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,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 of viral replication and cytolysis.,Lancet 09 May, 2003,The clinical progression of SARS Phase II,As the disease progressed into week 2 Recurrence of fever, onset of diarrhoea, and oxygen desaturation. Strikingly, nearly half the patients had shifting radiographic shadows.,Lancet 09 May, 2003,Lancet 09 May, 2003,Seroconversion of IgG,The 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.,Lancet 09 May, 2003,Viral loads of nasopharyngeal aspirate,Progressive decrease in rates of viral shedding from nasopharynx, stool, and urine from day 10 to 21 after onset of symptoms.,Lung pathology of fatal SARS,SARS 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 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, 2003,The clinical progression of SARS Phase III,20% of patients in this cohort progressed to the third phase, characterised by ARDS necessitating ventilatory support.,Lancet 09 May, 2003,Lancet 09 May, 2003,SARS發病的可能病理過程,Acute lung injury and SARS virus,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藥物副作用、免疫抑制,感染 -7,發病 0,7,14,第一期,第二期,第三期,Goals,Prevent transmission: reduce viral sheddingReduce mortalityPrevent intubation: improve oxygenation, stop clinical progression to ARDSShorten hospitalization: rapid recoveryReduce long-term sequelae,Standard treatment protocol for SARS in adult patients,Antibacterial treatment Cover typical and atypical pneumonia. Ribavirin Methylprednisolone Ventilation,Standard treatment protocol for SARS in adult patients,Antibacterial treatment Cover typical and atypical pneumonia. Start levofloxacin 500 mg once daily intravenously or orally Or clarithromycin 500 mg twice daily orally plus coamoxiclav (amoxicillin and clavulanic acid) 375 mg three times daily orally if patient 18 years, pregnant, or suspected to have tuberculosis,Lancet 10 May, 2003,Standard treatment protocol for SARS in adult patients,Ribavirin and methylprednisolone Add combination treatment when: Extensive or bilateral chest radiographic involvement Or persistent chest radiographic involvement and persistent high fever for 2 days Or clinical, chest radiographic, or laboratory findings suggestive of worsening Or oxygen saturation 95% in room air,Lancet 10 May, 2003,Ribavirin regimen,Ribavirin regimen for 1014 days Ribavirin 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) orally,Lancet 10 May, 2003,Corticosteroid regimen,Standard for 21 daysMethylprednisolone 1 mg/kg every 8 h (3 mg/kg daily) intravenously for 5 days Then methylprednisolone 1 mg/kg every 12 h (2 mg/kg daily) intravenously for 5 days Then prednisolone 05 mg/kg twice daily (1 mg/kg daily) orally for 5 days Then prednisolone 05 mg/kg daily orally for 3 days Then prednisolone 025 mg/kg daily orally for 3 days Then off,Lancet 10 May, 2003,Pulsed methylprednisolone,Give pulsed methylprednisolone if clinical condition, chest radiograph, or oxygen saturation worsens (at least two of these), and lymphopenia persists Give as methylprednisolone 500 mg twice daily intravenously for 2 days, then back to standard corticosteroid regimen,Lancet 10 May, 2003,Ventilation,Consider non-invasive ventilation or mechanical ventilation if oxygen saturation 6 L per min oxygen or if patient complains of increasing shortness of breath,Lancet 10 May, 2003,Treatment regimen,Ribavirin Guanosine analogueinhibits replication of many RNA and DNA viruses,Ribavirin,Treatment regimen,Ribavirin activities RSV Influenza A and B, HSV-1 and HSV-2 ParainfluenzaAerosol therapy:- not employed may help spreading of virus,Clinical studies,RSV bronchiolitis and pneumonia in hospitalized children: aerosol +/- IVIG Chronic hepatitis C: oral ribavirin + IFN Lassa 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,Mechanism of action:,3 hypotheses: decrease intracellular pools of guanosine triphosphate, suppress synthesis of viral nucleic acid synthesis of RNA with abnormal 5 cap structures leads to inefficicent translation of viral transcripts direct suppressive effect on viral polymerase activities,