Herpes Simplex Virus
Herpes Simplex Virus (HSV) belongs to the alphaherpesvirus subfamily of the herpesvirus. Herpesvirus is a linear ds DNA enveloped virus with viral glycoprotein spikes with a genome of 150kb. HSV share some of its antigens with other herpesviruses, in particular Varicella Zoster Virus (VZV). HSV can be classified into 2 subtypes based on serology between genomes HSV 1 and HSV 2 which share 50-70% homology. Both are ubiquitous and contagious
HSV is spread by contact (close/sexual/maternal) as the virus is shed in saliva, tears, genital and other secretions. The primary infection is usually trivial and subclinical in most individuals, 2 peaks of primary infection usually found those younger than 5 years of age or when sexually active. Around 10% of population acquires HSV infection through the genital route. Generally HSV 1 causes infection in the facial area, HSV 2 causes mainly genital herpes. Following primary infection, 45% of orally infected and 60% of patients with genital herpes will experience recurrences.
During primary infection, HSV spreads locally and viraemia is rare which has localised infection at site of entry and then the virus spreads down neurones where it becomes latent in the craniospinal ganglia. There’s three distinct stages involved which are establishment, maintenance and reactivation. The virus establishes latency in the cransiospinal ganglia. The exact mechanism of latency in not known but this is where HSV is able to escape the immune response and persist indefinitely in the latent state. The mechanism may be either
a) True latency – virus is non-replicative and maintained within the cell by integration into the cellular chromosome or in an episomal form.
b) Virus persistence – can be described as dynamic latency whereby there is a tightly controlled low grade productive virus infection not leading to the lysis of the cell.
During latent infection, HSV express Latency Associated Transcript (LAT) RNA. LAT is known to regulate host cell genome and interferes with apoptosis. By maintaining the host cells, LAT expression preserves the virus and outbreaks of non-latency occurs. Reoccurency can be asymptomatic/symptomatic, viral shedding occurs to produce further infection. Herpesvirus DNA contains a gene protein called ICP4, which is an important transactivator of genes associated with HSV 1. ICP4 binds to a protein known as human neuronal restrictive silencing factor. This prevents the initiation of transcription from the gene and other viral genes involved in the lytic cycle. Another HSV protein reverses the inhibition of ICP4 protein synthesis. ICP0 dissociates (NRSF) from ICP4 and prevents silencing of viral DNA. Which is reactivated which triggers off reoccurances, this can be by physical, psychological stress, infection (pneumococcal, meningococcal), fever, irradiation (sunlight), menstruation etc. the usual site for implantation is skin or the mucous membrane.
HSV is involved in a variety of clinical manisfestations which include:
1) Acute gingivostomatitis – most common in herpetic infection, pain and bleeding in gums, ulcers, enlarged neck glands, lasts 13 days.
2) Herpes labialis (cold sore) – 45% experience reactivation
3) HSV genitalis – can be primary, recurrent or initial, lesions are prone to secondary bacterial infection e.g. S.aureus, streptococcus, trichomonas and candida albicans. Dysuria is the common compliant in severe cases, may be urinary retention.
4) Ocular Herpes – lesions in the external eye to the inner eye
5) HS encephalitis (HSE) – most complicated HSV. There are 2 forms – neonatal and focal. Neonatal where the brain is almost liquefied. Focal is where the temporal lobe is mostly affected. Without treatment mortality rate is 70%. In all general practice IV acyclovir is given in all cases for suspected HSE until results are available.
6) Neonatal herpes – baby is infected perinatally during passage through the birth canal. Premature rupturing of both membranes are a recognised risk factor. It disseminates when there is a florid primary infection in the mother. There is a smaller risk from recurrent lesions in the mother, probably due to the lower viral load and the presence of specific antibody.
7) Herpetic whitlow – arises from the implantation of the virus into the skin and affecting fingers.
8) Eczema Herpeticum – occurs in patients who have eczema.
9) Meningitis – milder than bacterial infection.
Neonatal herpes may be caused by HSV1 or 2 which either type may be caused by genital herpes. Almost all cases occur due to direct contact with infected maternal secretions although some cases are due to postnatal transmission. Risks become greater in the third trimester of pregnancy, within 6weeks of delivery as viral shedding may persist and the baby is likely to be born before the development of protective maternal antibodies. Therefore viral cultures are taken every week during the last 6 weeks of pregnancy to detect any recurrent herpes episodes, positive cultures near labour would undergo caesarean section.
Data from USA suggest around 2% of women acquire genital HSV infection in pregnancy, most of these are asymptomatic or unrecognised. Its difficult to distinguish clinically between recurrent and primary genital HSV as many first HSV infections are not try primary infections.
Disseminated herpes is commonly reported in immunocompromised pregnant women, as those infected with HIV. Both HSV and HIV results in an increased replication of both viruses, genital reactivation of HSV may increase the risk of perinatal transmission of both HIV and HSV.
Symptomatic genital herpes is confirmed by direct detection of HSV. Specimens from ulcerated lesions are sampled by swabbing the base of the ulcer and vesicular lesions are de-roofed and fluid is swabbed, this is analysed by PCR. Although HSV seriological testing (IgG antibodies to HSV 1 and 2) is now widely available, but the management of herpes in pregnancy has not yet been fully understood.
Pregnant women with genital herpes should be put onto IV acyclovir as it reduces the duration and severity of symptoms which decreases the duration of viral shedding. Acyclovir is well tolerated in pregnancy so dose adjustment is not necessary. The presence of antibodies of the same type of HSV isolated from genital swabs would confirm the episode to be recurrent rather than a primary infection.
The rationale for elective caesarean section for the prevention of neonatal herpes is implanted to reduce exposure of the foetus to HSV in genital secretions. However an observational study in USA indicated that caesarean section was not protective against neonatal herpes when the membranes had been ruptured for more than 4 hours. The membranes should be left intact for as long as possible. invasive procedures such as foetal scalp electrode monitoring and foetal blood sampling may also associate with neonatal transmission. The neonate will then need to consider treatment with IV acyclovir.
Another study showed 46 pregnant women whose first episode of genital herpes showed in pregnancy and at 36 weeks they received a daily dose of acyclovir or placebo until delivery. The protocol permitted vaginal delivery only if there were no HSV lesions at the time of delivery. No child developed neonatal herpes with either groups.
Accurate way of determing the risk of acquiring HSV infection in pregnancy is by a sensitive type-specific serological tests which are commercially available and it determines a woman’s susceptibility to HSV infection in pregnancy. This should be taken either in early pregnancy or in the third trimester. And HSV-seropositive woman can be reassured that her risk of transmission to the neonate is very low. An HSV-seronegative woman is susceptible to genital herpes, in which case they can reduce the risks further by acyclovir treatment.
HSV diagnosis is by:
1) Light microscopy – cells from the base of the lesion or mucous surface may reveal intranuclear inclusion (Lipschutz inclusion bodies). Infected cells may show ballooning and fusion.
2) Electron microscopy – its not a sensitive tool for the detection of HSV, except in the case of vesicle fluids containing 108 per millilitre. However microscopy cannot distinguish between different herpes viruses.
3) Direct examination by antigen detection – specimens are treated in ice-cold acetone. FITC is generally used for staining, its 90% sensitive and 90% specific than light and electron microscopy, however expertise is more demanding. PCR from swabs is used routinely for the diagnosis of HSE.
4) Virus culture – HSV 1 and 2 are easier to cultivate, fresher the lesion the better chance of recovery. Inoculation carried out asap. A typical cytopathic effect can be seen after day 1. Other viruses can mimic CPE of HSV, identification can be carried out by immunofluorescence.
5) Serology – complement fixation tests (CFTs) and indirect haemagglutination (IFT). Weak antigenic cross reaction with VZV causes problems in these tests. So ELIZAs and RIAs are gradually replacing them.
Treatment of HSV is usually via the administration of Acyclovir which selectively inhibits HSV DNA polymerase and causes premature chain termination when it competes with the guanine triphosphate for the newly synthesised viral DNA.
Varicella Zoster Virus
VZV is a dsDNA enveloped virus which has only one antigenic serotype although there is some cross reaction with HSV.
Primary varicella is an endemic disease and is one of the classic diseases of childhood, mostly prevalent at 4-10years of age. Most people become infected before adulthood but 10% of young adults remain susceptible and it occurs sporadically and evenly throughout the year and peaks in sring.
The virus gains entry via the respiratory tract and spreads shortly after to the lymphoid system. After an incubation period of 14days, the virus arrives as its main target organ, the skin! Following primary infection, the virus remains latent in the cerebral or posterior root ganglia. In 10-20% of individuals, a single recurrent infection occurs after several decades. The virus reactivates in the ganglion and tracks down the sensory nerve to the area of the skin innervated by the nerve, producing a varicella form rash in the distribution of a nerve dermatome.
Congenital VZV occurs in women which the primary infection is rare during pregnancy. In the first 20 weeks of pregnancy, there is up to 3% chance of transmission to the foetus which leads to scarring of the skin, hypoplasia of limbs, CNS and eye defects, death in infancy.
Neonatal VZV can cross the placenta in the late stages of pregnancy to infect the foetus congenitally. Neonatal varicella may vary from a mild disease to a fatal disseminated infection. If a rash in the mother occurs more than 1 week before delivery then sufficient immunity would have been transferred to the foetus. Zoster immunoglobulin should be given to the susceptible pregnant woman and also given to infants whose mothers develop VZV during the last 7 days of pregnancy or the first 14 days after delivery.
Clinical presentations of VZV are so characteristic that laboratory confirmation is rarely required, it is usually required for atypical presentations in the immunocompromised.
Skin legions progress rapidly through the stages of macules to papules to vesicles which rapidly breakdown crust formation. Patients with VZV are considered to be infectious 2 days before the appearance of rash, and 7 days after onset when vesicles have crusted.
Diagnosis same as HSV- Immunofluorescence on skin scrapings can distinguish between the two. Serology – presence of VZV IgG is indicative of past infection and immunity. The presence of IgM is indicative of recent primary infection.
Acyclovir is given promptly to immunocompromised individuals with varicella infection. The Internation Herpes Management Forum recommends that antiviral therapy should be offered routinely to all patients over the age of 50 with VZV.
Preventative measures should be considered for individuals at risk of contracting severe varicella infection, so a passive immunisation should be given. Zoster immunoglobulin (ZIG) is the preparation of choice but its very expensive, where ZIG is not available HNIG should be given instead. Also a live attenuated vaccine is available however the virus may become latent and reactivate later on in immunocompromised individuals.
CMV belonds to beta herpesvirus subfamily and is a dsDNA enveloped virus. The structure of the genome for CMV is similar to other herpesviruses, however it has a total of 4 different isomers. CMV is one of the most successful human pathogens that be transmitted vertically or horizontally with little effect on the host.
Transmission may occur in utero, prenatally or postnatally (saliva but sometimes can be sexually transmitted through blood). Once infected the person carries the virus for life which may be activated from time to time which infectious virions appear in the urine and saliva. Reactivation can lead to vertical transmission in people who have experienced primary infection to be reinfected with another or same strain of CMV.
In developed countries 40% of adolescents are infected and ultimately 70% of the population is infected. In developing countries over 90% of people are infected.
Clinical manisfestations of congenital infection may result in cytomegalic inclusion disease. CMV is not the second common cause of mental retardation after Down’s Syndrome. Perinatal and postnatal infections are usually asymptomatic. Immunocompromised patients such as transplant recipients and AIDS patients are prone to severe CMV in which case reactivation is symptomatic.
Diagnosis of CMV same as HSV
1) Direct detection - PCR for CMV-DNA can be used in some centres however there are problems with interpretation (how its diagnosed now)
2) Viral isolation – useful is DEAFF which provides a result in 24-48 hours as the fluorescent detects early antigens.
Congenital infections – mother is usually told about the chances of her baby having cytomegalic inclusion disease and its complications. She can decide whether or not she wants to keep the baby. Unlike rubella congental infection with CMV is not trimester related.
Perinatal and postnatal infection – not necessary to treat patients.
Immunocompromised patients – necessary to make early diagnosis of CMV infection to give prompt antiviral therapy such as ganciclovir, forscarnet and cidofovir.
Epstein-Barr Virus (EBV)
EBV belongs to the gamma herpesvirus subfamily of herpesvirus. Its membrane is derived from budding of immature particles through the cell membrane which is required for infectivity. The genome is a linear dsDNA which does not normally integrate into cellular DNA but forms circular episomes which reside in the nucleus.
Two epidemiological patterns are seen with EBV. In developed countries there are 2 peaks of infection, one at a very young age (1-6yrs) and the other in adolescents (14-20yrs). In developing countries infection occurs at a much earlier age (2years) by which 90% of children are seropositive.
The virus is transmitted by contact with saliva, in particularly through kissing. Once infected a lifelong carrier state develops whereby a low grade infection is kept in check by the immune defences. Low grade virus replication and shedding can be demonstrated in the epithelial cells of the pharynx of all seropositive individuals. EBV is able to immortalise B-lymphocytes in vitro and in vivo. EBV is associated with several different diseases where it may act directly or as one of the several co-factors e.g.
1) Infectious mononucleosis (glandular fever)
2) Burkitt’s lymphoma
3) Nasopharyngeal carcinoma
4) Lymphoproliferative disease
5) And many others
Acute EBV infection is usually made by heterophil antibody test/detection of anti-EBV VCA IgM.
Burkitt’s lymphoma – diagnosed by histology. The tumour can be stained with antibodes to lambda light chains which should reveal a monoclonal tumour of B-cell origin. In over 90% cases cells express IgM at cell surface.
NPC – diagnosed by histology. The determination of titre anti-EBV VCA IgA screening for early lesions are used for monitoring treatment.
Patients with non specific symptoms should be given a thorough examination.
Vaccines against EBC prevent primary EBV infection should be able to control both BL and NPC. The vaccine would be useful in seronegative organ transplant recipients, severe IM and male proliferative syndrome carriers. The antigen chosen for vaccine development is MA antigen gp 340/220 as antibodies against this antigen are virus neutralising, this is currently being tried in Africa.
Large group of dsDNA, ubiquitous, medically important especially in pregnancy and immunocompromised individuals.
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