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ACOFP / AOA’s 122nd Annual Osteopathic Medical Conference & Exposition

OCTOBER 7 - 10PHILADELPHIA, PENNSYLVANIA29.5 Category 1-A CME credits anticipated

OMED 17®

Joint Session with ACOFP and Cleveland Clinic: Managing Chronic Disease

Herpes Zoster: Diagnosis, Treatment and Prevention

Leonard Calabrese, DO

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Herpes Zoster: Diagnosis, Treatment and PreventionHerpes Zoster: Diagnosis, Treatment and Prevention

Leonard Calabrese

Professor of Medicine

Cleveland Clinic Lerner College of Medicine

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Herpes Zoster: Diagnosis, Treatment and PreventionHerpes Zoster: Diagnosis, Treatment and Prevention

• Biology & Epidemiology

• Clinical Aspects

• Treatment and prevention

Varicella Zoster VirusVaricella Zoster Virus

• Family: herpesviridae

• Subfamily: alpha herpesviridae

• Ubiquitous

• 99+% of adults have immunologic memory

• Transmission: airborne; via fomites from skin lesions

• 2 clinical forms:- Varicella (primary)

- Herpes zoster (reactivation)

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HistoryHistory

• Molecular link between VZV and HZ first demonstrated by Stephen Straus (NEJM 1984)

• Latency in dorsal root ganglia molecularly demonstrated by Donald Gilden (NEJM 1990)

Straus SE., et al. Endonuclease analysis of viral DNA from varicella and subsequent zoster infections in the same patient. NEJM 1984;311:1362-4.Mahalingham, et al. Latent varicella zoster viral DNA in human trigeminal and thoracic ganglia. NEJM 1990;323:627-31.

IR1000 PYs

Rough estimates based on multiple studies expressed as cases per 1000 pt/yrs

GENERAL RISKS –AGE, F>M, trauma, recurrent 2-4%

Incidence increasing globally over 50 years

In the USA alone 1 million cases/yr

Lifetime risk is about 20-30% with a 50% likelihood if survive to 85 yoa

Patients with IMIDS are 2 x the risk of

immunocompetent patients

Risk of HZ50

40

30

20

10

02-3

411 10

6-3239

45

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Incidence of HZ by Age Category1945‐2007*

0

2

4

6

8

10

12

1945‐49 1950‐60 1980‐1989 1990‐1999 2000‐2007

 <50 y 50‐59 y 60‐69 y

Cases per 1000 Person‐

Years

*Population includes adults and children residing in Olmsted County, MN. 

Kawai K, et al. Clin Infect Dis. 2016;63:221‐226.

HZOI? Or Not?

HZOI? Or Not?

Ann Rheum Dis. 2015 Dec;74(12):2107-16. doi: 10.1136/annrheumdis-2015-207841. Epub 2015 Sep 22.

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Diagnosis & TreatmentDiagnosis & Treatment

ClinicalClinical• Prodrome

- Pain, itching, paresthesias- dysesthesias, allodynia

• Rash- Papules vesicles- Scab over in 7-10 days

• Limited to 1-3 dermatomes• In most, resolution of skin lesions

accompanied by decreased pain• Complete resolution of pain in 4-6 weeks

Prodrome

(2-3 d)

Vesicles*

(3-7 d)

Pustular Lesions

(4-6 d)

Crusting of Lesions

(7-10 d)

Resolution of Rash

(2-4 wk)

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DiagnosisDiagnosis• Classic presentation with vesicular, dermatomal rash and

neuralgic pain

• Papules to vesicles; 7-10 days’ 1-3 dermatomes

• Complete resolution 4-6 weeks

• Laboratory testing

- For difficult diagnosis

- PCR: high sensitivity and specificity

PCR, polymerase chain reaction.Schmader KE, et al. Clin J Pain. 2007;23:490-496.

Areas Typically Affected by HZ

By Grant, John Charles Boileau ‐ An atlas of anatomy, by regions, 1962.Public Domain,https://commons.wikimedia.org/w/index.php?curid=30017222. 

By Henry Vandyke Carter ‐ Henry Gray (1918)Anatomy of the Human Body: Gray's Anatomy, Plate 784. Public Domain, https://commons.wikimedia.org/w/index.php?curid=531758.

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Diagnostic ChallengesDiagnostic Challenges

• Prodromal pain may suggest other conditions, e.g., myocardial infarction, cholecystitis, appendicitis, migraine, trigeminal neuralgia

• Skin manifestations may be confused with HSV, contact dermatitis, impetigo, folliculitis, CA-MRSA, fungal infections

• Atypical HZ in immunized individuals

• HZ sine Herpete (2.4%) (Hato Ann Neurol 2000)

HSV, herpes simplex virus; CA-MRSA, community-associated methicillin-resistant Staphylococcus aureus.

Neurologic Ophthalmic• PHN• Motor neuropathy• Cranial palsy• Encephalitis• Transverse myelitis

• Stroke*

• Stromal keratitis• Iritis• Retinitis• Visual impairment• Episcleritis• Keratopathy

Cutaneous Visceral• Bacterial superinfection• Permanent scarring/changes in

pigmentation

• Pneumonitis• Encephalitis• Hepatitis

Complications of Acute HZComplications of Acute HZ

CDC. 2016. http://www.cdc.gov/shingles/hcp/clinical-overview.html.Schmader K. Clin Geriatr Med. 2016;539-553. Whitley R, et al. J Infect Dis. 1999;175:9-15.Forbes HJ, et al. Pain. 2016;157:30-54.CDC. 2016. http://www.cdc.gov/shingles/hcp/clinical-overview.html.Calabrese L et al Arth Rheum 2017

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PHN: Rates Increase with Age*PHN: Rates Increase with Age*

55

10

1720

0

5

10

15

20

25

*Data from adults 22 y residing in Olmsted County, MN.

Yawn BP, et al. Mayo Clin Proc. 2007;82:1341-1349.

Age (y)

Per

cent

of

patie

nts

with

pai

n P

ersi

stin

g

90

da

ys

6

17

0

5

10

15

20

<65 65+Age (y)

Per

cent

of

patie

nts

with

pai

n P

ersi

stin

g

90

da

ys

Severity of HZ and Duration of Chronic Pain inAdults Ages  50 y

ZAP, zoster‐associated pain.

RiskGroup

Patient Characteristics at Baseline

1 • No or mild pain and 20 lesions 

2 • No or mild pain and 21–46 lesions or

• Moderate pain and 20 lesions

3 • No or mild pain and 47 lesions or

• Moderate pain and 21 lesions or

• Severe pain and <47 lesions

FromWhitley RJ, et al. Herpes zoster: risk categories for persistent pain. Journal of Infectious Diseases. 1999, 179 (1):9‐15, by permission of the Infectious Diseases Society of America.

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Other Complications of HZ

• Zoster ophthalmicus

• Bacterial superinfection of HZ lesions

• Cranial and peripheral nerve palsies

• Disseminated zoster

• Visceral involvement

• Stroke

• Myocardial infarctionWhitley R, et al. J Infect Dis. 1999;175:9‐15.Forbes HJ, et al. Pain. 2016;157:30‐54.CDC. 2016. http://www.cdc.gov/shingles/hcp/clinical‐overview.html. 

HZ and StrokeOlder Era

HZ and StrokeOlder Era

• Children: 1/15,000 varicella infections associated with stroke within 12 months

• HZ of Cranial Nerve V (HZO) associated with rare episodes of ‘contralateral hemiplegia’ weeks to months following HZ with evidence of direct vascular invasion

• Severely immunocompromised individuals may experience ischemic and hemorrhagic events with angiitis and evidence of direct viral invasionLiesegang AA Opth 2008

Horian et al Sem Ped Neurol 2012Grose,C Ped Inf Dis J 2010

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HZ and StrokeNew Era >2009HZ and StrokeNew Era >2009

• 2009 Kang et al (Taiwan National Health Research Database) found in 7760 HZ cases an adjusted hazard rate for stroke (1 yr follow up) of 1.31

• Six subsequent epidemiologic studies from Taiwan, Denmark, and UK each revealed significant associations with stroke following HZ ranging from 1.26 to 4.52 with varying influences: type of HZ, time of follow up, antiviral therapy, age, and CVD confounders

• No study has specifically examined immunosuppressed individuals for the association of stroke and HZ Kang et al Stroke 2009

Lin Neurology 2010Sreenivasan Plos One2013

Breuer Neurology 2014 Langan CID 2014

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Increased risk of stroke of 1.4- 3.3 (HR in the first month after HZ

Treatment of Acute HZ (Non Complex)Treatment of Acute HZ (Non Complex)

• Immunocompromised patients- Antiviral Therapy in ALL Patients Regardless if > 72hrs

• Acyclovir 800mg 5 x day 7 days

• Valacyclovir 1Gr 3x day 7 days

• Famciclovir 500mg 3x day x 7 days

• Brivudin

- Reduce pain, promote healing, reduce shedding, PHN? (Cochrane data base 2009)

- Treat Pain• Short acting narcotics, glucocorticoids(60mg prednisone with

10 day taper Whitely et al Ann Int Med 1996)

• Other neuroleptic meds- tricyclics, gabapentin etc

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Treatment Complex ZosterTreatment Complex Zoster• Hospitalization & IV antivirals

- Complex cases – disseminated, CNS, visceral

• Herpes Zoster Opthalmicus- Absolute indication for anti-virals, PO in uncomplicated forms

- With ocular involvement ophthalmology consultation essential

- Severe HZO hospitalization and IV anti-virals

• PHN – complex pain management

Inn the Clinics Herpes Zoster Ann Int Med 2011Sauerbrei A et al Eur J Clin Micro Infect Dis 2016

PreventionPrevention

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Date of download: 3/5/2013

Copyright © The American College of Physicians. All rights reserved.

From: Recommended Adult Immunization Schedule: United States, 2017*

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Cell‐Mediated Immunity to VZVDecreases with Age

10

12

14

16

18

20

20‐2930‐3940‐4950‐5960‐69

Skin Test Results

60.0

80.0

100.0

120.0

ELISPOT Count

Diameter 

(mm)

Age Group (y)

Age Group (y)

ELISPOT: interferon‐ enzyme‐linked immunospot. 

Sadaoka K, et al. J Infect Dis. 2008; 198:1327‐1333.

Number

Herpes Zoster Vaccine: dosage and Administration

Herpes Zoster Vaccine: dosage and Administration

• (Zoster Vaccine Live [OKa/Merck]) is a lyophilized preparation of the Oka/Merck strain of live, attenuated VZV

• For subcutaneous administration

• Administered in a single dose of 0.65 mL

• Stored frozen

• Should be reconstituted immediately upon removal from freezer

• Diluent should be stored separately

• Discard reconstituted vaccine if not used within 30 minutes

(package insert) Whitehouse Station, NJ. Merck & Co, 2007

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Disposition of SPS SubjectsDisposition of SPS Subjects

Oxman M et al. Engl J Med 2005;352:2271-2284 2005 Massachusetts Medical Society. All rights reserved.

Placebo(n=19,276)

Completed study18,357 (95.2%)

Subjects enrolled

(n=38,546)

Zoster vaccine(n=19,270)

Completed study18,359 (95.3%)

Terminated before study end793 (4.1%) Died57 (0.3%) Withdrew61 (0.3%) Lost to follow-up

Terminated before study end792 (4.1%) Died

75 (0.4%) Withdrew52 (0.2%) Lost to follow-up

Herpes Zoster Vaccine Trials: SummaryHerpes Zoster Vaccine Trials: Summary

• Zoster vaccine efficacy1 (age 60 +; no previous HZ)

- 66.5% reduction in the incidence of PHN

- 51.3% reduction in the incidence of HZ

- 61.1% reduction in the HZ burden of illness (BOI)

• The clinical trials found an approximately 18% efficacy in people age 80 and older as compared with 64% efficacy in people age 60 through 69 years.

• Loss of efficacy over 5 years though no recommendations on re-vaccination Oxman M et al. Engl J Med 2005;352:2271-2284

Hornberger J and Robertus K. Ann Int Med 2006;145:317-325

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Vaccination Stimulates CMI

Zoster Threshold

VZV HZ

VZV

Exposur

e

HZ 

Vaccinati

onSilent 

Reactivatio

n?

VZV

 T 

Cells

AgeCMI, cell‐mediated immunity.Adapted from Arvin A. N Engl J Med. 2005;352:2266‐77. 

Kaplan-Meier Estimates of the Cumulative Risk of Herpes Zoster by

Herpes Zoster Vaccination Status

Kaplan-Meier Estimates of the Cumulative Risk of Herpes Zoster by

Herpes Zoster Vaccination Status

No. at risk

Unvaccinated 227,283 208,374 158,887 128,920 77,367 29,226

Vaccinated 75,761 73,722 58,425 48,658 30,574 12,527

UnvaccinatedVaccinated

Her

pes

Zo

ster

In

cid

ence

, %

Follow-up, y0 0.5 1.0 1.5 2.0 2.5 3.0

1

2

3

4

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Risk of Development of Herpes Zoster after Vaccination

Cunningham AL et al. N Engl J Med 2016;375:1019-1032

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Physician‐Level Barriers 

41

7695 96

47

20

5 411 31 1

0%

20%

40%

60%

80%

100%

Recommendagainst

Do notrecommend

Recommend

Stronglyrecommend

*301 general internists and 297 family medicine physicians.

Hurley LP, et al. Ann Intern Med. 2010;152:555‐560.

PCPs’* Recommendations HZ vs Other Adult Vaccines

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PCP‐Level Barriers to Administeringthe HZ Vaccine*

Barrier

Responses (%)

Major Barrier

Somewhat of a Barrier

Minor Barrier

Not a Barrier

Cost concerns for my patients 53 30 10 7

Reimbursement challenges for my practice

52 25 10 13

Up‐front costs of purchasing the vaccine for my practice

43 21 17 19

Need for my patients to pick up the vaccine at a pharmacy

23 25 18 34

Need to store the vaccine in the freezer in a sealed separate compartment

16 20 22 42

More pressing medical issues taking precedence over the vaccine

12 23 30 35

*Survey of 301 general internists and 297 family medicine physicians.

Hurley LP, et al. Ann Intern Med. 2010;152:555‐560.

The Physician‐Patient DisconnectResults from Two Recent Surveys

87%

18%31%

21%

“I talk to all of my patients about vaccines” 

“Yes, I regularly discuss vaccines with my HCP”

“I occasionally discuss vaccines with my HCP”

“I don’t recall ever discussing 

vaccines”

Results based on telephone interviews with 1013 adults ages 28y and 300 PCPs who spend 67% of their time seeing adult patients.NFID. 2010. http://www.nfid.org/newsroom/news‐conferences/2010‐news‐conferences/2010‐cdc‐vaccination‐rates‐news‐conference/2010‐survey‐backgrounder.pdf.

What Physicians Said What Patients Said

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Patient Misconceptions/Questions

Patient Misconceptions/Questions

Common questions• I already had shingles. Doesn’t that mean I’m immune?

• I never had chickenpox. Why would I need the shingles vaccine?

• My family member is immunocompromised. Can she catch shingles from me?

The best strategy for preventing complications of HZ is to prevent HZ

=Importance of HZ vaccination

for all healthy adults ages 60 yoAll immunosuppressed rheumatology

patients > 50 yo

The best strategy for preventing complications of HZ is to prevent HZ

=Importance of HZ vaccination

for all healthy adults ages 60 yoAll immunosuppressed rheumatology

patients > 50 yo

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