5 important issues about varicella zosterFrom chickenpox to shingles Show Chwan health system

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5 項重要議題帶狀皰疹

彰濱秀傳 神經內科 施懿恩

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划手機前Line: neuroshih

個人部落格www.ian-shih.com

中風部落格stroke.ian-shih.com

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為什麼是神經科

1 歲 4 個月大，女性，未婚

Herpes simplex 單純皰疹病毒 herpetic gingivostomatitis 皰疹唇齦炎

Ramsay-Hunt syndrometype2

Herpes zoster ophthalmicus帶狀皰疹病毒眼症

鼻頭的病灶暗示有眼角膜的侵犯眼科醫師林靖洋醫師提供

眼角膜樹枝狀病灶眼科醫師林靖洋醫師提供

有限資源下的中風醫學發展策略從 3小時血栓溶解治療到後急性中風照護秀傳醫療體系

今年 3 月全院演講

真實個案蜘蛛網膜下出血

59y/o Male, zoster related neuralgia over left trunk

Dizziness 不應該出現在帶狀皰疹病毒病人

EEG: diffuse cortical dysfunction

異常結果，安排影像學檢查

Arrange brain MRI

異常腦波→腦部磁振造影

腦部磁振造影正常

疑似癲癎

Pregabalin is good for epilepsy and post-herpetic neuralgia

病人未回診達三個月之久

Subrachinoid hemorrhage

真實個案蜘蛛網膜下出血梗塞性腦中風

2013/11(5months ago)70M, DM, Left MCA embolic

infarction

2014/4/1

zoster attack 10 days ago

2014/4/10

Acute cerebral infarction over left parietal lobe

Vasoconstriction?

No lumbar puncture

Start valaciclovir 1000mg TID for 7days

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健保資料庫研究為什麼是神經科

彰濱秀傳胸腔科趙志浩醫師發現腸躁症不舉率倍增

1st population-based study

Stroke. 2009;40:3443-3448北醫林恆慶教授

高血壓糖尿病冠心症共病較多

腎臟病心臟衰竭共病較多

周邊動脈疾病多收入較高

帶狀皰疹病毒眼症後一年中風風險上升 328%

帶狀皰疹發作後一年中風機率上升 31%

皰疹組中風發生率較對照組高

不同性別沒有差別

年紀大於 45 歲較有中風風險

Opportunity?Herpes zoster ophthalmicus帶狀皰疹病毒眼症

Neurology 2010;74:792-797

Increased AHR at 4.52 without difference in antiviral treatment

ImplicationAntiviral drug is too

late

需要別種方式的治療或是預防

Neurology 2014;82:206-212英國研究

Especially for age<40

Median follow-up 6.3 yearsAdd myocardial infarction

帶狀皰疹：比較胖 /抽煙族

Stroke 隨時間增加

TIA隨時間增加

MI 隨時間增加

心肌梗塞和暫時性腦缺血

18-40yr: 加碼中風

Age<40得到 herpes zoster 的人比起沒得的人

StrokeTIA

風險增加的比率都會比較高

Age<40得到 herpes zoster 的人比起沒得的人

得到 Stroke風險增加的比率隨時間會越來越高

Varicella zoster vasculopathy帶狀皰疹血管病變

Known issue-small study

Case series NEJM 2002

Vasoconstriction

Known issue-Varicella zoster vasculopathy

Lancet neurology 2009

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Herpes zoster in Taiwan

32.2% 63

Herpes zoster in Taiwan

The estimated lifetime risk of developing herpes zoster was 32.2%.

Hospitalization/cost increases with age

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Herpes zoster in Taiwan

The estimated lifetime risk of developing herpes zoster was 32.2%.

Zoster-related hospitalizations and medical cost per patient increased with age.

2/3 of adult case: older than 40 y/o 1/3 of adult case: within their lifetime

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60 歲以上是 high risk

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Italy: Age>50

*

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Cancer/DM/SLE/AIDSvs zoster

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Age>60/DM/LeukemiaSLE/AIDS vs PHN

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健保規定：先使用NSAID

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為什麼是神經科健保資料庫研究其它相關併發症

Varicella zoster帶狀皰疹

潛伏在神經節95%

Shingles皮蛇

Clinical Manifestations“Grape-like” lesions

clustered on an erythematous base1,2

Dermatomes most commonly affected1,2:

Thoracic (~50% of cases)1,2

Ophthalmic branch of trigeminal (~10% to 25%)1–3

More likely multiple dermatomes/disseminated in immunocompromised persons1

Considerably less contagious than chickenpox4

Transmissible to susceptible persons, resulting in chickenpox4

Aerosol transmission of HZ: extremely rareContact transmission: possible, 1/3 chance of

chickenpoxViral particle in vesicles in the fist 7 days 1. Oxman MN. In: Arvin AM et al, eds. Varicella-Zoster Virus: Virology and Clinical Management. Cambridge, UK: Cambridge University Press;2000:246–275.

2. Lycka BAS, Williamson D, Sibbald RG. Herpes Zoster and Postherpetic Neuralgia, 2nd Revised and Enlarged Edition. Vol 11. Amsterdam, The Netherlands: Elsevier Science B.V.; 2001:97–106. 3. Harpaz R et al. MMWR Morb Mortal Wkly Rep. 2008;57(RR-5):1–30. 4. Centers for Disease Control and Prevention (CDC). cdc.gov/vaccines/vpd-vac/shingles/downloads/shingles-vac-msg-2008.pdf. Accessed November 21, 2011.

Courtesy of the American College of Physicians(www.acponline.org/shell-cgi/printhappy.pl/bioterro/smallpox_mimics.htm).

© Phototake. Reprinted with permission.

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Pavan-Langston D, Ophthalmic zoster, In: Arvin AM, Gershon AA, eds, Varicella-Zoster Virus: Virology and Clinical Management, 276–298, Copyright © 2000 Cambridge University Press. Reprinted with permission.. Reprinted with permission

ComplicationsNeurologic1,2

Postherpetic neuralgia (PHN) most commonOccurs in 10% to 18% of patients with zoster

Loss of sensation, allodynia, cranial and motor neuron palsies (Ramsay-Hunt syndrome),

meningoencephalitis, hearing loss, vertigo

Ophthalmic1,2

Herpes zoster ophthalmicus (HZO)Occurs in 10% to 25% of patients with acute zoster

Visual impairment, ptosis, pain, facial scarring KeratitisOccurs in about 2/3 of patients with HZO

Cutaneous2

Scarring, bacterial superinfection

Disseminated2

More likely in immunocompromised patients

1. Harpaz R et al. MMWR Morb Mortal Wkly Rep. 2008;57(RR-5):1–30.2. Oxman MN. Varicella-Zoster Virus: Virology and Clinical Management. Cambridge University Press; 2000:246–275.78

腎臟科

帶狀皰疹發作在慢性腎臟病病人將導致洗腎機會增加 36%

帶狀皰疹發作在慢性腎臟病病人若合併高血壓、糖尿病將導致洗腎機會增加 771%

洗腎病人帶狀皰疹發生機會增加 98%

慢性腎病病人帶狀皰疹發生率從腎移植 +746%腹膜透析 +261% ．血液透析 35%

風濕免疫科

帶狀皰疹發作使慢性疲勞症候群發生率增加 29%

紅斑性狼瘡使帶狀皰疹發生率增加 145%

男性 7.51/ 女性 2.10 ． 18-24 歲相對危險

肝膽腸胃科

肝硬化病人帶狀皰疹反而可能減少 (AHR 0.77)

肝硬化病人帶狀皰疹發作發生率並不會增加

心臟科

帶狀皰疹發作使心律不整增加 16% 冠心症增加 11%

帶狀皰疹發作使急性冠心症發生率增加 15%

腫瘤科

帶狀皰疹發作可能是淋巴癌的症狀 (+68% 機會 )

帶狀皰疹發作可能是潛在癌症的症狀 (+58% 機會 )

尤其是肺癌

帶狀皰疹病毒眼症使癌症發生率增加 825%

精神科

精神疾病患者帶狀皰疹發作發生率增加 29%

帶狀皰疹發作使重度憂鬱症發生率增加 49%

帶狀皰疹發作使憂鬱相關疾病發生率增加 32%

胸腔科

慢性阻塞性肺病帶狀皰疹發生機會增加 68%

吸入型類固醇增加 109% ．口服類固醇 200%

神經科

帶狀皰疹發作使多發性硬化症發生率增加 296%

婦產科

剖腹產使用全身麻醉帶狀皰疹發生率增加 29%

眼科

帶狀皰疹發作使虹彩炎發生率增加 67%

若發生帶狀皰疹病毒眼症 ，發生率增加到 12 倍

醫療人員比較會發生帶狀皰疹

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治療皮蛇方式

為什麼是神經科健保資料庫研究其它相關併發症

Treatment is Difficult• Multifaceted approach.1–4

• Antiviral treatment for acute zoster should be initiated within 72 hours after the appearance of skin lesions, but patients may present after that period has elapsed.1–3

PHN = postherpetic neuralgia.1. Gnann JW et al. N Engl J Med. 2002;347:340–346. 2. Johnson RW. Herpes. 2007;14(Suppl 2):30A–34A. 3. Harpaz R et al. MMWR Recomm Rep. 2008;57(RR–5):1–30.4. Watson CPN et al. Pain. 1991;46:195–199.

While PHN may resolve over time,some patients are refractory to all treatments.2,4

HerpesZoster PHN

Non-narcotic analgesicsAntivirals

Narcoticanalgesics

Anticonvulsants for pain

management

Topical agents, TENS, nerve block

Corticosteroids

Postherpetic neuralgia

Postherpetic neuralgia (PHN) is a chronic neuropathic pain syndrome

caused by peripheral sensory nerve damage and altered central nervous system signal processing

3 types of PHN: Constant pain : burning, aching, thrumbing pain

Intermittent pain : stabbing, shooting Allodynia1. Johnson RW, Bouhassira D, Kassianos G, et al BMC Medicine 2010,8:37.

Prodromal Pain Acute PainSubacute Herpetic

Neuralgia Chronic Pain: Postherpetic Neuralgia (PHN)

Acute Phase Chronic Phase

Day 0 1 Month 3 Months Months/Years

Rash HealingRash Onset

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Back to the case

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5 預防方式

為什麼是神經科健保資料庫研究其它相關併發症治療皮蛇方式

Chickenpox水痘

水痘疫苗

台北市 1998 年底

2004 年全面施打水痘疫苗

Zostavax2 clinical trials

藥物廣告不得宣傳療效

同樣是廣告，這個沒事

ZOSTAVAX Efficacy and Safety Trial(ZEST)

50-60y/o

Long follow up

Double-blinded RCT

Shingle Prevention Study(SPS)

>60y/o

Short follow up

Double-blinded RCT

用 vaccine 喚醒 memory T cell

Reprinted with permission from Arvin A. N Engl J Med. 2005;352:2266–2267. Copyright © 2005 Massachusetts Medical Society. All rights reserved.

SPS: zoster incidence

Oxman MN et al. N Engl J Med. 2005;352:2271–2284. CI = confidence interval; SPS = Shingles Prevention Study.

SPS: by age group

NNT 也是遞增 48→71→133Harpaz R et al. MMWR Recomm Rep. 2008;57(RR-5):1–30 CI = confidence interval; SPS = Shingles Prevention Study.

ZEST: 皰疹發生率

6.60→1.99 ，減少 69.8%CI = confidence interval; ZEST = ZOSTAVAX Efficacy and Safety Trial. Schmader KE et al. Efficacy, Safety, and Tolerability of Herpes Zoster Vaccine in Persons Aged 50-59 Years, Clin Infect Dis, 2012;54:922–928.

1000 人年可以減少 4.6 個 shinglesNNT:217 所以一般建議 >60 歲較划算

皰疹後神經痛 (PHN)

除了 shingles 減少，連 PHN 發生率也減Harpaz R et al. MMWR Recomm Rep. 2008;57(RR-5):1–30 HZ = herpes zoster; PHN = postherpetic neuralgia; SPS = Shingles Prevention Study. aAge-adjusted estimate based on the age strata (60–69 and ≥70 years of age) at randomization.

ZEST: 皰疹後疼痛

0.49→0.13 ，減少 73%CI = confidence interval; ZEST = ZOSTAVAX Efficacy and Safety Trial. Schmader KE et al. Efficacy, Safety, and Tolerability of Herpes Zoster Vaccine in Persons Aged 50-59 Years, Clin Infect Dis, 2012;54:922–928.

SPS ADR profile

可局部冰敷Oxman MN et al. N Engl J Med. 2005;352:2271–2284.

大部份是局部相關副作用

ZEST ADR profile

CI = confidence interval; ZEST = ZOSTAVAX Efficacy and Safety Trial. Schmader KE et al. Clin Infect Dis, 2012;54:922–928.

SPS: VZV 專一抗體增加量

6 周後抗體產生量明顯增加Harpaz R et al. MMWR Morb Mortal Wkly Rep. 2008; 57(RR-5):1–30.gpELISA = glycoprotein enzyme-linked immunosorbent assay; SPS = Shingles Prevention Study. aAs measured by gpELISA.

Why AICP suggest >60y/o

Why FDA approve Zostavax>50y/o

1. Schmader KE et al. Clin Infect Dis. 2012; 54: 922-928. 2. Oxman MN et al. N Engl J Med, 2005;352:2271–2284.

各國預防注射指引US: Advisory Committee on Immunization

Practices/Centers for Disease Control and Prevention: Age ≥60: permissive recommendation1

Canada: National Advisory Committee on Immunization: Age ≥50: No recommendation, data insufficient2

Australia: Australian Technical Group on Immunization: Age ≥60: permissive recommendation3

1. Harpaz R et al. MMWR Recomm Rep. 2008;57(RR-5):1–30; 2. National Advisory Committee on Immunization. CCDR. 2010;36:1–19; 3. Australian Technical Advisory Group on Immunization. Zoster (herpes zoster). Australian Immunization Handbook. 9th ed. Australian Government. 2008:296–304.

2010 年台北榮民總醫院神經醫學中心專科醫師

2010-2012 年玉里榮院公費下鄉

精神疾病患者帶狀皰疹發作發生率增加 29%

Zostavax 其它臨床試驗

1. Sanford M et al. Drugs Aging 2010;27:159–176. 2. ClinicalTrials.gov identifier: NCT00851786. 3. ClinicalTrials.gov identifier: NCT00546819. 4. European Medicines Agency. Zostavax Scientific Discussion. June 21, 2007. ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion_-_Variation/human/000674/WC500053464.pdf. Accessed May 10, 2012. 5. ClinicalTrials.gov identifier: NCT01245751.

ZostavaxImmunnocompetent >60y/oHigh risk: DM/Renal diseaseHigh CVD risk group>50y/o

回顧

帶狀皰疹　 大重點

帶狀皰疹　 大重點

各種科別的併發症和相關疾病除了皮蛇外

台灣健保資料庫巨量資料威力

各種科別的併發症和相關疾病除了皮蛇外

台灣健保資料庫巨量資料威力

急性皰疹發作時的急性治療藥物及止痛藥

Valaciclovir 1000mgTID+prednisolone 20mg BID for 7 days

NSAIDPregabalin

讓學習變得更切身相關，同時與他人交流

Valaciclovir 1000mgTID+prednisolone 20mg BID for 7 days

NSAIDPregabalin

成人皰疹疫苗的適合年紀和可能併發症SPS/ZEST study

感謝

眼科林靖洋醫師

放射科陳泰逸醫師

彰化彰濱神經醫學部魏誠佑主任

台北榮總神經醫學中心王署君教授

台北榮總新藥臨床試驗中心江晨恩教授

戰略、戰術、訓練

跨科合作創造雙贏

Peter Holt經營智慧和長遠規畫

5 important issues about varicella zosterFrom chickenpox to shingles Show Chwan health systemQ&A