Herpes

Question 1

Types and description of human herpesviruses (HHV)

Answer 1

-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

Question 2

Types of Infection

Answer 2

-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)

Question 3

Describe the Herpes Virus

Answer 3

-Protein capsid
-dsDNA core
-Proteinaceous layer
-Lipid envelope derived from host cell membrane
=Spikes of viral glycoproteins

Question 4

Virus Identification

Answer 4

-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)

Question 5

Prevalence and infection of HSV

Answer 5

-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

Question 6

Transmission of HSV

Answer 6

Transferred by direct contact with infectious lesions/fluid

Question 7

Types of HSV

Answer 7

-Type 1 (HSV-1)
=Generally associated with mouth, eye and CNS

-Type 2 (HSV-2)
=Generally associated with the genital tract

Question 8

3 glycoproteins essential for production of infectious virus

Answer 8

-gB and gD: penetration of cells (with gC)
-gH: fusion at entry (with gL) and release of virus

Question 9

Describe primary infection of HSV

Answer 9

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

Question 10

How is HSV latency established?

Answer 10

-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]

Question 11

Reactivation of HSV

Answer 11

-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

Question 12

Clinical features of primary infection

Answer 12

Initial acquisition of virus
=Any site; often mucous membranes of mouth, lips, skin of face, nose, eye or genital tract

Question 13

Clinical features of HSV recurrence

Answer 13

-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

Question 14

Examples of oral infection of HSV

Answer 14

Acute febrile gingivostomatitis

Question 15

Describe acute febrile gingivostomatitis

Answer 15

-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

Question 16

Examples of HSV skin infections

Answer 16

-Herpetic Whitlow
-Eczema Herpeticum

Question 17

Describe Herpetic Whitlow

Answer 17

-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

Question 18

Describe Eczema Herpeticum

Answer 18

-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

Question 19

Describe HSV eye infections

Answer 19

-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

Question 20

How can HSV reach the brain?

Answer 20

-During HSV viraemia
-From affected neurones
-In cells traversing blood-brain barrier
-Directly from nasal mucosa (olfactory tract)
-From the trigeminal ganglia (likely)

Question 21

HSV meningitis

Answer 21

-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)

Question 22

HSV Encephalitis

Answer 22

-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

Question 23

Describe Primary Genital Tract infection of HSV

Answer 23

-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

Question 24

Describe recurrent genital tract infection

Answer 24

-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

Question 25

Describe neonatal herpes

Answer 25

-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

Question 26

Therapy for neonatal herpes

Answer 26

-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

Question 27

Overview of HSV manifestations

Answer 27

See

Question 28

Prevalence of Varicella Zoster Virus (VZV)

Answer 28

-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)

Question 29

2 Forms of VZV

Answer 29

1. Primary infection: varicella (or chickenpox) is a generalized eruption
2. Reactivated infection: zoster (or shingles) is localized to one (or a few) dermatomes

Question 30

Smallpox vs chickenpox

Answer 30

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

Question 31

Describe transmission and development of Varicella virus

Answer 31

-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

Question 32

Describe transmission and development of Zoster virus

Answer 32

-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

Question 33

Clinical features of chickenpox (Varicella)

Answer 33

-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

Question 34

Describe the chickenpox rash

Answer 34

-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)

Question 35

Complications of chickenpox

Answer 35

-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

Question 36

Describe VZV Pneumonitis

Answer 36

• 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

Question 37

Describe VZV in CNS

Answer 37

-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

Question 38

2 types of intra-uterine Varicella infection in pregnancy

Answer 38

-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

Question 39

Clinical features of Shingles (Zoster)

Answer 39

-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

Question 40

Describe Ophthalmic Zoster

Answer 40

-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)

Question 41

Describe Post-Herpetic Neuralgia

Answer 41

-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

Question 42

Therapy for Varicella Zoster virus

Answer 42

-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

Question 43

Describe primary infection with EBV

Answer 43

-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)

Question 44

Describe EBV

Answer 44

-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

Question 45

Clinical features of IM

Answer 45

-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)

Question 46

Describe CMV

Answer 46

-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