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

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

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)

Transmission & Seroepidemiology of Herpesviridae Straus SE. In: Mandell, Douglas, & Bennett (eds). Principles and Practice of Infectious Diseases, 6th Ed. 2005;1756-1762

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

Herpes Simplex Viruses (HSV)

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

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

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

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

Primary herpes, male

Herpes, female

Herpes cervicitis

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

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

HSV – Cold Sore

HSV – Cold Sore

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)

HSV Complications CNS infections Perinatal/Congenital

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

Herpes Simplex Encephalitis CT Scan Autopsy

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%

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

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

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)

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%)

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

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

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

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 1998:5 33-38 Ashley R.L.

HSV Type-specific Serology: Clinical Role?

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

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

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

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

HHV-6: Roseola Infantum

Common Childhood Infections

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 Burkitt’s lymphoma and naso-pharyngeal carcinoma

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

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

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 - 20 - 60% develop infection Neonates - CMV isolated in urine of 1:100 infants

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

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

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