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, 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 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 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 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 resistant 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

required 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

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

genetically 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,

cardiovascular 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 people

� 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

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

77.7

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

Lab findings of 1054

hospitalized pH1N1 infected: I

Variable On admission

WBC 5270±2390

leukopenia 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 1054

hospitalized pH1N1 infected: II

Variable On admission

CD4 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 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

Oseltamivir and viral shedding

by RT-PCR 1023/1054 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 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, 2008

CID 405:1568, 2007

Oseltamivir treatment effect in

H5N1 infection

Virus Survivors/Tre

ated (%)

Survivors/Unt

reated (%)

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

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 from 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

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 2009

Lancet 29 July 2009

Case fatality rate by time from symptom onset 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: oseltamivir

treatment 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 pH1N1

virus

� 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 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?

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

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