【病毒外文文献】2017 Fatality risks for nosocomial outbreaks of Middle East respiratory syndrome coronavirus in the Middle East and Sout

ORIGINAL ARTICLE Fatality risks for nosocomial outbreaks of Middle East respiratory syndrome coronavirus in the Middle East and South Korea Jianping Sha 1 Yuan Li 2 Xiaowen Chen 3 Yan Hu 1 Yajin Ren 1 Xingyi Geng 4 Zhiruo Zhang 5 Shelan Liu 6 Received 25 July 2016 Accepted 12 September 2016 C211 Springer Verlag Wien 2016 Abstract Middle East respiratory syndrome coronavirus MERS CoV was first isolated in 2012 The largest known outbreak outside the Middle East occurred in South Korea in 2015 As of 29 June 2016 1769 labora tory confirmed cases 630 deaths 35 6 case fatality rate CFR had been reported from 26 countries partic ularly in the Middle East However the CFR for hospital outbreaks was higher than that of family clusters in the Middle East and Korea Here we compared the mortality rates for 51 nosocomial outbreaks in the Middle East and one outbreak of MERS CoV in South Korea Our findings showed the CFR in the Middle East was much higher than that in South Korea 25 9 56 216 vs 13 8 24 174 p 0 003 Infected individuals who died were on average older than those who survived in both the Middle East 64 years 25 98 vs 46 years 2 85 p 0 000 and South Korea 68 years 49 82 vs 53 5 years 16 87 p 0 000 Similarly the co morbidity rates for the fatal cases were statistically higher than for the non fatal cases in both the Middle East 64 3 36 56 vs 28 1 45 160 p 0 000 and South Korea 45 8 11 24 vs 12 0 18 150 p 0 000 The median number of days from onset to confirmation of infection in the fatal cases was longer than that for survivors from the Middle East 8 days 1 47 vs 4 days 0 14 p 0 009 Thus older age pre existing concurrent dis eases and delayed confirmation increase the odds of a fatal outcome in nosocomial MERS CoV outbreaks in the Middle East and South Korea Introduction The first report of Middle East respiratory syndrome MERS was identified in Saudi Arabia in June 2012 The Middle East respiratory syndrome coronavirus MERS CoV isolated from this patient was similar to severe acute respiratory syndrome coronavirus SARS CoV which caused an epidemic in 2002 2003 49 Both novel viruses are single stranded RNA viruses belonging to the genus Betacoronavirus 25 48 and the diseases they cause share common clinical characteristics including fever cough diarrhea and shortness of breath 5 Jianping Sha Yuan Li and Xiaowen Chen equally contributed to this work Electronic supplementary material The online version of this article doi 10 1007 s00705 016 3062 x contains supplementary material which is available to authorized users the case fatality rate CFR was 35 6 630 1769 46 A total of 26 countries in the world have been affected including countries in the Middle East Egypt Iran Jordan Kuwait Lebanon Oman Qatar Saudi Arabia United Arab Emirates Yemen Africa Algeria Tunisia Europe Austria France Germany Greece Italy the Netherlands Turkey the United Kingdom Asia China the Republic of Korea Malaysia Philippines Thailand and North America United States http www who int emergencies mers cov en So far all cases of MERS have been linked through travel to or residence in countries in or near the Middle East Generally the Middle East is the primary region where MERS CoV originates circulates and is exported In contrast since the first report of SARS CoV in China in 2003 a total of 8096 SARS cases including 774 deaths have been reported to WHO These have involved 19 countries predominantly in South East Asia with only one case identified in Kuwait in 2003 and no cases were found in the Middle East since then http www who int csr sars country table2004 04 21 en The fatality risk for MERS CoV is much higher than that for SARS CoV which has a CFR of 9 6 9 24 Further more the CFR for patients with co morbidities is greater 60 in MERS vs 46 in SARS than those without pre existing diseases 49 Generally the CFR is attributed to both host factors and virus factors e g virus replication and mutation and local medical expertise 3 14 One unique common epidemiological characteristic of these two diseases is that the spread of both MERS CoV and SARS CoV infection has been largely driven by human to human transmission in healthcare settings 25 Failures in infection prevention and control in healthcare settings have occasionally resulted in large numbers of secondary cases in nosocomial outbreaks The earliest identified nosocomial MERS outbreak was traced back to March 2012 from clusters of severe respiratory illness among healthcare personnel HCP in Jordan 43 Since then a series of nosocomial MERS outbreaks in small numbers have been identified in the Middle East Jordan in 2012 Saudi Arabia in 2014 2015 1 6 10 18 36 In 2015 the largest known outbreak of MERS outside the Middle East occurred in the Republic of Korea as of 19 June 2015 186 laboratory confirmed cases including 36 deaths had been reported This outbreak was associated with a traveller returning from the Middle East http www cdc gov coronavirus mers about index html Although the genome sequences of MERS CoV isolates from the Republic of Korea are similar to those isolated from the Middle East http www who int mediacentre news mers briefing notes update 15 06 2015 en the epidemiology of MERS in South Korea is very different to that observed in the Middle East On the one hand a MERS CoV isolate that was responsible for an outbreak in South Korea showed a higher transmissibility than other previous MERS CoV isolates The epidemic thus far has undergone four generations of infec tious events in South Korea through nosocomial super spreading episodes 11 On the other hand an overall CFR of only 19 4 36 186 in hospital based outbreaks in South Korea is substantially lower than the overall CFR of cases most of which originate in the Middle East 38 444 1163 65 2 15 23 1 6 To date it is not clear what has caused the observed differences between the CFRs of South Korea and the Middle East In this study we conducted a preliminary mortality risk factor analysis for nosocomial MERS CoV outbreaks in South Korea and the Middle East The findings from this study might help to reduce the severity and number of deaths from hospital clustered cases by leading to the adoption of appropriate control measures Materials and methods In 2015 scientists in the Republic of Korea and China completed full genome sequencing of coronaviruses from the MERS outbreak in Korea The findings were analysed by a group of virologists convened by WHO and prelim inary results suggested that the MERS CoV viruses isolated in the Republic of Korea were similar to those isolated in the Middle East http www who int mediacentre news mers briefing notes update 15 06 2015 en MERS CoVs associated with the Korean and Middle East outbreak belong to lineage 5 of MERS CoV which has been the predominant infectious agent in Saudi Arabian camels since November 2014 41 The MERS CoV variants associated with the recent outbreak of human infections in South Korea e g ChinaGD01 v1 2015 and KOR KNIH 002 05 2015 show the highest similarity 99 96 99 98 full genome to a camel virus Camel Riyadh Ry159 2015 sampled in March 2015 followed by the latest strain KT026453 prevalent in Saudi Arabia 99 92 identified 26 However the MERS CoVs in Korea have the ability to cause large outbreaks in environments that are different from that of the Middle East http www who int emer gencies mers cov en Ethical statement The National Health and Family Planning Commission of China determined that the collection of data from one human MERS CoV infection imported from Korea was part of the public health investigation of an outbreak and was exempt from institutional review board assessment J Sha et al 123 All other MERS cases were obtained from publicly avail able data sources All data were supplied and analysed without access to personal identifying information Data sources Information on all laboratory confirmed MERS cases was obtained from various publicly available sources including WHO Global Alert and Response updates documents officially released by the local health bureau news releases from Middle Eastern and South Korean authorities the Weekly Epidemiological Record ProMed posts and liter ature published from 1 April 2012 to 29 June 2016 http www who int csr don archive disease coronavirus infections en The latest cases that had not been officially announced by WHO were identified by searching ProMed posts which confirmed announcements by individual countries ministries of health Based on the available data we initially established a database of a line list of human nosocomial MERS out breaks Supplementary Tables S1 S2 and S3 Case definitions MERS definitions According to the WHO s 14 July 2015 interim reporting definition http www who int csr disease coronavirus infections case definition en a person with MERS has a laboratory confirmed MERS CoV infection irrespective of clinical signs or symptoms A case may be laboratory confirmed by detection of viral nucleic acid or serology The presence of viral nucleic acid can be confirmed by either a positive reverse transcription polymerase chain reaction RT PCR result on at least two specific genomic targets or a single positive target with sequencing of a second target A case confirmed by serology requires demonstration of seroconversion in two samples ideally taken at least 14 days apart by enzyme linked immunosorbent assay ELISA by indirect fluorescent antibody IFA screening or by a neutralization assay 25 49 MERS cluster definitions A direct epidemiological link with a confirmed MERS CoV patient may include 1 healthcare associated expo sure including providing direct care for MERS CoV patients working with healthcare workers infected with MERS CoV visiting patients or staying in the same close environment of individuals infected with MERS CoV 2 working together in close proximity or sharing the same classroom environment with individuals infected with MERS CoV or 3 travelling together with individuals infected with MERS CoV in any kind of conveyance or living in the same household as individuals infected with MERS CoV In addition the epidemiological link may have occurred within a 14 day period before or after the onset of illness in the case under consideration 25 Statistical analysis We used a comparative epidemical analysis of the dates of onset of illness and the characteristics of the fatal and surviving cases All statistical analysis was conducted using the Statistical Analysis System version 9 2 SAS Institute Cary NC USA Quantitative measurements are presented as the median and range of the observed values and qualitative measurements are presented as relative and absolute frequencies An analysis of variance F test was applied to the measurement data v 2 tests were used to compare the distribution of the different variables of qualitative measurements between fatalities and survivors Fisher s exact test was used in the analysis of contingency tables when the sample sizes were small the expected values in any of the cells of a contingency table were below 5 the number of total samples was no more than 40 the data were very unequally distributed among the cells of the table Any p values given were two sided and considered statistically significant at 0 05 Results Fatality risk factors for human clusters and sporadic cases of MERS CoV infection As of 31 March 2016 we had identified 47 human labo ratory confirmed clusters with MERS CoV involving 179 cases of which 53 were fatal All clusters had been reported to WHO or published by the local authority or in PubMed These MERS clustered cases were distributed in nine countries 29 clusters from the Kingdom of Saudi Arabia KSA six from the United Arab Emirates UAE four from Jordan three from Qatar and one each from France Iran Italy Tunisia and the United Kingdom UK The numbers of clusters per year were as follows three clusters including 18 cases in 2012 33 clusters including 108 cases in 2014 and 11 clusters including 53 cases in 2014 For the control groups we chose a total of 504 sporadic cases of MERS CoV composed of 129 fatal and 375 nonfatal cases from the following countries 350 cases from the KSA 125 cases from the UAE 10 cases from Jordan 10 from Qatar and 9 from Tunisia The numbers of sporadic cases per year were as follows 110 cases in 2012 350 cases in 2013 and 44 cases in 2014 Fatality risks for nosocomial MERS outbreaks 123 The results showed that the percentages of HCP in MERS clusters were much higher than those in sporadic cases 32 4 58 179 vs 10 7 54 504 p 0 000 Table 1 and Table S1 However the HCP specific CFR was much lower than the overall CFR from MERS clusters 5 6 3 54 vs 29 6 53 179 p 0 000 and spo radic cases 7 4 4 54 vs 25 6 129 504 p 0 003 Table 1 Of the 53 fatal cases analysed in the MERS cluster groups 67 9 36 53 had concurrent health conditions which was a much higher percentage than that for nonfatal cases 22 2 28 126 p 0 000 A similar result was obtained for the sporadic groups 66 7 86 129 vs 33 3 125 375 p 0 000 However the percentage of co morbidities in fatal and nonfatal infections of HCP was much lower than that for fatal cases overall 67 9 36 53 vs 22 2 28 126 p 0 001 and nonfatal cases in the cluster groups 33 3 1 3 vs 7 8 4 51 p 0 000 Table 1 The mean age in the fatal cases was significantly higher than in the nonfatal cases in the clustered cases 57 years range 19 94 vs 38 years range 2 86 p 0 000 and sporadic cases 60 years range 0 94 vs 46 years range 2 90 p 0 000 In contrast the mean age of the sur vivors in clusters was slightly lower than in sporadic cases 38 years range 2 86 vs 46 years range 2 90 p 0 000 The median age in fatal cases in HCP was much lower than in fatal cases overall 46 5 years 33 56 vs 57 years 19 94 p 0 000 Table 1 We stratified the age groups between the fatal and nonfatal cases groups The results showed a statistical difference in the distribution of the 0 14 15 29 30 44 45 59 and 60 year olds between the two groups p 0 000 Males dominated both the fatal and nonfatal groups of the clustered and sporadic cases p 0 05 Table 1 A history of exposure to camels prior to onset of disease was not significantly correlated with survival 7 5 4 53 vs 5 6 7 126 p 0 612 Similarly there was no significant correlation between survival and exposure to other animals including sheep goats and horses 3 8 2 53 vs 0 8 1 126 p 0 156 Similar results were found for the sporadic cases for exposure to camels 3 9 5 129 vs 1 9 7 375 p 0 197 or to sheep goats and horses 0 8 1 129 vs 1 3 5 375 p 0 614 In contrast the percentage of survivors infected by human human transmission was slightly higher than in the group of fatal cases 92 9 117 126 vs 64 2 34 53 p 0 000 Table 1 Five time periods useful for public health surveillance were evaluated The median time from onset to confirma tion of infection in the fatal groups was much longer than that for survivors in MERS clusters 12 5 days 2 19 vs 9 days 0 24 p 0 041 and in sporadic MERS cases 12 days 1 41 vs 9 days 0 30 p 0 003 However there were no statistical differences in the median time from onset to hospital admission onset to hospital dis charge and subsequent death or the number of hospitalized days between the fatal and nonfatal cases for the two groups Table 1 Fatality risk factors in human nosocomial outbreaks of MERS CoV infection in the Middle East and South Korea By 30 March 2016 we had obtained data on 51 nosocomial outbreaks involved in 216 confirmed cases all 51 noso comial outbreaks were from the Middle East the above 47 clusters were not included in these outbreaks including Iran one cluster KSA 41 clusters Jordan three clus ters France one cluster and UAE five clusters We also had one nosocomial outbreak with 174 con firmed cases with MERS CoV in South Korea Table 2 and Table S2 The observed average cluster size 174 for MERS from South Korea was much greater than that for the Middle East 4 range 2 28 Human nosocomial outbreaks with MERS CoV in the Middle East occur throughout the year and peak in the spring especially February to April MERS outbreaks in South Korea were reported from March to June 2015 concomitant with peaks in the reporting of MERS noso comial outbreaks in the Middle East Table 2 The overall CFR of the nosocomial outbreaks with MERS CoV in the Middle East 25 9 56 216 was significantly higher than in South Korea 13 8 24 174 p 0 003 In contrast the HCP specific CFR 4 2 3 71 was slightly lower than the overall CFR in the Middle East p 0 000 Only one healthcare worker had died of MERS as of 15 July 2015 in South Korea HCP specific CFR 3 2 1 31 Table 2 The percentage of HCP in outbreaks with MERS CoV in the Middle East was much higher than in South Korea 32 9 71 216 vs 18 7 31 166 p 0 002 but the percentage visiting a hospital in the Middle East was lower 18 5 40 216 vs 30 1 50 166 p 0 008 Interestingly no difference was identified in the per centage of hospitalized patients 48 6 105 216 vs 51 2 85 166 p 0 615 between these two areas Table 2 For the two groups the percentage of co morbidities in those that died was statistically greater than that for sur vivors 64 3 36 56 vs 28 1 45 160 p 0 000 in the Middle East 45 8 11 24 vs 12 0 18 150 p 0 000 in South Korea Table 2 The average age in the fatal groups was much higher than that in the survival groups 64 years old 25 98 vs J Sha et al 123 46 years old 2 85 p 0 000 in the Middle East group 68 years old 49 82 vs 53 5 years old 16 87 p 0 000 in the South Korea group The over 60 year old groups had the highest proportion of deaths while the 45 to 59 year old groups had the largest number of survivors We found no difference in the gender distribution between the fatal and nonfatal cases in these two groups male vs female ratio 2 5 1 0 vs 1 28 1 0 in the fatal and nonfatal cases respectively from the Middle East p 0 057 2 0 1 0 vs 1 4 1 0 in the fatal and nonfatal cases respec tively from Korea p 0 509 Table 2 We found no difference between the fatal and nonfatal cases with respect to exposure to camels and other animals horses sheep and goats In contrast the level of human human transmission was much higher in the nonfatal cases in the Middle East than in the fatal cases 86 3 138 160 vs 57 1 32 56 p 0 000 The percentage of inter human transmission was much higher in the fatal cases in South Korea than in the Middle East 57 1 32 56 vs 100 0 24 24 p 0 000 Table 2 The Middle East group showed a statistical difference between fatal and nonfatal cases for the median days from Table 1 Epidemical and clinical comparison of fatal and nonfatal cases in human clusters and sporadic cases with MERS CoV as of 31 March 2016 Characteristic MERS clusters N 47 clusters 179 cases MERS sporadic cases N 504 Outgroup comparison Fatal n 53 Nonfatal n 126 p 1 value Fatal n 129 Nonfatal n 375 p 2 value p 3 value p 4 value Case fatality rate Overall CFR no 29 6 53 179 25 6 129 504 0 297 Male specific CFR no 31 7 40 126 27 9 84 301 0 425 HCP specific CFR no 5 6 3 54 7 4 4 54 0 696 Percentage of HCP no 32 4 58 179 10 7 54 504 0 000 Concurrent health condition in overall cases no 67 9 36 53 22 2 28 126 0 000 66 7 86 129 33 3 125 375 0 000 0 870 0 019 Concurrent health condition in HCP no 33 3 1 3 7 8 4 51 0 000 25 0 1 4 8 0 4 50 0 000 0 334 0 778 Mean age overall years 57 19 94 38 2 86 0 000 60 0 94 46 2 90 0 000 0 241 0 000 Mean age HCP years 46 5 33 56 37 24 60 0 000 41 5 26 54 39 24 48 0 000 0 333 0 431 Percent of male cases no 79 2 42 53 66 7 84 126 0 092 65 1 84 129 56 8 213 375 0 098 0 061 0 059 Age group no 0 14 0 0 0 53 7 1 9 126 0 000 1 6 2 129 2 9 11 35 0 000 0 000 0 000 15 29 7 5 4 53 30 2 38 126 6 2 8 129 18 7 70 375 30 44 18 9 10 53 32 5 41 126 10 1 13 129 31 7 119 375 45 59 35 8 19 53 23 29 126 27 9 36 129 24 8 93 375 60 37 7 20 53 7 1 9 126 54 3 70 129 21 9 82 375 Exposure history no Exposure to any animal 11 3 6 53 6 3 8 126 0 258 4 7 6 129 3 2 12 375 0 444 0 258 0 118 Exposure to a camel 7 5 4 53 5 6 7 126 0 612 3 9 5 129 1 9 7 375