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 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 Lab-confirmed in Chile, EU & EFTA, Japan, Panama, Mexico 40 35 30 25 20 15 % of cases 10 5 0 0-9 10-19 20-29 30-39 40-49 50+

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 % 80 70 60 77.7 N=661 78.7 N=628 71.1 N=572 50 40 30 20 10 2.3 2.6 10.1 Obstetrical dealth Flu & pneumonia dealth 0 2007 2008 2009

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 (10 9 /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 nonimmunized 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 8 7 6 5 4 3 2 Viral shedding days Mean=6.4 days 1 0 No <24 h 24-47 h >48 Onset to oseltamivir

Oseltamivir treatment in hospitalized patients with sh1n1 % Fatal cases Location, season Toronto, 2005-6 Patients Oseltamivir No oseltamivir Adults 3.9% (4/103) 10.1% (22/219) Odd ratio (95% CI) 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 Presumed clade 2 45/82 (55%) 6/26 (23%) 0.06 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 Number (%) Virus Positive on Hospital Day 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

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 Fatalities in pregnancy, USA ARDS/ICU, Michigan Hospitalization, California 18 14 (78%) Mean 8 days (n=11) + 2-10 days post admission (n=3) 6 6 (100%) Mead 9 days (6-15 days) 10 10 (100%) Mead 8 days (5-12 days) 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 70 60 50 40 30 Deceasesd (%) 20 10 0 Untreated Treated 0 to 2 3 to 4 5 to 6 7 to 8 9 to 10 11+ Treatment status and time from symptom onset to treatment (days)

Risk of death: oseltamivir treatment vs no antiviral 0.1 0 0 to 2 3 to 4 5 to 6 7 to 8 9 to 10 11+ -0.1-0.2 Risk of death -0.3-0.4-0.5 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 crossreactive 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

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 Target region for seasonal influenza Target region for H5N1 detection Image obtained from www.nlm.nih.gov

When to Collect CDC 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 Swab continued 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 tongue 3. Swab the posterior pharynx 4. 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

Packing Specimens for Transportation 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

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