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

2. Herpesviridae - 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

3. 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)

5. Transmission & Seroepidemiology of Herpesviridae
Straus SE. In: Mandell, Douglas, & Bennett (eds). Principles and Practice of Infectious Diseases, 6th Ed. 2005;

6. 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

7. Herpes Simplex Viruses (HSV)

8. 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

9. 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 days

10. Herpes Simplex Virus - Clinical Manifestations
HSV-2 Primary Infection:
incubation period 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

11. 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

12. Primary herpes, male

13. Herpes, female

14. Herpes cervicitis

15. 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 %
recurrent genital lesions in %
frequency depends on sex, HSV type, titre of neutralizing antibody
precipitating factors include: sunlight, fever, local trauma, menstruation, emotional stress

16. Herpes Simplex Virus - Clinical Manifestations
Recurrent Infections:
i) Herpes labialis (“cold sore”) - pain, burning, itching 6 hrs ( hrs) before lip lesion
vesicles to ulcer/crust in 48 hrs; healing within days
ii) Genital lesions -
pain, itching, burning for several hours before vesicles appear; healing within days

17. HSV – Cold Sore

18. HSV – Cold Sore

19. 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 <1
HSV-2 recurrence rates vary widely across people:
26% women and 8% of men have none in first year
14% women and 26% men: >10 recurrences
Recurrence rates trend down (frequency and severity) over the long term
HSV-2 shedding: 5-32% of days (40% subclinical)

20. HSV Complications
CNS infections
Perinatal/Congenital

21. 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

22. Herpes Simplex Encephalitis
CT Scan
Autopsy

23. 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%

24. 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

25. 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; % 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

26. 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)

27. HSV – Congenital/Perinatal
Clinical manifestations of perinatal infection:
disseminated ± CNS disease (49%)
liver, lungs, eyes, CNS
% mortality
localized to CNS, skin, eyes, oral cavity (50%)
% mortality
asymptomatic infection (1%)

28. 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

29. 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

30. Immunoglobulin Response in HSV Infection
IgM Arrives approximately 7 days before IgG
IgM can reappear during recurrences
Recurrences
IgM
IgG
Detectable Level

31. 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 1998: Ashley R.L.

32. HSV Type-specific Serology: Clinical Role?

33. 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

34. 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
Patient’s 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 partner’s status for treatment and counseling

35. 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

36. Human herpes virus type 6 (HHV - 6)
isolated in 1988
roseola infantum - fever x days: resolves followed by rash
many infections are asymptomatic
diagnosis - clinical; serology
treatment is symptomatic
latent within lymphoid tissue; ? reactivation disease

37. HHV-6: Roseola Infantum

38. Common Childhood Infections

39. Epstein Barr Virus (EBV)
most childhood infections are asymptomatic
teens, adults - infectious mono (“kissing disease”)
incubation period weeks
spread by intimate contact with saliva
fever, lymphadenopathy, fatigue, sore throat, hepatosplenomegaly, atypical lymphocytes
resolves wks but may take months
latent in lymphoid tissue; ? Reactivation disease
associated with Burkitt’s lymphoma and naso-pharyngeal carcinoma

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

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

42. 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
- >90% infected at autopsy
Transplants % develop infection
Neonates - CMV isolated in urine of 1: infants

43. Cytomegalovirus (CMV)
Intrauterine (Congenital) Infections:
symptoms present in <25% 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

44. 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

45. Cytomegalovirus (CMV)
Treatment:
Immunocompetent patients:
None
Immunocompromised patients:
Ganciclovir
Foscarnet
Prevention:
No vaccine