Herpes Viruses

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Herpesviridae - 1
T. Mazzulli, MD, FRCPC Department of
Microbiology Mount Sinai Hospital
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Herpesviridae - Objectives

1. To review the members of the Herpesviridae family
2. To understand the concepts of primary infection,
   latent infection and reactivation disease
3. To recognize the common clinical syndromes
   associated with each virus and the principles of
   management

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Herpesviridae Family

• double stranded DNA viruses with envelope
• ubiquitous, world-wide distribution
• 8 human herpesviruses recognized species
  specific
• Latency - once infected, always infected
• - site varies with virus type
• - HSV 1 2, VZV - sensory nerve
  ganglia
• - CMV, EBV, HHV6, HHV7 lymphocytes
• Replication occurs in the nucleus of infected
  cell
• Viral DNA remains episomal (i.e. not integrated
  into host cell DNA)

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Transmission Seroepidemiology of Herpesviridae
Straus SE. In Mandell, Douglas, Bennett (eds).
Principles and Practice of Infectious Diseases,
6th Ed. 20051756-1762
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Herpesviridae

• Transmission
• do not survive for prolonged periods in the
  environment
• requires inoculation of fresh virus-containing
  body fluid of infected person into susceptible
  tissue of uninfected person
• may be transmitted during primary or reactivation
  infections often the person shedding virus is
  asymptomatic

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Herpes Simplex Viruses (HSV)
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Herpes Simplex Virus

• Spread via contact with infected secretions
• transmission both during lesions or from
  asymptomatic excretor
• 1-15 of adults excrete HSV-1 or HSV-2 at any
  given time
• efficiency of transmission of HSV-2 is lower than
  HSV-1
• Clinical Disease Primary vs Recurrent

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Herpes Simplex Virus - Clinical Manifestations

• HSV-1 Primary Infection
• incubation period 2 to 12 days
• usually asymptomatic
• gingivostomatitis, pharyngitis
• multiple small vesicles in clusters or singly
• resolves in 10-14 days

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Herpes Simplex Virus - Clinical Manifestations

• HSV-2 Primary Infection
• incubation period 2 - 7 days
• vesicular lesions anywhere in genital tract
• may be associated with fever, malaise, anorexia,
  tender bilateral inguinal adenopathy
• lesions may ulcerate very painful if involves
  urethra may lead to urinary retention
• lesions may persist for weeks

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Epidemiology of HSV Infections

• Only 10-15 of HSV-2 primary infections are
  symptomatic
• 4 out of every 5 people with genital herpes have
  not been diagnosed three out of five people have
  symptoms that are unrecognized as genital herpes
• Recurrent disease can be either symptomatic or
  asymptomatic

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Primary herpes, male
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Herpes, female
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Herpes cervicitis
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Herpes Simplex Virus - Clinical Manifestations

• Recurrent Infection
• common with both HSV-1 and HSV-2 due to
  reactivation of endogenous virus despite
  antibodies
• recurrent lip or perioral lesions in 20 - 40
• recurrent genital lesions in 60 - 90
• ?frequency depends on sex, HSV type, titre of
  neutralizing antibody
• precipitating factors include sunlight, fever,
  local trauma, menstruation, emotional stress

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Herpes Simplex Virus - Clinical Manifestations

• Recurrent Infections
• i) Herpes labialis (cold sore) - pain, burning,
  itching 6 hrs (24 - 48 hrs) before lip lesion
• vesicles to ulcer/crust in 48 hrs healing within
  8 - 10 days
• ii) Genital lesions -
• pain, itching, burning for several hours before
  vesicles appear healing within 6 - 10 days

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HSV Cold Sore
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HSV Cold Sore
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Recurrences of Genital HSV

• HSV-2 versus HSV-1 genital herpes rates
• Reactivates 49 days versus 310 days after primary
• 4.5 recurrences per year versus lt1
• HSV-2 recurrence rates vary widely across people
• 26 women and 8 of men have none in first year
• 14 women and 26 men gt10 recurrences
• Recurrence rates trend down (frequency and
  severity) over the long term
• HSV-2 shedding 5-32 of days (40 subclinical)

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HSV Complications

• CNS infections
• Perinatal/Congenital

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Herpes Simplex Virus CNS Infections

• Encephalitis
• temporal lobes are the principle target
  hemorrhagic necrosis
• all ages, all seasons, both sexes
• sudden onset or after flu-like prodrome
• may be no signs of HSV elsewhere

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Herpes Simplex Encephalitis
CT Scan
Autopsy
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Herpes Simplex Virus CNS Infections

• Encephalitis
• MRI may detect earlier changes than CT
• untreated, rapid deterioration over few days with
  60-80 mortality 90 of survivors have
  significant neurological sequelae
• acyclovir treatment reduces mortality by 50

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Herpes Simplex Virus CNS Infections

• Meningitis
• most commonly associated with primary HSV-2
  infection less likely with recurrences of
  genital herpes
• benign, self-limited (contrast with encephalitis)
• usually affects sexually active young adults
• no neurologic sequelae not clear if acyclovir
  treatment alters course of mild meningitis

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HSV Congenital/Perinatal

• Intrauterine infection rare follows 10
  infection
• Perinatal infection
• 75 are due to HSV 2 acquired during delivery
• many women unaware they are infected 60 - 80
  have no signs or symptoms of genital herpes at
  time of labour (asymptomatic shedders)
• HSV-1 acquired from maternal genital, oral or
  breast lesions, paternal or other family member,
  or nosocomial infection from other infected babies

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HSV Congenital/Perinatal

• Perinatal Infections
• pregnancy is associated with state of
  immuno-suppression?? shedding, ??reactivation,
  ?recurrences
• subclinical infection in neonates is uncommon
• not all infants of infected mothers will become
  infected depends on 10 (30 50 risk) vs
  recurrent disease (1 3 risk)

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HSV Congenital/Perinatal

• Clinical manifestations of perinatal infection
• disseminated CNS disease (49)
• liver, lungs, eyes, CNS
• 80 - 85 mortality
• localized to CNS, skin, eyes, oral cavity (50)
• 10 - 40 mortality
• asymptomatic infection (1)

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HSV Congenital/Perinatal

• Treatment
• Mother - acyclovir relatively contraindicated
  during pregnancy
• Neonate - acyclovir if mother has active lesions
  or prolonged membrane rupture
• Prevention
• maternal history, surveillance
• if active lesions at time of delivery then
  C-section indicated

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Herpes Simplex Virus - Diagnosis

• History and physical examination
• Vesicle fluid culture, EM, immunofluorescence,
  molecular (e.g. PCR)
• Serology
• difficult to distinguish HSV-1 and HSV-2 no
  reliable IgM test
• seroprevalence
• cannot distinguish 1 infection from recurrent
  disease
• ? Value of type-specific serology

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Immunoglobulin Response in HSV Infection

• IgM Arrives approximately 7 days before IgG
• IgM can reappear during recurrences

Recurrences
IgM
IgG
Detectable Level
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HSV Serology

• Patients with Recurrent HSV Infection
• 65 only IgG
• 35 both IgG and IgM

• Patients with Primary Infection
• 18 -30 with both IgG and IgM antibodies

Type Specific Antibodies to HSV 1 and 2 Review
of Methodology. Herpes 19985 33-38 Ashley R.L.
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HSV Type-specific SerologyClinical Role?
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Why do we need to know who has HSV 2?

• A)To stop the epidemic spread of genital herpes.
  HSV is quickly and silently spreading at varying
  rates across Canada and not just in the high risk
  populations
• B)To permit high risk groups to be able to
  protect themselves better. HSV has been shown to
  increase the chance of acquiring HIV by two to
  three fold and accelerate the rate of HIV disease
  progression
• C)To identify women at risk of acquiring HSV in
  pregnancy endangering the baby. HSV is
  potentially fatal in infants if the mother is
  shedding virus at the time of delivery.
• D)To provide counseling HSV-2 infected patients
  can expect several outbreaks per year and are
  more likely to benefit from suppression therapy
  than HSV-1 patients
• E)To determine partner sero-status- 75 of source
  partners find out about their own infection only
  when their newly-infected partner is diagnosed

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When should we test for HSV 2?

• Symptomatic patients Use to supplement virus
  detection tests when
• Lesions are negative or not sampled for virus
• Recurring symptoms suggest atypical or
  undiagnosed herpes
• Lesions appear herpetic but may have other
  etiology
• High risk patients but not symptomatic
• Patient has history of symptoms
• Patients partner has genital herpes
• Patient has a history of other STDs
• Patient is at risk of HIV infection
• Pregnancy
• To screen for HSV-2 unrecognized infection
• To determine risk of acquiring infection
• To determine partners status for treatment and
  counseling

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Herpes Simplex Virus - Prevention and Treatment

• i) Supportive
• education, psychological support, analgesics,
  keep area clean and dry
• ii) Antiviral (Acyclovir / Famciclovir /
  Valacyclovir)
• topical, oral, intravenous
• all effective in 1 genital herpes - ??shedding /
  duration
• minimal effect on recurrent attacks
• pattern and natural history not affected
• suppressive (oral) therapy for severe and/or
  frequent attacks once stopped, episodes may
  recur
• iii) No vaccine

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Human herpes virus type 6 (HHV - 6)

• isolated in 1988
• roseola infantum - fever x 3 - 4 days resolves
  followed by rash
• many infections are asymptomatic
• diagnosis - clinical serology
• treatment is symptomatic
• latent within lymphoid tissue ? reactivation
  disease

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HHV-6 Roseola Infantum
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Common Childhood Infections
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Epstein Barr Virus (EBV)

• most childhood infections are asymptomatic
• teens, adults - infectious mono (kissing
  disease)
• incubation period 4 - 7 weeks
• spread by intimate contact with saliva
• fever, lymphadenopathy, fatigue, sore throat,
  hepatosplenomegaly, atypical lymphocytes
• resolves 2 - 3 wks but may take months
• latent in lymphoid tissue ? Reactivation disease
• associated with Burkitts lymphoma and
  naso-pharyngeal carcinoma

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Epstein Barr Virus (EBV)
Diagnosis monospot (heterophile
antibodies) serology IgM, IgG isolation -
not done Treatment treatment is supportive
protect spleen from trauma no vaccine
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Cytomegalovirus (CMV)

• Transmission
• 1) Sexual
• 2) Perinatal / Intrauterine
• 3) Blood / Blood product transfusion
• 4) Organ / tissue transplantation
• 5) Close contact
• most infections transmitted asymptomatically

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Cytomegalovirus (CMV) - Clinical Manifestations

• acute infection is usually asymptomatic or mild
  may present as mono-like illness and / or
  hepatitis
• severe disease in
• AIDS - 25 develop site or life - threatening
  disease
• - gt90 infected at autopsy
• Transplants - 20 - 60 develop infection
• Neonates - CMV isolated in urine of 1100
  infants

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Cytomegalovirus (CMV)

• Intrauterine (Congenital) Infections
• symptoms present in lt25 of infected infants
• cytomegalic inclusion disease (CID) - jaundiced,
  hepatosplenomegaly, petechial rash, microcephaly,
  cerebral calcifications, chorioretinitis
• may develop symptoms (hearing loss, behavioral
  changes, mental retardation) years later

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Cytomegalovirus (CMV)

• Diagnosis
• Culture - slow growing, may take weeks for virus
  to grow
• Electron microscopy - morphology of herpes
  viruses
• Immunofluoresence techniques
• Serology - IgM for acute infection
• - IgG for past infection
• PCR, DNA hybridization

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Cytomegalovirus (CMV)

• Treatment
• Immunocompetent patients
• None
• Immunocompromised patients
• Ganciclovir
• Foscarnet
• Prevention
• No vaccine