® OCTOBER 7 - 10 OMED 17 PHILADELPHIA, PENNSYLVANIA 29.5 Category 1-A CME credits anticipated

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

Joint Session with ACOFP and Cleveland Clinic: Managing Chronic Disease

Herpes Zoster: Diagnosis, Treatment and Prevention

Leonard Calabrese, DO

The American College of Osteopathic Family Physicians is accredited by the American Osteopathic Association Council to sponsor continuing medical education for osteopathic physicians.

The American College of Osteopathic Family Physicians designates the lectures and workshops for Category 1-A credits on an hour-for-hour basis, pending approval by the AOA CCME, ACOFP is not responsible for the content. 10/5/2017

Herpes 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 Prevention • Biology & Epidemiology • Clinical Aspects • Treatment and prevention

Varicella Zoster Virus

• Family: • Subfamily: alpha herpesviridae • Ubiquitous • 99+% of adults have immunologic memory • : airborne; via fomites from skin lesions • 2 clinical forms: - Varicella (primary) - Herpes zoster (reactivation)

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History

• 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.

GENERAL RISKS – AGE, F>M, trauma, Risk of HZ recurrent 2-4% 50 45 39 Incidence increasing IR 40 6-32 globally over 50 years 1000 30 In the USA alone 1 PYs 20 million cases/yr 11 10 10 4 2-3 Lifetime risk is about 0 20-30% with a 50% likelihood if survive to 85 yoa

Patients with IMIDS are 2 x the risk of Rough estimates based on multiple studies immunocompetent expressed as cases per 1000 pt/yrs patients

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Incidence of HZ by Age Category 1945‐2007* <50 y 50‐59 y 60‐69 y 12 ‐ 10 Person

8 6 1000

4 per

2 Years Cases 0 1945‐49 1950‐60 1980‐1989 1990‐1999 2000‐2007

*Population includes adults and children residing in Olmsted County, MN. Kawai K, et al. Clin Infect Dis. 2016;63:221‐226.

HZ OI? 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 & Treatment

Pustular Crusting of Resolution Prodrome Vesicles* Lesions Lesions of Rash (2-3 d) (3-7 d) Clinical (4-6 d) (7-10 d) (2-4 wk)

• 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

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Diagnosis

• 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 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.

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

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Diagnostic 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, ; CA-MRSA, community-associated methicillin-resistant Staphylococcus aureus.

Complications of Acute HZ

Neurologic Ophthalmic • PHN • Stromal keratitis • Motor neuropathy • Iritis • Cranial palsy • Retinitis • Encephalitis • Visual impairment • Transverse myelitis • Episcleritis • Stroke* • Keratopathy Cutaneous Visceral • Bacterial superinfection • Pneumonitis • Permanent scarring/changes in • Encephalitis pigmentation • Hepatitis

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*

25 20 20 20 17 17 15 15 90 days  90 days

10 10  10 5 5 6

Persisting 5

Persisting 5 Percent of patients with Percent of patients with pain 0 Percent of patients with Percent of patients with pain 0 <65 65+ Age (y) Age (y) *Data from adults 22 y residing in Olmsted County, MN. Yawn BP, et al. Mayo Clin Proc. 2007;82:1341-1349.

Severity of HZ and Duration of Chronic Pain in Adults Ages  50 y Risk Patient Characteristics at Group 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

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

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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 infarction 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.

HZ and Stroke Older 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 2012 Grose,C Ped Inf Dis J 2010

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HZ and Stroke

• 2009 KangNew et al (Taiwan Era National >2009 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 Kang et al Stroke 2009 association of stroke and HZ Lin Neurology 2010 Sreenivasan 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)

• 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 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 2011 Sauerbrei A et al Eur J Clin Micro Infect Dis 2016

Prevention

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

Date of download: Copyright © The American College of Physicians. 3/5/2013 All rights reserved.

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Cell‐Mediated Immunity to VZV Decreases with Age Skin Test Results ELISPOT Count 20 120.0

18 16 100.0

(mm) 14 Number 80.0 Diameter 12 60.0 10 20‐2930‐3940‐4950‐5960‐69 Age Group Age Group (y) ELISPOT: interferon‐ enzyme‐linked(y) immunospot. Sadaoka K, et al. J Infect Dis. 2008; 198:1327‐1333.

Herpes Zoster : 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 Subjects

Subjects enrolled (n=38,546)

Zoster vaccine Placebo (n=19,270) (n=19,276)

Terminated before study end Terminated before study end 793 (4.1%) Died 792 (4.1%) Died 57 (0.3%) Withdrew 75 (0.4%) Withdrew 52 (0.2%) Lost to follow-up 61 (0.3%) Lost to follow-up

Completed study Completed study 18,359 (95.3%) 18,357 (95.2%)

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

Herpes 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

VZV Exposur e Silent Reactivatio n?

HZ Vaccinati on T

Cells VZV

Zoster Threshold VZV HZ

Age CMI, 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

4 Unvaccinated 3 Vaccinated

2

1 Incidence, % Herpes Zoster

0 0.5 1.0 1.5 2.0 2.5 3.0 Follow-up, y 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

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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

PCPs’* Recommendations HZ vs Other Adult 100% 11 4 11 3 5 20 80% Recommend against 60% 47 95 96 Do not 40% 76 recommend 20% 41 Recommend

0% Strongly recommend

*301 general internists and 297 family medicine physicians. Hurley LP, et al. Ann Intern Med. 2010;152:555‐560.

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PCP‐Level Barriers to Administering the HZ Vaccine* Responses (%) Major Somewhat of a Minor Not a Barrier Barrier Barrier Barrier Barrier Cost concerns for my patients 53 30 10 7 Reimbursement challenges for my 52 25 10 13 practice Up‐front costs of purchasing the 43 21 17 19 vaccine for my practice Need for my patients to pick up the 23 25 18 34 vaccine at a pharmacy Need to store the vaccine in the 16 20 22 42 freezer in a sealed separate compartment More pressing medical issues taking 12 23 30 35 precedence over the vaccine

*Survey of 301 general internists and 297 family medicine physicians. Hurley LP, et al. Ann Intern Med. 2010;152:555‐560.

The Physician‐Patient Disconnect Results from Two Recent Surveys

“I talk to all of my patients about vaccines” 87%

“I occasionally discuss vaccines “I don’t recall “Yes, I regularly with my HCP” ever discussing discuss vaccines vaccines” with my HCP” 31% 18% 21% What Physicians Said What Patients Said

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.

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Patient Misconceptions/Questions Common questions • I already had shingles. Doesn’t that mean I’m immune? • I never had . 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 yo All immunosuppressed rheumatology patients > 50 yo

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