Update of 2009 pandemic H1N1 influenza

衛生署 疾病管制局中區傳染病防治醫療網

王任賢 指揮官

Update of pH1N1 influenza

各國流行病學資料 病毒之毒性 pH1N1 (H1N1pdm) 流感重症之臨床表現 pH1N1 流感輕症之轉診準則 克流感之治療與預防效果 克流感抗藥性病毒株之流行病學及臨床重要性 sH1N1 疫苗是否對 pH1N1 有交叉保護力

Global status of human infection with H1N1 virus and influenza

pandemic preparedness

Background Seasonal influenza epidemics occur every year

Caused by existing virus families of viruses that evolve over time

Influenza pandemics differ in important ways Infrequent events (1918, 1957, 1968) Emergence & spread (among people) of new family of virus Can result in higher levels of illness, hospitalization & death Can have different epidemiological and clinical features Can significantly affect social functions

Brief Timeline of Events 1997-2009

Strong concern that avian H5N1 could evolve into next pandemic

Pandemic preparedness actions started by some countries

April 2009 12: outbreak of influenza-like illness in Veracruz, Mexico, R

eported to WHO 15-17: two cases of newA(H1N1) virus infection identified i

n Southern California 23: new influenza A(H1N1) virus infection confirmed in sev

eral patients in Mexico

Timeline of Events April 2009

24: WHO declares public health event of international concern (PHEIC)

27: WHO declares pandemic phase 4-sustained community transmission in Mexico

29 : WHO declares pandemic phase 5 (2 countries affected)

June 2009 11: WHO declares pandemic phase 6 (spread to 2 WHO

regions) In 9 weeks: all WHO regions reporting cases of pH1N1 2009

WHO global pandemic response plan

Monitor and track disease progression Generate and transfer knowledge Guide and support countries Accelerate access to vaccines Accelerate access to antivirals Global health leadership and collaboration

Critical observation Pandemic virus spread worldwide very rapidly Preparedness has made a very significant

difference Continued work still needed to improve awareness,

knowledge, national and international capacities

Many remaining significant uncertainties Will important clinical, epidemiological or viral features

change ? Will other events intervene such as changes in H5N1

activity ? How much vaccine will available ?

Critical lessons Flexibility is critical

Re-examine & modify existing plans, surveillence and control strategies to meet realities of the situation

Communications

Global solidarity is a necessity & not a luxury In a globalized world, viruses spread worldwide in weeks w

hile rumors and fears affecting economic spread in hours No country can address this situation without help & cooper

ation of all other countries Sharing of access to vaccines & other critical benefits and

capacities as important as sharing of information & viruses

Pandemic impact in WPR Pandemic impact still remains uncertain and

is currently being monitoring Impact of the pandemic on a population has

many dimensions: health, social and economic

No reported severe impact on health care service as a result of acute respiratory failure

Pressures on local hospitals and potential economic loss reported from some countries

病毒之毒性

2009 pandemic (H1N1) virus

To date, viruses characterized are antigenically similar

Sensitive to neuraminidase inhibitors Resistant to amantadine and rimantadine Increasing number of sporadic oseltamivir resista

nt virus isolates No genetic markers of virulence identified

Viruses from severe cases do not have different genetic sequences

Pathogenesis and transmissibility of pH1N1 virus in animal model

Intranasal inoculation of ferrets, guinea pigs, and monkey with pH1N1 vs sH1N1 Increase morbidity Replication in high titer in lung tissues Diarrhea and virus recovery from intestines Less efficient respiratory droplet transmission

Virulence of pH1N1 is potentially higher than sH1N1 Some adaptation, eg E627K in PB2, is likely require

d to become more transmissible in humans

No difference in viral factors between severe/fatal and mild cases

Most patients show very mild symptoms similar to seasonal flu, while those in high risk groups and otherwise healthy younger generation may develop severe illness

So far, there is no significant difference in genetic and phenotypic characteristics between virus isolated from severe/fatal and mild cases

No difference in viral factors between severe/fatal and mild cases Most patients show very mild symptoms similar

to seasonal flu, while those in high risk groups and otherwise healthy younger generation may develop severe illness.

So far, there is no significant difference in genetic and phenotypic characteristics between viruses isolated from severe/fatal and mild cases.

Summary of genetic and antigenic analysis of pH1N1

The combination of gene segments of pH1N1 virus was not reported previously

Reassortment had occurred between North American triple reassortment and Eurasian lineage of swine viruses

No genetic markers for severe disease pH1N1 viruses circulating worldwide are genetic

ally and antigenically homogeneous, suggesting a single and recent introduction into humans

pH1N1 流感重症之臨床表現

Distribution of pandemic cases by age

0

5

10

15

20

25

30

35

40

0-9 10-19 20-29 30-39 40-49 50+

% of cases

Lab-confirmed in Chile, EU & EFTA, Japan, Panama, Mexico

pH1N1 in USA (2009-8-7 止 )

確診病例 : 28,210 住院治療病例 : 6506 (23%) 死亡病例 : 435 (1.54%, 6.69%)

Clinical picture of pH1N1 infection

Most people have uncomplicated and self resolving disease

Severe or fatal illness occur most often in younger adults 50-80% have conditions such as asthma, other lung disorders, cardi

ovascular diseases, diabetes, immunosuppression, neurologic disorders, pregnancy

Obesity may be newly recognized risk factor but needs more study 20-50% severe illness occurring in previously healthy peopl

e Majority of known deaths associated with respiratory failure

Consistent with viral pneumonia, multi-organ failure, shock Bacterial co-infection has not been prominent

Severe pH1N1 cases in Michigan 10 cases, mean age=46 y 9 obese (BMI>30), 7 severe obese (BMI>40),

4 on steroid 平均出現症狀 8 天候開使用抗病毒藥

Profile of death in Mexico

163 cases proven pH1N1 death Male: female=51%:49% 43.95% of confirmed dealths correspond to p

eople between 20-39 y/o Special risk group: pregnancy

Special risk group: Pregnancy

0

10

20

30

40

50

60

70

80

2007 2008 2009

Obstetrical dealth

Flu & pneumoniadealth

77.7

71.1

78.7

N=572N=628N=661

10.12.62.3

%

Pandemic (H1N1) 2009 fatal cases WPR Total death 136 Clinical picture (n=48)

75% with underlying condition 3 death among pregnant women, all without underlying medical

conditions Clinical course (n=27)

9 days-medium interval from onset of symptoms to death (range 4-14)

5 days-medium interval from onset of symptoms to hospitalization (range 2-8)

3 days-medium interval from hospitalization to death (range 2-9) Final diagnosis (n=42)

62% severe pneumonia 14% congestive heart failure 12% ARDS

pH1N1 流感輕症之轉診準則

北京朝陽醫院 1054 pH1N1 輕症案例 潛伏期 2.2 天 發燒 2-3 天 咳嗽 4-6 天 Viral shedding 6-7 天 Pneumonia 6%

潛伏期、發燒、咳嗽、 Viral shedding 均同於無肺炎者

pH1N1 之轉診時機 流感病患持續 3 日以上之高燒 流感病患出現肺炎

克流感之治療與預防效果

Oseltamivir treatment of pH1N1, Vietnam, May-June 2009

0 1 2 3 4 5-7

RT-PCR (n=44)

44 (100%)

25 (57%)

21 (48%)

8

(18%)

8

(18%)

0

Culture (n=13)

10/11 (91%)

6/11 (55%)

4/13 (31%)

6/13 (46%)

2/7 (27%)

NR

R van Doorn et al. ProMED 8 July 2009, 8 August 2009

Number (%) Virus Positive on Hospital Day

Oseltamivir treatment of pH1N1 illness, Vietnam, 29 May-6 Aug 2009

297 pH1N1 rtPCR positive patients Standard oseltamivir treatment (75 mg bid in adult)

Prolonged RNA detection fro URT in minority Day 6(2), 10(1), 11(1), 12(1) All culture negative

Oseltamivir susceptibility testing in 16 patients (23 specimens) positive > 3 days All sensitive by NA inhibition assay

Oseltamivir treatment in hospitalized patients with sH1N1

% Fatal cases

Location, season

Patients Oseltamivir No oseltamivir

Odd ratio (95% CI)

Toronto, 2005-6

Adults 3.9% (4/103) 10.1% (22/219)

0.21

(0.06-0.80)

Thailand, 2004-6

Adults+ Children

1.6% (5/318) 13.0% (17/131)

0.14

(0.04-0.44)

Hong Kong, 2004-5

Adults 2.2% (5/232) 5.6% (7/124) 0.26

(0.08-0.87)

CID 46:1323, 2008CID 405:1568, 2007

Oseltamivir treatment effect in H5N1 infection

Virus Survivors/Treated (%)

Survivors/Untreated (%)

P Value

Presumed clade 1

45/82 (55%) 6/26 (23%) 0.06

Presumed clade 2

43/106 (41%) 1/30 (3%) <0.001

Total 88/188 (47%) 7/56 (12%) <0.001

NEJM 358:261, 2008

Time to oseltamivir Tx in pH1N1

Patient group, location

No. of patients

No. (%) treated

Days to antiviral therapy

Pneumonia, hospitalization, Mexico

18 14 (78%) Mean 8 days (n=11) + 2-10 days post admission (n=3)

Fatalities in pregnancy, USA

6 6 (100%) Mead 9 days (6-15 days)

ARDS/ICU, Michigan

10 10 (100%) Mead 8 days (5-12 days)

Hospitalization, California

30 15 (50%) 5 (17%)<2 days

NEJM 29 June 2009Lancet 29 July 2009

NAI chemoprophylaxis in seasonal influenza

Seasonal (4-6 wks) prophylaxis with once daily oseltamivir or zanamivir is protective in non-immunized adults (67-84% efficacy)

Post-exposure prophylaxis (PEP) in households Oseltamivir once daily for 7-10 days: 68-89% efficacy

Possible low efficacy in young children Zanamivir on daily for 10 days: 79-80% efficacy

Limited to those age>5 y

Rare resistance in prophylaxis failures

克流感抗藥性病毒株之流行病學及臨床重要性

克流感抗藥性 : sH1N1

在 2007 年克流感抗藥性大人僅 1-2%, 小孩 5-6%, 日本較高也只有 18%, 但只有一例是瑞樂沙有抗藥性 , 社區型的幾乎沒有抗藥性

2007-2008 流感季節首度在歐洲出現 H274Y之突變株 , 克流感抗藥性增加 1500 倍

2008-2009 全世界 95% 之分離株是 H274Y 之突變株 , 可見其 fitness 是不差的

克流感抗藥性 : pH1N1

至 2009-7-31 權世界之分離株有 162,000 12 株抗藥株分離出 , 全部是 H274Y 突變株 病例分布：

Under prophylaxis: 丹麥、日本 (4) 、加拿大、香港 、中國 (no evidence of transmission)

免疫異常 + 克流感治療 : 美國 (2) 克流感治療 : 新加坡 沒接觸過克流感 : 香港

Questions regarding Oseltamivir Resistance during prophylaxis pH1N1

How often is this occurring? What are the viral dynamics?

Transmission of resistant virus from treated ill index case? Resistant emergence in contact with prophylaxis? How often is non-compliance contributory?

If resistance emergence during incubation period, might therapeutic oseltamivir doses reduce risk?

Should zanamivir be used preferentially when prophylaxis is indicated?

Oseltamivir resistance in pH1N1 virus

Small number of sporadic detection All with H274Y mutation No reassortment with seasonal H1N1 Geographically dispersed- Denmark, Japan, HK SAR, Can

ada, Singapore, USA >50% detect in PEP prophylaxis failure (75 mg once daily) 1 in nondrug recipient travelling from San Fancisco

No apparent onward transmission Mostly mild self-limited illness

Except immunocompromised hosts

Sensitivity to antiviral agents pH1N1 is sensitive to neuraminidase inhibitors, b

ut resistant to amantadine However, oseltamivir-resistant viruses with H275

Y change in NA, which are still sensitive to zanamivir, have been isolated sporadically from patients in several countries, who, except one case, receive prophylactic use of oseltamivir

Gene reassortment with the NA gene of seasonal H1N1 virus did not occur

Further transmission of the resistant virus was not reported so far

sH1N1 疫苗是否對 pH1N1 有交叉保護力

Serum NA in the elderly cross- reactive with pH1N1 virus

About 40% of the elderly over 65 y/o possessed serum antibody cross-reactive to pH1N1 virus, while the majority of children and adult younger than 65 did not have such antibody

Vaccination with seasonal vaccines did neither induce nor boost immune response in any age group

克流感使用規範

法源 健保局公布將自 980815 後對於資格符合的病例給付克流感及流感快速篩檢

新型流感已自第一類傳染病移至第四類傳染病 醫院必須自行收治新型流感病例，不得逕行轉至專

責醫院

本院克流感給付來源 健保局 疾管局 自費

健保局給付克流感之條件 符合類流感定義：

突然發燒 ( 耳溫 >38C) 及呼吸道症狀 具有肌肉酸痛、頭痛、極度倦怠感其中之ㄧ者 須排除單純性流鼻水、扁桃腺炎、與支氣管炎

流感快速篩檢 A 病毒陽性 ( 試驗費健保給付 ) 症狀發生 48 小時內 必須三者同時存在才予給付

疾管局給付克流感之條件 疑似或確認流感重症 聚集事件 ( 是否給藥由該區指揮官核定 )

本院之克流感使用規定 自費克流感：不設限 公費克流感：由疾管局給付的部份

只用於住院病患 必須通報疾管局 由感控負責批准

健保給付之克流感：用於輕症病患 限制在住院與門診之ㄧ般內科、感染科、胸腔科、

小兒科、家醫科、耳鼻喉科，其他科別欲開立處方必須轉診

必須完全符合三個條件 ( 由電腦管控 )

門診開立克流感前必須出現之電腦問卷 符合類流感定義：

突然發燒 ( 耳溫 >38C) 及呼吸道症狀 具有肌肉酸痛、頭痛、極度倦怠感其中之ㄧ者 須排除單純性流鼻水、扁桃腺炎、與支氣管炎

流感快速篩檢 A 病毒陽性 ( 自動抓取檢驗資料 )

症狀發生 48 小時內

必要之相關配套門診檢驗室及急診檢驗是必須能執行流感快篩

應於 30-60min 內完成，並輸入報告 24 小時服務 相關之門急診必須配備採檢拭子

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