Alpha Viruses

Herpesviruses Alphaherpesviruses

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Objectives • Knowledge of the general properties of herpesviruses • To know how each type is transmitted or acquired • To know the clinical presentation and the pathogenesis of each type • To be familiar with the effective method of laboratory diagnosis •

To know how to treat or prevent these infections

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Herpesviruses • Are a leading cause of human viral diseases; second only to influenza and cold viruses • The name herpes comes from the Greek word herpein which means to creep: creeping or spreading nature of the skin lesions • Can cause active disease or remain silent lifelong to be reactivated • Reactivation are more likely to take place during periods of immunosuppression 10/15/08

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Chronic versus latency • Chronic and latent infections are strategies that some viruses used to avoid host immune responses • In chronic infections the virus continues to replicate at low level • In latent infections viral genomes are maintained in specific cell types without virus replications

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Herpesviruses: subfamilies 1. Alphaherpesviruses – Herpes simplex virus (HSV-1) – Herpes simplex virus (HSV-2) – Varicella zoster virus (VZV) 2. Betaherpesviruses – Cytomegalovirus (CMV) – Human herpes virus-6 (HHV-6) – Human herpes virus-7 (HHV-7) 3. Gammaherpesviruses – Epstein bar virus (EBV) – Human herpes virus-8 (HHV-8) 10/15/08

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Herpesvirus Particle • Enveloped, icosahedral, double

stranded DNA viruses. • •Genome consisits of long and short fragments •All herpesviruses have identical morphology •Cannot be distinguished under electron microscopy

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Properties of Herpes Simplex Viruses (HSV) • Are very large viruses • Types: HSV-1 & HSV-2 • The genome of HSV-1 and HSV-2 share 50 - 70% homology. • Man is the only natural host for HSV • Grow in cell culture easily 10/15/08

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Epidemiology • The virus is shed in saliva, tears, genital and other secretions: Spreads by:

– Kissing – Sexual contact – Use of utensils contaminated with saliva – Mother to child during birth and postnatal – Mother to fetus in utero – 60-90% of adults have HSV-1 10/15/08

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Sites of HSV 1 & 2 Infection

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Almost any human cell type can be infected by HSV

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Pathogenesis Primary infection • Is usually subclinical in most individuals • Disease mainly of very young children <5 years and young adults • Generally HSV-1 causes infection above the waist and HSV-2 below the waist – 40% of genital sores are due to HSV-2 – 5% of facial herpes are due to HSV-2 • HSV spreads locally and a short-lived viraemia occurs 10/15/08

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Pathogenesis • Virus replicates in the lesion • Travels retrograde along the neurons to the ganglion – In orofacial herpes to the trigeminal ganglia – In genital herpes to the sacral ganglia • The virus can also travel in the opposite direction to arrive at the mucosa that was initially infected • Vesicles containing infectious virus are formed on the mucosa and the virus spreads • The vesicle heals and there is usually no scar as a result

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Pathogenesis

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Latency in ganglia

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Pathogenesis • Reactivation occurs due to: – Physical or psychological stress – Infection – Fever – Irradiation including sunlight – Menstruation (stressful conditions) • 45% of orally infected individuals and 60% of patients with genital herpes will experience recurrences • Recurrence occurs at same spot each time 10/15/08

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The Immune Response to HSV 1 and 2  Interferon & NK cells limit the initial infection The cellular response • Cytotoxic T cells and macrophages kill infected cells The humoral response • Antibodies lead to neutralization • The virus can spread from one cell to another without entering the extracellular space and do not come in contact with antibodies. So

• Cell-mediated response is vital in controlling infection • The cell mediated and inflammatory response lead to some of the disease symptoms

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Clinical Manifestations

HSV clinical manifestations include;

1. Acute gingivostomatitis 2. Herpes Labialis (cold sore) 3. Ocular Herpes 4. Herpes Genitalis 5. Other forms of cutaneous herpes 7. Meningitis 8. Encephalitis 9. Neonatal herpes 10/15/08

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Oral-facial Herpes Acute Gingivostomatitis • The commonest manifestation of primary herpetic infection • Pain and bleeding of the gums • Ulcers with necrotic bases • Neck glands are commonly enlarged • Fever • Usually a self limiting disease which lasts around 13 days.

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Oral-facial Herpes

Herpes labialis (cold sore) • Is a recurrence of oral HS in about 45% of individuals • A prodrome of tingling, warmth or itching at the site • About 12 hours later, redness appears followed by papules and then vesicles

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Ocular Herpes A broad spectrum disease: from mild superficial lesions of the external eye, to severe sight-threatening diseases of the inner eye. – Primary HSV keratitis – dendritic ulcers – Recurrent HSV keratitis – HSV conjunctivitis – Iridocyclitis, chorioretinitis and cataract

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Genital Herpes • May be primary or recurrent • Primary mostly asymptomatic • Infection sites can be the penis, vagina, cervix, anus, vulva, bladder, the sacral nerve routes, and the meninges • Redness on the external genitalia followed by itching papules and then vesicles • Dysuria is a common complaint, in severe cases, there may be urinary retention. • The lesions are prone to secondary infection eg. S.aureus, Streptococcus, Trichomonas and Candida Albicans • 60% of patients with genital herpes experience recurrences 10/15/08

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Herpes Simplex Encephalitis (HSE) Is one of the most serious complications of herpes simplex disease. There are two forms: Neonatal: there is global involvement of the brain • The brain is almost liquefied • The mortality rate approaches 100% Focal disease – the temporal lobe is commonly affected • Appears in children and adults The mortality rate is high (70%) without • treatment IV acyclovir is given in all cases of suspected • HSE before laboratory results 10/15/08

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Neonatal Herpes Simplex • Infection acquired:

– During birth or – Oral lesions from mother – A herpetic whitlow in a nurse

• May be a mild skin infection to a fatal disseminated infection involving liver, adrenals and the brain

– A large proportion have residual disabilities

Treatment: • Acyclovir given promptly in all suspected cases Prevention: • Caesarean section to mothers with florid genital HSV lesions 10/15/08

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Other Cutaneous Manifestations Eczema Herpeticum • A potentially serious disease that occurs in patients with eczema Herpetic Whitlow • Arise from implantation of the virus into the skin and typically affect the fingers

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Herpetic Whitlow

Herpetic Whitlow

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HSV in immunocompromised • Mostly disseminated infection • The widespread chickenpox-like lesions • Many organs may be involved e.g. liver, spleen, lungs, and CNS.

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Laboratory Diagnosis • Direct Detection – Electron microscopy of vesicle fluid - rapid result but cannot distinguish between HSV and VZV – Immunofluorescence of skin scrappings can distinguish between HSV and VZV – PCR of CSF in HSV encephalitis • Virus Isolation – HSV-1 and HSV-2 are among the easiest viruses to cultivate. It usually takes only 1 - 5 days for a result to be available. (CPE) • Serology – Not that useful in the acute phase because it takes 1-2 weeks for before antibodies appear after infection. 10/15/08

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CPE eosinophilic intra nuclear inclusion bodies (HSV)

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Treatment Only a few indications of antiviral chemo­therapy: – Severe primary infection – Sight-threatening ocular herpes – Herpes simplex encephalitis

Acyclovir • I.V. (immunocompromised patients) • Oral (mucocutaneous herpes and prophylaxis of HSV in immunocompromised patients) • Cream (infection of the skin and mucous membranes) • Ophthalmic ointment Famciclovir and valacyclovir 10/15/08

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Properties of Varicella-Zoster Virus (VZV or HHV 3) Chickenpox (Varicella), usually in childhood. Is a primary infection •

•Shingles

(Zoster), later in life. Is a reactivation of an earlier varicella infection

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Pathogenesis

Entry of virus via respiratory tract

Reactivation

Lymphoid system

Becomes latent in the cerebral or posterior root ganglia

Viremia

After 14 days reaches the main Target: the skin

Epithelium at different sites 10/15/08

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Varicella • Is a primary infection with incubation period of: 14-21 days • Highest prevalence in the 4 - 10 years old age group • The patient is considered infectious from approximately 48 h before the onset of the rash until all the vesicles have crusted over and there is no new visicle formation • Presents fever, lymphadadenopathy. a widespread vesicular rash. • Characteristic features: diagnosis can be made on clinical grounds alone. • Is highly communicable, with an attack rate of 90% in close contacts. Complications are rare: • In immunocompromised patients secondary bacterial infection of the vesicles may occur • Severe complications include viral pneumonia, encephalititis, and haemorrhagic chickenpox. 10/15/08

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Rashes of Chickenpox

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Varicella-Zoster In Pregnancy • 90% of pregnant women already immune, therefore primary infection is rare during pregnancy. • Primary infection during pregnancy carries a greater risk of severe disease, in particular pneumonia. First 20 weeks of Pregnancy • Up to 3% chance of transmission to the fetus, recognised congenital varicella syndrome;

– – – –

Scarring of skin Hypoplasia of limbs CNS and eye defects Death in infancy normal

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Herpes Zoster (Shingles) •

Is a reactivation of an earlier varicella infection

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Mainly affects a single dermatome of the skin

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Any age but majority >50 years of age

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The latent virus reactivates in a sensory ganglion and tracks down the sensory nerve to the appropriate segment

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Characteristic vesicles often accompanied by intensive pain which may last for months (postherpetic neuralgia)

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Herpes Zoster (Shingles) • Herpes zoster affecting the eye and face may pose great problems • A far greater problem in immunocompromised • Complications are rare and include encephalitis and disseminated herpes zoster.

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Laboratory Diagnosis • Characteristic clinical presentations • Laboratory confirmation is rarely required • Only required in immunocompromise – Direct detection - electron microscopy on vesicle fluids but cannot distinguish between HSV and VZV. – Immunofluorescense on skin scrapings can distinguish between the two – Virus Isolation - requires 2-3 weeks for a results – Serology • VZV IgG is indicative of past infection and immunity • VZV IgM indicates recent primary infection

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Management Varicella • Uncomplicated varicella is a self limiting disease • Acyclovir given in: – Immunocompromised individuals – Serious complications Herpes Zoster • Acyclovir, valicyclovir, and famciclovir to all patients over 50 years of age with herpes zoster • The main problem is postherpetic neuralgia 10/15/08

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Prevention • Isolating an infected person from others until the disease is no longer contagious is perhaps the most well-known preventative measure • For urgent protection passive immunization with Zoster immunoglobulin (ZIG) • A live attenuated vaccine is available (between 1-12 years) • The vaccine is often given during the same visit as the measles -mumps-rubella (MMR) vaccine. – However, recent data suggests that the vaccine is safe, even in children with leukaemia provided that they are in remission.

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Case presentation A 25-year-old woman presented with genital ulceration. This was accompanied by malaise and low grade fever. The patient complained of considerable local discomfort with a burning sensation of the external genitalia which preceded the development of genital ulceration. On questioning she gave no history of previous episodes of genital ulceration. An association inguinal lymphadenopathy was noted on clinical examination 10/15/08

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Questions • What is your clinical diagnosis? • How is this disease transmitted? • What complication may be associated with this clinical condition? • How would you confirm your clinical diagnosis in the laboratory? • What is your differential diagnosis?

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Case presentation A 7-year-old child was taken to her general practitioner with a rash that was mainly centripetal in distribution, with lesions being most prominent on the abdomen. On examination the child had a temperature of 37.50C. The skin rash consisted of papules, vesicles and scabs

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Questions • • • • • •

What is your clinical diagnosis? How would you confirm the clinical diagnosis in the laboratory? What complication may occur? What group of children is likely to develop severe diseases? For how long would the expect the child to be infectious? What therapeutic options are available?

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