SARS 病人之药物治疗

1、SARS 病人之藥物治療中國醫藥學院附設醫院內科部 感染科 陳志銘1.2.3.4.The clinical progression of SARS Phase I Week 1 was characterised by fever, myalgia, and other systemic symptoms that generally improve after a few days. The increasing viral load during this phase suggests that the symptoms are largely related to the effect

2、of viral replication and cytolysis. Lancet 09 May, 20035.The clinical progression of SARSPhase II As the disease progressed into week 2Recurrence of fever, onset of diarrhoea, and oxygen desaturation. Strikingly, nearly half the patients had shifting radiographic shadows. Lancet 09 May, 20036.Lancet

3、 09 May, 2003Seroconversion of IgGThe timing of the IgG seroconversion, which starts on day 10, seems to correlate with falls in viral load, which occurs from between day 10 and 15.7.Lancet 09 May, 2003Viral loads of nasopharyngeal aspirateProgressive decrease in rates of viral shedding from nasopha

4、rynx, stool, and urine from day 10 to 21 after onset of symptoms.8.Lung pathology of fatal SARSSARS is associated with Epithelial-cell proliferation and an increase in macrophages in the lung. The presence of haemophagocytosis supports the contention that cytokine dysregulation may account, at least

5、 partly, for the severity of the clinical disease.Lung damage at this phase is related to immunopathological damage as a result of an overexuberant host response, rather than uncontrolled viral replication. Lancet 16 May, 20039.The clinical progression of SARS Phase III20% of patients in this cohort

6、 progressed to the third phase, characterised by ARDS necessitating ventilatory support. Lancet 09 May, 200310.Lancet 09 May, 200311.SARS發病的可能病理過程12.Acute lung injury and SARS virus13.SARS的致病機制及治療1.第一期（17天）：病毒複製期，抗病毒藥物2.第二期（714天）：細胞激素風暴期（cytokine storm），肺部發炎、破壞，用類固醇3.第三期（14天-）：肺纖維化（呼吸治療）、繼發細菌真菌感染應注意

7、藥物副作用、免疫抑制感染 -7發病 0714第一期第二期第三期14.Goals Prevent transmission: reduce viral shedding Reduce mortality Prevent intubation: improve oxygenation, stop clinical progression to ARDS Shorten hospitalization: rapid recovery Reduce long-term sequelae15.Standard treatment protocol for SARS in adult patientsAn

8、tibacterial treatment Cover typical and atypical pneumonia.Ribavirin MethylprednisoloneVentilation16.Standard treatment protocol for SARS in adult patientsAntibacterial treatment Cover typical and atypical pneumonia.Start levofloxacin 500 mg once daily intravenously or orallyOr clarithromycin 500 mg

9、 twice daily orally plus coamoxiclav (amoxicillin and clavulanic acid) 375 mg three times daily orally if patient 18 years, pregnant, or suspected to have tuberculosisLancet 10 May, 200317.Standard treatment protocol for SARS in adult patientsRibavirin and methylprednisoloneAdd combination treatment

10、 when:Extensive or bilateral chest radiographic involvementOr persistent chest radiographic involvement and persistent high fever for 2 daysOr clinical, chest radiographic, or laboratory findings suggestive of worseningOr oxygen saturation 95% in room airLancet 10 May, 200318.Ribavirin regimenRibavi

11、rin regimen for 1014 daysRibavirin 400 mg every 8 h (1200 mg daily) intravenously for at least 3 days (or until condition becomes stable)Then ribavirin 1200 mg twice daily (2400 mg daily) orallyLancet 10 May, 200319.Corticosteroid regimenStandard for 21 days Methylprednisolone 1 mg/kg every 8 h (3 m

12、g/kg daily) intravenously for 5 daysThen methylprednisolone 1 mg/kg every 12 h (2 mg/kg daily) intravenously for 5 daysThen prednisolone 05 mg/kg twice daily (1 mg/kg daily) orally for 5 daysThen prednisolone 05 mg/kg daily orally for 3 daysThen prednisolone 025 mg/kg daily orally for 3 daysThen off

13、Lancet 10 May, 200320.Pulsed methylprednisoloneGive pulsed methylprednisolone if clinical condition, chest radiograph, or oxygen saturation worsens (at least two of these), and lymphopenia persistsGive as methylprednisolone 500 mg twice daily intravenously for 2 days, then back to standard corticost

14、eroid regimenLancet 10 May, 200321.VentilationConsider non-invasive ventilation or mechanical ventilationif oxygen saturation 6 L per min oxygen orif patient complains of increasing shortness of breathLancet 10 May, 200322.Treatment regimenRibavirinGuanosine analogueinhibits replication of many RNA

15、and DNA virusesRibavirin23.Treatment regimenRibavirin activitiesRSVInfluenza A and B,HSV-1 and HSV-2ParainfluenzaAerosol therapy:- not employedmay help spreading of virus24.Clinical studiesRSV bronchiolitis and pneumonia in hospitalized children: aerosol +/- IVIGChronic hepatitis C: oral ribavirin +

16、 IFNLassa fever + elevated AST or high-titer viremia: IV or oral ribavirin (within 6 days of illness)Viral hemoorhagic fever with renal syndrome Hantavirus pulmonary syndrome Post-exposure prophylaxis in contacts of Lassa fever and other viral hemorragic fever 25.Mechanism of action:3 hypotheses:dec

17、rease intracellular pools of guanosine triphosphate, suppress synthesis of viral nucleic acidsynthesis of RNA with abnormal 5 cap structures leads to inefficicent translation of viral transcriptsdirect suppressive effect on viral polymerase activities26.Ribavirin - mechanisms of action27.RibavirinCo

18、ntraindications:chronic anemia and Hb 10g/dlCrCl 30ml/minhypersensitivity to the drugPrecautions:predisposition goutrenal and hepatic impairment (dosage reduction)28.RibavirinContraindications:chronic anemia and Hb 10g/dlCrCl 2gm/dl：49%Hemolysis：76%Bradycardia：14%Sore throat：4%Aminotransferase：40%18

19、%病人因副作用而停止用藥。31.PrecautionsTeratogenicity: contraceptive cover 6 months after cessation females & males32.類固醇治療約在發病7天後（進入細胞激素風暴期），才開始使用。一種劑量使用五天後，才開始減少劑量。Methylprednisolone 效果比Decadron好。33.恢復期血清療法香港中文大學醫學院，40位SARS病患甲組：使用康復者血清 20位 無人死亡乙組：沒有使用康復者血清 20位 3人死亡34.恢復期血清療法香港中文大學沈祖堯醫師發病兩週內使用恢復期血清療法：住院及發燒時間縮短

20、死亡率降低35.恢復期血清療法限制：需由康復者捐出需選擇合適血型有病毒血症之問題適應症：病情發展快，有生命危險之人有潛在疾病之老年人孕婦36.Neuramidase In SARS? The significance of neuramidase in SARS is this: There is NO KNOWN neuramidase in any known coronavirus.Neuramidase is found in influenza viruses.SARS appears possibly to be an influenza orthomyxovirus - coro

21、navirus hybrid.Neuramidase cleaves sialic acid inside cells and mediates viral attachment to the respiratory epithelium of the host and consequent infection of susceptible cells.37.Neuramidase In SARS?If this is, in fact, neuramidase, this would be the first known appearance of neuramidase in any co

22、ronavirus and would further suggest that SARS is an orthomyxovirus - coronavirus hybrid. Interestingly, the hemagglutinin-esterase in SARS shows some relationship to a Type C Influenza as well - but SARS IS a coronavirus. a very weird coronavirus. but still a coronavirus.If SARS coronavirus is a nat

23、urally occurring coronavirus, efforts should be directed toward discovery of other orthymyxovirus-coronavirus hybrid-like viruses. There may be sufficient evidence developed in time to reveal that SARS is not a true coronavirus nor a true orthomyxovirus and so become an entirely new species of virus

24、 all together.38.Neuramidase In SARS?Oseltamivir phosphate (Tamiflu)Action: inhibition of influenza virus neuraminidase with possible alteration of virus particle aggregation and release.39.Neuramidase In SARS?廣東鍾南山醫師Tamiflu 75mg 每天一顆口服，給工作人員使用，可降低染病率，若染病，症狀亦較輕微。40.威爾斯醫院治療經驗138 位病人 SARS 病人Positive response:退燒超過四天X光片infiltra