Herpes Virus

Question 1

General Properties - structure (size, shape, envelope), 4 features

Answer 1

Herpesviridae - 95-105 nm, “fried egg”, enveloped dsDNA, 8 viruses (HHV)

1. large family of viruses infection almost every species
   - cross species infection is very rare
2. Ubiquitous, no geographic restriction, efficient transmission usually in early childhood
3. Latency - persist in host for life and can be reactivated
   - stimulus e.g. stress, UV light, immunosuppression
4. Oncogenic property e.g. HHV4 i.e. EBV associated NPC or Burkett’s lymphoma, HHV8 associated Kaposi’s sarcoma

Question 2

Specific characteristics of Herpes viruses (3)

Answer 2

All have high prevalence (>90%) except HHV-2, 8

Neuro-latency: all except HHV-4,5,8
Lympho-latency: all except HHV-1,2,3

Dermatotropic: all except HHV4,5

Question 3

HHV-1/ HSV-1: primary infection (route, symptoms, duration), latency (site), reactivation (stimulus, symptoms)

Answer 3

Primary infection

• early childhood, affecting >95% population
• transmitted by kissing (virus shed in saliva of parents)
• may be initially asymptomatic then progress to symptomatic
• symptoms (above waist): gingivostomatitis (painful blister-like ulcers on oral mucosa); pharyngitis and tonsilitis in older children
• other symptoms? herpes keratitis (lid swelling) and encephalitis
• duration: 2-3 weeks

Latency: local sensory dorsal root ganglion; trigeminal ganglia – reactivation possible in brain

Reactivation

• stress, UV light, injury to innervated tissue, immunosuppression
• activate at ganglion and virus travels down to nerve ending
• 40-50% have herpes labialis (cold sores)
• herpes simplex encephalitis

Question 4

HHV-2/ HSV-2: primary infection (route, symptoms, associations, duration), neonatal herpes, latency (site), reactivation (frequency, symptoms, duration)

Answer 4

Primary infection

• sexual transmission (1-10%)
• genital infection causing vesicular lesions over genitalia (herpes genitalis)
• symptoms: fever, pain, dysuria (proctitis)
• associated with aseptic meningitis and radiculomyelitis (usually self-limiting)
• duration: 3 weeks (more severe than HSV1)
• may cause neonatal herpes (infected during vaginal delivery due to high viral load contact) –> mucosa infected, dissemination, encephalitis with high mortality (more details elsewhere)

Latency: local sensory dorsal root ganglion; sacral ganglia – reactivation impossible in the brain

Reactivation

• more frequent than oral infection (few episodes/yr)
• fewer vesicles, less painful
• 1-2 weeks

Question 5

Other herpes infections by direct contact or auto-inoculation (3)

Answer 5

Herpes keratitis

• lid swelling (conjunctiva has lots of nutrients for pathogens to use)
• e.g. poor hand hygiene in nurses

Herpetic whitlow
- infection on the fingers of dentists due to patient shedding virus onto any open wounds

Eczema herpeticum
- atopic eczema causing break in natural barrier (skin) so virus can invade

Question 6

HHV-3/ VZV: primary infection (route, symptoms, complications in adults), latency (site), reactivation (risk, symptoms, duration, complications - 2), other outcomes (3)

Answer 6

Primary infection : CHICKENPOX

• airborne transmission - highly infectious
• very common childhood infection (decreasing now due to universal vaccination)
• clear vesicular rash spreading from face to trunk to limbs (sequence important in diagnosis); may have pus due to bacterial infection
• more complications if in adults e.g. pneumonitis, encephalitis

Latency: dorsal root ganglia e.g. trigeminal, thoracic etc.

Reactivation: ZOSTER

• higher risk in >60 yrs
• shingles - pain/numbness followed by rash and scabs in area of nerve supply
• usually lasting 1 week
• post-herpetic neuralgia in 15% (40% of >60yrs old) = persistent pain >4 wks after healing due to nerve damage

Complications:

• Ramsay Hunt Syndrome = facial nerve palsy due to reactivation in geniculate ganglion
• Ophthalmic zoster (distinguish by involvement of nose in lesions) = poor prognosis due to eye lesions (iritis, keratitis, retinitis)

Other outcomes of VZV:

• disseminated zoster in immunocompromised
• congenital varicella syndrome (congenital infection in 1st 20 wks) - skin scarring, extremity atrophy, neurological and eye problems
• neonatal infection (5 days before-2 days after birth)

Question 7

VZV prevention and protocol for healthcare workers

Answer 7

Vaccine:

• live attenuated
• Chickenpox: primary primary infection (universal immunisation)
• Zoster: prevent reactivation (>60 yrs old)

Immunoglobulin: HNIG, VZIG
- Post-exposure prophylaxis for high risk patients: susceptible pregnant women/ immunocompromised/ neonate

Healthcare workers:

• check VZV IgG immune status
• 2 doses of vaccine for susceptible
• approx 10% adults in HK are VZV IgG-ve

Question 8

Diagnosis of HSV and VZV: sample, method, why not other methods?

Answer 8

Typical clinical presentations, seldom need lab investigation

CSF sample: viral nucleic acid detection by PCR (sensitive and specific)
Skin scrape sample: viral antigen detection by IF (rapid and sensitive if good samples)

Vesicular fluid: PCR and virus isolation (HSV easy to grow but takes a few days, not sensitive for VZV and takes 1 wk)

Others:

• serology not useful – cross reaction between HSV and VZV, can’t distinguish primary and secondary infection
• EM – rapid but poor sensitivity, unable to differentiate between HSV and VZV

Question 9

HHV-4/ EBV: primary infection (route, symptoms in young children and teenagers), persistence and latency (site), reactivation (symptoms)

Answer 9

Primary infection: Young children

• common within 1st few years
• transmission by kissing
• most ASYMPTOMATIC
• occasionally infectious mononucleosis (fever, cervical LN, sore throat)
• rarely X linked lymphoproliferative syndrome (severe infection as can’t clear virus)

Primary infection: Teenagers

• escaped childhood infection
• transmission by kissing, sexual behaviour
• 1/4 have pharyngitis, tonsillitis or infectious mononucleosis

Persistence and Latency: B lymphocytes; frequent shedding in oropharynx

(Transmit through saliva and genital secretions, >90% adults infected)

Reactivation:

• Immunocompromised: lymphoproliferative disorder
• Malignancy: NPC, Burkett’s lymphoma, CA stomach, Hodgkin and Non-Hodgkin lymphoma

Question 10

EBV Diagnosis in IM, lymphoproliferative disease and NPC

Answer 10

IM in primary infection:

• IgM against EBV VCA (viral capsid Ag)
• Monospot (heterophile Ab produced due to B cell mitogenesis)

Lymphoproliferative disease:

• histology (definitive)
• EBV DNA viral load as adjunct test

NPC:

• histology (definitive)
• IgA against EBV VCA and EA (early Ag) used as screening in high risk population
• plasma EBV DNA?

Question 11

HHV-5/ CMV: primary infection (route, symptoms in different age groups - 4), persistence and latency (site), reactivation (risk, symptoms)

Answer 11

Primary infection:

• premature infants – hepatomegaly, pneumonitis, hepatitis etc
• infants (very common) – always asymptomatic; transmission during contact at vaginal delivery, breast milk, saliva, urine
• adults (% susceptible varies) – mostly asymptomatic, IM occasionally

In utero infection from mother – cytomegalic inclusion disease (asymptomatic/ blindness, hearing impairment/ multi organ…) - outcome depends on whether primary infection or reactivation in mother

Persistence: frequent shedding from salivary glands and kidneys (transmission)

Latency: Haematopoietic progenitors

Reactivation:

• opportunistic infection in immunocompromised e.g. AIDS, transplant recipients, immune-suppressive therapy
• –> severe disease: CMV retinitis, pneumonitis, hepatitis, enteritis

Question 12

CMV status mismatch in transplant/ transfusion

Answer 12

Due to latency in haematopoietic progenitors –> transmission possibly in blood transfusion and organ transplant

CMV IgG +ve donor –> CMV IgG -ve recipient can cause severe primary infection in immunosuppressed patients

Use leukocyte depleted blood
Check and match CMV IgG status of organ. marrow donors/ recipients

Question 13

CMV diagnosis difficulties

Answer 13

Infection vs Disease

• CMV virus shedding in urine and saliva is common in all ages –> isolation of CMV does not necessarily mean suffering disease (need further evidence)
• detection of virus e.g. Owl’s eye, from tissue with pathology gives better etiological correlation but still not definitive

Primary vs Secondary

• no reliable test to distinguish
• primary more severe in pregnant women and immunosuppressed
• CMV IgM and 4 fold rise in Ab occurs in both
• to confirm primary infection: need prior serum with CMV IgG-ve

Treatment of CMV is quite toxic hence need good evidence to support infection before starting!

Question 14

HHV-6: primary infection (route, symptoms, associations), latency (site), reactivation (risk, symptoms)

Answer 14

Primary infection

• 90% infected from 6mths-2yrs (not <6 mths since there is maternal Ab)
• transmitted by kissing
• exanthem subitem (roseola infantum): HIGH FEVER THEN RASH
• a/w febrile convulsion, hepatitis, lymphadenitis

Latency: T lymphocytes, brain

Transmission: saliva

Reactivation:

• HSCT patient - encephalitis, rash
• ? possible a/w chronic fatigue syndrome and multiple sclerosis

Question 15

HHV-7 clinical picture

Answer 15

Similar to clinical picture to HHV-6 but:

• later infection
• symptomatic primary infection less frequent
• reactivation disease unclear

Question 16

HHV-8: prevalence, age of infection in endemic vs non-endemic areas, route of transmission, associated diseases (2)

Answer 16

Not common, only in specific areas

Endemic: 25-70% prevalence e.g. Africa

• infection at early age
• virus found in breast milk, saliva
• sexual and non-sexual route of tranmission

Non-Endemic: <5% prevalence e.g. Europe, US, Asia

• infection rises in adulthood
• sexual route, especially MSM
• +/- blood borne

Kaposi’s sarcoma

• all subtypes a/w HHV-8
• in HIV +ve (more common MSM) and -ve (more common in mediterranean elderly men, transplant immunosuppression)

Lymphoproliferative disorders

• B-lymphotropic
• in immunocompromised patients
• e.g. multi centric Castleman’s disease