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 10 - 21 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:Transmission:

Source Infection Exposed Non-Immune Acquires

ChickenpoxChickenpox ChickenpoxChickenpox

Zoster/ShinglesZoster/Shingles ChickenpoxChickenpox

Varicella Zoster Virus

A) Chickenpox - fever, irritability, vesicles spread over 4 - 7 days

• majority uncomplicated - more severe in adults, pregnant women

• disseminated in immunocompromised patients

3 Clinical Syndromes:

77

VZV: Latency

1. Straus SE, Oxman MN. In: Freedberg IM, Eisen AZ, Wolff K, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 5th ed. Vol 2. McGraw-Hill; 1999:2427-50

2. Silverstein S, Straus SE. In: Arvin AM, Gershon AA, eds. Varicella-Zoster Virus: Virology and Clinical Management. Cambridge, UK: Cambridge University Press; 2000:123-141

Posterior column spinal cord

Dorsal root ganglion

Chickenpox rash

Skin

VZV establishes latency in the dorsal root ganglion

VZV moves along the sensory nerveto 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 CanadaImmunocompromised 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 hospitalizations4 million cases/yr in USA – 11,000 hospitalizations– Complications (175,000/yr):Complications (175,000/yr):

22oo bacterial skin and soft tissue infections including bacterial skin and soft tissue infections including invasive Group A Strep (40 to 60 fold increase), invasive Group A Strep (40 to 60 fold increase), necrotizing fasciitis, toxic shock-like syndromenecrotizing fasciitis, toxic shock-like syndromeOtitis media, bacteremia, pneumonitis, osteomyelitis, Otitis media, bacteremia, pneumonitis, osteomyelitis, septic arthritis, endocarditisseptic arthritis, endocarditisEncephalitis, cerebellar ataxia, hepatitisEncephalitis, cerebellar ataxia, hepatitisCongenital Varicella (2%)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 1990 - 1994

0

50

100

150

200

250

Chickenpox Deaths from otherVaccine-preventable

diseases

Diphtheria (1)

Rubella (4)

Hib (12)

Cong Rubella (12)

Hepatitis A (15)

Pertussis (32)

Hepatitis B (39)

Measles (70)

No

. o

f d

eath

s in

pat

ien

ts <

20

yrs

of

age

MMWR 1998;47(18)

239 185

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 ageAdvancing age1,21,2

– Level of VZV-specific, cell-mediated immunity (CMI) Level of VZV-specific, cell-mediated immunity (CMI) naturally wanes with increasing agenaturally wanes with increasing age22

– Severity of shingles increases with ageSeverity of shingles increases with age11

ImmunosuppressionImmunosuppression11

– HIV – AIDSHIV – AIDS11

– Organ TransplantsOrgan Transplants11

– MalignancesMalignances11

– Immunosuppressive therapiesImmunosuppressive therapies11

1. Gnann J et al. NEJM 2002; 347:340-462. Arvin A et al. NEJM 2005; 352:226-67

Incidence of Herpes Zoster by Age

Johnson R. et al. JID 2007 11(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: 1986 - 2002

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 reactivation1; ~50% if live to 80 years of age

Estimated 129,882 cases of Shingles per year1

~90% of cases occur in immunocompetent people; >2/3 in patients >50 years of age4

~15% of shingles episodes will result in PHN

– 19,865 episodes/year2

– 31% in adults over 65 y.o.2

1. Brisson M. et al. Epidemiol. Infect. 2001; 127:305-14 2. Brisson M. CIC 20043. Jung et al, Neurology 2004; 62:1545-514. 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;1999:2427-50

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. 4th ed. Vol 2. New York, NY: Lippincott Williams & Wilkins; 2001:2731-67Straus SE, Oxman MN. Varicella and herpes zoster. 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; 1999:2427-50

Shingles: Dermatomal Distribution

RegionRegion Frequency Frequency

ThoracicThoracic 55%55%

CranialCranial 25%25%

LumbarLumbar 14%14%

CervicalCervical 12%12%

SacralSacral 3%3%

GeneralizedGeneralized 1%1%

Dworkin RH et al. In: Watson CPN, Gerson AA, eds. Herpes Zoster and Postherpetic Neuralgia, 2nd Revised and Enlarged Edition. Vol 11. Amsterdam, The Netherlands: Elsevier Science B.V. 2001; 39-64

Shingles: Complications

NeurologicNeurologic

OphthalmicOphthalmic

CutaneousCutaneous

DisseminationDissemination

Shingles: Neurologic ComplicationsPost-herpetic neuralgia (PHN) (10 – 20%):

– Pain along cutaneous nerves persisting >30 days after lesions have healed

– Most common complication; Allodynia; May lead to depression1

– 30 to 50% in adults over 65 y.o.; lasts >6 mos in 30-50%3

Motor neuropathies (1- 5%): – Cranial: Ramsey Hunt syndrome2 (shingles around the ear

with loss of taste in the anterior 2/3 of tongue & ipsilateral facial palsy)

– Peripheral: diaphragmatic paralysis & lower motor paresis2

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; 299-316; 3. Brisson M. CIC 2004

Kost R et al. N Engl J Med. 1996;355:32-42.

Perc

en

t of

pati

en

ts

rep

ort

ing

pain

Age (years)

0

100

80

60

40

20

0-19 20-29 30-39 40-49 50-59 60-69 ≥79

>1 yr

<1 mo

6 - 12 mo

1 - 6 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 scarring1

1. Opstelten, W. BMJ 2005; 331:147-1512. Pavan-Langston Ophthalmic zoster in herpes zoster and postherpetic neuralgia, 2nd

revised and enlarged edition 2001: 119-129

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,2nd revision and enlarged edition 2001; 97-106

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,2nd revision and enlarged edition 2001; 97-106

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

TestTest Sensitivity (%)Sensitivity (%) Specificity (%)Specificity (%)

Immunofluorescent Immunofluorescent Antigen Antigen

77 to 8277 to 82 70 to 7670 to 76

PCRPCR 94 to 9594 to 95 100100

VZV specific IgMVZV specific IgM 48 to 6148 to 61 --

Virus CultureVirus Culture 2020 100100

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: 317-25

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 healing 86% 87%

At 1 month post rash 64% 62%

At 3 months post rash 32% 34%

At 6 months post rash 19% 19%

Tyring SK et al. Antiviral therapy for herpes zoster. Arch Fam Med 2000;9:863-9.

Antiviral Therapy for Herpes ZosterRandomized, 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 age1

– Patients with severe acute shingles2

– Patients with shingles ophthalmicus2

– Immunocompromised patients2

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; 1999:2427-50

2. Gnann JW, Whitley RJ. N Engl J Med. 2002;347:340-46

Varicella Zoster Virus

Treatment:– Antiviral therapy for zoster should be started within Antiviral therapy for zoster should be started within

72 hours; After 72 hrs - use in elderly, patients with 72 hours; After 72 hrs - use in elderly, patients with severe acute pain, & immunocompromisedsevere 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 III Varilrix1 dose (12 m to 12 yrs):

98% @ 5 years

96% @ 7 years

1 dose:1 dose:

12 to 36 m - >98%12 to 36 m - >98%

5 to 7 yrs – 97% @ 6 weeks5 to 7 yrs – 97% @ 6 weeks

Antibodies persist for 7 yrs in those Antibodies persist for 7 yrs in those vaccinated 12 to 15 mvaccinated 12 to 15 m

2 doses (>13 yrs, 4 to 8 wks apart):

75% to 95% and 99% @ 4 to 6 wks after 1st and 2nd dose respectively;

97% @ 5 years after 2 doses

2 doses:

100% @ 6 weeks

96% @ 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 recommendedWomen 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 <2 mg prednisone/kg daily to a maximum of 20 mg/day for <2 wks and in children >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

VZVT-cells

Arvin A. Aging, Immunity, and the varicella-zoster virus. N Engl J Med 2005;352(22):2266-7.

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-2004

38,546 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):2271-84.

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):2271-84.

Number Needed to Vaccinate (NNV):Comparison to other Adult Vaccines

Age at Vaccination Annual Incidence of

Disease*

Vaccine Efficacy

Duration of Protection

NNV to Prevent 1

Case

Zoster vaccine for HZ >60 yrs of age

8.9 51% 5 yrs ~44

Zoster Vaccine for PHN >60 yrs of age

1.5 to 2.3 67% 5 yrs ~130-200

Influenza vaccine >50 yrs of age

40 60% 1 yr ~42

Pneumococcal vaccine >50 yrs of age

0.5 to 1t 60% 5 yrs ~335-670

*Incidence rate per 1,000; tAnnual 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