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

Varicella Zoster Virus (VZV) highly contagious; >90% of cases occur in children <9 years of age infectious 2 days before until full crusting winter, spring; incubation period days airborne; direct contact with lesions subclinical infections are - uncommon immunity is lifelong but latent in nerve root ganglia  - reactivation (shingles / zoster)

Varicella Zoster Virus Transmission: Source InfectionExposed Non- Immune Acquires ChickenpoxChickenpox Zoster/ShinglesChickenpox

Varicella Zoster Virus A)Chickenpox -fever, irritability, vesicles spread over days majority uncomplicated - more severe in adults, pregnant women disseminated in immunocompromised patients 3 Clinical Syndromes:

7 VZV: Latency 1.Straus SE, Oxman MN. In: Freedberg IM, Eisen AZ, Wolff K, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 5 th ed. Vol 2. McGraw-Hill; 1999: Silverstein S, Straus SE. In: Arvin AM, Gershon AA, eds. Varicella-Zoster Virus: Virology and Clinical Management. Cambridge, UK: Cambridge University Press; 2000: Posterior column spinal cord Dorsal root ganglion Chickenpox rash Skin VZV establishes latency in the dorsal root ganglion VZV moves along the sensory nerve to the dorsal root ganglion

Complications from Varicella Case fatality rates (per 100,000 cases): – –Adults: 30 deaths – –Infants: 7 deaths – –Children (1 to 19 yrs): 1 – 1.5 deaths 37/53 (70%) chickenpox deaths from 1987 to 1996 occurred in those >15 yrs of age in Canada Immunocompromised Children: – –Dissemination in 30% – –Mortality in 7 to 10% CCDR Feb 2004:30

Varicella (Chickenpox) Pre-Vaccine: –4 million cases/yr in USA – 11,000 hospitalizations –Complications (175,000/yr): 2 o bacterial skin and soft tissue infections including invasive Group A Strep (40 to 60 fold increase), necrotizing fasciitis, toxic shock-like syndrome Otitis media, bacteremia, pneumonitis, osteomyelitis, septic arthritis, endocarditis Encephalitis, cerebellar ataxia, hepatitis Congenital Varicella (2%) CCDR, Feb 4, 2004:30; Galil et al. Pediatr Infect Dis J. 2002:21; Plotkin, Pediatr 1996:97(2)

Vaccine Preventable Deaths in Children and Adolescents from No. of deaths in patients <20 yrs of age MMWR 1998;47(18)

Varicella Zoster Virus B)Zoster (Shingles) - dermatomal distribution; reactivation of latent virus zoster infectious to others - they get chickenpox, not zoster scarring; post-herpetic neuralgia

Shingles: Risk Factors Advancing age 1,2 –Level of VZV-specific, cell-mediated immunity (CMI) naturally wanes with increasing age 2 –Severity of shingles increases with age 1 Immunosuppression 1 –HIV – AIDS 1 –Organ Transplants 1 –Malignances 1 –Immunosuppressive therapies 1 1. Gnann J et al. NEJM 2002; 347: Arvin A et al. NEJM 2005; 352:226-67

Incidence of Herpes Zoster by Age Johnson R. et al. JID (Suppl 2) S43-48 The incidence of herpes zoster increases significantly with age, with 67% of cases occurring in persons over 50 years of age.

Alberta Incidence Rates of HZ: Russell ML Epidemiology Infect. 2007: 1-6 Zoster rate is increasing, and this increase is accelerating. Alberta Public Varicella Vaccine Program Initiated

Shingles: Canadian Epidemiology Estimated ~30% lifetime risk of one VZV reactivation 1 ; ~50% if live to 80 years of age Estimated 129,882 cases of Shingles per year 1 ~90% of cases occur in immunocompetent people; >2/3 in patients >50 years of age 4 ~15% of shingles episodes will result in PHN – –19,865 episodes/year 2 – –31% in adults over 65 y.o. 2 1.Brisson M. et al. Epidemiol. Infect. 2001; 127: Brisson M. CIC Jung et al, Neurology 2004; 62: Straus SE, Oxman MN In: Freedberg IM, Eisen AZ, Wolff K, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 5th ed. Vol 2. New York, NY: McGraw-Hill;1999:

Shingles: Clinical Disease Vesicular rash: Healthy: unilateral (does not cross the midline) involving a single dermatome; heals within 4 weeks Immunocompromised: may disseminate Lesions usually crust over and heal by 4 weeks Acute pain: Pain & paraesthesia usually precede rash 40% of pts experience pain >4 days before rash May be sharp/stabbing/shooting/burning/throbbing Occurs in >90% of pts >60 yrs Oxman MN. In: Arvin AM, Gershon AA. Eds. Varicella-Zoster Virus, Virology and Clinical Management. Cambridge Press 2000

VZV: Reactivation Posterior column spinal cord Dorsal root ganglion Site of VZV replication Arvin AM. Varicella-zoster virus. In: Knipe DM, Howley PM, eds. Fields Virology. 4 th ed. Vol 2. New York, NY: Lippincott Williams & Wilkins; 2001: Straus SE, Oxman MN. Varicella and herpes zoster. In: Freedberg IM, Eisen AZ, Wolff K, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 5 th ed. Vol 2. New York, NY: McGraw-Hill; 1999:

Shingles: Dermatomal Distribution Region Frequency Thoracic 55% Cranial 25% Lumbar 14% Cervical 12% Sacral 3% Generalized 1% Dworkin RH et al. In: Watson CPN, Gerson AA, eds. Herpes Zoster and Postherpetic Neuralgia, 2 nd Revised and Enlarged Edition. Vol 11. Amsterdam, The Netherlands: Elsevier Science B.V. 2001;

Shingles: Complications NeurologicOphthalmicCutaneousDissemination

Shingles: Neurologic Complications Post-herpetic neuralgia (PHN) (10 – 20%): – –Pain along cutaneous nerves persisting >30 days after lesions have healed – –Most common complication; Allodynia; May lead to depression 1 – –30 to 50% in adults over 65 y.o.; lasts >6 mos in 30-50% 3 Motor neuropathies (1- 5%): – –Cranial: Ramsey Hunt syndrome 2 (shingles around the ear with loss of taste in the anterior 2/3 of tongue & ipsilateral facial palsy) – –Peripheral: diaphragmatic paralysis & lower motor paresis 2 Other: Meningitis, Encephalitis (0.1 – 0.2%) 1.Gilden, D. Herpes 2004; 11(suppl):89A-94A; 2. Gilden DH In: Arvin AM, Gershon AA, eds. Varicella-Zoster Virus,Virology and Clinical Management. Cambridge Press 2000; ; 3. Brisson M. CIC 2004

Kost R et al. N Engl J Med. 1996;355: Percent of patients reporting pain Age (years) ≥79 >1 yr <1 mo mo mo Prevalence of PHN and Duration of Pain Associated With PHN Increase With Age

Shingles: Ophthalmic Complications Herpes Zoster Ophthalmicus: 10% of shingles cases affect the Ophthalmic Branch of the Trigeminal Nerve (forehead and upper face) 93% suffer acute pain, which persists at 6 months in 1/3 of cases (70% of cases > 80 years old) 2 All layers of the eye may be affected: conjunctivitis (mainly), iritis, keratitis, uveitis, optic neuritis, glaucoma, corneal scarring 1 1.Opstelten, W. BMJ 2005; 331: Pavan-Langston Ophthalmic zoster in herpes zoster and postherpetic neuralgia, 2 nd revised and enlarged edition 2001:

Shingles: Cutaneous Complications Bacterial superinfection – –2% of cases – –Most commonly due to Staphylococcus aureus and Group A Streptococcus – –Can lead to cellulitis and scarring Lycka BAS et al. Dermatologic aspects of herpes zoster in herpes zoster and postherpetic neuralgia, 2 nd revision and enlarged edition 2001;

Shingles Complications: Dissemination Cutaneous dissemination – –Definition: 20 lesions outside the principally affected dermatome – –Occurs in 2% of shingles cases Visceral dissemination – – Pneumonia, hepatitis, encephalitis – – Often associated with cutaneous dissemination – – Occurs in 15-30% of immunocompromised hosts – – Potentially fatal Lycka BAS et al. Dermatologic aspects of herpes zoster in herpes zoster and postherpetic neuralgia, 2 nd revision and enlarged edition 2001;

Varicella Zoster Virus C)Varicella in pregnancy and newborn 1.Congenital: uncommon; 2% of fetuses borne to mothers with chickenpox in 1st 20 wks limb hypoplasia, CNS retardation, muscular atrophy 2.Perinatal: Risk if mother develops chickenpox 5 days before or up to 48 hours postpartum High risk of disseminated disease with multi-organ involvement Mortality as high as 30%

Congenital Varicella

Varicella Zoster Virus Diagnosis: clinical diagnosis serology for immune status direct detection - EM, immunofluorescence isolation - vesicular fluid

Varicella: Diagnosis Test Sensitivity (%) Specificity (%) Immunofluorescent Antigen 77 to to 76 PCR 94 to VZV specific IgM 48 to 61 - Virus Culture Laboratory Diagnosis: Mounsey AL. Amer Fam Physician 2005;72(6)

Herpes Zoster: Approach to Treatment Antivirals: – –Acyclovir – –Famciclovir – –Valacyclovir Supportive Care General: – –Topical (eg. Calamine lotion), Analgesics, Antidepressants, ? steroids Volpi A et al. Am J Clin Dermatal. 2005; 6:

Varicella Zoster Virus Treatment: Chickenpox/zoster – ACV can be used in normal and immunocompromised host Normal host with chickenpox: shortens duration by 1 day, number of lesions by 25% and decreases constitutional symptoms by 1/3 Started within 24 hours Normal host with zoster: Reduces acute neuritis and accelerates cutaneous healing

Shingles: Antiviral Treatment Valacyclovir: 1000 mg po tid x 7 d – –PHN in pts >50 yrs; median duration of pain = 38 d vs 51 d with acyclovir (p = 0.001) Famciclovir: 500 mg po q8h x 7 d – –PHN in pts >50 yrs; median duration of PHN = 63 d vs 163 d with placebo (p = 0.004) Acyclovir: 800 mg po 5x/d x 7 d – –Median time to pain resolution 41 d vs 101 d in those >50 yrs; 2-fold acceleration of pain resolution and decrease PHN at 3 & 6 months compared to placebo J Microbiol Immunol Inf 2004;37:75; Antimicrob Agents Chemother 1995;39:1546; Clin Infect Dis 1996;22:341

Percentage of patients with pain Valacyclovir (n=297) Famciclovir (n=300) Upon or after rash healing86%87% At 1 month post rash64%62% At 3 months post rash32%34% At 6 months post rash19% Tyring SK et al. Antiviral therapy for herpes zoster. Arch Fam Med 2000;9: Antiviral Therapy for Herpes Zoster Randomized, Controlled Clinical Trial of Valacyclovir and Famciclovir Therapy in Immunocompetent Patients 50 Years of Older Treatment Groups – Randomized to valacyclovir (1g TID) or famciclovir (500mg TID) for 7 days. Mean Age 68  Follow-up – 24 weeks Main Outcome Measures: Assess resolution of zoster-associated pain and PHN, rash healing, and treatment safety.

Shingles: Antiviral Therapy Patients who derive the most benefit from treatment include: – –Adult patients ≥50 years of age 1 – –Patients with severe acute shingles 2 – –Patients with shingles ophthalmicus 2 – –Immunocompromised patients 2 1.Strauss SE, Oxman MN. In: Freedberg IM, Eisen AZ, Wolff K et al, eds. Fitzpatrick’s Dermatology in General Medicine. 5th ed. Vol 2. New York, NY: McGraw-Hill; 1999: Gnann JW, Whitley RJ. N Engl J Med. 2002;347:340-46

Varicella Zoster Virus Treatment: –Antiviral therapy for zoster should be started within 72 hours; After 72 hrs - use in elderly, patients with severe acute pain, & immunocompromised Use of corticorsteroids in treatment of zoster remains controversial Aspirin is contraindicated in persons with varicella because of the risk of Reye’s syndrome Valacyclovir and Famciclovir licenced for zoster

Varicella Zoster Virus Prevention: Varicella zoster immune globulin (VZIG); prolongs incubation period to 28 days; given within 96 hr of exposure

Varicella Zoster Virus Prevention: Vaccines: Varicella (chickenpox) vaccine Zoster (shingles) vaccine

Varicella Zoster Virus Prevention: Varicella Vaccines: live attenuated virus >95% antibody response; 85% protection at least 10 years of protection

Varicella Vaccination 2 formulations available in Canada since 2002: – –Varivax III and Varilrix Live attenuated vaccines (Oka strain) Minimum potency ranges from 1350 to 1995 pfu Subcutaneous Can be given with MMR, DTaP, IPV, Hib, pneumococcal conjugate-7, meningococcal C- conjugate, Hepatits B, and Influenza vaccines using separate syringes at separate sites 2 doses being recommended

Varicella Vaccination: Immunogenicity Varivax IIIVarilrix 1 dose (12 m to 12 yrs): 5 years 7 years 1 dose: 12 to 36 m - >98% 12 to 36 m - >98% 5 to 7 yrs – 6 weeks Antibodies persist for 7 yrs in those vaccinated 12 to 15 m 2 doses (>13 yrs, 4 to 8 wks apart): 75% to 95% and 4 to 6 wks after 1 st and 2 nd dose respectively; 5 years after 2 doses 2 doses: 6 weeks 1 year

Varicella Vaccines: Efficacy Clinical breakthrough: – –70 – 90% vaccine efficacy for varicella of any severity and 93 – 100% for moderate to severe disease – –Majority occur in day care and schools Herpes Zoster: – –Varivax – 14 cases/100,000 person-years (compared to 68/100,000 after natural infection) – –Varilrix – 7.7 cases per 10,000 child-months of observation Mortality: – –56% decrease compared to pre-vaccine era CCDR Feb 2004:30; Davis M. Expert Rev Vaccines 2006:5(2)

Varicella Vaccine: Indications Healthy children >12 mos (1 dose) – –Publicly funded for 1yr old OR 5 yr old susceptible children (OR high risk persons) Healthy individuals >13 yrs (2 doses at least 28 days apart) – –If unknown or negative history of varicella, may check serology as 80% are immune despite negative history Post-vaccination serologic testing is NOT recommended Women should avoid pregnancy for 1 month after vaccination CCDR Feb 2004:30

Varicella Vaccine: Indications Susceptible, immunocompromised individuals (up to 2 doses): – –Contraindicated in T-cell immunodeficiency; OK for those with humoral, neutrophil, complement deficiencies and asplenia – –Varilrix may be used in children with acute lymphocytic leukemia (ALL) in remission – –May be used in those taking 12 mos with asymptomatic HIV CCDR Feb 2004:30

Zoster (Shingles) Vaccine

Arvin A, NEJM 352:2266, 2005 Varicella Exposure Silent reactivation? Zoster vaccination Zoster Threshold Varicella Herpes Zoster Age Aging & Zoster Risk VZV T-cells Arvin A. Aging, Immunity, and the varicella-zoster virus. N Engl J Med 2005;352(22):

Zoster (Shingles) Vaccine Vaccine type: – –Live attenuated OKA/MERCK VZV vaccine (Zoster Vaccine) Administration: – –Subcutaneaous injection of 0.5 ml Vaccine potency: – –Range from 18,700 to 60,000 PFU – –Median potency: 24,600 PFU – –Minimal potency of the Zoster Vaccine at least 14 times greater than the Varicella live attenuated Oka/ Merck VZV vaccine.

Shingles Vaccine Prevention Study Double-blind, placebo-controlled, multi-centered trial, 22 sites - -Study timeline: Nov-1998 to Apr ,546 subjects ≥ 60 years of age - Age-stratified (60 to 69 years, ≥70 years) - -90% had one of more underlying medical conditions Randomized 1:1 to receive VZV vaccine or placebo Median 3.12 years of surveillance for HZ Oxman MN. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. New Eng J Med 2005;352(22):

Shingles Vaccine Prevention Study Confirmed cases: 315 in vaccine group vs 642 in placebo group PCR positive for VZV DNA (wild-type) in 93.3% and 93.5% respectively [NO vaccine strain DNA detected in any patient with suspected HZ] Vaccine effectiveness: – –Herpes Zoster: 51% – –Post-herpetic neuralgia: 61.1% – –Burden of illness: 66.5% Oxman MN. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. New Eng J Med 2005;352(22):

Number Needed to Vaccinate (NNV): Comparison to other Adult Vaccines Age at VaccinationAnnual Incidence of Disease* Vaccine Efficacy Duration of Protection NNV to Prevent 1 Case Zoster vaccine for HZ >60 yrs of age 8.951%5 yrs~44 Zoster Vaccine for PHN >60 yrs of age 1.5 to 2.367%5 yrs~ Influenza vaccine >50 yrs of age 4060%1 yr~42 Pneumococcal vaccine >50 yrs of age 0.5 to 1 t 60%5 yrs~ *Incidence rate per 1,000; t Annual incidence rate in >65 yrs of age Kelly H et al. Vaccine 2004:22(17-18)

Prevention of Herpes Zoster: ACIP Recommendations Routine vaccination of all persons aged  60 years with 1 dose of zoster vaccine Persons who report a previous episode of zoster can be vaccinated Persons with chronic renal failure, diabetes mellitus, rheumatoid arthritis and CPD can be vaccinated Vaccination of those <60 years is probably safe and effective, but data are insufficient to recommend MMWR 2008;Vol. 57:1-30

Prevention of Herpes Zoster: ACIP Recommendations Simultaneous Administration with Other Adult Vaccines: Immunogenicity of zoster vaccine and trivalent inactivated influenza not compromised when given together – –(separate needles & sites) In general, simultaneous admin. of most widely used live, attenuated and inactivated vaccines has not resulted in impaired immune response or an increase rate of adverse events – –Zoster vaccines can be given with other indicated vaccines during the same visit Td, and Tdap vaccines: separate syringe at a different site No Data exists on administration of zoster vaccine with other vaccines routinely recommended for persons  60 years MMWR: Prevention of Herpes Zoster: ACIP Recommendations: 2008:Vol: 57:1-30. MMWR 2008;Vol. 57:1-30