against HSV-2 infection (217).
For these reasons, use of IVIG in the management of neonates with HSV disease cannot be recommended at this time.
Shock, anger, guilt, low self-esteem, fear of transmission of the infection to others, and impaired sexual function are common and can interfere substantially with relationships (2).
An end-of-therapy lumbar puncture should be performed to document that the CSF has become PCR-negative prior to stopping parenteral antiviral therapy. Those persons who remain PCR-positive should continue to receive intravenous antiviral therapy until PCR-negativity is achieved. Viral surface glycoproteins mediate attachment and penetration of HSV into cells, and provoke host immune responses.
Since the late 1970s, seroprevalence rates for HSV-2 in the United States have increased by 30% (75), although recent data suggest that this trend may be diminishing (262). Despite these high seroprevalence rates, most HSV-2-infected American adults do not report ever having had genital herpes, and it is this lack of recognition of one’s own infection which contributes to the surreptitious spread of this virus. Lesions usually crust within three to four days, and healing is complete within eight to 10 days. Viral reactivation from latency and subsequent antegrade translocation of virus back to skin and mucosal surfaces produces a recurrent infection.
Constitutional symptoms such as fever, headache, malaise, and myalgias are seen in two-thirds of women with clinically apparent first-episode genital herpes caused by HSV-2, as compared with ~ 40% of men (Table 2).
Approximately half of patients experience prodromal symptoms ranging from mild tingling sensations to sacral neuralgia prior to the development of at least some of their clinically apparent recurrences (Table 3).
During the first year following acquisition of genital HSV-1 infection, 60% of persons will develop one or more clinical recurrences. Transmission to a sexual partner may occur during such periods of subclinical shedding (188). With high-dose acyclovir therapy, the mortality rate for disseminated neonatal HSV disease is 29% (112). At most, only 2-6% of patients recovering from neonatal SEM disease will experience any neurologic sequelae if they receive optimal diagnostic and therapeutic support during the acute period.
Clinical signs and symptoms reflect the area(s) of the brain affected, with disease typically localized to the temporal lobe (259). Of all patients with HSE, approximately one-third have primary infections and two-thirds have recurrent infections (161,A 260).
Nuchal rigidity and detection of HSV in CSF occurs much more frequently with HSV-2 genital herpes than with HSV-1 genital herpes (165,A 206). In the latter group, a negative HSV serology result means that genital herpes can be ruled out as the cause of ulceration (10,A 54,A 130).
Furthermore, intrathecal immune responses may be delayed or absent when antiviral therapy is started early (138). As a result, serologic studies generally play no role in the diagnosis of neonatal HSV disease. Thus, sending CSF for viral culture in cases of suspected HSV CNS disease (HSE or neonatal HSV disease with CNS involvement), which requires significant volumes of CSF to be plated on cell lines for subsequent attempts at HSV isolation, has been replaced in recent years with performing HSV PCR on these limited and precious CSF specimens. PCR may be particularly useful in detecting viable or nonviable viral genomes in genital lesions which have already crusted but which do not yield positive cultures.
These 77 infants had been previously enrolled during the 1980s in a comparative study of vidarabine and acyclovir for the treatment of neonatal HSV disease.
Sites on the herpes simplex genome which mediate this propensity for neurovirulence have been mapped to the thymidine kinase (TK) gene as well as the termini of the L component.
With periodic reactivation brought on by events such as physical or emotional stress, fever, ultraviolet light, and tissue damage, the virus is transported back down the axon to replicate again at or near the original point of entry into the body (Figure 4).


The viral surface glycoproteins gB and gD are the most reactive immunodeterminants (223) and, indeed, account for the majority of neutralizing antibodies. Following preferential uptake by infected cells, acyclovir is monophosphorylated by virus encoded TK; host cell TK is approximately 1 millionfold less capable of converting acyclovir to its monophosphate derivative. Acyclovir is effectively removed by hemodialysis but not by continuous ambulatory peritoneal dialysis (124). If given by rapid intravenous infusion or to poorly hydrated patients or those with pre existing renal compromise, intravenous acyclovir can cause reversible nephrotoxicity due to the formation of acyclovir crystals precipitating in renal tubules and causing an obstructive nephropathy. Concomitant administration of probenicid decreases renal clearance of acyclovir and prolongs its half life; conversely, acyclovir can decrease the clearance of drugs such as methotrexate that are eliminated by active renal secretion.
Although causation has not been established, use of valaciclovir at such high doses should involve evaluation of potential risks and benefits. Penciclovir is approximately 100 fold less potent thanA acyclovirA in inhibiting herpesvirus DNA polymerase activity.
Topical acyclovir cream may also modestly decrease the duration of a clinical recurrence of herpes labialis by approximately half a day (approximately four and a half days for topical acyclovir recipients, compared with approximately five days for placebo recipients) (213), although benefit of topical acyclovir is not conferred by acyclovir ointment, which has a polyethylene glycol base (201,A 209). In one study of 400 mg of oral acyclovir administered twice daily for four months, clinical recurrences were reduced by more than half, and culture-confirmed recurrences were reduced by more than two-thirds (189). Faster healing and pain resolution occurs both among patients who first apply penciclovir cream in the prodrome and erythema stages and among those who start treatment in the papule and vesicle lesion stages (214). Acyclovir therapy for the treatment of first episode genital herpes reduces the duration of viral shedding by about a week, time to healing of lesions by approximately four days, and time to complete resolution of signs and symptoms by approximately two days (36,A 146).
When started within 24 hours of the onset of a genital herpes recurrence, oral acyclovir reduces the duration of viral shedding by approximately two days, time to healing by just over a day, and time to complete resolution of signs and symptoms by approximately a day (230). Daily administration of acyclovir maintains a high degree of efficacy and little toxicity, even after more than 5 years of continuous suppressive therapy (85).
For the episodic treatment of recurrent genital HSV disease, the dosage of famciclovir is 125 mg twice daily, administered for 5 days (Table 8). It should be administered for three to five days when administered as episodic treatment (5,A 133). This study will determine whether subclinical reactivation of HSV within the brain contributes to the neurologic impairment experienced by many HSE survivors. Immunocompromised patients receiving acyclovir have a shorter duration of viral shedding and more rapid healing of lesions than patients receiving placebo (150). A variety of oral dosing regimens, ranging from 200 mg 3 times daily to 800 mg twice daily, have been used successfully. As such, it is difficult to envision a circumstance whereby passive antibody immunotherapy will play a role in the management of genital HSV infection and disease. Any development of a monoclonal antibody against HSV would of course require extensive testing in humans before therapeutic recommendations could be made. Anecdotal experience suggests that the diagnosis of neonatal herpes has a similar negative impact on the parents' relationship, with guilt and anger over the baby's illness and its association with genital herpes often leading to separation and divorce. Acute respiratory disease of university students with special reference to etiologic role of herpes virus hominis.
Additionally, the unique L and S components can invert relative to one another, yielding four linear isomers. A similarly high prevalence of antibodies to HSV-1 exists among persons worldwide, although variability from country to country is seen. Approximately one in five adult Americans have acquired HSV-2 (75,A 262), although most do not realize that they have been infected. Symptomatic disease is characterized by fever to 104oF, oral lesions, sore throat, fetor oris, anorexia, cervical adenopathy, and mucosal edema.
Recurrences occur only rarely in the mouth or on the skin of the face of immunocompetent patients. The incubation period following genital acquisition of HSV-1 or -2 is approximately four days (range, 2-12 days).
The duration of viral shedding is shorter during recurrent infection, and there are fewer lesions present. HSV-1 genital infections can result from either genital-genital contact or oral-genital contact with an infected person who is actively shedding virus.
Regardless of the viral type causing genital infection, recurrence rates decrease over time (21). Given that 20-25% of the United States population is infected with HSV-2, as discussed above, subclinical viral shedding likely accounts for the majority of spread of genital herpes. Survivors, however, are likely to do very well, with only 17% experiencing neurologic sequelae (112). While no signs are pathognomonic for HSE, a progressively deteriorating level of consciousness, fever, abnormal cerebrospinal fluid (CSF) indices, and focal neurologic findings in the absence of other causes should make this disease highly suspect. Aseptic meningitis associated with genital HSV lesions appears to be a benign disease in immunocompetent persons, with full recovery expected.
Type-specific serology could also prove helpful for couples in long-term monogamous relationships where one partner has developed genital herpes. Two methods for diagnosis of HSE by detection of intrathecal antibodies have been validated. Viral culture is widely available, and results in the attainment of a viral isolate, which can then be typed. As with any test, though, false-negatives can occur, and in the case of neonatal HSV disease involving the CNS a positive cutaneous or mucosal culture and evidence for CNS involvement such as seizures, abnormal CSF indices, abnormal neuroimaging studies, etc., will suffice to confirm the CNS disease.
The sensitivity of PCR for the diagnosis of HSE in children and adults from these studies range from 95-100% (12,58,A 87,A 128). Of note, the gene identified as I?134.5 is required for replication in central nervous system tissue and prevents apoptosis of infected neuronal cells.
Such reactivation can result in clinically apparent disease (lesions) or clinically inapparent (asymptomatic, or subclinical) infection.
Mucocutaneous herpes is more severe in patients with impaired or defective cell mediated immunity (171,A 254), but not in patients with agammaglobulinemia. Depending upon the time following infection, commercially available laboratory testing can detect both HSV-specific IgM and IgG.
Subsequent diphosphorylation and triphosphorylation are catalyzed by host cell enzymes, resulting in acyclovir triphosphate concentrations that are 40 to 100 times higher in HSV-infected cells than in uninfected cells (69). Administration of acyclovir by the intravenous route occasionally is associated with rash, sweating, nausea, headache, hematuria, and hypotension. The area under the drug concentration time curve approximates that seen after intravenous acyclovir.
By virtue of its high intracellular concentrations and long intracellular half-life (7 to 20 hours), though, it remains an effective antiviral agent. The plasma half life of penciclovir is about 2.5 hours, and almost three quarters is recovered unchanged in the urine.
Although it is uncommon, genital herpes caused by acyclovir resistant isolates has also been reported in immunocompetent hosts who usually have received chronic acyclovir therapy (122,A 156). Application of medicine should begin as early as possible, preferably during the prodromal phase, and should be continued every two hours during waking hours for four days (Table 7).
Episodic treatment does not reduce the length of time to subsequent recurrence (163,A 184,A 193). Suppressive therapy reduces the frequency of asymptomatic shedding of HSV in the genital tract by more than 80% (239,A 242). The recommended dose for suppression of genital HSV is 250 mg twice daily for up to one year (Table 8). Valaciclovir is also effective in suppressing recurrences of genital HSV when administered as once-daily suppressive therapy (185). At the current time, however, no evidence exists to suggest that suppressive oral valaciclovir therapy is beneficial in preventing neurologic complications. Neonates with higher neutralizing antibody titers are less likely to become infected with HSV following perinatal exposure of passage through an infected birth canal (174), illustrating the protective effects of preexisting antibody in preventing neonatal HSV disease. A listing of helpful resources which provide reliable herpes information can be found inA Table 9. In conclusion, pediatric personnel with pharyngitis and a negative history of herpetic gingivostomatitis or herpes labialis should bear the possibility of oral HSV infection in mind.
Each intact HSV virion contains only one of these four isomers, and each of the four are equally virulent (functionally equivalent) in the host cell. Glycoprotein D is the most potent inducer of neutralizing antibodies and appears related to viral entry into a cell, and gB also is required for infectivity.
Oral lesions initially are vesicular but rapidly rupture, leaving 1- to 3-mm shallow gray-white ulcers on erythematous bases. As with primary HSV-1 infection, recurrent infection may occur in the absence of clinical symptoms.
The overwhelming majority of both men and women with clinically apparent first-episode genital HSV-2 disease have localized symptoms such as pain at the site of the lesions and tender regional adenopathy, with pruritis, dysuria, and vaginal or urethral discharge also occurring commonly. However, there is considerable interpatient and intrapatient variability in the severity and duration of disease from recurrence to recurrence.
Given the decreased propensity of HSV-1 to reactivate at the genital site, however, it is likely that oral-genital contact accounts for most genital HSV-1 infections (126). Over the course of several years, the frequency of subclinical HSV shedding generally diminishes. Diagnostic evaluations should be initiated immediately, since other treatable diseases mimic HSV encephalitis (40,A 252). This finding is followed by evidence of hemorrhage and midline shift in the cortical structures. The role of antiviral therapy in the management of aseptic meningitis associated with genital herpes has not been systematically evaluated, although use of systemic antiviral therapy in the treatment of primary genital herpes decreases the subsequent development of aseptic meningitis (47). In such circumstances, it is imperative to test for both HSV-1 and HSV-2, since a negative HSV-2 serologic test does not exclude the diagnosis of genital herpes.
The first is a calculation of an HSV-specific antibody index, and the second is HSV-specific immunoblotting of oligoclonal IgG (155). Typing of the viral isolate can provide useful prognostic information regarding reactivation and transmission, which can be used in counseling the patient. HSV DNA was detected by PCR in the CSF of almost one-quarter of infants who had previously been categorized as having SEM disease (111). Genetically engineered HSV virions lacking the I?134.5 gene are currently being investigated as therapies for brain tumors (143,A 144). The mechanisms by which HSV establishes latency are being intensely investigated, but remain incompletely understood at this time. As the lesions heal, vesicular fluid becomes purulent as more inflammatory cells are recruited to the site of infection.
Of note, the intensity of host immune response to virus-specific polypeptides and the quantitative levels of neutralizing antibodies are not protective against recurrences. Acyclovir triphosphate prevents viral DNA synthesis by inhibiting the viral DNA polymerase.A In vitro, acyclovir triphosphate competes with deoxyguanosine triphosphate as a substrate for viral DNA polymerase. Measurable penciclovir concentrations are not detectable in plasma or urine following topical administration of penciclovir cream. The acyclovir dose when used as suppressive therapy is 400 mg administered twice daily (Table 8). Note that the lack of harmonization of treatment regimens resulted from different doses of famciclovir being studied in the clinical trials; this produced the unusual dosage recommendation of decreasing the suppression dose to treat a genital HSV recurrence.
All patients with CNS HSV involvement should have a repeat lumbar puncture at the end of intravenous acyclovir therapy to determine that the specimen is PCR-negative in a reliable laboratory, and to document the end-of-therapy CSF indices (113). Among HSV-infected neonates, anti-HSV neutralizing antibody titers have been shown to correlate with the extent of the disease (223), with babies with higher neutralizing antibody titers being more likely to have localized disease (and less likely to have disseminated disease) once they are infected. Animal vectors for human HSV infections have not been described, and humans remain the sole reservoir for transmission to other humans. These infection rates and their rise over the past two decades suggest that genital herpes is nearing epidemic proportions. These lesions are distributed on the hard palate, the anterior portion of the tongue, along the gingiva, and around the lips (Figure 1). Local symptoms peak at about one week following onset, and generally resolve by the end of the second week.
Whites with genital herpes are more likely than blacks with genital HSV to have infection caused by HSV-1 (126).
With education regarding the clinical signs and symptoms of genital disease and including photographs, HSV-2 seropositive women without previously recognized genital HSV infection can begin to recognize atypical signs and symptoms as being associated with HSV recurrences (78,A 129).
Several additional tests which claim to distinguish between HSV-1 and HSV-2 antibody are commercially available, but high cross-reactivity rates due to their use of crude antigen preparations limit their utility to documentation of primary seroconversion, rather than distinguishing between viral types (8).
Both require comparison of HSV-specific antibody reactivity in CSF and serum samples taken on the same day. Among infants with disseminated neonatal HSV disease, HSV DNA was detected in the CSF of 13 (93%) of 14 infants classified as having disseminated disease, while 26 (76%) of the 34 infants categorized as having CNS disease were PCR-positive in their CSF. Because acyclovir triphosphate lacks the 3'-hydroxyl group required to elongate the DNA chain, the growing chain of DNA is terminated. The safety and efficacy of famciclovir therapy beyond one year of treatment have not been established. Suppression of recurrent oral herpes infections also has been accomplished with single daily doses of 500 mg. Those persons who remain PCR-positive should continue to receive intravenous antiviral therapy until PCR-negativity is achieved (111,A 113). Similarly, high maternal or neonatal anti-HSV ADCC antibody levels or high neonatal antiviral neutralizing levels are each independently associated with an absence of disseminated HSV infection (121). Virus is transmitted from infected to susceptible individuals during close personal contact. Viral shedding as detected by culture lasts 10-12 days, and lesions resolve over 16-20 days.
This possibly relates to the younger ages at which orolabial HSV-1 infection acquired among minorities, thereby providing a degree of protection against genital HSV-1 infection in adulthood. This finding is of importance in educational programs on genital herpes which have a focus on reduction of HSV transmission.
This is remarkably similar to the Swedish experience of applying PCR to stored specimens from patients with neonatal HSV diagnosed between 1973 and 1996, where 78% of neonates with CNS HSV disease were found to be PCR-positive from CSF (141). In the presence of the deoxynucleoside triphosphate complementary to the next template position, the viral DNA polymerase is functionally inactivated (182). Protein binding ranges from 9% to 33% and less than 20% of drug is metabolized to biologically inactive metabolites. Primary genital herpes caused by HSV-1 are more likely to be symptomatic than are those caused by HSV-2 (130). When infection involves mucous membranes, shallow ulcers are more common than vesicles because of rapid rupture of the very thin cornified epithelium present at mucosal sites.
In addition, acyclovir triphosphate is a much better substrate for the viral polymerase than for cellular DNA polymerase I±, resulting in little incorporation of acyclovir into cellular DNA. Because infection is rarely fatal and HSV establishes latency, over one third of the world's population has recurrent HSV infections and, therefore, the capability of transmitting HSV during episodes of productive infection. Primary gingivostomatitis results in viral shedding in oral secretions for an average of seven to 10 days.
In comparison, the sensitivities of PCR assays used in two other investigations of neonatal HSV disease were 100% (116) and 75% (228), and the specificities were 100% in both studies (116,A 228).



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Comments
  1. brodyaga_vechniy 25.05.2014 at 12:31:38
    And Acyclovir are generic today and really and herpes zoster, but with Professor David.
  2. Bakino4ka 25.05.2014 at 10:35:43
    Five occasions per day till cures and treatments for the benefits and dangers of such therapy.