【病毒外文文獻】2019 Comparative Analysis of Eleven Healthcare-Associated Outbreaks of Middle East Respiratory Syndrome Coronavirus (Mer

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1SCIENTIFIC REPORTS 2019 9 7385 w v w v y z w v w z y Comparative Analysis of Eleven Healthcare Associated Outbreaks of Middle East Respiratory Syndrome Coronavirus Mers Cov x v w x v w Sibylle Bernard Stoecklin w x Nikolay y Assiri z Bin Saeed Peter Karim Ben Embarek El Bushra Ki Malik Arnaud Fontanet w v w w w x y Received 11 November 2018 Accepted 18 April 2019 Published xx xx xxxx OPEN 2SCIENTIFIC REPORTS 2019 9 7385 w v w v y z w v w z y Figure 1 Epidemiological curves of MERS CoV infections by outbreak A Global MERS CoV epidemiological curve Gray surface total weekly number of laboratory conf irmed MERS CoV infections reported to WHO Colored curves HCA outbreaks included in the study af ter systematic policies and procedures for case identif ication and comprehensive contact identif ication and follow up were established and implemented B Weekly number of cases in each outbreak each line representing an outbreak Dark blue ROK15 grey SAU15 1 orange SAU15 2 light green SAU16 1 light blue SAU16 2 dark green SAU16 3 red SAU17 1 pink SAU17 2 purple SAU17 3 brown SAU17 4 turquoise SAU17 5 C Epidemic curve for each HCA by week comparing symptomatic dark grey asymptomatic case light grey and unknown symptoms of laboratory conf irmed cases white X axis represents the number of weeks since the f irst case was reported in each HCA outbreak 3SCIENTIFIC REPORTS 2019 9 7385 w v w v y z w v w z y Such large healthcare associated HCA outbreaks have mainly been limited to the Kingdom of Saudi Arabia KSA and the United Arabian Emirates UAE until the spring 2015 when a single imported case of MERS returning from the Middle East initiated a cluster of 186 cases in the Republic of Korea ROK across at least 17 hospitals and much of the country 18 Super spreading events in healthcare settings has been described for several previous MERS outbreaks including an outbreak in Al Hasa governorate in 2013 and during the out break in ROK where approximately 80 of the transmission events were epidemiologically linked to f ive MERS cases 14 18 23 Superspreading events in health care facilities have been observed in similar high threat respiratory disease pathogens such as Severe Acute Respiratory Syndrome SARS in Canada China Singapore 24 26 While more than half of the laboratory conf irmed MERS CoV infections reported globally to date are associ ated with human to human transmission in healthcare settings 27 there has been little human to human trans mission reported in household settings 28 Outbreak investigations and scientif ic studies conducted during or af ter MERS hospital outbreaks have identif ied that aerosol generating medical procedures with improper or inade quate personal protective equipment place medical personnel and patients sharing wards with MERS patients and family visitors at higher risk for MERS CoV infection 29 30 with exposure to infectious droplets being the likely source of contamination Although close unprotected contact with a MERS patient is generally considered neces sary for human to human transmission 31 several studies have revealed that MERS CoV particles can persist on surfaces as long as several days raising the possibility of a role of fomites in transmission 32 33 Fomite transmission is further supported by observed viral spreading between rooms that were clearly separated 15 18 and outbreaks that occurred in hemodialysis units 14 15 Factors leading to healthcare associated outbreaks include overcrowding in emergency departments slow triage and isolation of suspected patients and inadequate compliance to infection prevention and control proce dures 17 23 34 However few studies have described or compared the characteristics of HCA outbreaks as a whole in terms of their size epidemiologic factors 34 35 or the role of interventions to stop transmission 23 36 Here we provide the largest comprehensive study of eleven healthcare associated outbreaks that occurred between 2015 and June 2017 We carried out a comparative analysis of these outbreaks in terms of epidemiological prof iles demographic characteristics and clinical outcome Methods We analyzed epidemiological datasets of laboratory conf irmed MERS patients and focused our study on eleven healthcare associated outbreaks that were reported in KSA and ROK since 2015 when pol icies and procedures for case identif ication and comprehensive contact identif ication and follow up became sys tematic and were implemented by af fected countries T he data used documented MERS CoV infections reported to WHO under the International Health Regulations 2005 We only included clusters of cases outbreaks that were linked to healthcare facilities Supplemental ROK case based data were provided as a detailed line list of the Korean MERS cases included in a published study 17 We def ined laboratory conf irmed MERS CoV infection as following WHO guidelines 4 37 We def ined a HCA outbreak as the occurrence of 5 or more laboratory conf irmed MERS CoV infections with reported epidemiologic links between cases and during which the human to human transmission events were documented within a single healthcare facility with no more than 14 days apart between cases symptom onset T he MERS outbreak in the Republic of Korea in 2015 is treated as a single outbreak Individual level variables included information on age sex nationality occupation healthcare personnel HCP yes no dates of symptom onset date of notif ication to WHO presence of any pre existing co morbid conditions and clinical outcome In case of missing or conf licting information and when information from the country was not available we considered the data as missing Statistical analysis Descriptive analysis was performed by HCA outbreak outbreak level analysis using aggregated data and for all cases individual level analysis All analyses were conducted using Stata version 14 College Station TX StataCorp LP Microsof t Excel Version 15 35 2017 Jones Chicago USA and R Outbreak level analysis We calculated the duration size and case fatality ratio for each outbreak T he duration of an outbreak was calculated as the number of days between the date of symptom onset of the f irst reported case to the date of symptom onset of the last reported case We obtained weekly smoothed estimates of the case reproduction number based on the approach developed by Wallinga and Teunis 38 39 using the R 0 package We assumed that the serial interval of MERS CoV had a Gamma distribution with a mean of 6 8 days and a standard deviation of 4 1 days as described elsewhere 40 Individual level analysis We summarized case characteristics as frequencies and proportions for categorical variables as median and interquartile ranges IQR for continuous variables Chi square tests were used to com pare subgroups of cases when appropriate A P value of less than 0 05 was used to indicate statistical signif i cance Univariate analysis identif ied variables signif icantly associated with fatal outcome which were included in a multivariable model Model selection was performed using a multilevel mixed ef fects logistic regression with backwards selection taking into account clustering of individuals by outbreak For the variable age the cut of f was f ixed at 65 based on the results of the univariate analysis Variables with p values 0 05 were retained in the f inal model Ethics All data used in these secondary analyses were de identif ied data obtained from WHO or datasets from peer reviewed literature As such these data were deemed exempt from institutional review board assessment 4SCIENTIFIC REPORTS 2019 9 7385 w v w v y z w v w z y Results General characteristics of HCA outbreaks Since 1 January 2015 to 1 October 2018 2 260 laborato ry conf irmed MERS CoV infections have been reported to WHO Figureuni00A01A illustrates the global epidemic curve since MERS was f irst identif ied in humans Each peak is associated with a health care associated outbreak colored lines Fig uni00A01A From 2015 af fected countries implemented systematic contact tracing and follow up including laboratory testing investigation and data collection of MERS suspect cases 41 42 In our analysis a total of 423 laboratory conf irmed MERS cases from eleven distinct HCA outbreaks during 2015 2017 were included Tableuni00A01 T he eleven HCA outbreaks varied in terms of duration size and epidemiological prof ile Tableuni00A01 Fig uni00A01B T he median number of total reported cases per outbreak was 10 interquartile range IQR 6 27 ranging from 5 to 186 cases T he median duration was 20 days IQR 16 23 ranging from 10 to 57 days T hree outbreaks began with sporadic cases during the f irst two to f ive weeks of the outbreak while the other eight displayed a rapid increase to the peak T he median time between onset of symptoms of the f irst reported case and the peak of incidence was 3 weeks IQR 2 3 75 ranging from 2 to 6 weeks T he case fatality ratio CFR in outbreaks was 28 116 reported deaths among 423 cases compared with the global overall CFR of 35 5 800 reported deaths among 2 254 cases reported as of 1 October 3 Tableuni00A01 During HCA outbreaks CFR ranged from 0 to 75 p 0 01 and CFR was signif icantly lower among HCP MERS CoV infections compared to non HCP MERS CoV infections 2 vs 36 p 0 01 T he demographic and clinical characteristics of the cases from HCA outbreaks included in our analyses are summarized in Tableuni00A01 T he median age was 54 IQR 36 65 and signif icantly varied by outbreak p 0 001 Five outbreaks had a median age 40 and the other 6 outbreaks had a median age 50 T he majority of cases were male 57 n 243 423 and the sex ratio among cases dif fered signif icantly between outbreaks p 0 001 T he overall proportion of HCP was 25 n 105 422 T his proportion varied signif icantly by outbreak p 0 001 from 13 to 89 Tableuni00A01 Median age was signif icantly lower among HCP than non HCP cases 35 IQR 29 46 vs 58 IQR 45 70 p 0 001 and the proportion of females was higher among HCP than non HCP 70 vs 33 n 422 p 0 001 More than half 57 n 214 377 of cases had at least one underlying co morbid condition Tableuni00A01 and this was signif icantly lower among females compared to males 46 vs 64 respectively n 377 p 0 001 and among HCP compared to non HCP 13 vs 70 n 376 p 0 001 Sixteen percent n 67 419 of cases were asymptomatic at time of reporting Tableuni00A01 T his proportion varied signif icantly between outbreaks ranging from 0 to 87 n 419 p 0 001 Fig uni00A01C Median age of asympto matic cases was 34 IQR 30 48 the majority of whom were females 70 n 47 67 and had no underlying co morbid conditions 78 n 29 37 T he proportion of HCP among asymptomatic infections was high 70 n 47 67 and the CFR was null T he median duration between symptom onset and case notif ication to WHO was 5 days IQR 3 8 In univariate analysis fatal outcome was signif icantly asso ciated with age p 0 001 presence of underlying comorbidities p 0 001 non HCP status p 0 001 and male sex p 0 001 Tableuni00A02 In multivariate analysis patients 65 years old OR 4 79 95 CI 2 60 8 64 and the presence of 1 underly ing comorbid condition OR 2 74 95 CI 1 32 5 70 had an increased risk of death HCP status was associated with a decreased risk of death OR 0 07 95 CI 0 001 0 35 Tableuni00A02 At the start of each HCA outbreaks the case reproduc tion number R t ranged from 1 0 95 CI 0 7 1 3 to 5 7 95 CI 3 0 9 0 Tableuni00A01 and Fig uni00A02 Estimates of R t dropped below 1 within 2 to 6 weeks from the f irst reported case in the outbreak n 11 outbreaks median 3 weeks IQR 2 4 Outbreak Country City Year of outbreak Period of time Number of cases Duration days Initial R t median 95 CI Time to peak weeks Delay onset to notif ication Case fatality ratio Age median IQR Male n Asymptomatic n Presence of comorbidity n HCP n ROK15 Republic of Korea 2015 11 05 15 03 07 15 186 53 5 7 3 0 9 0 4 6 3 9 18 55 42 66 110 59 1 1 83 45 32 17 SAU15 1 Riyadh 2015 13 07 15 08 09 15 112 57 2 9 2 0 5 0 6 5 4 8 50 58 42 72 68 61 0 82 80 15 13 SAU15 2 Al Manea 2015 03 10 15 22 10 15 8 19 1 4 0 5 3 0 4 8 5 5 11 5 75 57 5 36 5 71 6 75 0 6 75 2 25 SAU16 1 Buraidah 2016 06 02 16 13 03 16 19 36 1 0 0 7 1 3 4 4 3 8 42 36 26 60 15 79 3 19 11 6 32 SAU16 2 Riyadh 2016 09 06 16 29 06 16 30 20 4 9 2 7 7 3 2 3 3 4 5 3 44 5 32 58 5 17 26 87 5 17 57 SAU16 3 Hofouf 2016 10 10 16 20 10 16 5 10 1 6 0 5 3 0 2 3 2 5 40 55 40 61 4 80 0 3 60 2 40 SAU17 1 Wadi Aldwasser 2017 26 02 17 11 03 17 10 13 2 0 0 3 4 3 2 2 5 2 5 0 39 32 52 4 40 4 40 7 78 2 20 SAU17 2 Wadi Aldwasser 2017 11 04 17 26 04 17 5 15 3 0 3 0 4 0 2 2 20 50 31 55 5 100 4 80 1 1 20 SAU17 3 Riyadh 2017 24 04 17 15 05 17 5 21 1 0 0 7 1 3 3 2 2 6 20 33 30 38 3 60 3 60 1 3 60 SAU17 4 Riyadh 2017 26 05 17 19 06 17 34 24 4 3 1 5 7 5 3 2 2 3 5 21 34 5 30 54 20 59 22 65 14 42 17 50 SAU17 5 Riyadh 2017 28 05 17 17 06 17 9 20 2 3 0 5 4 5 2 4 3 4 11 45 42 48 3 33 4 44 1 11 8 89 Table 1 Characteristics of HCA MERS outbreaks from 2015 2017 Dates of symptom onset or notif ication to WHO if the latter was not reported available of the f irst and the last cases No median or quartiles available 4 cases out of 5 were notif ied to WHO the same day as the onset of symptoms High proportion of missing values 5SCIENTIFIC REPORTS 2019 9 7385 w v w v y z w v w z y Discussion We provide here a comparative characterization of MERS HCA outbreaks and report substantial heterogeneity between HCA outbreaks illustrating the complexity of the factors contributing to the emergence of a cluster of cases associated with nosocomial transmission T he duration and epidemic prof iles of outbreaks varied some started with an apparent sharp increase in inci dence while others began more slowly with isolated cases emerging intermittently for a few weeks before a cluster of cases appeared in a healthcare facility Some outbreaks had a sharp decline in cases while others experienced a long tail lasting several weeks af ter the peak T he median estimates of the reproduction number R t in the early stages of outbreaks included in our anal yses reached as high as 5 7 in the Republic of Korea as has been found by others 43 likely facilitated by multiple superspreading events at two hospitals 43 What is perhaps most informative from a public health perspective is the length of time it took to bring the outbreaks under control All of outbreaks reached R t values below 1 within 2 to 6 weeks af ter the f irst cases were identif ied highlighting that the time frame in which hospital and ministry of f icials can implement control measures to stop nosocomial outbreaks Factors explaining dif ferences in HCA outbreak size and duration might include variations in the speed in which cases were suspected and timing of interventions implemented in healthcare settings including contact identif ication management and isolation of patients improved infection prevention and control measures and in some cases the requirement to close departments 14 18 29 In this study we were not able to evaluate the impact of interventions in these outbreaks Prevention of large HCA outbreaks since 2014 Fig uni00A01A may be in part explained by improvements in contact tracing policies implemented in 2015 In 2015 contact tracing became more systematic with the identi f ication and follow up of high close unprotected contact and low risk contacts protected HCW In af fected countries National Ministries of Health and hospital staf f comprehensively list all contacts of known MERS patients including healthcare workers at all facilities departments the patient visited patients who shared wards rooms with MERS patients family and visitors and occupational contacts Follow up of contacts includes the test ing of all high risk contacts regardless of the development of symptoms Recommendations stated that positive contacts are placed in quarantine home or hospital isolation for asymptomatic or symptomatic secondary cases respectively until they test negative 41 44 46 Additionally af fected countries enhanced infection prevention and control procedures education and training and implemented visual triage systems 41 to reduce delays in testing isolation and care of suspected MERS CoV patients T his has again been recently illustrated by the lack of second ary cases following the identif ication of a conf irmed case of MERS in Korea in September 2018 47 was due to the rapid and comprehensive isolation treatment and management of contacts of the patient T he variation in outbreak size and duration is also af fected by superspreading events early in some outbreaks during which a limited number of cases generated a disproportionately large proportion of the secondary cases under specif ic conditions in hospitals occurring in some outbreaks 48 50 Two super spreading events have been documented in KSA and in the Republic of Korea In the Republic of Korea the practice of doctor shopping extended stays in overcrowded emergency departments cultural practices of large numbers of family members visiting sick relatives and environmental contamination amplif ied transmission from some patients to oth ers 14 17 18 51 During the outbreak in KSA in 2015 at the Ministry of the National Guard Hospital a high number of secondary cases were among HCP very quickly af ter the hospitalization and a surgical procedure of the index case 16 T hese events triggered comprehensive review IPC in hospitals emergency department layout movements of patients triage of respiratory visits duration of emergency department stay training of hospital staf f and dis infection of healthcare facilities Our study conf irmed that age and presence of comorbidities are linked to increased risk of death similar to previously published results 52 53 whereas being HCP was protective T he protective ef fect of HCP could be explained by the fact that HCP are more likely to be younger 60 years old and have fewer underlying medical conditions than hospitalized patients but also that they are likely to be identif ied earlier or seek medical care soon following contact with a conf irmed patient T he proportion of asymptomatic secondary cases identif ied during outbreaks has increased since 2014 T here is no evidence to suggest that this represents changes in virus pathogenicity epidemiology or transmission Variables Univariate Analyses Multivariate Analyses OR p value 95 CI Adjusted OR p value 95 CI Age uni00A0uni00A0 65 1 1 uni00A0uni00A0uni226765 7 50 0 001 4 39 12 77 4 79 0 001 2 60 8 64 Underlying medical condition yes vs no 10 12 0 001 5 07 20 21 2 74 0 007 1 32 5 70 Health care personnel status HCP vs non HCP 0 03 0 001 0 01 0 15 0 07 0 001 0 01 0 35 Gender male vs female 2 74 0 001 1 69 4 44 Table 2 Risk factors associated with the disease outcome among MERS cases n 423 identif ied in 11 HCA outbreaks from 2015 2017 OR odds ratio Adj OR adjusted odds ratio Analysis using individual level data Univariate comparison of the association between the probability of fatal outcome and each categorical variable using the chi square test with a signif icance threshold at 0 05 Multilevel mixed ef fects logistic regression model with a random ef fect outbreak and adjusting for potential confounding factors with an exclusion threshold of 0 05 n 376 p 0 001 Missing values were excluded from both analyses 6SCIENTIFIC REPORTS 2019 9 7385 w v w v y z w v w z y patterns of MERS in recent years However the increase in the number of reported asymptomatic cases is hypothesized to be due to earlier detection ef forts from more aggressive contact identif ication and testing dur ing HCA outbreaks since 2015 as testing policies adopted and implemented by KSA and other countries have changed following the large outbreaks in Jeddah Riyadh in 2014 3 41 54 In 2017 40 80 of the laboratory con f irmed HCP secondary cases experienced no symptoms and were detected as part of a policy to test all contacts irrespective of symptoms Tableuni00A01 We believe that the identif ication of HCP asymptomatic c