Herpes simplex virus (HSV) is an etiological agent of 2 widespread diseases in humans: orofacial infection, the so called “cold sores”, and genital herpes (GH). There are two closely related species of HSV, HSV-1 and HSV-2. Both are large enveloped viruses containing double-stranded DNA. HSV-1 is normally (but not always) associated with orofacial infections whereas HSV-2 causes mainly GH (though it could also cause orofacial infections, clinically indistinguishable from those caused by HSV-1). Both viruses could be transmitted from infected mothers to neonates.
HSV infects its host at mucosal or epithelial surfaces and causes primary infection of the epithelium. Then the virus enters sensory neurons and is transported by retrograde flow along axons that connect the point of entry into the body to nuclei of sensory neurons. Viral multiplication occurs in a small number of sensory neurons; the viral genome then remains in a latent state for the life of the host.
HSV frequently reactivates from latency and infects epithelial cells adjacent to neuron where it resides. This process results in lesions with viral shedding or with asymptomatic shedding alone. Reactivation is triggered by another infection, psychological stress, tissue damage, etc.
HSV causes benign vesicular and ulcerative lesions in immunocompetent adults and may cause severe systemic disease in neonates and immunosuppressed hosts.
In children >5 years old and immunocompetent adults duration of the first attack is 2-4 weeks. Symptoms of recurrent outbreaks are typically shorter in duration (7-10 days) and even less severe than the first outbreak of genital herpes.
The course of disease is more severe in small children (the so-called neonatal herpes (NH) and immunocompromised persons. Complications of herpes in these patients could remain localized and affect only eyes, mouth and skin; infection could spread to the central nervous system causing meningitis, myelitis, and encephalitis; in the last, disseminated, stage, infection involves multiple organs.
To initiate infection, HSV must contact either mucosal surfaces or abraded skin. Transmission usually occurs by direct oral-oral, oral-genital or genital-genital contact. Orofacial herpes is transmitted mainly by household contact during childhood whereas GH is a disease mainly transmitted by sex. Neonatal HSV infection most commonly results from contact between the newborn and HSV that is present in the birth canal of the mother during delivery.
HSV can be transmitted to child under primary or recurrent herpes, both in the presence or absence of symptoms. However, under recurrent herpes, the risk of transmission to a newborn is low even if open sores are present at the time of birth (the risk is 3/100). On the contrary, the risk is considerably higher if the primary infection is acquired in the third trimester, and especially in the last 6 weeks of pregnancy (the risk increases to around 50%). As a result, seronegative women in the third trimester of pregnancy are the main group at risk, especially, if their partner is seropositive. Intrauterine infection, contrary to neonatal one, is a relatively rare event.
The two currently recognized viral species, HSV-1 and HSV-2, were primarily recognized as serotypes. The serological differentiation was later extended with biochemical and genetic analyses of HSV-1 and HSV-2 DNA and proteins.
HSV infection occurs worldwide. Estimated prevalence of the HSV-1 infection is highest in Africa (87%) and lowest in the Americas (40-50%). The prevalence of HSV-2 infection is much lower: in Africa-31.5%, in Americas-14.4%.
The incidence of NH is different in various countries. For example, in USA, the disease affects around 20-50 babies in every 100 000 live births whereas in UK there are only 1-2 cases/100 000 live births.
Immune response plays a vital role in maintaining the latent state and in rapidly eliminating reactivated virus. IgG antibodies appear after primary HSV infections 2 weeks after onset of clinical lesions, and the titer increases until 3-4 weeks after clinical symptoms. Later, the IgG antibody titers to HSV usually remain stable even after clinical recurrent infections.
Infected newborns have been found to produce IgM specific for HSV within 1 to 3 weeks after onset of infection. These antibodies continue to increase during the first 2 months and may be detectable for as long as 1 year, but sometimes rises in titers of IgM can be demonstrated later, after recurrences.
HSV-1 and HSV-2 encode at least 84 different polypeptides, approximately half of which are structural proteins that comprise the virus particle, and the rest are non-structural proteins, for example, transcriptional regulators and enzymes.
Twelve to fourteen proteins from either HSV-1 or HSV-2 are precipitated by human sera; the majority of them are surface glycoproteins. There are 11 known viral glycoproteins (B–M). Although the majority of immunogenic epitopes are shared between HSV-1 and -2, one envelope protein, glycoprotein G (gG-1 in HSV-1 and gG-2 in HSV-2), elicits a predominantly type-specific immune response, and is widely used in differential diagnostics of HSV-1 and HSV-2.
The main target group in the diagnostics of herpes infection are pregnant women. In this group of patients diagnostics is aimed mainly at prevention of NH among their children. This task includes following two steps:
a) to disclose serological status of women early in the pregnancy and to provide this group of patients with recommendations how to protect themselves from herpes infection, chiefly GH;
b) to reveal new infections late in the pregnancy. If GH symptoms are present, a cesarean delivery is recommended to prevent HSV transmission to the infant.
Methods used for diagnostics of herpetic infection and aimed at prevention of NH should meet following criteria:
a) differentiate between infection with HSV-1/HSV-2;
b) indicate the localization of herpetic infection. For example, in the most typical case of oral infection with HSV-1, genital infection with HSV-1 is excluded, but genital infection with HSV-2 is possible;
c) differentiate between recurrent and new infections, since recurrent infections are less dangerous for newborns.
Genital herpetic infection often lacks specific symptoms and in the vast majority of cases goes unrecognised. Therefore, several laboratory methods should be used simultaneously to satisfy diagnostic criteria mentioned above.
The widespread methods in the diagnostics of herpes are virus isolation in cell culture or PCR detection of HSV DNA. Both methods permit localization of infection and virus typing, but they are not sensitive enough because of intermittent viral shedding, and they do not allow distinguishing between recurrent and new infections.
Serologic assays could determine whether there is a recurrent or new infection. In new infections, IgG is still negative in acute phase whereas in recurrent infections IgG is positive.
Modern ELISA assays distinguish antibodies to HSV-1 from HSV-2. Yet, they are unable to localize herpetic infection, which should be done by local symptoms, culture or PCR.
In neonates, diagnosis of herpes is confirmed by culture and identification of species-specific IgM within the first 2-3 weeks of life.
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