Severe Acute Respiratory Syndrome (SARS) 嚴重急性呼吸道症候群

1. Severe Acute Respiratory Syndrome (SARS) 嚴重急性呼吸道症候群 陳宜君醫師 臺大醫院內科部

2. SARS • SARS是世界衛生組織(WHO)在2003年3月15日新公布的名稱，在這之前稱為非典型肺炎。 • SARS流行事件開始於2003年2月26日越南河內的一位美國商人發病就醫，後來送香港治療後死亡。之後在香港、越南陸續出現非典型肺炎合併有呼吸道感染症狀的案例。 • 其特點為發生瀰漫性肺炎及呼吸衰竭，較過去所知病毒、細菌引起的非典型肺炎嚴重，因此取名為嚴重急性呼吸道症候群(Severe Acute Respiratory Syndrome, SARS)

3. 與時間賽跑SARS的全球疫情 • 3月12日，世界衛生組織針對SARS提出全球警訊 • 3月14日，美國疾病管制局啟動緊急醫療中心，並派出專家至亞洲國家協助世界衛生組織進行疫情調查。 • 3月14日，台大醫院通報國內第一、二例SARS極可能病例。第一例是境外移入的指標病例，第二例是家族內傳播的第一例本土病例。 • 3月5日，加拿大多倫多第一例SARS病例死亡。 • 自2003年2月1日起兩個月內，已經超過1800人被診斷SARS ，分佈在17個國家。

4. WHO 5/8/2003 Country/ Cumulative # of # of Date last area # of cases death recovered probable case reported China   4698     224   1529   8/May/2003 Hong Kong 1661     208   1008   8/May/2003 Taiwan   131     13   26   8/May/2003   Singapore   204   27   153   5/May/2003 Total   7053     506   2959    

5. Case Definitions for Surveillance of SARS WHO 5/1/2003 • Objective To describe the epidemiology of SARS and to monitor the magnitude and the spread of this disease, in order to provide advice on prevention and control • Introduction The surveillance case definitions based on available clinical and epidemiological data are now being supplemented by a number of laboratory tests and will continue to be reviewed as tests currently used in research settings become more widely available as diagnostic tests.

6. Introduction (cont.) Preliminary clinical description of Severe Acute Respiratory Syndrome summarizes what is currently known about the clinical features of SARS. • Countries may need to adapt case definitions depending on their own disease situation. • Retrospective surveillance is not expected.

7. Case Definitions for Surveillance of SARSSuspect case WHO 5/1/2003 1.   A person presenting after 11/1/2002 with history of: -  high fever (>38C) AND -  cough or breathing difficulty AND one or more of the following exposures during the 10 days prior to onset of symptoms: -  close contact with a person who is a suspect or probable case of SARS; -  history of travel, to an area with recent local transmission of SARS-  residing in an area with recent local transmission of SARS

8. Case Definitions for Surveillance of SARSSuspect case WHO 5/1/2003 2.  A person with an unexplained acute respiratory illness resulting in death after 11/1/2002, but on whom no autopsy has been performed AND one or more of the following exposures during to 10 days prior to onset of symptoms: -  close contact, with a person who is a suspect or probable case of SARS; -   history of travel to an area with recent local transmission of SARS-  residing in an area with recent local transmission of SARS

9. Case Definitions for Surveillance of SARSProbable case WHO 5/1/2003 1. A suspect case with radiographic evidence of infiltrates consistent with pneumonia or respiratory distress syndrome (RDS) on chest X-ray. 2. A suspect case of SARS that is positive for SARS coronavirus by one or more assays. 3. A suspect case with autopsy findings consistent with the pathology of RDS without an identifiable cause.

10. Case Definitions for Surveillance of SARSWHO 5/1/2003 • Exclusion criteria A case should be excluded if an alternative diagnosis can fully explain their illness. • Reclassification of cases

11. Case Definitions for Surveillance of SARS Reclassification of cases WHO 5/1/2003 • As SARS is currently a diagnosis of exclusion, the status of a reported case may change over time. • A patient should always be managed as clinically appropriate, regardless of their case status. • A case initially classified as suspect or probable, for whom an alternative diagnosis can fully explain the illness, should be discarded after carefully considering the possibility of co-infection.

12. Case Definitions for Surveillance of SARS Reclassification of cases WHO 5/1/2003 • A suspect case who, after investigation, fulfils the probable case definition should be reclassified as "probable". • A suspect case with a normal CXR should be treated, as deemed appropriate, and monitored for 7 days. Those cases in whom recovery is inadequate should be re-evaluated by CXR. • Those suspect cases in whom recovery is adequate but whose illness cannot be fully explained by an alternative diagnosis should remain as "suspect".

13. Case Definitions for Surveillance of SARS Reclassification of cases WHO 5/1/2003 • A suspect case who dies, on whom no autopsy is conducted, should remain classified as "suspect". • If this case is identified as being part of a chain transmission of SARS, the case should be reclassified as "probable". • If an autopsy is conducted and no pathological evidence of RDS is found, the case should be "discarded".

14. Case Definitions for Surveillance of SARSWHO 5/1/2003 • The surveillance period begins on 11/1/2002 to capture cases of atypical pneumonia in China now recognized as SARS. International transmission of SARS was first reported in March 2003 for cases with onset in February 2003. • Close contact: having cared for, lived with, or had direct contact with respiratory secretions or body fluids of a suspect or probable case of SARS. • Reporting procedures - All probable SARS cases should be managed in the same way for the purposes of infection control and outbreak containment

15. Case Definitions for Surveillance of SARSWHO 5/1/2003 • At this time, WHO is maintaining surveillance for clinically apparent cases only ie probable and suspect cases of SARS. • Testing of clinically well contacts of probable or suspect SARS cases and community based serological surveys are being conducted as part of epidemiological studies which may ultimately change our understanding of SARS transmission. However, persons who test SARS CoV positive in these studies will not be notified as SARS cases to WHO at this time.

16. Case Definitions for Surveillance of SARSWHO 5/1/2003 • Where laboratory tests are not available or not done, probable SARS cases as currently defined above should continue to be reported in the agreed format. • Suspect cases with positive laboratory results will be reclassified as probable cases for notification purposes only if the testing laboratories use appropriate quality control procedures.

17. Case Definitions for Surveillance of SARSWHO 5/1/2003 • No distinction will be made between probable cases with or without a positive laboratory result and suspect cases with a positive result for the purposes of global surveillance. • WHO will negotiate sentinel surveillance of SARS with selected partners to collect detailed epidemiological, laboratory and clinical data. • Cases that meet the surveillance case definition for SARS should not be discarded on the basis of negative laboratory tests at this time.

18. Rationale for retaining the current surveillance case definitions for SARS WHO 5/1/2003 • The reason for retaining the clinical and epidemiological basis for the case definitions is that at present there is no validated, widely and consistently available test for infection with the SARS coronavirus. • Antibody tests may not become positive for three or more weeks after the onset of symptoms. We do not yet know if all patients will mount an antibody response.

19. Rationale for retaining the current surveillance case definitions for SARS WHO 5/1/2003 • Molecular assays must be performed using appropriate reagents and controls under strictly controlled conditions, and may not be positive in the early stages of illness using currently available reagents. • We are not yet able to define the optimal specimen to be tested at any given stage of the illness.

20. This information is accruing as more tests are being performed on patients with known exposures and/or accompanied by good clinical and epidemiological information. We hope that in the near future an accessible and validated diagnostic assay(s) will become available which can be employed with confidence at a defined, early stage of the illness.

21. SARS 臨床症狀 • SARS的潛伏期通常為2至7天，但也可能長達10天。 • 疾病通常先以發燒為前趨症狀（>38℃），通常為高溫，有時會發冷及寒顫； • 有時尚伴隨著其他症狀包括頭痛、倦怠及肌肉痛。 • 有些病人發病時會產生輕微的呼吸道症狀。 • 雖然有部份病人在發燒時會發生腹瀉，但通常並不會有皮疹及神經或腸胃道症狀。

22. SARS 臨床症狀 • 3至7天後進入下呼吸道期（lower respiratory phase），開始沒有痰的乾咳，或因呼吸困難而導致血氧過低。 • 有10-20%的病人，呼吸道疾患嚴重到必須插管及使用呼吸器。 • 合乎目前世界衛生組織SARS極可能（probable）及疑似病例定義者之致死率約為3%。

23. SARS胸部X光攝影 • 在發燒前驅症狀，甚至整個病程，胸部X光攝影可能正常。 • 不過在大部份的病患，呼吸道時期（respiratory phase）的特性為從早期的局部（focal）浸潤，進展到較廣泛性、斑狀（patchy）、間質性浸潤， • 有些SARS晚期病人的胸部X光攝影可見部份區域實質化（consolidation）。

24. 傳播方式 • 飛沫傳染：近距離、反覆接觸。 • 空氣傳染 • 口糞傳播： • 有些動物的糞便可培養出冠狀病毒 • 許多台大的病人初期有腹瀉 • Vector-borne：fomites，因為冠狀病毒可在環境中生存數小時之久。

25. A Hospital Outbreak of Severe Acute Respiratory Syndrome in Hong Kong Lee et al., www.nejm.org April 7, 2003 • From March 11 to 25, 2003, a total of 156 patients were hospitalized with SARS at the Prince of Wales Hospital • 138 cases were identified as having either secondary or tertiary cases and were admitted to the isolation wards of

26. Clinical features • Symptoms: • fever (100%); chills, rigors, or both (73.2%); myalgia (60.9%) • cough (57.3%), headache (55.8%), dizziness (42.8%); • sputum production (29.0), sore throat (23.2%), coryza (22.5%), nausea & vomiting (19.6%), diarrhea (19.6%) • Physical findings on admission: fever 38.4C (35~40.3C), inspiratory crackles at the base of the lung

27. Laboratory findings • lymphopenia (69.6%) • thrombocytopenia (44.8%) • elevated lactase dehydrogenase (71.0%) • creatine kinase levels (32.1%)

28. CXR • At the onset of fever, 78.3% had abnormal CXR, • all showed air-space consolidation, indistinguishable from those associated with other causes of bronchopneumonia, peripheral- zone involvement predominant • unilateral focal involvement (54.6%), unilateral multifocal or bilateral involvement (45.4%) • Thoracic CT: Peripheral air-space consolidation, similar to those found in bronchiolitis obliterans organizing pneumonia

29. Prospective study of the clinical progression of SARS in a community outbreak • The fever and pneumonia initially responded to treatment. • However, patients developed recurrent fever (85.3%) on day 8.9 ± 3.1 (range 4 to 18), watery diarrhoea (73.3%) on day 7.5 ± 2.3 (range 3 to 15), radiological deterioration (80%) on day 7.4 ± 2.2 (range 3 to 13) and respiratory deterioration (45.3%) on day 8.6 ± 3 days (range 5 to 19). Peiris et al., and members of the HKU / UCH SARS Study Group. Lancet 2003

30. Prospective study of the clinical progression of SARS in a community outbreak • In 45.3% of patients, marked improvement of initial pulmonary lesions was closely associated with appearance of new radiological lesions at other sites. • 20% progressed to acute respiratory distress syndrome (ARDS) during the third week. • Age and chronic HBV infection are independent significant risk factors for progression to ARDS on multivariate analysis.

32. Subsequent analysis of clinical specimen of 20 patients with initial NPA RT-PCR positive and antibody seroconversion to SARS associated coronavirus Day after 10 13 16 19 21 onset NPA (positivity rate) 95% 90% 90% 75% 47.4% Stool (positivity rate) 100% 100% 95% 80% 66.7% Urine (positivity rate) 50% 45% 35% 30% 21.1%

33. Clinical progression and viral load of SARS associated coronavirus pneumonia • Quantitative RT-PCR of nasopharyngeal aspirates in 14 patients (4 had ARDS and 10 without ARDS) consistently demonstrated a peak viral load at day 10 and a decrease to admission level at day 15. • Faecal excretion of coronavirus was present and continued through the period of follow-up. • Seroconversion and RT-PCR of nasopharyngeal aspirates and stool are useful for confirmation of SARS.

34. Interpretation: • The consistent clinical progression, shifting radiological infiltrates and an inverted V viral load profile suggested that deterioration during the second week is not related to uncontrolled viral replication but may rather be related to immunopathological damage.

35. Incubation period 潛伏期 • Incubation period:Intervals between exposure to the index patient or ward and the onset of fever • SARS • Tsang et al., NEJM, Mar 31, 2003: 2-11 days • Lee et al. NEJM, Apr 7, 2003: 2~16 days (median, 6 days) • Common atypical pneumonia • Mycoplasma pneumoniae: 6-32天（14天） • Clamydia pneumoniae: 10-30天 • Leginella pneumoniae: 不會人傳給人

36. Incubation period WHO5/7/2003 • WHO has also reviewed estimates of the incubation period of SARS, using individual case data. • On the basis of this review, WHO continues to conclude that the current best estimate of the maximum incubation period is 10 days. • The incubation period can vary from one case to another according to the route by which the person was exposed, the dose of virus received, and other factors, including immune status.

37. The incubation period, which is the time from exposure to a causative agent to onset of disease, is particularly important as it forms the basis for many recommended control measures, including contact tracing and the duration of home isolation for contacts of probable SARS cases. • Knowledge about the incubation period can also help physicians make diagnostic decisions about whether the presenting symptoms and clinical history of a patient point to SARS or to some other disease.

38. Prompt isolationWHO5/7/2003 • WHO continues to recommend the earliest possible isolation of all suspect and probable cases of SARS. A short time between onset of symptoms and isolation reduces opportunities for transmission to others. • It also reduces the number of contacts requiring active follow-up, and thus helps relieve some of the burden on health services. In addition, prompt hospitalization gives patients the best chance of receiving possibly life-saving care should their condition take a critical course.

39. A comparison of the courses of common-source and propagatedepidemics

40. High infectivity of SARS agent • 112 secondary cases: • 69 health care workers and 16 medical students, who were work in the index ward; • 54 patients who were either in the same ward or had visited their relatives there • 26 tertiary cases: family members of the infected HCWs • Transmission by droplets and possibly by fomites were suspected.

41. High infectivity of SARS agent • The use of a jet nebulizer to administer aerosolized albuterol in the index patient had probably aggravated the spread of the disease by droplet infections. • Airborne precautions and contact precautions were instituted therefore, as recommended by the CDC.

42. Course and outcome • 23.2% were admitted to ICU • 13.8% required mechanical ventilation • 5 of 138 patients died, all of whom had coexisting conditions. Lee et al., www.nejm.org April 7, 2003

43. Independent predictors of an adverse outcome • advanced age (OR per decade of life, 1.80; 95% CI, 1.16 to 2.81; P=0.009) • high peak lactate dehydrogenase level (OR per 100 U per liter, 2.09; 95%CI, 1.28 to 3.42; P=0.003) • high absolute neutrophil count on presentation (OR, 1.60; 95%CI, 1.03 to 2.50; P=0.04). Lee et al., www.nejm.org April 7, 2003

44. SARS case fatality ratio5/7/2003 • Case fatality ratio WHO has today revised its initial estimates of the case fatality ratio of SARS. The revision is based on an analysis of the latest data from Canada, China, Hong Kong SAR, Singapore, and Viet Nam. • On the basis of more detailed and complete data, and more reliable methods, WHO now estimates that the case fatality ratio of SARS ranges from 0% to 50% depending on the age group affected, with an overall estimate of case fatality of 14% to 15%.

45. The likelihood of dying from SARS in a given area has been shown to depend on the profile of the cases, including the age group most affected and the presence of underlying disease. • Based on data received by WHO to date, the case fatality ratio is estimated to be < 1% < 24 years 6% 25 to 44 years 15% 45 to 64 years > 50% 65 years

46. Tsang et al., NEJM 3/31/2003

47. Tsang et al., NEJM 3/31/2003

48. Poutanen et al. NEJM 3/31//2003

49. Poutanen et al. NEJM 3/31//2003

50. SARS致病菌 • 2003年3月24日美國疾病管制局及香港專家，宣布分離出一種冠狀病毒(coronavirus)。 • 目前正針對已知的冠狀病毒polymerase基因的核酸序列比對，發現與已知的人類病毒不同。 • 數個病人的急性期及恢復期血清顯示有血清陽轉(seroconversion) 。