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Human herpesviruses

The family of herpesviruses is very large and its members infect most vertebrate species. There are 8 herpesviruses which are known to infect humans:

Herpes Simplex virus 1 and 2
Varicella-Zoster virus
Cytomegalovirus
Epstein-Barr virus
Human Herpesvirus 6 (and 7)
Human Herpesvirus 8

Structure of the Virion
All herpesviruses are morphologically identical: They have a large double stranded DNA genome. The virion consists of an icosahedral nucleocapsid which is surrounded by a lipid bilayer envelope. Between the capsid and the envelope is an amorphous layer of proteins, termed the tegument.

A characteristic of all herpesviruses is that, following primary infection, the virus establishes a latent infection in the host and may reactivate at any stage. Reactivation is frequently, but not always, associated with further disease.

Herpes Simplex 1 and 2

There are two closely related viruses termed Herpes Simplex 1 and 2.
Both cause painful vesicles on the skin at the site of inoculation.
HSV1 is usually associated with oro-facial lesions
HSV2 is usually associated with genital lesions

Epidemiology
Infection with HSV1 is almost universal. We know this because, although many infections are sub-clinical, virtually 100% of adults have HSV 1-specific antibodies in their serum. Most individuals become infected with HSV1 in the first few years of life. HSV2 is acquired later in adolescence and adulthood (predominantly spread by sexual intercourse) the adult prevalence is lower than for HSV1. Approximately 40% of adults have antibodies.
Virus is shed from the infected area of skin or mucous membrane and spread occurs as a result of direct contact with lesions. For example, through kissing (HSV1) or sexual intercourse (HSV2)
Both HSV1 and 2 reactivate frequently although lesions are not always clinically apparent. Virus can be shed from clinically inapparent lesions.

Clinical features:
There are 2 clinical patterns of disease:
a) Primary Infection, and
b) Recurrent disease

Primary Infection:
The vast majority of primary infections are asymptomatic But in clinically apparent cases, the typical presentation is of a painful blistering rash that usually develop 1-3 days post exposure. Vesicles usually remain localised to the site of inoculation, but spread to other areas of skin and mucous membranes can occur through auto-inoculation.

Symptoms are determined by the site of inoculation:

Gingivo-stomatitis
Most common form of primary infection; inoculation is usually through kissing. There is a wide spectrum of severity, from trivial to extensive disease. Painful vesicles develop inside the mouth on the bucchal mucosa and gums; on the lips and skin around the mouth. The vesicles inside the mouth ulcerate and become covered with greyish slough. Lesions may occur at other sites on the head and neck as well. The primary eruption is often associated with fever and cervical lymphadenopathy. The illness is self limiting and lesions usually heal within 14 days.

Eczema Herpeticum
Super infection of eczematous skin with HSV

Herpetic Whitlow
Inoculation of virus into the fingers; an occupational hazard of doctors, nurses and dentists.

Conjunctivitis, Keratitis
A herpetic lesion on the cornea is called a dendritic ulcer because of its branching appearance. Pain and photophobia are prominent features. Conjunctivitis and oedema of the lids commonly accompany primary infection. Lesions usually heal within 3 weeks.

Genital Herpes
Usually due to HSV 2 but 20-30% of cases are due to type HSV 1; sexually transmitted. Vesicles develop on the genitalia and/or peri-anal area. In females, infection may be confined to the cervix. The primary eruption lasts approximately 14-21 days and may be associated with aseptic meningitis.

Latency

Following primary infection, the virus enters sensory nerve endings at the site of inoculation, travels up the axon and establishes a latent infection in the ganglion supplying that area of skin.
Genital area - sacral ganglia
Oro-facial trigeminal ganglion
The viral genome persists in an episomal form (plasmid) in the nucleus of the neurone. Infection is life long.
Periodically the virus reactivates from its latent state: a cycle of viral replication occurs in the neurone and new virus particles travel down the axon to re-infect the skin or mucous membrane in the area supplied by the nerve.
Reactivation may be provoked by a number of stimuli: including sunlight, stress, febrile illnesses, menstruation or immunosuppression. Reactivation is very common, but often clinically in-apparent.

Clinical manifestations of reactivation:

Cold sores (follows gingivo-stomatitis); vesicles erupt on the muco-cutaneous junctions of the nose or mouth. The lesions are more localized than the primary infection and heal more rapidly (7-10 days). Eruption is often preceded by paraesthesia of the involved area.

Recurrent genital herpes: . Lesions are less extensive and heal more rapidly than the primary infection. Recurrence with HSV 2 infections is more common than with HSV1.

Rarely, patients may develop aseptic meningitis (Mollaret's syndrome) associated with reactivation of HSV2.
Keratitis: This follows a primary herpes infection of the eye. After reactivation, the virus reaches the cornea via the ophthalmic branch of the trigeminal nerve. The clinical lesion is termed a dendritic ulcer. It heals more rapidly than the primary infection


Rare, Life threatening syndromes caused by HSV:

1. Acute necrotizing encephalitis
Infection of the brain by HSV: Neurons of the temporal lobe are most commonly involved. Infection is severe and necrotising. Clinical features include: sudden onset of fever, headache, confusion and alteration in personality

Mortality is high and neurological impairment in the survivors is invariable. Encephalitis may occur during primary infection or following reactivation of latent virus.

2. Neonatal Infection

This is a very rare, but serious condition. Neonates have poor cell mediated immunity and are therefore at increased risk of disseminated infection if they are exposed to HSV in the peri-natal period.
Exposure may occur:
1) During birth, if the mother has genital herpes at the time of delivery. (This is only a significant risk if the mother is experiencing a primary infection)
2) In the post natal period, if the baby is handled by people with herpetic lesions

The disease may take one of three forms: cutaneous, encephalitic or generalized infection.
Cutaneous:- Lesions are confined to the skin; this has a good prognosis.
Generalized infection: Virus disseminates throughout the organs. This is a serious condition, with a high fatality rate. Clinical features include: jaundice, hepato-splenomegaly, thrombocytopenia, pneumonia and encephalitis. Lesions on the skin maybe trivial
Encephalitis:- Infection of brain tissue by HSV. As in the case of generalised infection, the prognosis is poor.

3. Disseminated HSV infection in adults:
Disseminated infections occur on rare occasions in apparently healthy adults. The illness usually follows a fulminant course and patients may die before the diagnosis is made. The disease may manifest as a fulminant hepatitis, pneumonitis, multi-organ failure or encephalitis.

Laboratory Diagnosis:

Direct detection- Electron microscopy - herpesvirus particles in vesicle fluid
Immunofluorescence - viral antigen in smears from vesicles

Cell culture - Clinical material from skin lesions may be inoculated onto cell mono layers which are monitored for the development of characteristic cytopathic effect.

Serology - IgG indicates immunity (past exposure)
IgM marker of primary or recurrent infection, but is not a reliable marker.

PCR - Detects viral genome in clinical material. HSV PCR on CSF is the test of choice for confirming the diagnosis of HSV encephalitis.

Therapy:

The drug of choice for treating HSV infections is Acyclovir. It is a nucleoside anologue of guanosine. It interferes with viral replication, but is not active against latent virus. It has activity against HSV and VZV infections and has very low toxicity. Oral, topical and IV formulations are available.

Varicella Zoster Virus

There are two clinical entities:

(1) varicella - chicken pox and
(2) zoster - shingles

Varicella

This is a common childhood infection that presents as a mild febrile illness associated with a generalized vesicular rash. After a prodromal period, vesicles erupt in successive "crops" so that lesions of different ages are present at the same time. The lesions progress from macule papule vesicle pustule scab. In children the disease is usually trivial and complications are rare. If infection is delayed until adulthood the disease may be more severe and complications such as pneumonia, are more frequent.
The incubation period is long, about 21 days. Infection is transmitted either by respiratory droplets or by direct contact with skin lesions
Primary infection is followed by long lasting immunity.

Complications

Post infectious Encephalomyelitis - self limiting condition, with a good prognosis
Pneumonia - a common complication of varicella in adults.
Haemorrhagic varicella - fulminating infection in immunocompromised patients: high fatality rate.

Congenital varicella syndrome (vertical transmission)
Infants born to mothers who have varicella in the first 20 weeks of pregnancy may develop a congenital infection syndrome consisting of: limb hypoplasia, muscular atrophy, mental retardation and skin scarring. In addition, affected infants may develop shingles (VZV reactivation ) in the first 18 months of life. This condition is extremely rare (0.4 - 2.0%).

Perinatal varicella (post natal transmission)
Varicella is highly infectious and an infant will inevitably acquire the disease post natally if its mother has varicella in the peri-natal period. If the mother develops the rash more than five days before delivery, the neonate is likely to have a mild infection because it will be protected by maternal anti-varicella antibodies acquired trans-placentally. However, if the mother develops the rash less than 5 days before delivery, the infant is likely to have a severe infection because there is not enough time for varicella specific antibodies to cross the placenta to protect the baby. These infants (and indeed any infant less than 6 months who is exposed to varicella post natally) should receive an injection of VZ hyperimmune globulin. This provides passive protection from infection.

Shingles (Zoster)

Reactivation lesion of VZV

Like HSV, VZV establishes a latent infection in sensory ganglia. Reactivation usually occurs many years after primary infection and is often associated with immunosuppresion of the host. After a cycle of infection in the ganglion, virus particles travel down the axon to re-infect the dermatome supplied by the sensory ganglion. This gives rise to painful vesicles on the skin. Common sites include the thoracic dermatomes and those supplied by the trigeminal nerve. Post herpetic neuralgia is a common complication especially in the elderly.
Ramsay Hunt syndrome: Zoster involving one of the branches of the trigeminal nerve. Patients present with uni-lateral facial nerve palsy, ear pain and vesicles in the external auditory meatus.

Vaccine:
A live attenuated strain of varicella zoster virus has been developed as a vaccine. It was released for general use in South Africa in 2002. It is widely used in Japan and USA to immunize healthy children and has also been used in children's oncology units to protect immunocompromised children who have not been exposed to wild type varicella zoster virus. These patients may develop severe, life threatening infections if infected with the wild type virus. It is also highly effective as post exposure prophylaxis if given within 72 hours of exposure.

Laboratory Diagnosis

PCR: most sensitive technique for detecting virus in clinical samples
Cell culture - inoculation of cell monolayers; virus grows slowly with the production of typical cytopathic effect
Serology - IgM antibodies are present during both primary infection (varicella) as well as during reactivation (zoster).
IgG antibody, if present indicates immunity.

Treatment:

Uncomplicated chicken pox normally resolves without specific treatment. Acyclovir is the drug of choice for severe varicella zoster virus infections. Patients at risk for varicella complications (adults, immuno-compromised children) should receive acyclovir. Therapy should be started as soon as possible (within 48 hours) of disease onset.

Cytomegalovirus

Most individuals are infected by human cytomegalovirus (HCMV) in the first few years of life and by adulthood 70-90% of people have IgG antibodies. HCMV rarely causes disease in healthy people, particularly when infection occurs in childhood. When primary infection occurs in adulthood, patients may develop an infectious mononucleosis-like illness associated with, fever, sore throat and lymphadenopathy.
Like other herpesviruses, following primary infection, the virus becomes latent and may reactivate at any stage.

Transmission:
(1) The virus is shed asymptomatically in the saliva and other body fluids of healthy carriers and transmission usually occurs through close contact
(2) Mother to child: in utero, peri-natally or through breast feeding.
(3) Blood transfusion, organ transplantation

There are two clinical situations where infection with CMV may cause serious disease.
(A) Congenital infection
(B) Immunosuppressed individuals

A) Congenital infection

World-wide, Cytomegalovirus is the commonest viral cause of congential abnormalities. However, the risk to the foetus of congenital infection is difficult to predict. Infants are at greatest risk of damage if the mother experiences primary CMV infection during pregnancy. Fortunately most women of child bearing age have already been exposed to CMV and are latently infected with the virus. Nevertheless CMV reactivation in pregnancy is common and can also result in foetal infection.
(1) Maternal CMV reactivation is usually asymptomatic
(2) The vast majority of HCMV infected babies do not develop congenital abnormalities.
(3) Exposure any stage during pregnancy may result in foetal damage.
(4) Either re-activation or primary infection in the mother can result in foetal infection although severe infection in the foetus is generally the result of a primary infection during pregnancy.
Clinical features:
Most infected babies appear normal at birth. However, affected infants may later develop deafness or mental retardation.
Rarely a severe generalized infection of the neonate may occur (Cytomegalic inclusion disease). This condition is associated with jaundice, hepatosplenomegaly, thrombocytopenia, haemolytic anaemia and microcephaly. The histology of affected organs shows enlarged cells - ‘cytomegalo', with owl's eye inclusions. The prognosis for this condition is poor.

B) Infection in immunosuppressed patients:

Transplant patients and patients with AIDS, may develop life threatening disease following either primary infection with HCMV or reactivation. Common syndromes include:
Interstitial pneumonia
Retinitis
Enteritis
Disseminated infection
CMV pneumonia (following primary CMV infection in the first months of life) is a common cause of death in HIV infected infants in this country.

Treatment:
The nucleoside anologue ganciclovir has activity against actively replicating CMV. It is used to treat severe, life threatening CMV infections in immunocomopromised patients. It has toxic side effects and is expensive.

Laboratory Diagnosis

It is important to remember that all sero-positive individuals harbour HCMV in their tissues and that the virus can reactivate and be shed reularly throughout life without causing disease. Thus isolation of virus from a sick patient does not necessarily mean that the virus is playing a pathogenic role.

Direct detection - HCMV antigen in patient's white blood cells by immunofluorescence (pp65 antigen). A positive pp65 is a good indication that HCMV is causing significant disease.

Cell culture - monolayers of human fibroblasts; HCMV grows slowly and produces a characteristic cytopathic effect

Serology
IgG indicates previous exposure. All IgG positive individuals harbour latent virus.
IgM indicates recent primary infection or reactivation (an unreliable marker)

PCR: the most sensitive method for detecting virus in clinical samples.

Epstein-Barr Virus

Infection is widespread. Most people have been infected by the time they reach adulthood. Following primary infection, the virus persists in a latent form in the B lymphocytes of the host. Periodic reactivation of the virus is associated with shedding of virus in saliva.
Transmission is by close contact, especially kissing.

Clinical Syndromes associated with EBV infection:

1) Infectious Mononucleosis (primary infection syndrome)
2) Lympho-proliferative disorders in immunocompromised patients
3) Burkitts Lymphoma and other Non Hogkins lymphomas
4) Naso-pharyngeal Carcinoma
5) Other tumours e.g. certain forms of Hodgkins disease
6) Oral hairy leuko-plakia

Infectious Mononucleosis

Illness results from primary infection with EBV. A clinically apparent illness usually only develops when primary infection occurs in adolescence or adulthood.
Clinical Features:
incubation period - 4 to 7 weeks
route of infection - close contact, kissing. Virus is secreted intermittently in the saliva of asymptomatic carriers.
Signs and symptoms - fever, generalised lymphadenopathy, sore throat, malaise, tiredness, splenomegaly, hepatomegaly, abnormal liver function tests and atypical lymphocytosis in the peripheral blood. The disease is self limiting, but convalescence may be prolonged in some cases.
Laboratory Diagnosis

Heterophile antibody - Paul-Bunnell test (Monospot):
Screening test for acute IM; 70-80% of patients with acute IM develop IgM antibodies that agglutinate sheep red blood cells.

Specific serological tests:
Antibody to the viral capsid and nuclear antigens are useful for confirming the diagnosis of acute IM:
IgG and IgM to Viral capsid antigen (VCA): detectable early during the acute phase
VCA IgM: only present during acute phase
IgG to EBV nuclear antigens (EBNA): detectable late in convalescence (> 6 months post infection)

B cell and Latency

EBV infects B cells and establishes a latent infection. The viral genome enters the nucleus and persists in an episomal form. Six viral genes, termed EBNA 1-6 are expressed during this (latent) stage. They transform the B cell into an immortal, continuously dividing cell. Everyone who has been infected with EBV in the past has some EBV transformed cells in their circulation. Their numbers are controlled by the host's immune response.

Lymphoproliferative disorders
Immunosuppressed patients (especially organ transplant patients) may develop a polyclonal proliferation of their own EBV-transformed B cells due to an impaired ability of their CTLs to eliminate EBV infected cells. Occasionally these proliferating cells may undergo malignant transformation, resulting in the development of a mono-clonal malignant tumour. These non hodgkins lymphomas are usually highly aggressive and occur in atypical locations (e.g. CNS in AIDS patients).

Burkitt's Lymphoma (BL)
This is a high grade B cell lymphoma which occurs endemically in equatorial Africa and New Guinea and, sporadically, world-wide.
Almost 100% of equatorial BL tumours are known to be associated with EBV. EBV is believed to be an important cofactor in causing this malignancy.
Tumour development is a step-wise process: the first event is EBV transformation of the B cell, followed by polyclonal proliferation. DNA damaging events may occur in these rapidly dividing cells leading to malignant transformation. (A common event is the translocation of the c-myc oncogene which becomes placed under the control of an immuno-globulin gene promoter.)
The parts of the world where BL is endemic are also hyperendemic for Malaria and it is thought that the malignant change in EBV-transformed B cells may follow infection with Malaria.

Nasopharyngeal Carcinoma
This is a malignant tumour of the squamous epithelium of the nasopharynx. Undifferentiated forms of this tumour are associated with EBV.

Hodgkins disease:
Monoclonal EBV genomes have been identified in the Reed Sternberg cells in certain histological forms of HD. Mainly mixed cellularity and lymphocyte depleted forms. A history of adult infectious mono-nucleosis is associated with a three fold increase in incidence of HD.

Other Malignancies:
EBV has been implicated as a cofactor in a number of other malignancies, including leiomyosarcomas in AIDS patients and. But the role of EBV in the aetiology of these conditions has yet to be resolved.

Oral hairy Leukoplakia:
Proliferation of oral squamous epithelium caused by EBV. Lesions present as painless white plaques on the tongue. Most commonly seen in patients with AIDS.

Human herpesvirus 6 (HHV6)

Primary infection is usually acquired early in life and, like other herpesviruses, the virus establishes a latent infection.
Clinical Features
Most infections are probably asymptomatic. Diseases which have been found to be associated with HHV6 infection include:
1)Roseola Infantum -(primary infection in babies) a febrile illness with rash which usually occurs in the first few months of life.
2)Infectious mononucleosis-like illness in adults experiencing primary infection.
3)Interstitial pneumonitis in immunosuppressed patients
4) Encephalitis in immuno-compromised patients

Human herpesvirus 7 (HHV7)

Closely related to HHV6. Has been isolated from peripheral blood mononuclear cells
It is not known whether it causes any disease.

Human herpesvirus 8 (HHV8, KSHV)

In 1994 a new human herpesvirus was identified in the tissues of a patient with Kaposi Sarcoma. An unusual feature of this virus is that its prevalence is low in most parts of the world (only 0.2-10% people have antibodies). In central Africa and Eastern Mediterranean countries the prevalence is higher (30-50% adults have antibodies). Like for other herpesviruses, following exposure, the virus establishes a persistent (latent) infection in the host. It does not appear to be pathogenic in healthy individuals, but it is thought to play a role in the malignant process of all forms of Kaposi sarcoma as well as primary effusion lymphomas in AIDS patients and multicentric Castleman's disease.