Update of 2009pandemic H1N1influenza

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 infectionwith H1N1 virus and influenza

pandemic preparedness

Background Seasonal influenza epidemics occur every year

Caused by existing virus families of viruses that evolve overtime

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 nextpandemic

Pandemic preparedness actions started by some countries

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

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

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

several patients in Mexico

Timeline of Events April 2009

24: WHO declares public health event of internationalconcern (PHEIC)

27: WHO declares pandemic phase 4-sustainedcommunity 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 responseplan

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 andcontrol 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

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

cooperation 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 andeconomic

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

Pressures on local hospitals and potentialeconomic 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

resistant virus isolates No genetic markers of virulence identified

Viruses from severe cases do not have differentgenetic sequences

Pathogenesis and transmissibility ofpH1N1 virus in animal model

Intranasal inoculation of ferrets, guinea pigs, andmonkey 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

required to become more transmissible in humans

No difference in viral factors betweensevere/fatal and mild cases Most patients show very mild symptoms

similar to seasonal flu, while those in high riskgroups and otherwise healthy youngergeneration may develop severe illness

So far, there is no significant difference ingenetic and phenotypic characteristicsbetween virus isolated from severe/fatal andmild cases

Summary of genetic andantigenic analysis of pH1N1

The combination of gene segments of pH1N1virus was not reported previously

Reassortment had occurred between NorthAmerican triple reassortment and Eurasianlineage of swine viruses

No genetic markers for severe disease pH1N1 viruses circulating worldwide are

genetically and antigenically homogeneous,suggesting a single and recent introduction intohumans

pH1N1流感重症之臨床表現

Distribution of pandemic casesby 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 resolvingdisease

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

cardiovascular diseases, diabetes, immunosuppression,neurologic disorders, pregnancy

Obesity may be newly recognized risk factor but needs morestudy

20-50% severe illness occurring in previously healthypeople

Majority of known deaths associated with respiratoryfailure 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

people 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

77.771.1

78.7

N=572N=628N=661

10.12.62.3

%

Pandemic (H1N1) 2009 fatalcases 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 (range4-14)

5 days-medium interval from onset of symptoms tohospitalization (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

Lab findings of 1054hospitalized pH1N1 infected: IVariable On admissionWBC 5270±2390leukopenia 242/1021 (23.7%)leukocytosis 22/1021 (2.15%)lymphocyte count 1684.83±776.73 (1004)lymphocyte<1500 (adult) 139/289 (48.10%)lymphocyte<3000 (children) 695/715 (97.20%)hemoglobin g/l 136.15±15.6 (975)Platelet count (109/l) 198.23±55.76 (1005)

Lab findings of 1054hospitalized pH1N1 infected: IIVariable On admissionCD4 614.11±498.09 (488)CD8 441.30±298.16 (489)CD4/8<1.4 245/486 (50.41%)ALT>40 69/878 (7.86%)AST>40 73/842 (8.67%)CK>200 40/347 (11.53%)LDH 193.28±64.84 (364)K 3.81±0.42 (876)Hypokalemia (<3.5) 175/876 (19.98%)Na 139.08±3.08 (871)Cl 102.63±4.13 (862)

pH1N1之轉診時機 流感病患若有症狀後第三日仍高燒不退就是

impending重症 應給予照胸部X光、鼻咽採檢、或投與克流感

pH1N1重症病患治療原則 克流感 +類固醇 (decadron 5 mg q6h) 類固醇給藥時機為出現肺炎就給，而且越早越好

克流感之治療與預防效果

NAI chemoprophylaxis inseasonal 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

Oseltamivir and viral sheddingby RT-PCR1023/1054 mild pH1N1 cases

0

1

2

3

4

5

6

7

8

No <24 h 24-47 h >48

Viral shedding days

Onset to oseltamivir

Mean=6.4 days

Oseltamivir treatment inhospitalized patients with sH1N1

% Fatal casesLocation,season

Patients Oseltamivir Nooseltamivir

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 inH5N1 infectionVirus Survivors/Tre

ated (%)Survivors/Untreated (%)

P Value

Presumedclade 1

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

Presumedclade 2

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

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

NEJM 358:261, 2008

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 pH1N1illness, Vietnam, 29 May-6 Aug 2009

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

Prolonged RNA detection from URT inminority Day 6(2), 10(1), 11(1), 12(1) All culture negative

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

Time to oseltamivir Tx in pH1N1Patient group,location

No. ofpatients

No. (%)treated

Days to antiviraltherapy

Pneumonia,hospitalization,Mexico

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

Fatalities inpregnancy, USA

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

ARDS/ICU,Michigan

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

Hospitalization,California

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

NEJM 29 June 2009Lancet 29 July 2009

Case fatality rate by time from symptomonset to treatment with oseltamivir

0

10

20

30

40

50

60

70

Untreated Treated 0 to 2 3 to 4 5 to 6 7 to 8 9 to 10 11+

Deceasesd (%)

Treatment status and time from symptom onset to treatment (days)

Risk of death: oseltamivirtreatment vs no antiviral

-0.5

-0.4

-0.3

-0.2

-0.1

0

0.1

0 to 2 3 to 4 5 to 6 7 to 8 9 to 10 11+

Risk of death

Time from symptom onset to treatment (days)

Conclusion Earlier antiviral treatment increases survival

likelihood overall Oseltamivir beneficial if started≦8 days from

onset Early signs and symptoms are nonspecific

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

Oseltamivir resistance in pH1N1virus Small number of sporadic detection

All with H274Y mutation No reassortment with seasonal H1N1 Geographically dispersed- Denmark, Japan, HK SAR,

Canada, 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

Questions regarding OseltamivirResistance 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 whenprophylaxis is indicated?

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/opossessed serum antibody cross-reactive topH1N1 virus, while the majority of childrenand adult younger than 65 did not have suchantibody

Vaccination with seasonal vaccines didneither induce nor boost immune response inany 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

健保局公布將自980825後對於有肺炎傾向或併發症之類流感病患能及時投予克流感，即使無快篩試劑或快篩陰性亦可

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

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)

CMUH之克流感使用規定 自費克流感：無法開立

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

醫院該備之克流感存量

克流感應使用於重症或impending重症的病患 輕症中6% pneumonia之病例應為合理之估計 醫院該備之克流感量= 1,336,445 (中區預估感染人數) X 6% X 20% (CMUH市佔率)=16,037

病毒性呼吸道檢體採集之安全措施

Specimen Collection Kit Personal protective

equipment Collection vials with

VTM Polyester fiber-tipped

applicators Tongue depressors Items for blood

collection

Secondary container/cooler

Ice packs Suspect case forms A pen or marker for

labeling samples Labels

Personal ProtectiveEquipment Gloves Mask Gown Eye protection

Polyester Fiber-TippedApplicator

Should be drayon,rayon, or polyester fiberswabs

Do not use calciumalginated or cottonswabs nor ones withwooden sticks; theyinhibit PCR

How to choose VTM Can be made in a lab or purchased Different types of VTM:

For collection of animal specimens For viral isolation For molecular testing

(Do not use phosphate-based media If VTM is not available, 100% ethanol can be used

for molecular testing

Viral Transport Media

Viral TransportMedia

Storing VTM

Sterile collection vialscontaining 2-3 ml of VTM

Vials can be stored in a freezerat -20 ºC until use

Vials can be stored for shortperiods of timeat 4 - 6 ºC

How to Safely And CorrectlyCollect Specimens

Image obtained from www.nlm.nih.gov

Target regionfor seasonalinfluenza

Targetregion for H5N1detection

When to CollectCDC recommends laboratory testing for:

Suspected cases Symptoms consistent with influenza Epidemiologic link to avian influenza A (H5N1)

Nasopharyngeal Swab

1. Insert dry swab intonostril and back tonasopharynx

2. Leave in place for afew seconds

3. Slowly removeswab while slightlyrotating it

Nasopharyngeal Swabcontinued

4. Use a different swab forthe other nostril

5. Put tip of swab into vialcontaining VTM,breaking applicator’sstick

Oropharyngeal Swab

1. Ask the subject toopen his or hermouth

2. Depress the tongue3. Swab the posterior

pharynx4. Avoid the tonsils

How to Store RespiratorySpecimens

For specimens in VTM: Transport to laboratory as soon as possible Store specimens at 4°C before and during

transportation within 48 hours Store specimens at -70°C beyond 48 hours Do not store in standard freezer – keep on dry ice or

in refrigerator Avoid freeze-thaw cycles

Better to keep on ice for a week than to have repeat freezeand thaw

Transporting Specimens fromField to Lab

Keep specimens at 4 ºC Fill a cooler with ice packs or coolant packs Double-bag specimens if you use dry ice

Include an itemized list of specimens withidentification numbers and laboratoryinstructions

Packing Specimens forTransportation

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