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Update of 2009 pandemic H1N1 influenza

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.

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Update of 2009 pandemic H1N1 influenza

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  1. 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

  2. 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

  3. Global status of human infection with H1N1 virus and influenza pandemic preparedness

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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 ?

  9. 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

  10. 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

  11. 病毒之毒性

  12. 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

  13. 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

  14. 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

  15. 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.

  16. 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

  17. pH1N1流感重症之臨床表現

  18. Distribution of pandemic cases by age Lab-confirmed in Chile, EU & EFTA, Japan, Panama, Mexico

  19. 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%)

  20. 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

  21. 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

  22. 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

  23. Special risk group: Pregnancy 77.7 78.7 71.1 % N=661 N=628 N=572 2.3 2.6 10.1

  24. 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

  25. pH1N1流感輕症之轉診準則

  26. 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

  27. 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

  28. 克流感之治療與預防效果

  29. Oseltamivir treatment of pH1N1, Vietnam, May-June 2009 Number (%) Virus Positive on Hospital Day R van Doorn et al. ProMED 8 July 2009, 8 August 2009

  30. 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

  31. Oseltamivir treatment in hospitalized patients with sH1N1 CID 46:1323, 2008 CID 405:1568, 2007

  32. Oseltamivir treatment effect in H5N1 infection NEJM 358:261, 2008

  33. Time to oseltamivir Tx in pH1N1 NEJM 29 June 2009 Lancet 29 July 2009

  34. 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

  35. 克流感抗藥性病毒株之流行病學及臨床重要性

  36. 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

  37. 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

  38. 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?

  39. 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

  40. Sensitivity to antiviral agents • pH1N1 is sensitive to neuraminidase inhibitors, but resistant to amantadine • However, oseltamivir-resistant viruses with H275Y 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

  41. sH1N1疫苗是否對pH1N1有交叉保護力

  42. 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

  43. 克流感使用規範

  44. 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

  45. 本院克流感給付來源 • 健保局 • 疾管局 • 自費

  46. 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

  47. 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)

  48. 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)

  49. 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

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