Abstract
In humans, eight different types of herpes viruses have been reported so far, which belong to three subgroups. These subgroups are based on the site of latency (defined as the persistence of viral genomes in cells that do not produce infectious virus) and most frequently infected cell types.
In humans, eight different types of herpes viruses have been reported so far, which belong to three subgroups. These subgroups are based on the site of latency (defined as the persistence of viral genomes in cells that do not produce infectious virus) and most frequently infected cell types.
1) α-group viruses
This group includes herpes simplex virus types 1, 2 (HSV1, HSV2) and herpes zoster virus (VZV), which infect epithelial cells and produce latent infection in neurons.
2) Lymphotrophic β-group viruses
This group includes Cytomegalovirus (CMV), human herpes virus-6 (Roseolovirus more commonly known as the sixth disease or Roseola Infantum, and human herpes virus-7 (not yet classified).
3) γ-group viruses
These viruses produce latent infection mainly in lymphoid cells and include Ebstein B virus (EBV) and Kaposi’s sarcoma-associated herpes virus KSHV/HHV-8, which causes Kaposi sarcoma.1
Herpes Simplex Virus Infection
Herpes simplex is a very common infectious disease globally, affects both women and men and is caused by both known types of viruses, herpes simplex virus 1 (HSV1) and herpes simplex virus 2 (HSV2).
1. HSV1 is mainly transmitted by oral to oral contact and may cause cold sore, gingiva-stomatitis or rare life-threatening disseminated visceral infections and encephalitis. It is usually acquired in childhood.
2. HSV2 is sexually transmitted, causes genital herpes and is usually acquired later in life. Genital herpes simplex virus (HSV) is a recurrent disease that can occur throughout life and has no known cure.2 Genital herpes negatively affects the quality of life and work productivity of patients.2
Virology and Pathogenesis
HSV1 and 2 are double-stranded DNA viruses, distinguished by their surface glycoprotein that exhibit only 50 per cent of genetic homology with one another, so infection with one type does not prevent infection from the other.
Pathogenesis and Transmission
The incubation period after contact transmission is four to six days.
Acute infection starts as HSV (1 or 2) enters the body through the skin or mucosa by direct sexual contact with secretions or mucosal surfaces of an infected person and replicates at the site of entry. It produces infectious virions and causes vesicular lesions of the epidermis. The viruses then spread to sensory neurons that innervate the primary site of replication.
Primary HSV infection resolves in a few weeks in an immune-competent host, but the virus remains latent in cells. From the sensory ganglia it reactivates and travels down the axon to the skin on the mucosal surface, resulting in symptomatic shedding or clinically apparent disease. Asymptomatic shedding is the most common mechanism of sexual HSV transmission.3
Risk of transmission appears to be greatest when active vesicular lesions are present and during the prodromal phase (early sign or symptom which often indicates the onset of a disease before more diagnostically specific signs and symptoms develop).
The patients should be advised to abstain from sexual contact during this time.
Transmission can occur in the absence of lesion recurrence as a result of subclinical viral shedding.
The efficacy of condoms to prevent sexual transmission has not been formally assessed. However, in a multivariable analysis, condom use during more than 25 per cent of sex acts was associated with protection against HSV2 acquisition for women but not for men.4 [EL 2, B recommendation]
Genital Herpes
Signs and Symptoms (Primary and Latent Stages and Recurrent Episodes)
Primary Herpes
The first infection with either herpes simplex virus type 1 (HSV1) or type 2 (HSV2) is the primary infection. The first herpes outbreak is the most severe, particularly in women. Symptoms tend to resolve within two to three weeks.
The signs of a primary episode of genital herpes in women:
1. Multiple blisters in the genital area (vagina, vulva, buttocks, anus and thighs). Blisters on the outer labia may crust over and heal.
2. Painful ulcers. The blisters then turn into painful ulcers. New lesions may develop between five and seven days after the first group appears.
3. Lymph node involvement. The infection may affect the groin lymph nodes which may be tender and swollen.
4. Systemically, there may be flu-like symptoms, joint pains, fever and headache.
The Latent Stage
This is an asymptomatic stage. After the initial outbreak, the virus travels to the bundle of nerves at the base of the spine, where it remains dormant for or a period of time.
Recurrent Infection (Episodes)
Recurrence occurs frequently in many patients, especially in those with HSV type 2.
Recurrent episodes of genital herpes occur when the virus travels through nerves to the skin’s surface, causing an outbreak of ulcers. The recurrent episodes are usually milder than the initial outbreak.
In the recurrent episodes, the ulcers may develop in the same area as those of the first outbreak, or may appear in other areas.
Around 50 per cent of infected people with a recurrent outbreak experience mild symptoms (itching, tingling, or pain in the buttocks, legs or hips).
Recurrences tend to become less frequent and less severe after the first year.
The clinical features of primary or recurrent herpes do not differ in pregnancy and non-pregnant women except for the fact that recurrence appears to increase in frequency over the course of pregnancy.
The incidence of reactivation of latent genital HSV virus infection and asymptomatic virus shedding on any day in pregnancy is 1 per cent.5
Complications of Genital Herpes
The most serious rare clinical complication is disseminated herpes, which may present with pneumonia, encephalitis, hepatitis, disseminated skin lesions or a combination of these conditions.
It is more commonly reported in pregnancy, particularly in immunocompromised women.
The maternal mortality associated with disseminated disease (involvement of the central nervous system (CNS), liver and adrenal dysfunction, shock and coagulopathy) is as high as 50 per cent.6
Psychological complications of genital herpes are sometimes very distressing and may affect sexual life and future relations, particularly with the knowledge it is not a curable disease.
Laboratory Diagnosis7
1 Direct Virus Isolation
Swabs taken from the base of the lesion (vesicles should be unroofed with a needle or scalpel blade) and placed in viral transport medium are the most accurate method as they directly demonstrate the virus HSV DNA detection and allow for virus typing.7 [EL 1, A recommendation]
Virus typing of HSV1 and HSV2 is recommended in all patients with first-episode genital herpes to guide further counselling and management.
However, culture sensitivity is low, especially for recurrent lesions, and declines as lesions heal.
2 Polymerase Chain Reaction (PCR)
PCR is a technique to amplify any trace amounts of DNA (and in some instances, RNA) located in or on almost any liquid or surface where DNA strands may be deposited. Viruses contain DNA (or RNA) genetic material such as sequences unique to their species, and to the individual member of that species.
If a sample contains segments of DNA or RNA, PCR amplifies these unique sequences.
These amplified unique consequences can then be used to determine with a very high degree of accuracy the identity of the source pathogenic organism.
3 Nucleic Acid Amplification Test
The same technique as for the PCR is utilised for a nucleic acid amplification test.
Women with suspected genital herpes should be referred to a genitourinary medicine physician to confirm or exclude the diagnosis by viral PCR, advise on management of genital herpes and arrange a screen for other sexually transmitted infections (STIs).
4 Serological Testing
Serological testing for immunoglobulin G (IgG) has high false-negative results at low index values (1.1–3.5).
Fetal Vertical Transmission and Fetal Implications
Rarely, congenital herpes may occur as a result of transplacental intrauterine infection.
Case reports suggest that the skin, eyes and CNS may be affected and there may be fetal growth restriction or fetal death.8 [EL 2]
Herpes infection can be passed from mother to child during pregnancy or childbirth.
Factors associated with transmission to the fetus in utero include:9
The type of maternal infection (primary or recurrent)
The presence of transplacental maternal neutralising antibodies
The duration of rupture of membranes before delivery
The use of fetal scalp electrodes and the mode of delivery
The risks are greatest when a woman acquires a new infection (primary genital herpes) in the third trimester, particularly within six weeks of delivery, as viral shedding may persist, and the baby is likely to be born before the development of protective maternal antibodies. Development of antibodies to HSV usually requires four to six weeks. These antibodies cross the placenta and reduce the transmission risk from 50 per cent in case of primary infection to 0–4 per cent in case of recurrent disease.
Fetal implications may include:
Primary infection occurring in the first or second trimester is associated with an increase in spontaneous abortion and/or prematurity and fetal growth restriction.
Transplacental transmission causes severe in utero congenital infection. The fetal manifestations include microcephaly, hepatosplenomegaly, intrauterine growth restriction (IUGR) and intrauterine fetal death (IUFD).
Neonatal Herpes10
Neonatal herpes is very rare but is a serious viral infection with a high morbidity and mortality. This virus could affect skin, eyes, CNS etc.
Neonatal infection occurs as the result of an infection at the time of birth.
Neonatal herpes may be caused by HSV1 or HSV2.
Most cases of neonatal herpes occur as a result of direct contact with infected maternal secretions. In 25 per cent of cases, a close relative is the possible source of postnatal infection.
Postnatal infection may occur as a result of exposure to oro-labial herpes infection.
Neonatal herpes is divided into three groups:
1. Disease localised to skin, eye and/or mouth10
These comprise approximately 30 per cent of cases and have the best prognosis. With appropriate antiviral treatment, the ocular and neurological morbidity is less than 2 per cent.
2. Local CNS disease (encephalitis alone)9
Infants with local CNS disease often present late (generally between 10 days and four weeks of age). With timely antiviral treatment, mortality from local CNS disease is around 6 per cent and neurological morbidity (which may be lifelong) is 70 per cent.
3. Disseminated infection with multiple organ involvement9
Disseminated infection carries the worst prognosis; with appropriate antiviral treatment, mortality is around 30 per cent, and 17 per cent have long-term neurological sequelae.
Management of the Neonate
A) Babies born by Caesarean Section in Mothers with Primary HSV Infection in the Third Trimester
These babies are at low risk.
1. No active treatment is required for the baby.
2. Normal postnatal care of the baby with a neonatal examination at 24 hours of age, after which the baby can be discharged from the hospital if well and feeding is established.
3. Parents should be educated regarding good hand hygiene and due care to reduce risk of postnatal infection.
4. Parents should ask for medical help if they have concerns and should look for skin, eye and mucous membrane lesions, lethargy/irritability and poor feeding.
B) Babies Born by Spontaneous Vaginal Delivery in Mothers with a Primary HSV Infection within the Previous Six Weeks
These babies are at high risk of disease and transmitted infection.
If the baby is well:
1. Swabs of the skin, conjunctiva, oropharynx and rectum should be sent for diagnosis of infection (herpes simplex PCR).
2. Empirical treatment with intravenous (IV) aciclovir (20 mg/kg every eight hours) should be initiated until evidence of active infection is ruled out.
3. Breastfeeding should continue unless the mother has herpetic lesions around the nipples.
4. Warning signs of early infection (poor feeding, lethargy, fever or any suspicious lesions) should prompt patients to seek medical help.
If the baby is unwell:
1. Swabs of the skin, lesions, conjunctiva, oropharynx and rectum should be taken to confirm infection.
2. A lumbar puncture should be performed even if CNS features are not present.
3. Intravenous aciclovir (20 mg/kg every eight hours) should be initiated until there is no evidence of active infection.
C) Babies Born to Mothers with Recurrent HSV Infection in Pregnancy with or without Active Lesions at Delivery
These babies have a low risk of infection because maternal IgG will be protective.
1. Normal postnatal care of the baby with a neonatal examination at 24 hours of age, after which the baby can be discharged from hospital if well and feeding is established.
2. Parents should be educated regarding good hand hygiene and due care and are advised to seek medical help if they have concerns.
3. If there are any concerns, intravenous aciclovir (20 mg/kg every eight hours) should be given while awaiting cultures.
Treatment of the Mother11
Primary Infection
1 First or Second Trimester Acquisition until 27+6 Weeks of Gestation
Pregnant women with suspected genital herpes should be referred to a genitourinary medicine physician to confirm the diagnosis by viral PCR, arrange proper management and arrange a screen for other STIs.
Aciclovir in standard doses (400 mg three times daily, usually for five days) is not licensed in pregnancy but is safe to use. Its use is associated with a reduction in the duration and severity of symptoms and a decrease in the duration of viral shedding.
Paracetamol and topical lidocaine 2 per cent gel can be offered for symptomatic relief. Neither is harmful in pregnancy in standard doses.
Because of less experience with the valaciclovir and famciclovir in pregnancy, they are not recommended as first-line treatment in pregnancy.
Daily suppressive aciclovir 400 mg three times daily from 36 weeks of gestation reduces HSV lesions at term and hence the need for delivery by caesarean section.
Providing that delivery does not ensue within the next six weeks, the pregnancy should be managed expectantly, and vaginal delivery anticipated.
2 Third Trimester Acquisition (from 28 Weeks of Gestation) of Primary Genital Herpes11
Treatment should not be delayed. It will usually involve the use of oral (or intravenous for disseminated HSV) aciclovir in standard doses (400 mg three times daily, usually daily until delivery).
Caesarean section should be recommended to all women presenting with primary episode genital herpes lesions within six weeks of the expected date of delivery or at the time of delivery, in order to reduce exposure of the fetus to HSV which may be present in maternal genital secretions.
Recurrent and Secondary Infection
It is sometimes difficult to differentiate between primary and secondary infection.
If available, the presence of antibodies of the same type as the HSV isolated from genital swabs at the time of primary infection would confirm this episode to be a recurrence rather than a primary infection and elective caesarean section would not be indicated to prevent neonatal transmission.
In women who choose to deliver vaginally, particularly in the presence of primary genital herpes lesions, invasive procedures (application of fetal scalp electrodes, fetal blood sampling, and artificial rupture of membranes and/or instrumental deliveries) should be avoided.12
With recurrent genital herpes, the risk of neonatal herpes is low (0–3 per cent for vaginal delivery) even if lesions are present at the time of delivery.
Daily suppressive aciclovir 400 mg three times daily should be considered from 36 weeks of gestation.
Prior to 36 weeks treatment is not recommended.
There is no increased risk of preterm labour, preterm prelabour rupture of membranes or fetal growth restriction associated with women seropositive for HSV.
Primary Herpes Infection and Preterm Rupture of Membranes
If immediate delivery is indicated, then caesarean section is the best option.
If conservative management is decided based upon obstetric and other reasons, then the mother should be offered IV aciclovir 5 mg/kg every eight hours.
Prophylactic corticosteroids should be considered for lung maturity.
Recurrent Herpes Infection and Preterm Rupture of Membranes (PPROM)
In the case of PPROM before 34 weeks, expectant management is appropriate, including oral aciclovir 400 mg three times daily for the mother, with antenatal steroids for the baby.
After 34 weeks, it may be best to deliver by caesarean section.
Postpartum
Maternal oro-labial or ano-genital lesions require proper hand washing and contact prevention to avoid exposure of the infant.
Those with oral herpetic lesions (cold sores) should not kiss the neonate.
Aciclovir use in breastfeeding could be considered if needed.
Breastfeeding is not recommended if there are active lesions on the breast.
Management of HIV-Positive Women with HSV Infection12
HIV-positive women with primary genital HSV infection in the last trimester of pregnancy should be managed according to the recommendations for all women with primary genital HSV infection.
There is some evidence that HIV antibody positive women with genital HSV ulceration in pregnancy are more likely to transmit HIV infection independent of other factors. However, this is not a consistent finding across all studies.
Women who are HIV antibody positive and have a history of genital herpes should be offered daily suppressive aciclovir 400 mg three times daily from 32 weeks of gestation to reduce the risk of transmission of HIV infection, especially in women where a vaginal delivery is planned. Starting therapy at this earlier gestation than usual should be considered in view of the increased possibility of preterm labour in HIV-positive women.
The mode of delivery should be according to obstetric factors and HIV parameters such as HIV viral load.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
