Title: Herpes Viruses
1Herpesviridae - 1
T. Mazzulli, MD, FRCPC Department of
Microbiology Mount Sinai Hospital
2Herpesviridae - Objectives
- To review the members of the Herpesviridae family
- To understand the concepts of primary infection,
latent infection and reactivation disease - To recognize the common clinical syndromes
associated with each virus and the principles of
management
3Herpesviridae 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)
4(No Transcript)
5Transmission Seroepidemiology of Herpesviridae
Straus SE. In Mandell, Douglas, Bennett (eds).
Principles and Practice of Infectious Diseases,
6th Ed. 20051756-1762
6Herpesviridae
- 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
7Herpes Simplex Viruses (HSV)
8Herpes 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
9Herpes 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
10Herpes 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
11Epidemiology 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
12Primary herpes, male
13Herpes, female
14Herpes cervicitis
15Herpes 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
16Herpes 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
17HSV Cold Sore
18HSV Cold Sore
19Recurrences 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)
20HSV Complications
- CNS infections
- Perinatal/Congenital
21Herpes 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
22Herpes Simplex Encephalitis
CT Scan
Autopsy
23Herpes 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
24Herpes 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
25HSV 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
26HSV 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)
27HSV 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)
28HSV 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
29Herpes 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
30Immunoglobulin Response in HSV Infection
- IgM Arrives approximately 7 days before IgG
- IgM can reappear during recurrences
Recurrences
IgM
IgG
Detectable Level
31HSV 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.
32HSV Type-specific SerologyClinical Role?
33Why 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
34When 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
35Herpes 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
36Human 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
37HHV-6 Roseola Infantum
38Common Childhood Infections
39Epstein 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
40Epstein Barr Virus (EBV)
Diagnosis monospot (heterophile
antibodies) serology IgM, IgG isolation -
not done Treatment treatment is supportive
protect spleen from trauma no vaccine
41Cytomegalovirus (CMV)
- Transmission
- 1) Sexual
- 2) Perinatal / Intrauterine
- 3) Blood / Blood product transfusion
- 4) Organ / tissue transplantation
- 5) Close contact
- most infections transmitted asymptomatically
42Cytomegalovirus (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
43Cytomegalovirus (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
44Cytomegalovirus (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
45Cytomegalovirus (CMV)
- Treatment
- Immunocompetent patients
- None
- Immunocompromised patients
- Ganciclovir
- Foscarnet
- Prevention
- No vaccine