【病毒外文文献】2014 Clinical aspects and outcomes of 70 patients with Middle East respiratory syndrome coronavirus infection_ a single-

International Journal of Infectious Diseases 29 2014 301 306 Contents lists available at ScienceDirect International Journal of Infectious co Clinical aspects and outcomes of 70 patients with Middle East respiratory syndrome coronavirus infection a single center experience in Saudi Arabia Mustafa Saad a Ali S Omrani a b Kamran Baig c Abdelkarim Bahloul a Fatehi Elzein a Mohammad Abdul Matin d Mohei A A Selim e Mohammed Al Mutairi f Daifullah Al Nakhli a c Amal Y Al Aidaroos a c Nisreen Al Sherbeeni a Hesham I Al Khashan e Ziad A Memish g Ali M Albarrak a a Division of Infectious Diseases Prince Sultan Military Medical City Riyadh Kingdom of Saudi Arabia b King Saud University Riyadh Kingdom of Saudi Arabia c Department of Infection Prevention and Control Prince Sultan Military Medical City Riyadh Kingdom of Saudi Arabia d Department of Medicine Prince Sultan Military Medical City Riyadh Kingdom of Saudi Arabia e Department of Family and Community Medicine Prince Sultan Military Medical City Riyadh Kingdom of Saudi Arabia f Department of Radiology Prince Sultan Military Medical City Riyadh Kingdom of Saudi Arabia g Ministry of Health 402 new cases were reported from Saudi A R T I C L E I N F O Article history Received 25 September 2014 Accepted 25 September 2014 Corresponding Editor Eskild Petersen Aarhus Denmark Keywords Middle East respiratory syndrome coronavirus MERS CoV Saudi Arabia Epidemiology Clinical S U M M A R Y Objectives To report the experience with Middle East respiratory syndrome coronavirus MERS CoV infection at a single center in Saudi Arabia Methods Cases of laboratory confirmed MERS CoV occurring from October 1 2012 to May 31 2014 were reviewed retrospectively Information sources included medical files infection control outbreak investigations and the preventive medicine database of MERS CoV infected patients Data were collected on clinical and epidemiological aspects and outcomes Results Seventy consecutive patients were included Patients were mostly of older age median 62 years male 46 65 7 and had healthcare acquisition of infection 39 55 7 Fever 43 61 4 dyspnea 42 60 and cough 38 54 3 were the most common symptoms The majority developed pneumonia 63 90 and required intensive care 49 70 Infection commonly occurred in clusters Independent risk factors for severe infection requiring intensive care included concomitant infections odds ratio OR 14 13 95 confidence interval CI 1 58 126 09 p 0 018 and low albumin OR 6 31 95 CI 1 24 31 90 p 0 026 Mortality was high 42 60 and age C2165 years was associated with increased mortality OR 4 39 95 CI 2 13 9 05 p 0 001 Conclusions MERS CoV can cause severe infection requiring intensive care and has a high mortality Concomitant infections and low albumin were found to be predictors of severe infection while age C2165 years was the only predictor of increased mortality C223 2014 The Authors Published by Elsevier Ltd on behalf of International Society for Infectious Diseases This is an open access article under the CC BY NC ND license http creativecommons org licenses by nc nd 3 0 Corresponding author E mail address zmemish Z A Memish http dx doi org 10 1016 j ijid 2014 09 003 1201 9712 C223 2014 The Authors Published by Elsevier Ltd on behalf of International Society for Infectious Diseases This is an open access article under the CC BY NC ND license http creativecommons org licenses by nc nd 3 0 jou r nal h o mep ag e w ww elsevier Diseases m loc ate ijid Statistical analyses were performed using Microsoft Excel 2007 Microsoft Corp Redmond USA and IBM SPSS Statistics software version 21 0 IBM Corp Armonk NY USA 3 Results 3 1 Characteristics of the study patients A total of 70 consecutive patients were included in the study The majority of patients were males 46 65 7 of older age median 62 years residents of Riyadh 57 81 4 and of Saudi nationality 57 81 4 Comorbid conditions were documented in 57 81 4 patients with a median age adjusted Charlson comorbidity index CCI score of 5 interquartile range IQR 0 25 6 0 Over half of MERS CoV infections 39 55 7 were healthcare associated Only seven 10 0 patients were obese and nine 12 9 were smokers A history of exposure to animals including camels within the 2 weeks preceding the onset of MERS CoV infection was very uncommon Table 1 The majority of patients 67 95 7 with confirmed MERS CoV infection were symptomatic The most common symptoms were fever 43 61 4 shortness of breath 42 60 0 and cough 38 54 3 Non respiratory symptoms were also relatively common including generalized fatigue 29 41 4 vomiting or diarrhea 21 30 0 abdominal pain 17 24 3 confusion 18 25 7 and myalgia or arthralgia 14 20 Most patients had pneumonia 63 90 The most common radiological abnormality on chest X rays was bilateral pulmonary infiltrates which were reported in 53 75 7 patients For patients with community acquired MERS CoV infection the median time from onset of symptoms to hospital admission was 5 0 IQR 3 0 8 5 days Table 2 Overall the median time from illness onset to diagnosis was 7 IQR 3 0 13 8 days M Saad et al International Journal of Infectious Diseases 29 2014 301 306302 Arabia alone during the period April 11 to June 9 2014 2 This in turn has raised concerns about the pandemic potential of MERS CoV infection MERS CoV is capable of causing a spectrum of illness ranging from asymptomatic infection to severe pneumonia requiring intensive care unit ICU admission 4 While the infection is still associated with high mortality specific antiviral therapy is lacking and management remains mainly supportive 2 5 The available literature describing the clinical and epidemio logical features and outcomes of MERS CoV infection is limited to case reports and descriptions of relatively small cohorts 3 6 14 We describe herein our clinical experience with 70 laboratory confirmed MERS CoV infection patients diagnosed at Prince Sultan Military Medical City PSMMC over a period of 20 months PSMMC is a 1200 bed tertiary medical center in Riyadh Saudi Arabia with around 40 000 annual admissions and 118 000 emergency room visits per year 2 Methods This was a retrospective study of all patients who were diagnosed with a laboratory confirmed MERS CoV infection at our center over the period October 1 2012 to May 31 2014 Patients were identified from the microbiology and infection control records In addition to the medical file review data were collected from infection control outbreak investigations and the preventive medicine database of MERS CoV infected patients Demographic and clinical details epidemiological exposures laboratory inves tigations and outcomes were collated A consultant radiologist reviewed and summarized all radiological investigations Patients were followed until discharge from the hospital or death MERS CoV infection was diagnosed by reverse transcriptase PCR RT PCR testing of respiratory tract samples for the MERS CoV upE ORF 1b and N genes 15 All RT PCR tests for MERS CoV were performed at the Saudi Ministry of Health National Laboratories in Jeddah and Riyadh Saudi Arabia The study was approved by the institutional research ethics committee 2 1 Definitions Infection was classified as healthcare associated if the onset of MERS CoV illness was more than 48 h after the current admission or if the onset of illness was within 14 days of discharge from a clinical area where cases of MERS CoV infection had been documented A cluster was defined as two or more persons with onset of symptoms within the same 14 day period and who were associated with a specific setting healthcare or household 4 Concomitant infections included all bacterial fungal and viral infections that occurred within 14 days of the diagnosis of MERS CoV infection Severe infection requiring care in an ICU and death were considered poor outcomes 2 2 Statistical analyses The Chi square test or Fisher s exact test was used to compare categorical data while the Student s t test was used to compare continuous variables All p values were two tailed and considered statistically significant at a cut off of 0 05 Risk factors for a poor outcome were initially assessed in a univariate analysis Those factors that were found to be significant were then entered into competing logistic regression ICU care or Cox regression death in order to determine the independent risk factors for a poor outcome Graphical and statistical tests indicated that the proportional hazard assumption was not violated A forward stepwise method was used to identify the determinants of a poor outcome with the probability of entry set at C200 05 Table 1 Epidemiological characteristics of 70 patients with laboratory confirmed MERS CoV infection Characteristic Value Total n 70 100 Age years median range 62 1 90 Age group n 0 5 years 1 1 4 6 18 years 2 2 9 19 50 years 20 28 6 51 64 years 14 20 0 C2165 years 33 47 1 Gender n Male 46 65 7 Female 24 34 3 Nationality n Saudi Arabia 57 81 4 Philippines 9 12 9 Yemen 3 4 3 Egypt 1 1 4 City of residence n Riyadh 57 81 4 Al Kharj 6 8 6 Other 7 10 0 Occupation n Healthcare worker 10 14 3 Non healthcare worker 60 85 7 Age adjusted Charlson comorbidity index median IQR 5 0 25 6 0 Obese n 7 10 0 Pregnant n 1 1 4 Smoker n 9 12 9 Animal exposure within 2 weeks before illness onset n Camels 1 1 4 Cats 2 2 9 Acquisition of infection n Community acquired 31 44 3 Healthcare associated 39 55 7 IQR interquartile range MERS CoV Middle East respiratory syndrome coronavirus were isolated in 22 31 4 patients including carbapenem resistant Acinetobacter baumannii 17 episodes vancomycin resistant enterococci three episodes and methicillin resistant Staphylococcus aureus one episode Infection with respiratory viruses other than MERS CoV was not documented in any of the patients Laboratory abnormalities that were commonly present at the time of diagnosis included low hemoglobin median 10 7 g dl IQR 9 1 13 4 lymphopenia median 0 85 C2 10 9 l IQR 0 6 1 2 low albumin median 27 g l IQR 24 5 33 5 and elevated aspartate aminotransferase median 59 IU l IQR 29 87 Several abnormal laboratory parameters were commonly observed during the hospital course of the MERS CoV infection Table 3 3 2 Distribution and clustering of cases The distribution of new cases was variable during the study M Saad et al International Journal of Infectious Diseases 29 2014 301 306 303 Table 2 Clinical characteristics outcomes and time course of clinical progression of 70 patients with laboratory confirmed MERS CoV infection Characteristic Value Total n 70 100 Clinical symptoms n Fever 43 61 4 Cough 38 54 3 Sputum production 23 23 9 Hemoptysis 6 8 6 Shortness of breath 42 60 Fatigue 29 41 4 Myalgia or arthralgia 14 20 Abdominal pain 17 24 3 Vomiting or diarrhea 21 30 Headache 9 12 9 Confusion 18 25 7 Type of infection n Asymptomatic 3 4 3 Acute lung injury 28 40 acute kidney injury 30 40 9 and hepatic dysfunction 22 31 4 were the most common complica tions Cardiac arrhythmias including variable tachyarrhythmias and severe bradycardia requiring temporary pacemaker insertion occurred in 11 15 7 cases Table 2 Of the patients with MERS CoV infection 10 were healthcare workers one was an ICU nurse six were non ICU nurses two were physicians and one was a radiology technician Interestingly three 30 had only mild upper respiratory symptoms and three 30 were asymptomatic Only one healthcare worker had a communi ty acquired MERS CoV infection There were 58 episodes of concomitant infection in 30 42 9 patients with MERS CoV infection Types of infection included bacteremia 16 episodes bacterial pneumonia 18 episodes urinary tract infection nine episodes skin and soft tissue infection 12 episodes candidemia two episodes and Clostridi um difficile infection one episode Multidrug resistant bacteria Upper respiratory infection 4 5 7 Pneumonia 63 90 Radiological findings n Normal 3 4 3 Unilateral infiltrates 10 14 3 Bilateral infiltrates 53 75 7 Not done 4 5 7 Clinical outcome n Required hospital admission 64 91 4 Required ICU care 49 70 Required assisted ventilation a 49 70 Died in hospital 42 60 Currently hospitalized 3 4 3 Discharged home alive 19 27 1 Cases with concomitant infections n All cases 30 42 9 Cases with multidrug resistant organisms 22 31 4 Complications related to MERS CoV infection n Acute lung injury ARDS 28 40 Acute kidney injury 30 42 9 Liver dysfunction 22 31 4 Rhabdomyolysis 10 14 3 Pneumothorax 5 7 1 Arrhythmias 11 15 7 DIC 10 14 3 Seizures 6 8 6 Time from illness onset to hospital admission b days median IQR 5 0 3 0 8 5 Time from illness onset to diagnosis days median IQR 7 0 3 0 13 8 Time from illness onset to death days median IQR 20 5 11 8 28 0 Time from illness onset to discharge from hospital days median IQR 27 0 20 0 31 5 ARDS acute respiratory distress syndrome DIC disseminated intravascular coagulation ICU intensive care unit IQR interquartile range MERS CoV Middle East respiratory syndrome coronavirus a Invasive or non invasive ventilation b Only for patients with community acquired infections period with peaks of increased activity in September 2013 and April 2014 The increased disease activity in the community was associated with an increase in healthcare transmission of infection and overall testing of suspected cases Figure 1 Cases of laboratory confirmed MERS CoV infection occurred sporadically and in clusters There were three documented family clusters each involving two to four individuals Infected family members within those clusters received treatment in more than one hospital including four cases in our hospital Furthermore a total of eight clusters of healthcare associated MERS CoV infection were documented these ranged in size from two to 15 and involved patients in more than one clinical area The largest cluster which involved 15 individuals occurred in the emergency department and included 10 cases who had apparently acquired the infection from a single patient Figure 2 In addition Figure 2 documents multiple occurrences of secondary transmission of infection in the healthcare associated clusters However tertiary transmission of infection was only observed once in the healthcare associated cluster in March 2014 3 3 Outcomes Severe infection requiring ICU care occurred in the majority 49 70 0 of patients 46 65 7 of these patients required invasive mechanical ventilation and three 4 3 required non invasive ventilation In the univariate analysis factors associated with severe infection requiring ICU care were age C2165 years odds ratio OR 9 47 95 confidence interval CI 2 45 36 56 p 0 001 male gender OR 3 05 95 CI 1 05 8 84 p 0 04 higher age adjusted CCI score OR 1 35 95 CI 1 11 1 65 p 0 003 the presence of bilateral pulmonary infiltrates on chest X ray OR 4 89 95 CI Table 3 Laboratory abnormalities in 70 patients with laboratory confirmed MERS CoV infection at the time of diagnosis Parameter At MERS CoV diagnosis median IQR Maximum variation median IQR Hemoglobin g dl 10 7 9 1 13 4 7 6 6 7 9 9 White blood cell count C210 9 l 7 4 4 9 10 4 4 9 3 3 6 7 Absolute lymphocyte count C210 9 l 0 9 0 6 1 2 0 5 0 3 0 8 Absolute neutrophil count C210 9 l 5 4 3 4 8 6 3 2 1 8 4 6 Platelets C210 9 l 180 127 3 246 118 83 152 8 Creatinine mmol l 106 5 76 3 205 8 251 5 143 5 427 Albumin g l 27 24 5 33 5 21 19 26 Alanine aminotransferase IU l 29 19 49 3 54 35 115 Aspartate aminotransferase IU l 59 29 87 112 52 218 Bilirubin total mmol l 9 5 6 16 17 10 42 Alkaline phosphatase IU l 94 66 151 8 145 100 5 262 3 IQR interquartile range MERS CoV Middle East respiratory syndrome coronavirus Figure 1 Distribution of laboratory confirmed cases of MERS CoV primary axis and suspected cases secondary axis by month of diagnosis M Saad et al International Journal of Infectious Diseases 29 2014 301 306304 1 16 20 47 p 0 03 concomitant infections OR 12 66 95 CI 2 65 60 46 p 0 001 and serum albumin 35 g l at the time of MERS CoV diagnosis OR 8 0 95 CI 1 97 32 46 p 0 004 Table 4 Of note neutropenia was found to be associated with a lower risk of severe MERS CoV infection in the univariate analysis OR 0 24 95 CI 0 07 0 82 p 0 02 Table 4 However in the multivariate regression analysis the only independent risk factors for severe infection requiring ICU care were the presence of a concomitant infection OR 14 13 95 CI 1 58 126 09 p 0 018 and a low serum albumin OR 6 31 95 CI 1 24 31 90 p 0 026 Table 5 Overall 42 60 patients with MERS CoV infection died The median time from illness onset to death was 20 5 IQR 11 8 28 0 days All patients who died except one had severe MERS CoV infections requiring ICU care and were placed on mechanical ventilation Among those who died 33 78 6 had a progressive disease course until death while nine 21 4 patients had an initial clinical improvement before they eventually died Univari ate analysis showed that mortality was increased in patients aged C2165 years OR 4 39 95 CI 2 13 9 05 p 0 001 those with a higher age adjusted CCI score OR 1 27 95 CI 1 12 1 44 p 0 001 and those with concomitant infections OR 3 15 95 CI 1 60 6 18 p 0 001 Table 4 However multivariate analysis showed age C2165 years to be the only independent risk factor for associated with increased mortality OR 4 39 95 CI 2 13 9 05 p 11 C2 10 9 l 10 1 4 16 Neutropenia ANC 0 5 C2 10 9 l 16 11 0 24 Lymphopenia ALC 110 mmol l 25 5 2 62 Decreased albumin 3C2 ULN 4 1 1 77 ALC absolute lymphocyte count ALT alanine aminotransferase ANC absolute neutrophil MERS CoV Middle East respiratory syndrome coronavirus OR odds ratio ULN upper camels to humans Most patients with MERS CoV infection in our cohort were symptomatic nonetheless a significant proportion of patients had atypical presentations This coupled with the lack of known exposures in most of the community acquired cases led to the diagnosis being elusive and several cases went undiagnosed until a cluster of infection became apparent Assiri et al reported higher percentages with classical symptoms in their cohort of 47 patients with MERS CoV infection However all of their patients presented Table 5 Risk factors associated with severe infection requiring ICU care and death in 70 patients with laboratory confirmed MERS CoV infection multivariate regres sion model OR 95 CI p Value ICU care Concomitant infection 14 13 1 58 126 09 0 018 Decreased albumin 35 g l 6 31 1 24 31 90 0 026 Mortality Age C2165 years 4 39 2 13 9 05 0 001 CI confidence interval ICU intensive care unit MERS CoV Middle East respiratory syndrome coronavirus OR odds ratio with pneumonia 3 In a case control study Al Tawfiq et al found only a few differences in the clinical presentation of MERS CoV infected patients compared to controls 6 Combined with our results these observations highlight the limitations of the clinical presentation in differentiating MERS CoV infection from other causes of pneumonia MERS CoV related complications were frequently observed in our cohort of patients The lungs liver and kidneys were the most commonly affected organs Serious cardiac complications were not uncommon and were mainly in the form of arrhythmias These observations may reflect the systemic nature of the MERS CoV infection with its tendency to cause multi organ involvement Concomitant infections were commonly observed in our patients Unlike the study by Assiri et al in which only admission cultures were reported 3 we included all infections within 14 days of the diagnosis of MERS CoV infection The majority of concomi tant infections were healthcare associated and reported in patients who required ICU care Indeed we found concomitant infections to be an independent risk factor for severe MERS CoV infection requiring ICU care The reason behind this observation is not clear but it underscores the vulnerability of patients with severe MERS CoV infection and emphasizes the importance of with laboratory confirmed MERS CoV infection univariate logistic regression logistic regression In hospital mortality Univariate logistic regression CI p Value Yes No OR 95