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Clinical Diagnosis & Management of SARS

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Clinical Diagnosis & Management of SARS ClinicalClinical DiagnosisDiagnosis && ManagementManagement ofof SARSSARS Joseph SUNG MD, PhD Department of Medicine & Therapeutics Prince of Wales Hospital The Chinese University of Hong Kong Hospital Authority of Hong Kong SAR DiagnosisDiagnosis ofof SARSSARS WHO criteria (revised 1 May 2003) z High fever (>38°C) AND z Cough or breathing difficulty AND z 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 www.who.int/csr/sars/casedefinition/en 138 patients 20 doctors 34 nurses 15 allied health 16 medical students Common Symptoms ofSARS % of patients Common Symptoms ofSARS 100 10 20 30 40 50 60 70 80 90 0 Fever Chills & Rigor Myalgia Cough Headache Dizziness Sputum Sore throat Running nose Nausea & Vomiting Diarrhea ChestChest RadiographsRadiographs CTCT ThoraxThorax DiarrheaDiarrhea Diarrhea No Diarrhea 27% 38% 73% 62% Amoy Garden Prince of Wales Hospital N=75 N=138 FeaturesFeatures ofof DiarrheaDiarrhea z Large volume z Watery z No blood z No mucus DiarrheaDiarrhea isis associatedassociated withwith FeverFever N=75 Peiris et al. Lancet 2003 DiarrheaDiarrhea affectsaffects clinicalclinical outcomeoutcome Diarrhea (%) No diarrhea (%) p Male sex 28 (52.8) 37 (43.5) 0.29 Mean age in years ± SD 42.1 ± 16.5 37.8 ± 16.6 0.13 Comorbidity 11 (20.8) 9 (10.6) 0.1 Hospital stay (Day) 24.0 ± 14.6 20.0 ± 11.6 0.07 Ventilatory support 14 (26.4) 7 (8.2) 0.004 ICU care 26 (49.0) 10 (11.8) <0.001 Death 8 (15.1) 7 (8.2) 0.21 PWH cohort ColonColon A. lipofusin-laden macrphage B. Dilated ER & viral particle at microvilli C. Vesicles containing viral particles D. Viral particles on the luminal surface of villi TerminalTerminal IleumIleum E. Normal mucosa, sub- mucosa and muscle layer F. No inflammation G. Viral particles on villi H. Cytoplasmic vesicles with viral particles LymphopeniaLymphopenia 0.0227 750 0.0024 750 500 500 * (cells/ul) 250 (cells/ul) B cellnumber * 250 CD4 cell number 0 0 0 1 2 3 4 5 6 7 8 9 10111213141516 012345678 Day of Admission Day of Admission 750 5 0.0171 4 500 3 (cells/ul) 2 250 CD4/CD8 ratioCD4/CD8 CD 8 cell number cell 8 CD 1 0 0 012345678910111213141516 012345678910111213141516 Day of Admission Day of Admission ProlongedProlonged APTTAPTT 60.0 50.0 40.0 30.0 20.0 Percentage of patients Percentage 10.0 0.0 Day 1 Day 3 Day 5 Day 7 Day 10 Day 14 Day 17 Day 21 Week 4 Week 5 Day of illness Wong et al. BMJ 2003 ThrombocytopeniaThrombocytopenia 100 90 80 70 60 50 40 30 500-1000 Percentage of patients of Percentage 20 <500 10 0 Day 1 Day 3 Day 5 Day 7 Day 10 Day 14 Day 17 Day 21 Week 4 Week 5 Day of illness Wong et al. BMJ 2003 LymphLymph node,node, SpleenSpleen && BoneBone MarrowMarrow Wong et al. BMJ 2003 HongHong KongKong SARSSARS RegistryRegistry 1. Survival Analysis • Subject – 1,700+ SARS cases in e-SARS Registry 2. Retrospective Statistical Analysis • Subject – 1,315 SARS discharged cases with information captured into SARS Clinical Data Collection • Method – Univariate and Multivariate analyses (such as Logistic Regression, Discriminant Analysis) Survival Analysis Age Sex Cohort Comorbidity % Mean SaO2(lowest) IU/L Mean absolute LDH readings 99.0 1800 1600 97.0 1400 95.0 1200 93.0 1000 91.0 800 600 89.0 400 87.0 200 85.0 0 0 2 4 6 8 10121416182022242628303234363840 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 Day from symptom onset Day from symptom onset discharged death discharged death 10^9/L Mean Neutrophil readings 10^9/L Mean Lymphocyte readings 18 1.4 16 1.2 14 1.0 12 10 0.8 8 0.6 6 0.4 4 2 0.2 0 0 2 4 6 8 10121416182022242628303234363840 0.0 0246810121416182022242628303234363840 Day from symptom onset Day from symptom onset discharged death discharged death Nicholls, Yuen, Peiris, et al. Lancet 2003 May Peiris, Yuen, et al. Lancet 2003 Apr SARS:SARS: aa tritri--phasicphasic diseasedisease Viral replicative Immune hyperactive Pulmonary- phase phase destruction phase 40 C) o 39 38 37 Max. daily body temperature ( 36 1 2 3 4 5 6 7 8 9 101112131415161718 Days after onset of disease ProtocolProtocol Fever & Chills Suspected SARS IV Cefotaxime IV Levofloxacin De-saturation Oral Ribavirin 3.6g per day IV Ribavirin 1.2g per day Oral Prednisolone 1mg/kg/day IV hydrocortisone 100mg q6h IV Methyl-prednisolone 0.5 g/day For 3 consecutive days IV Methyl-prednisolone 0.5 g/day ProtocolProtocol For 2 consecutive days Fever persist Radiograph show sign of deterioration 3rd or 4th Pulse Steroid Convalescent serum therapy Fail to maintain oxygen saturation: ICU? Plasma exchange ResponseResponse toto RxRx Board-spectrum Ribavirin + IV Methyl- Antimicrobial* Corticosteroid# prednisolone+ (%) (%) (%) N=138 N=138 N=107 Sustained response 0 (0) 16 (11.6) 50 (46.7) Partial response 0 (0) 9 (6.5) 45 (42.1) No response 138 (100) 113 (81.9) 12 (11.2) Ribavirin 200µg/ml 100µg/ml 50µg/ml 25µg/ml 12.5µg/ml 6.25µg/ml Lopinavir 10µg/ml 5µg/ml 2.5µg/ml 1.25µg/ml 625ng/ml 3.125ng/ml Control: 100 PFU, CO2, 48 h, SARS-assocaiated coronavirus (HKU-39849 isolate) added. Study Subjects - SARS Patients Admitted before May 2003 - A B C Cases* K as Initial Rx K as Early K as Late rescue (n = 34) rescue (n = 33) (n = 33) Timing of treatment Dx made - Pulse MP if Intubation ribavirin/ CXR/ if pulse MP steroid SaO2↓ fails Matched Ribavirin Ribavirin Ribavirin cohort + Ever Pulse MP + Ever Pulse MP (4-D match) + Ever Intubation * All cases have Ribavirin KaletraKaletra asas InitialInitial RxRx Case_A Control_A P-value (n = 34) (n = 690) Death rate by Day 30 0% 10.4% 0.04 (standardised) Intubation rate 0% 12.6% 0.03 (standardised) By De-saturation rate 27.3% 27.9% 1.0 NS D21 (min SaO2<=90%) (standardised) De-saturation rate 63.6% 85.2% 0.003 (min SaO2<=95%) (standardised) KaletraKaletra asas earlyearly rescuerescue therapytherapy (with(with pulsepulse MP)MP) Case_B Control_B P-value (n =33) (n = 431) Death rate by D30 3.0% 8.8% 0.34 NS (standardised) Intubation rate 0% 19.5% 0.002 (standardised) By De-saturation rate 54.5% 35.4% 0.04 D21 (min SaO2<=90%) (standardised) De-saturation rate 93.9% 89.4% 0.56 NS (min SaO2<=95%) (standardised) KaletraKaletra asas latelate rescuerescue afterafter intubationintubation Case_C Control_C P-value (n = 33) (n = 77) Death rate by 21.2% 42.9% 0.03 Day 30 (standardised) SummarySummary z SARS has both pulmonary & extra- pulmonary manifestations z Age, gender, comorbidity, LDH, neutrophil & lymphocyte count affects mortality z SARS is a tri-phasic disease z Antiviral & immuno-suppressant may be beneficial z RCT for antiviral therapy is needed.
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