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Respirology 2004 9 173 183 Blackwell Science LtdOxford UKRESRespirology1323 77992004 Blackwell Science Asia Pty LtdMay 200492173183Original Article Coronavirus associated SARSAC W Lau et al Correspondence Arthur Chun Wing Lau Division of Respiratory and Critical Care Medicine Department of Medicine Pamela Youde Nethersole Eastern Hospital 3 Lok Man Road Hong Kong SAR PR China Email drcwlau Received 3 February 2004 revised 22 March 2004 accepted for publication 22 March 2004 RAPID COMMUNICATION Outcome of coronavirus associated severe acute respiratory syndrome using a standard treatment protocol Arthur Chun Wing LAU 1 Loletta Kit Ying SO 1 Flora Pui Ling MIU 1 Raymond Wai Hung YUNG 2 Edwin POON 1 Thomas Man Tat CHEUNG 1 AND Loretta Yin Chun YAM 1 1 Division of Respiratory and Critical Care Medicine Department of Medicine and 2 Department of Microbiology Pamela Youde Nethersole Eastern Hospital Hong Kong SAR PR China Outcome of coronavirus associated severe acute respiratory syndrome using a standard treat ment protocol LAU ACW SO LKY MIU FPL YUNG RWH POON E CHEUNG TMT YAM LYC Respirology 2004 9 173 183 Objective There is so far no consensus on the optimal treatment strategy for the coronavirus associated severe acute respiratory syndrome SARS We aimed to analyse the outcomes of a standard treatment strategy comprising antibiotics a combination of ribavirin a 3 week step down course of corticosteroids and the possibility of pulsed methylprednisolone rescue in the event of deterioration Methodology This was a prospective cohort study performed at a major public funded hospital in Hong Kong Eighty eight World Health Organisation Centers for Disease Control and Prevention probable cases of SARS 97 laboratory confirmed were treated with a standard protocol previously reported Seventy one patients treated de novo were analysed in detail with regard to time to clinical stabilization after combination treatment requirement of additional therapy pulsed methylpred nisolone assisted ventilation and final outcomes recovery mortality Results The mean age was 42 Twenty one patients 24 had comorbidities Three of 71 treated de novo recovered with antibiotics alone The remaining 68 received combination treatment at a mean of 5 8 days after symptom onset of whom 30 subsequently required pulsed methylprednisolone res cue independent predictors older age and higher LDH and 18 required assisted ventilation inde pendent predictors older age higher oxygen requirement and creatinine level Their median time to clinical stabilization was 8 0 days after combination treatment independent predictor for longer time to stabilization median age of 41 or above Common complications were hyperglycaemia 58 pneumo mediastinum thoraces 13 psychiatric manifestations 7 and ventilator associated pneumonia 2 One patient 1 died of SARS related respiratory failure All cause mortality was 3 4 occurring in patients aged 65 years only None of the discharged survivors required continuation of oxygen therapy Conclusions This standard treatment protocol resulted in overall satisfactory outcomes Random ized controlled trial is suggested to confirm its efficacy Key words corticosteroid outcome ribavirin severe acute respiratory syndrome standard treat ment protocol INTRODUCTION The coronavirus associated 1 4 severe acute respira tory syndrome SARS caused a worldwide out break in 2003 There is so far no consensus on the treatment strategy for this potentially deadly disease 5 8 We reported the development of a stan dard treatment protocol for our first 31 SARS patients comprising antibiotics and ribavirin and explained the rationale of how our corticosteroid regimen was derived by titration of dosages to achieve satisfactory clinical responses in our ini tial patients 9 In the following prospective obser vational cohort study we aimed to analyse in detail the outcomes of all patients treated with this protocol 174 AC W Lau et al METHODS Study population All consecutive patients admitted to Pamela Youde Nethersole Eastern Hospital Hong Kong between 9 March and 28 April 2003 were included in the analysis if they were diagnosed to be suffering from SARS and had ever been treated with the standard treatment protocol 9 All patients fulfilled the latest definitions for probable cases of SARS of both the World Health Organization WHO and the Centers for Disease Control and Prevention CDC 10 11 Study design We prospectively collected the demographic data exposure history comorbidities presenting features vital signs and oxygen requirements of all patients studied Daily blood tests included haematology complete blood counts with differentials and bio chemistry electrolytes glucose liver and renal func tions creatine kinase and lactate dehydrogenase Blood sputum and urine samples were collected for routine bacteriological studies Nasopharyngeal sam ples were collected for virological studies including immunofluorescent tests and cultures for influenza parainfluenza respiratory syncytial and adenovi ruses Clotted blood sera both acute and convales cent were collected for serological studies against Legionella species Chlamydia pneumoniae and Mycoplasma pneumoniae Human metapneumovirus was not specifically looked for Hepatitis B surface antigen HBsAg was checked Laboratory diagnosis of the SARS associated coronavirus SARS CoV was performed by reference laboratories at the University of Hong Kong and the Central Public Health Labora tory Hong Kong including nasopharyngeal and stool samples for reverse transcriptase polymerase chain reaction RT PCR studies of coronaviral ribonucleic acids RNA 12 and acute and convalescent sera tested in parallel for IgG antibody CXR of each patient on admission on starting com bination treatment on starting pulsed methylpred nisolone and on discharge were semiquantified using a scoring system previously described in which each lung was separated into six sections upper mid dle and lower zones medial and lateral divisions and scored on a four point scale 0 clear 1 subtle haziness or mild infiltrates 2 ground glass appear ance or prominent infiltrates and 3 confluent or dense opacities 9 Scoring was independently per formed by two pulmonologists blinded to the patients clinical information Treatment intervention We developed a treatment protocol for SARS compris ing antibiotics ribavirin and corticosteroids and finalized the dosage regimen of corticosteroids on 18 March 2003 9 Briefly antibiotics levofloxacin or amoxicillin clavulanic acid plus clarithromycin were given to all suspected SARS patients Combination treatment with ribavirin and corticosteroids was only started if any of the following occurred i extensive or bilateral CXR involvement or ii persistent CXR involvement and persistent high fever for 2 days or iii clinical CXR or laboratory findings suggestive of worsening or iv oxygen saturation S P O 2 10 mmol L Secondary outcomes were death or recovery Statistical analysis Interobserver agreement of CXR scores was assessed by Bland Altman plot 13 Mean scores were used for subsequent analysis Characteristics between patient groups were compared using Mann Whitney U test for continuous variables and c 2 test for categorical variables Statistical significance was taken as P 0 05 two tailed Independent predictors were studied with multiple logistic regression with forward step wise entry of parameters having P 0 05 Within subject comparisons were done using Wilcoxon signed rank test Kaplan Meier analysis with log rank tests was done to identify predictors for the time to clinical stabilization continuous variables were cate gorized using medians as cut off values Independent predictors were studied with Cox proportional haz ards regression analysis with forward stepwise entry of parameters having P 0 05 Fulfilment of the assumption of proportional hazards was confirmed Coronavirus associated SARS 175 with log minus log survival plots SPSS SPSS Inc Chicago IL USA version 9 was used for all analyses RESULTS Demographics Over a period of 51 days from 9 March to 28 April 2003 90 probable cases of SARS were admitted Two were excluded because they had never been treated according to our standard protocol one had been transferred from another hospital for continuation of treatment and the other for coronary care of acute myocardial infarction post SARS treatment with recovery Characteristics of the 88 patients recruited are shown in Table 1 Of these six had prior treatment in other hospitals before they were transferred for intensive care 11 were treated with the developmen tal phase protocol between 12 and 17 March and 71 Table 1 Patient characteristics of 88 cases treated using a standard protocol 9 Standard protocol de novo n 71 Standard protocol with prior treatment developmental phase protocol n 11 Standard protocol with prior treatment regimen of other hospital n 6 All patients n 88 Demographics Age years mean SD 42 5 14 8 39 6 10 5 41 5 10 9 42 1 14 0 Age years median range 41 13 74 38 27 65 41 29 55 40 5 13 74 Male gender 27 38 4 36 2 33 33 38 Smokers active ex 8 11 2 18 0 10 11 Alcohol drinkers 4 6 0 1 17 5 6 Exposure history Health care workers 9 13 7 64 1 17 17 19 Definite close contact 22 31 3 27 1 17 26 30 Housing estate outbreak 17 24 1 9 4 67 21 24 Travel to affected countries 13 18 0 0 14 16 Others 10 14 0 0 10 11 Comorbidities Any comorbidities 17 24 2 18 2 33 21 24 Diabetes mellitus 8 11 0 1 17 9 10 Coronary artery disease 3 4 0 0 3 3 Hypertensive heart disease 1 1 0 0 1 1 Underlying neoplasm 0 1 9 0 1 1 Chronic renal impairment 1 1 0 0 1 1 Asthma 1 1 0 0 1 1 Chronic obstructive pulmonary disease 0 0 0 0 Epilepsy 1 1 0 0 1 1 Psychiatric disease 3 4 0 1 17 4 5 Chronic Hepatitis B virus carrier 4 6 2 18 0 6 7 Presenting clinical features Symptom duration days 4 1 2 8 2 5 3 0 3 0 7 1 3 8 3 3 Temperature C 38 7 0 8 39 2 0 5 38 9 0 8 38 8 0 8 Respiratory rate breaths min 19 5 1 8 20 0 1 9 20 5 0 7 20 4 7 9 O 2 requirement L min mean SD 0 6 1 5 0 5 1 5 2 0 1 6 0 6 1 5 O 2 requirement L min range 0 8 0 5 0 4 0 8 Presenting blood test results Neutrophil count 10 9 L 4 6 2 5 3 4 1 3 3 1 1 2 4 3 2 4 Lymphocyte count 10 9 L 0 87 0 36 0 87 0 16 0 93 0 48 0 88 0 34 Platelet count 10 9 L 166 9 53 3 139 2 26 9 194 0 30 5 165 3 50 7 Creatinine m mol L 84 8 31 0 91 2 21 2 64 5 17 1 84 3 29 6 Alanine transaminase IU L 44 2 63 1 22 8 12 6 62 0 63 0 42 7 59 4 Creatine kinase IU L 303 3 548 4 178 3 125 8 137 3 143 9 286 2 520 2 Lactate dehydrogenase IU L 258 2 133 5 199 3 50 0 296 7 198 6 258 9 136 4 Positive laboratory diagnosis of SARS CoV 68 96 11 100 6 100 85 97 Admission chest radiograph score 7 9 5 7 7 9 4 9 10 2 8 2 8 1 5 8 Values are number or mean SD unless stated otherwise Conditions on presentation to other admitting hospitals Poorly differentiated non small cell carcinoma of chest wall 176 AC W Lau et al were treated de novo with the final protocol after 18 March 2003 Data from these 71 were analysed in detail and presented below Chest radiography We scored 305 CXR of these 71 patients with Bland Altman plot confirming good interobserver agree ment Fig 1 Mean SD scores at the time of ad mission n 71 commencement of combination treatment ribavirin and methylprednisolone n 68 pulsed methylprednisolone n 30 clinical stabilization n 68 and hospital discharge n 68 were 7 9 5 7 10 2 5 7 16 2 6 5 8 2 6 1 and 4 4 5 2 respectively Microbiology Positive laboratory diagnosis for SARS CoV infection was confirmed in 68 71 patients in Group C 67 68 had a four fold or greater rise of IgG titre in convales cent sera at a mean of 19 9 6 5 days after symptom onset Since the coronaviral RNA test by PCR and viral culture were only available in April 2003 21 49 were PCR positive in the nasopharyngeal samples and 25 39 had positive stool culture for the virus On admis sion five patients were coinfected with other organ isms Mycoplasma pneumoniae n 2 Haemophilus influenzae n 1 Klebsiella species n 1 and influ enza A virus n 1 Compared with those with nega tive samples patients with positive nasopharyngeal PCR for the SARS CoV were not associated with a longer time to stabilization P 0 1351 Compliance to treatment protocol All 71 patients received first line antibiotics as per protocol 9 in addition to amoxicillin clavulanic acid 65 received levofloxacin and six clarithromycin Of these three recovered on antibiotics alone nasophayngeal aspirate positive for SARS CoV n 1 nasopharyngeal aspirate PCR and SARS serology pos itive n 1 and stool culture and serology n 1 The remaining 68 were given the standard combination treatment 5 8 3 0 days after symptom onset 1 8 1 2 days after admission Of these 30 required additional pulsed methylprednisolone at 3 0 2 4 days and two required a second pulse at 15 5 13 4 days after commencement of combination treatment Compliance to protocol was confirmed by compar ing the administered doses of each drug against the standard regimens Ribavirin mean SD daily dose was 1052 7 106 3 mg 18 5 3 3 mg kg bodyweight intravenously and 2673 7 675 3 mg 46 1 13 9 mg kg orally for a total of 13 2 2 1 days Corticosteroids methylprednisolone was administered intravenously at daily doses of 2 9 0 7 mg kg followed by 2 0 0 3 mg kg for 10 2 1 1 days then prednisolone orally at 1 0 0 1 mg kg followed by 0 5 0 1 mg kg and 0 28 0 04 mg kg daily for a total of 11 5 0 6 days Pulsed methylprednisolone rescue 2266 7 626 1 mg intravenously per patient who required corticosteroid rescue Corticosteroid doses resumed after pulsed methylprednisolone therapy did not show any significant deviation from the standard regimens Appropriateness of pulsed methylprednisolone res cue was confirmed by the following comparisons oxygen requirement 1 8 2 4 L min at steroid com mencement vs 4 4 3 8 L min at pulsed steroid initi ation P 0 001 CXR score 12 3 5 9 vs 16 2 6 5 p 0 002 and lymphocyte count 0 71 0 28 vs 0 50 0 27 10 9 L P 0 002 were all significantly worse at the start of pulsed steroid rescue Predictors for additional therapy Pulsed methylprednisolone rescue was required in 30 68 patients given combination therapy 44 and non invasive or invasive ventilation in 18 68 26 Comparison of characteristics at commencement of combination treatment between those requiring and those not requiring such therapies is shown in Table 2 Multiple logistic regression showed the inde pendent predictors for pulsed methylprednisolone rescue to be age adjusted Odds ratio OR for every 10 years increase 1 54 95 confidence interval CI 1 05 2 27 P 0 0271 and LDH adjusted OR for ele vation by every 50 IU L 1 35 95 CI 1 09 1 67 P 0 0068 Independent predictors for assisted non invasive or invasive ventilation were age adjusted OR for every 10 years increase 2 08 95 CI 1 23 3 50 P 0 0059 need for oxygen supplementation adjusted OR 5 78 95 CI 1 44 23 16 P 0 0225 and creatinine level adjusted OR for elevation by every 10 mmol L 1 86 95 CI 1 09 3 16 P 0 0134 Time to clinical stabilization The time median SE to clinical stabilization of the 68 patients given combination therapy as estimated Figure 1 Bland Altman plot of CXR scores CXR scores from two independent observers blinded to clinical infor mation were compared The mean 2 SD score difference was 0 06 3 58 0246810 12 14 16 18 20 22 24 26 28 10 9 8 7 6 5 4 3 2 1 0 1 2 3 4 5 6 7 8 9 10 2SD 2SD Mean Diffe r e nce observ e r 1 o b server 2 Mean chest radiograph score Coronavirus associated SARS 177 by Kaplan Meier analysis was 14 0 0 9 95 CI 12 2 15 8 days after symptom onset and 8 0 1 2 95 CI 5 6 10 4 days after commencement of combination treatment Multivariate Cox regression analysis Table 3 showed that the only independent predictor for a longer time to stabilization was a median age of 41 or above adjusted hazards ratio 2 58 95 CI 1 50 4 45 P 0 0006 To further delineate its effect on out come age was stratified into three groups 30 30 to 60 and 60 years for analysis It could be shown that the older age groups took longer time to reach clinical stabilization Fig 2 Complications Of all 85 recruited patients ever treated with com bined ribavirin and corticosteroid no significant side effects were recorded from ribavirin Uncompli cated hyperglycaemia after corticosteroid occurred in 51 58 patients Eleven 13 developed pneumo mediastinum thoraces spontaneously n 6 or during assisted ventilation n 5 Thirty six patients were prescribed a second course of antibiotics pip eracillin tazobactam in 34 to treat possible sepsis as manifested by fever recrudescence and radiographic and or respiratory deterioration during treatment Two patients 2 had major sepsis due to ventilator associated pneumonia with acute respiratory distress syndrome one due to methicillin resistant Staphylo coccus aureus MRSA who subsequently died the other had Xanthomonas maltophilia and Escherichia coli and recovered The patient with MRSA was eld erly and was also the only one tried on IgM enriched immunoglobulin 5 mg kg day for 3 days Penta globin Biotest Pharma GmbH Dreieich Germany late in the course of the illness but without clinical efficacy None of the other 67 patients required other antivirals or immunomodulating agents Three 3 had urinary tract infection E coli n 2 or Group B streptococcus n 1 None of the six HBsAg positive patients had hepatitis flare up Two patients 2 had transient pancytopaenia associated with positive par vovirus B19 serology one of whom also had mild Table 2 Comparisons between patients who required and did not require additional therapy pulsed methylprednisolone assisted ventilation Characteristics at commencement of combination treatment Required additional pulsed methylprednisolone rescue P value Required assisted ventilation P value Yes n 30 No n 38 Yes n 18 No n 50 Age years 48 0 13 5 38 5 15 0 0 005 53 1 13 8 38 9 13 7 0 001 Male gender 15 50 12 32 0 123 11 61 16 32 0 030 Smoker active ex 4 13 4 11 0 721 3 17 5 10 0 452 Diabetes mellitus 5 17 3 8 0 265 5 28 3 6 0 014 Requirement of O 2 supplementation 13 43 8 21 0 048 11 61 10 20 0 001 Respiratory rate breaths min 20 8 4 6 18 8 2 3 0 030 21 6 5 7 19 0 2 3 0 041 Neutrophil count 10 9 L 5 0 2 7 3 9 2 4 0 028 5 2 2 4 4 1 2 6 0 038 Lymphocyte count 10 9 L 0 71 0 28 0 88 0 39 0 086 0 72 0 30 0 84 0 37 0 263 Platelet count 10 9 L 171 1 56 0 155 7 47 0 0 440 160 7 42 3 163 1 54 6 0 922 Creatinine mmol L 85 1 24 2 78 1 12 8 0 263 91 7 27 3 77 4 13 1 0 009 Alanine transaminase IU L 73 3 106 5 51 4 97 4 0 027 55 3 45 5 63 2 115 3 0 131 Creatine kinase IU L 428 4 747 4 142 9 160 3 0 026 589 7 918 3 153 4 184 3 0 012 Lactate dehydrogenase IU L 364 6 160 6 254 2 107 5 0 002 388 4 170 0 272 2 120 4 0 007 Chest radiograph score 12 3 5 9 8 5 4 9 0 005 12 7 6 5 9 3 5 1 0 031 Values are number or mean SD unless stated otherwise Either non invasive ventilation or mechanical ventilation Mann Whitney U test or c 2 tests Figure 2 Kaplan Meier plot of time to clinical stabiliza tion The median SE time to clinical stabilization from the commencement of combination treatment in patients treated de novo with standard protocol n 68 was 2 0 0 3 days for patients aged 30 n 16 10 0 1 3 days for aged 30 to 60 n 41 and 24 0 5 3 days for aged 60 n 11 P 0 0001 by log rank test Time to stabilization days 50454035302520151050 Patients not yet stabilized x100 1 1 1 0 9 8 7 6 5 4 3 2 1 0 0 censored cases 60 30 to 60 30 178 AC W Lau et al haemolytic anaemia Two elderly patients with diabe tes mellitus 2 had fatal vascular events acute myo cardial infarction n 1 and ischaemic brainstem stroke n 1 Six 7 had psychiatric manifesta tions acute confusion n 2 and anxiety depression n 4 which could have been related to corticoster oids or the illness per se Final outcome Outcomes of all 88 patients are summarized in Table 4 As of 15 July 2003 all patients have been observed for 104 13 days range 78 128 from admission There was one death 1 1 attributable to SARS and MRSA pneumonia and two due to comor bidities All cause mortality rate in thi