Herpes Flashcards
Types and description of human herpesviruses (HHV)
-Share structure, mode of replication, and capacity to establish life-long infections from which virus may be reactivated
-8 HHV are recognized; some are predominantly
=Neurotropic: HSV, VZV
=Lymphotropic: EBV, HHV6, HHV7
-HHV 1-7 infection is common in all populations
-HHV 8 infection is uncommon in developed countries
Types of Infection
-Latent infection
=Persistent infection (presence of viral genome) during which no infectious virus is produced, except during intermittent reactivation
-Reactivation
=Reactivation from latency manifest as asymptomatic virus shedding or clinical disease
-Recurrence or recrudescence
=Reactivated virus produces clinically apparent disease
-Lytic infection
=Productive infection involving rupture of host cell and release of infectious virus particles (virions)
Describe the Herpes Virus
-Protein capsid
-dsDNA core
-Proteinaceous layer
-Lipid envelope derived from host cell membrane
=Spikes of viral glycoproteins
Virus Identification
-Microscopy
=Light microscope (Stained/immunostained samples)
=Electron microscope
-Direct virus visualisation
-Virus isolation
=Cultured cells (tissue culture)
=Presumptive diagnosis (cytopathic effect, CPE)
=Confirmation by immunostaining
-Antigen detection
=Direct/indirect immunofluorescence (IF)
=Enzyme immunoassays (EIA)
-Antibody detection
=Direct/indirect immunofluorescence (IF)
=Enzyme immunoassays (EIA)
=Immunoblots
-Molecular analysis
=Nucleic acid amplification tests (NAATs)
-Polymerase chain reaction (PCR)
=Sequencing (genotype, drug resistance, epidemiology)
Prevalence and infection of HSV
-Ubiquitous, infecting majority of the world’s population early in life and persisting in a latent form with periodic reactivation and shedding of infectious virus
=60-90% of adults have acquired HSV-1
=Many more adults have acquired HSV-2 than give a history of genital herpes, but prevalence rates vary between populations
Transmission of HSV
Transferred by direct contact with infectious lesions/fluid
Types of HSV
-Type 1 (HSV-1)
=Generally associated with mouth, eye and CNS
-Type 2 (HSV-2)
=Generally associated with the genital tract
3 glycoproteins essential for production of infectious virus
-gB and gD: penetration of cells (with gC)
-gH: fusion at entry (with gL) and release of virus
Describe primary infection of HSV
Typical lesion is the vesicle:
-Ballooning degeneration of intra-epithelial cells (infectious fluid)
-Base of vesicle contains multinucleate (Tzanck) cells
-Infected cells contain eosinophilic inclusion bodies
-The roof of the vesicle breaks down and an ulcer forms that heals
=Virus enters sensory nerve endings at site of epithelial replication and are transported along the axon to nerve body (neurone) in the sensory (dorsal root) ganglion
=Virus replication in a neurone ends in lytic infection
How is HSV latency established?
-Latency is established in surviving neurones of the dorsal root ganglion (about 1% of cells in the affected ganglion)
=Trigeminal ganglion
=Other sensory and autonomic ganglia (for example, vagus)
=Brain
=Adrenal tissue
-Very few genes are expressed in the latent state [some latency associated transcripts (LATs) are found in cell nuclei]
Reactivation of HSV
-HSV DNA passes along nerve axon to nerve ending where infection of epithelial cells may occur (sometimes asymptomatic shedding)
-Mechanism of reactivation is unclear but can be induced by ultraviolet light (sunlight), fever, trauma, stress
Clinical features of primary infection
Initial acquisition of virus
=Any site; often mucous membranes of mouth, lips, skin of face, nose, eye or genital tract
Clinical features of HSV recurrence
-Prodrome [pain or paraesthesia (tingling, warmth, itch)] occurs at site in 2/3 of individuals with symptomatic recurrence
-Followed by erythema and a papule that progresses to a vesicle and ulcer that heals
=Most common sites are lips, chin and inside nose but can manifest at any site (innervated by affected neurone as determined by site of initial infection)
-Cold sore, fever blister
Examples of oral infection of HSV
Acute febrile gingivostomatitis
Describe acute febrile gingivostomatitis
-Often with herpetic dermatitis and pharyngitis
-Cervical lymphadenopathy and mononucleosis may occur
-Viraemia with dissemination to internal organs is rare
except in
=pregnancy
=the neonate
=the immunocompromised patient
Examples of HSV skin infections
-Herpetic Whitlow
-Eczema Herpeticum
Describe Herpetic Whitlow
-Classical primary finger lesion of a toddler with herpetic stomatitis (due to auto-inoculation); may recur; mostly HSV-1
-Accidental inoculation in healthcare workers (traumatic herpes); may recur; mostly HSV-1
-Recurrent hand lesion; young adults with genital herpes; mostly HSV-2
-Lymphangitis is often notable with the lesions above
Describe Eczema Herpeticum
-Severe cutaneous herpes in children with atopic eczema: vesicles appear on eczematous areas
-Extensive ulceration and viraemia is life threatening
-May occur in patients with pemphigus or patients with burns
Describe HSV eye infections
-May result from primary infection or auto-inoculation from a cold sore/fever blister
-Mostly caused by HSV-1
-Often associated with
=Periorbital herpetic dermatitis
=Conjunctivitis
=Keratoconjunctivitis
=Branching (dendritic) corneal ulcers
-Herpetic blepharitis is sometimes seen in HSV eye infections
-Most recurrence in the >50 years old
-Acute retinal necrosis may occur
How can HSV reach the brain?
-During HSV viraemia
-From affected neurones
-In cells traversing blood-brain barrier
-Directly from nasal mucosa (olfactory tract)
-From the trigeminal ganglia (likely)
HSV meningitis
-Aseptic HSV meningitis is much less serious than HSV encephalitis (typical temporal lobe lesion)
=Mostly HSV-2 (following radiculitis during genital herpes)
=Recurrence can occur (Mollaret’s meningitis)
HSV Encephalitis
-Rare – but the commonest sporadic fatal encephalitis (1-2 cases per million population annually)
-Mostly HSV-1, but HSV-2 can cause encephalitis in neonates and immunocompromised individuals
-70% of cases have serological evidence of past HSV infection
-Recurrent lesions are seldom apparent
-Often a prodrome of fever and malaise followed by headache, behavioural change and focal episode of seizure or paralysis
-Coma precedes death
-Temporal lobe is most frequently affected
-Virus replication in neurones, oedema and inflammation account for haemorrhagic necrosis and space-occupying symptoms/signs
-Brainstem encephalitis is another serious form
Describe Primary Genital Tract infection of HSV
-HSV-1 and -2 can infect the genital tract
=HSV-2 is more common; HSV-1 is increasingly detected
=Sexual contact (or autoinoculation)
=Incubation: 2-20 days (ave 7 days)
=Can be severe, especially in women
-In the male
=Shaft and glans of penis
=Around anus (sometimes proctitis)
-In the female
=Labia, vagina or cervix
-In both sexes
=May spread to adjacent skin sites
=Fever and malaise together with Lymphadenopathy, Urethritis, Vaginal discharge, Sacral radiculopathy
-Urinary retention
-Meningitis
-Whole episode lasts 3-4 weeks
Describe recurrent genital tract infection
-Can be as frequent as six or more episodes a year
-Recurrent episodes are milder and shorter (7-10 days)
-Socially and psychologically distressing
-Some patients experience a prodrome
-Virus shedding is often asymptomatic
-HSV-1 recurs less often than HSV-2
-Intra-uterine transmission is rare
-HSV-1 and -2
=Can transmit to neonate during childbirth
Describe neonatal herpes
-Rare - 1.65 per 100,000 live births in the UK
-Without therapy, carries high mortality (60%) and significant morbidity
-HSV (often HSV-2) acquired by passage through an infected genital tract
-Transmission rate
=50% if mother suffers primary HSV at time of delivery
=5% if mother suffers recurrence at time of delivery
-Three clinical forms
=Skin, eye and mucous membrane (SEM)
=10-12 days post-partum
=Vesicles on presenting part
=75% will progress to disseminated disease
-Disseminated disease
=During first few days of life
=Pneumonitis and hepatitis with/without
– Aseptic meningitis
– Encephalitis
-Encephalitis (with/without dissemination)
=In first 2-3 weeks of life
=Severe neurological morbidity or death
-Recurrence
=Can occur, especially at skin sites, in the first year of life
Therapy for neonatal herpes
-Aciclovir (ACV)
=Available for topical, oral and intravenous (iv) use
=Topical ACV is suitable for mild epithelial lesions
=Any lesions that are not simply mild and superficial ones
=HSV-associated disease in the immunocompromised host
=CNS and systemic infection (iv therapy is required)
=Any of the serious manifestations of HSV disease
-Dosage depends on site of infection (see BNF)
-Therapy must be maintained until clinical response is achieved
-Serious systemic disease necessitates iv therapy for 2-3 weeks (sometimes followed by suppressive oral treatment)
-Valaciclovir (oral pro-drug of ACV) produces significantly higher plasma levels after oral dosing than ACV
-Famciclovir (oral pro-drug of penciclovir) is another ACV derivative
-Valaciclovir and famciclovir can be administered less frequently than aciclovir
! Resistance can develop: f resistance emerges, foscarnet can be used
Overview of HSV manifestations
See
Prevalence of Varicella Zoster Virus (VZV)
-Partly seasonal: respiratory spread in winter and early spring
-Highly infectious
-Past history is a good indicator of immunity
-Approx 90% of adults have been infected with VZV (lower % in sub-tropical countries for unknown reasons)
2 Forms of VZV
- Primary infection: varicella (or chickenpox) is a generalized eruption
- Reactivated infection: zoster (or shingles) is localized to one (or a few) dermatomes
Smallpox vs chickenpox
Smallpox:
=Fever 2 to 4 days before rash
=Rash: pocks in same stage
=Slow development
=More pocks on arms and legs
=Usually present on palms and soles
=1 in 10 die
Chickenpox:
=Fever at all time of rash
=Pocks in several stages
=Rapid development
=More pocks on body
=Usually absent on palms and soles
=Ver uncommon death
Describe transmission and development of Varicella virus
-Virus enters through upper respiratory tract or conjunctivae; may multiply in local lymphoid tissue for a few days before entering blood and disseminating throughout body
-After replication in reticuloendothelial sites, a second viraemic stage precedes the appearance of the skin and mucosal lesions
-The vesicles lie in the middle of the epidermis and contain infectious virus; they dry up and scabs form that desquamate
-Lesions in all stages are present at any one time
Describe transmission and development of Zoster virus
-Latent virus is found in neurones and satellite cells in sensory ganglia
-Reactivation of VZV as zoster can occur at any age but is most often seen in individuals >60 years of age
- Shorter latent period is seen in immunocompromised patients and those who acquired VZV in utero or in the first year of life
-Stimulus to reactivation is largely unknown (sometimes it is trauma)
-Zoster is usually limited to one dermatome; in adults, this is usually the thoracic or upper lumbar regions, or in the area supplied by the ophthalmic division of the trigeminal nerve
-Viraemia may occur but is unusual in the immunocompetent host
Clinical features of chickenpox (Varicella)
-Incubation period of 10-21 days (ave 14 days)
-Individual is infectious from up to 1-2 days before, and for some days after, onset – while new vesicles are appearing and until all vesicles have crusted over
-Rash
Describe the chickenpox rash
-Centripetal
-Most dense on the head and trunk
-Generally not on palms of hands or soles of feet
-Macular through papular to vesicular
-Main differential diagnosis used to be smallpox but is now either HSV or, rarely, monkeypox (for example, from exotic African pets such as the Gambian rat)
Complications of chickenpox
-Secondary bacterial infection (resulting in scarring)
-Thrombocytopenic purpura (may lead to fatal haemorrhagic
chickenpox)
-Arthritis, myocarditis, hepatitis, glomerulonephritis, appendicitis
-The most frequent problems relate to the lungs and CNS
Describe VZV Pneumonitis
- VZV pneumonitis is a serious (even fatal) complication
=1:200 in otherwise healthy adults
=1:200,000 in otherwise healthy children
-More likely in
=Adults
=Smokers
=Pregnant women
=Immunocompromised host
-Cough, dyspnoea, tachypnoea and chest pains begin a few days after the vesicular rash
-Nodular infiltrates are seen on CXR
-Prompt antiviral therapy is required
Describe VZV in CNS
-Common complications include
=Cerebellar ataxia syndrome
=Aseptic meningitis
-Acute encephalitis is rare but more serious
-Differential diagnosis include the immunologically-mediated
=Post-infectious encephalopathy
=Transverse myelitis
=Guillain-Barrė syndrome
2 types of intra-uterine Varicella infection in pregnancy
-Congenital varicella syndrome (CVS): a rare consequence (1% in first trimester) of fetal infection in first half of pregnancy
=Scarring of skin
=Damage to musculoskeletal system: Muscular atrophy, limb hypoplasia, rudimentary/missing digits
=CNS damage: Cortical atrophy, psychomotor retardation
=Damage of eyes: Chorioretinitis, cataracts
-Neonatal varicella: varicella in first 4 weeks of life (usually from maternal varicella in late pregnancy)
=Serious (even fatal) disseminated VZV disease: Pneumonitis, Encephalitis
=Greatest risk if maternal varicella occurs within 6 days of, or up to 2 days after, delivery (no maternal IgG transferred to baby)
=Silent infection may only manifest as zoster in first year of life
Clinical features of Shingles (Zoster)
-Reactivation of VZV
=Localised eruption, usually confined to one dermatome
=Prodrome (pain and paraesthesia) in the area supplied by the affected sensory nerve
=Evolution of rash is similar to varicella except for confinement to dermatome
=Occasionally, there are no skin lesions: zoster sine herpete
-Occurs with increased incidence in
=Old age
=Immunocompromised individuals
-Disseminated zoster resembles varicella and may involve internal organs
=Pneumonitis
=Meningitis
=Encephalitis
=Myelitis
=Internal organ zoster may not be accompanied by a typical skin rash
Describe Ophthalmic Zoster
-Involvement of the ophthalmic division of the trigeminal nerve
-Occurs in up to 25% of zoster episodes with ocular
complications in >50% of the patients
-Complications include
=Corneal ulceration
=Stromal keratitis
=Anterior uveitis
=Scarring
=Acute retinal necrosis
=Granulomatous cerebral angiitis
=Ramsay-Hunt syndrome (facial palsy with aural zoster vesicles)
Describe Post-Herpetic Neuralgia
-The most common complication of zoster
-Intractable pain persisting for 1 month or more after the skin rash
-Constant pain at site or paraesthesia may continue
for 1 year or longer
-Exhausting and disabling
Therapy for Varicella Zoster virus
-Aciclovir (ACV)
=VZV is less sensitive to ACV than HSV; needs frequent iv high dosage
=Oral ACV accelerates healing and reduces new lesion formation during zoster in the immunocompetent patient; may lower rate of PHN
=Oral ACV should be considered for all adult cases of varicella
-Valaciclovir or famciclovir require less frequent dosing
-The following groups should receive oral or iv aciclovir therapy
=neonates (within first 4 weeks of life)
=immunocompromised patients
=ophthalmic zoster
=healthy individuals with varicella and a complicating factor
-A live-attenuated varicella vaccine is available
-The vaccine strain (Oka strain) can be distinguished from wild-type VZV
-Immunisation does not prevent latency, but incidence of zoster is not increased whereas incidence of varicella is significantly reduced
-Primary course consists of two vaccine doses administered intramuscularly 4-8 weeks apart; a booster dose may be required (not current guidance)
- In UK, the vaccine is not offered as part of the childhood immunisation programme but to 70/78yos as well as susceptible individuals who are in regular contact with those at risk of developing serious VZV illness
=Non-immune healthcare workers
=Healthy contacts of immunocompromised patients
Describe primary infection with EBV
-Is most often acquired in childhood when it is generally asymptomatic
-Gives rise to infectious mononucleosis (IM; also known as glandular fever) in up to a quarter of individuals when infection is delayed into adolescence
-Rare but serious complications of IM include airway obstruction, splenic rupture and neurological complications (including aseptic meningitis, encephalitis and the Guillain–Barré syndrome)
Describe EBV
-Link between EBV and a variety of epithelial/lymphoid tumours is clear
=EBV is an oncovirus; in particular, it can drive uncontrolled
(tumoriforming) B cell proliferation
-There is no antiviral drug treatment
-There is no EBV vaccine in routine use, yet
-Approx 90% of adults have acquired the virus which is transmitted in saliva (and perhaps in genital secretions)
-Latency is established in resting memory B lymphocytes
Clinical features of IM
-Primary infection is usually mild and unrecognised in childhood
-Infectious mononucleosis (IM) is seen when primary infection is delayed to young adulthood
- Incubation period is 30-50 days
-IM consists of a triad of sore throat (often severe pharyngitis/ tonsillitis), cervical lymphadenopathy (becomes generalised often with splenomegaly) and intermittent fever
-Often accompanied by malaise, headache, sweating (particularly at night), gastrointestinal discomfort, fatigue, and poor concentration
-Atypical mononucleosis is seen in blood and biochemical hepatitis may also be observed
-A faint maculopapular rash may become apparent (for example, following amoxicillin)
Describe CMV
-Approx 60% of individuals at 40 years of age have acquired CMV, and most by 60 years of age
-Incubation period is 4-6 weeks
-Mononuclear cells carry the latent CMV genome, and bone marrow progenitor cells may be the prime site of latency
-CMV replicates in vivo in epithelial cells in
– salivary glands
– the kidney
– the respiratory tract
– other epithelial (or endothelial) sites
-Aciclovir is not effective against CMV; alternative agents are ganciclovir, foscarnet and cidofovir (all have serious side effects that limit their use)
-No CMV vaccine is licensed for routine use yet
