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

77.771.1

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: 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 1054 hospitalized 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 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 casesLocation, 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 infectionVirus Survivors/Tre

ated (%)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

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 pH1N1Patient 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

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/opossessed 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

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 Protective Equipment Gloves Mask Gown Eye protection

Polyester Fiber-Tipped Applicator

Should be drayon, rayon, or polyester fiber swabs

Do not use calcium alginated or cotton swabs nor ones with wooden sticks; they inhibit 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 Transport Media

Storing VTM

Sterile collection vials containing 2-3 ml of VTM

Vials can be stored in a freezer at -20 ºC until use

Vials can be stored for short periods of time at 4 - 6 ºC

How to Safely And Correctly Collect Specimens

Image obtained from www.nlm.nih.gov

Target regionfor seasonalinfluenza

Target region for H5N1 detection

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 into nostril and back to nasopharynx

2. Leave in place for a few seconds

3. Slowly remove swab while slightly rotating it

Nasopharyngeal Swabcontinued

4. Use a different swab for the other nostril

5. Put tip of swab into vial containing VTM, breaking applicator’s stick

Oropharyngeal Swab

1. Ask the subject to open his or her mouth

2. Depress the tongue3. Swab the posterior

pharynx4. Avoid the tonsils

How to Store Respiratory Specimens

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 freeze and thaw

Transporting Specimens from Field 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 with identification numbers and laboratory instructions

Packing Specimens for Transportation

懇請賜教