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Accepted Manuscript Surveillance of the MERS Coronavirus Infection in Healthcare Workers after Contact with Confirmed MERS Patients Incidence and Risk Factors of MERS CoV Seropositivity Chung Jong Kim MD Won Suk Choi Younghee Jung Sungmin Kiem Hee Yun Seol Heung Jeong Woo Young Hwa Choi Jun Seong Son Kye Hyung Kim Yeon Sook Kim Eu Suk Kim Sun Hee Park Ji Hyun Yoon Su Mi Choi Hyuck Lee Won Sup Oh Soo Young Choi Nam Joong Kim Jae Phil Choi So Yeon Park Jieun Kim Su Jin Jeong Kkot Sil Lee Hee Chang Jang Ji Young Rhee Baek Nam Kim Ji Hwan Bang Jae Hoon Lee ShinAe Park Hyo Youl Kim Jae Ki Choi Yu Mi Wi Hee Jung Choi MD PhD PII S1198 743X 16 30241 5 DOI 10 1016 j cmi 2016 07 017 Reference CMI 660 To appear in Clinical Microbiology and Infection Received Date 25 March 2016 Revised Date 11 July 2016 Accepted Date 16 July 2016 Please cite this article as Kim C J Choi WS Jung Y Kiem S Seol HY Woo HJ Choi YH Son JS Kim K H Kim Y S Kim ES Park SH Yoon JH Choi S M Lee H Oh WS Choi S Y Kim N J Choi J P Park SY Kim J Jeong SJ Lee KS Chang Jang H Rhee JY Kim B N Bang JH Lee JH Park S Kim HY Choi JK Wi Y M Choi HJ Surveillance of the MERS Coronavirus Infection in Healthcare Workers after Contact with Confirmed MERS Patients Incidence and Risk Factors of MERS CoV Seropositivity Clinical Microbiology and Infection 2016 doi 10 1016 j cmi 2016 07 017 This is a PDF file of an unedited manuscript that has been accepted for publication As a service to our customers we are providing this early version of the manuscript The manuscript will undergo copyediting typesetting and review of the resulting proof before it is published in its final form Please note that during the production process errors may be discovered which could affect the content and all legal disclaimers that apply to the journal pertain M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 1 Surveillance of the MERS Coronavirus Infection in Healthcare Workers after Contact with Confirmed MERS Patients Incidence and Risk Factors of MERS CoV Seropositivity Chung Jong Kim1 Won Suk Choi2 Younghee Jung3 Sungmin Kiem4 Hee Yun Seol5 Heung Jeong Woo6 Young Hwa Choi7 Jun Seong Son8 Kye Hyung Kim9 Yeon Sook Kim10 Eu Suk Kim11 Sun Hee Park12 Ji Hyun Yoon13 Su Mi Choi14 Hyuck Lee15 Won Sup Oh16 Soo Young Choi17 Nam Joong Kim18 Jae Phil Choi19 So Yeon Park20 Jieun Kim21 Su Jin Jeong22 Kkot Sil Lee23 Hee Chang Jang24 Ji Young Rhee25 Baek Nam Kim26 Ji Hwan Bang27 Jae Hoon Lee28 ShinAe Park29 Hyo Youl Kim30 Jae Ki Choi31 Yu Mi Wi32 Hee Jung Choi1 1 Department of Internal Medicine Division of Infectious Diseases Ewha Womans University School of Medicine 2 Division of Infectious Diseases Department of Internal Medicine Korea University College of Medicine Seoul Korea 3 Department of Internal Medicine Konyang University Hospital 4 Department of Internal Medicine Inje University Haeundae Paik Hospital 5 Department of Internal Medicine Good GangAn Hospital 6 Department of Internal Medicine Hallym University Dongtan Sacred Heart Hospital 7 Department of Internal Medicine Ajou University Hospital 8 Department of Internal Medicine Kyung Hee University Hospital at Gangdong 9 Department of Internal Medicine Pusan National University Hospital 10 Division of Infectious Diseases Department of Internal Medicine Chungnam National University School of Medicine M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 2 11 Department of Internal Medicine Seoul National University Bundang Hospital 12 Department of Internal Medicine College of Medicine the Catholic University of Korea Daejeon St Mary s Hospital 13 Department of Internal Medicine Eulji University Hospital 14 Department of Internal Medicine College of Medicine the Catholic University of Korea Yeouido St Mary s Hospital 15 Division of Infectious Diseases Dong A University Hospital 16 Department of Internal Medicine Kangwon National University Hospital 17 Department of Neurology Dae Cheong Hospital 18 Department of Internal Medicine Seoul National University Hospital 19 Department of Internal Medicine Seoul Medical Center 20 Department of Internal Medicine Hallym University Kangdong Sacred Heart Hospital 21 Department of Internal Medicine Hanyang University Guri Hospital 22 Department of Internal Medicine Gangnam Severance Hospital 23 Department of Internal Medicine Myongji Hospital 24 Department of Internal Medicine Chonnam National University Hospital 25 Department of Internal Medicine Dankook University Hospital 26 Department of Internal Medicine Inje University Sanggye Paik Hospital 27 Department of Internal Medicine Borame Medical Center 28 Department of Internal Medicine Wonkwang University Hospital 29 Department of Family Medicine Seobuk Hospital Seoul Metropolitan Government 30 Department of Internal Medicine Wonju Severance Christian Hospital 31 Department of Internal Medicine College of Medicine the Catholic University of Korea Bucheon St Mary s Hospital 32 Department of Internal Medicine Samsung Changwon Hospital M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 3 Conflicts of Interest None Key Words Middle East Respiratory Syndrome Healthcare Personnel Incidence IgG Personal protective equipment Running title MERS incidence in Healthcare Personnel Study registration Clinicaltrials gov identifier No NCT02497885 Correspondence Hee Jung Choi MD PhD Department of Internal Medicine Division of Infectious Diseases Ewha Womans University School of Medicine 1071 Anyangcheon ro Yangcheon gu Seoul Korea Telephone 82 2 2650 6008 Fax 82 2 2655 2076 E mail heechoi ewha ac kr Alternate author Chung Jong Kim MD Department of Internal Medicine Division of Infectious Diseases Ewha Womans University School of Medicine 1071 Anyangcheon ro Yangcheon gu Seoul Korea Telephone 82 2 2650 5089 Fax 82 2 2655 2076 E mail erinus00 M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 4 Abstract 1 Objectives Given the mode of transmission of Middle East Respiratory Syndrome MERS 2 healthcare workers HCWs in contact with MERS patients are expected to be at risk of 3 MERS infections We evaluated the prevalence of MERS coronavirus CoV immunoglobulin 4 G IgG in HCWs exposed to MERS patients and calculated the incidence of MERS affected 5 cases in HCWs 6 Methods We enrolled HCWs from hospitals where confirmed MERS patients had visited 7 Serum was collected 4 6 weeks after the last contact with a confirmed MERS patient We 8 performed an enzyme linked immunosorbent assay ELISA to screen for the presence of 9 MERS CoV IgG and an indirect immunofluorescence test IIFT to confirm MERS CoV 10 IgG We used a questionnaire to collect information regarding the exposure We calculated 11 the incidence of MERS affected cases by dividing the sum of PCR confirmed and serology 12 confirmed cases by the number of exposed HCWs in participating hospitals 13 Results In total 1169 HCWs in 31 hospitals had contact with 114 MERS patients and 14 among the HCWs 15 were PCR confirmed MERS cases in study hospitals Serologic analysis 15 was performed for 737 participants ELISA was positive in five participants and borderline 16 for seven IIFT was positive for two of these 12 participants 0 3 Among the participants 17 who did not use appropriate personal protective equipment PPE seropositivity was 0 7 18 2 294 compared to 0 0 443 in cases with appropriate PPE use 19 Conclusions The incidence of MERS infection in HCWs was 1 5 17 1169 The 20 seroprevalence of MERS CoV IgG among HCWs was higher among participants who did not 21 use appropriate PPE 22 M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 5 Introduction 23 Middle East Respiratory Syndrome MERS is an emerging infectious disease first 24 described in Saudi Arabia 1 2 and mainly found within the Middle Eastern region 3 25 Only a few cases have been reported outside the Middle East 4 6 and no epidemic event 26 outside the Middle East was seen before 2015 However that year the largest single nation 27 outbreak outside of Saudi Arabia occurred in South Korea over 45 days with 186 confirmed 28 MERS patients including 38 deaths 7 8 Because the main mode of transmission of MERS 29 is respiratory droplet and the most of MERS transmission is occurred in nosocomial setting 30 healthcare workers HCWs in contact with confirmed MERS patients are at high risk of 31 MERS infections 3 9 10 In South Korea among the 186 laboratory confirmed MERS 32 patients 39 cases 21 0 were medical professionals or HCWs 8 11 33 The spectrum of clinical manifestations of MERS was diverse and some patients 34 including a number of affected HCWs showed relatively mild symptoms Therefore it was 35 suspected that asymptomatic or undetected MERS infection may present in some of the 36 HCWs who had been involved in managing confirmed MERS patients One previous study 37 reported that 25 of MERS coronavirus MERS CoV polymerase chain reaction PCR 38 positive patients were asymptomatic and among these 64 were HCWs 3 Moreover the 39 period in which MERS CoV is present in respiratory specimens is unknown because the 40 viral shedding mechanism is still ambiguous even in confirmed MERS patients and the PCR 41 positivity rate of asymptomatic patients is unknown as yet Therefore we aimed to evaluate 42 the seroprevalence of MERS CoV IgG in HCWs exposed to MERS patients and calculate 43 the incidence of MERS affected cases in HCWs Furthermore we aimed to identify risk 44 factors of MERS infection in HCWs 45 M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 6 Methods 46 Population 47 We enrolled HCWs from participating hospitals where confirmed MERS patients had 48 visited or been treated The participating HCWs included doctors nurses nursing assistants 49 radiologic technologists patient transporters and patient caregivers Others were also 50 included in the study if they had had direct contact with confirmed MERS patients This 51 study did not use mandatory surveillance and only those who agreed to participate in the 52 study were enrolled HCWs who were already diagnosed as PCR confirmed MERS were not 53 included in serologic assay but included in calculating the incidence 54 55 Definitions 56 We included as participants only individuals who had been in direct contact with 57 confirmed MERS patients Direct contact was defined as any of the following i sharing 58 conversations with a confirmed MERS patient within a 2 meter reach ii staying with a 59 patient in a closed room for longer than 5 minutes or iii direct contact with respiratory or 60 gastrointestinal secretions from a patient Environmental factors and air circulation conditions 61 were not considered because these varied markedly among the hospitals 62 Study hospitals were divided into two groups MERS referral hospitals are those to 63 which PCR confirmed MERS patients were referred for management whereas MERS 64 affected hospitals are those where patients suspected to have MERS had visited prior to 65 confirmation of their diagnosis That is patients who had fever and respiratory symptoms 66 visited MERS affected rather than MERS referral hospitals and if MERS was confirmed by 67 means of MERS CoV PCR these patients were transferred to designated MERS referral 68 hospitals In some of the hospitals initially visited by patients suspected cases were admitted 69 and managed following laboratory confirmation of MERS These hospitals serving as a 70 M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 7 single stop for patients were defined as MERS affected in this study 71 Some participating HCWs were quarantined or under contact surveillance after contact 72 with a confirmed MERS patient The decision between quarantine and contact surveillance 73 was made by national Epidemic Intelligence Service officers dispatched to specific hospitals 74 according to the national guidelines In brief if the HCW was a close contact with MERS 75 patients without appropriate protection the case was placed under quarantine If casual 76 contact occurred the case was placed under contact surveillance 12 HCWs who were 77 quarantined were confined at home or in a quarantine facility for 14 days If respiratory 78 symptoms or fever developed in quarantined HCWs MERS CoV PCR in respiratory 79 specimen was performed twice in a 48 hour period according to the national guidelines in 80 each institution 12 HCWs who were placed under contact surveillance were monitored 81 daily for fever and respiratory symptoms for 14 days but were not prohibited from working 82 in hospitals 83 The definition of appropriate personal protective equipment PPE was drawn from 84 previous recommendations 12 15 Appropriate PPE was defined as use of all of the 85 following i N95 respirator or powered air purifying respirator PAPR ii isolation gown 86 coverall iii goggles or face shield and iv gloves If any part of the PPE was missing that 87 was considered to be exposure without appropriate PPE 88 We defined aerosol generating procedures AGP as follows suction of airway 89 application of high flow O2 instrument bronchoscopy intubation and or cardiopulmonary 90 resuscitation In cases in which AGP were performed only PAPR not an N95 respirator was 91 considered appropriate PPE 12 92 93 Sample Collection and Survey 94 We collected the serum of participants to identify the presence of MERS CoV IgG 95 M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 8 Further we used a questionnaire survey to gather information regarding the HCWs 96 demographic characteristics and extent of exposure The survey questionnaire was based on a 97 WHO questionnaire 16 98 Serum was collected 4 6 weeks after the last contact with confirmed MERS patients 99 100 Laboratory Procedures 101 We performed an enzyme linked immunosorbent assay ELISA Euroimmun L beck 102 Germany to screen for the presence of MERS CoV IgG In cases in which the optical density 103 of the ELISA exceeded a predefined cutoff value 50 of the reference value we 104 performed an indirect immunofluorescence test IIFT Euroimmun to confirm MERS CoV 105 IgG and quantify antibody titers The cutoff ELISA values were 80 of the reference value 106 for a positive and 50 for borderline result Serum was diluted 100 fold according to the 107 protocol suggested by the manufacturer Antibody titer measurement was conducted by two 108 fold dilution from 1 100 to 1 3200 109 110 Statistical Analysis 111 The data were analyzed using SPSS Version 20 0 We compared MERS referral and 112 MERS affected hospitals using the chi squared test and the Mann Whitney U test All tests 113 were two sided and a p value of 0 05 or less was considered significant 114 Incidence was calculated as follows Incidence of MERS infected cases the number of 115 PCR confirmed MERS cases in participating hospitals the number of serology confirmed 116 MERS cases in participating hospitals total number of MERS exposed HCWs in 117 participating hospitals 118 119 Study Approval 120 M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 9 All participants enrolled in the study voluntarily and written informed consent was 121 acquired before participation The study protocol was approved by the institutional review 122 board of Ewha Womans University Mokdong Hospital in Seoul South Korea EUMC 2015 123 07 002 124 M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 10 Results 125 Baseline Characteristics 126 Eighteen MERS affected hospitals and 13 MERS referral hospitals participated in the 127 study Figure 1 A total of 114 cases of MERS patients were managed in the participating 128 hospitals A total 1169 HCWs had contact with MERS patients in study hospitals of whom 129 603 were in MERS affected hospitals and 566 were in MERS referral hospitals Among 130 these 15 were diagnosed as PCR confirmed MERS cases during quarantine all of whom 131 were in MERS affected hospitals Four hundred and seventeen HCWs did not agree to 132 participate in the study Therefore 737 HCWs were enrolled in the study Figure 2 Of these 133 participants doctors accounted for 19 4 nurses 69 1 and radiologic technologists 2 3 134 Table 1 In MERS affected hospitals 62 4 of participants were quarantined whereas only 135 2 5 of participants in MERS referral hospitals were quarantined The baseline 136 characteristics of participants are shown in Table 1 137 138 ELISA and IIFT 139 The ELISA result was positive in 5 737 0 7 participants and borderline in 7 737 140 0 9 participants The IIFT was positive in 2 among the 12 participants who showed 141 borderline or positive results on the ELISA 0 3 of the total Table 2 Quantitative IIFT 142 showed that the titer of antibody was 1 400 and 1 800 respectively 143 144 Calculation of Incidence 145 We found 2 seropositive cases among 737 participants Therefore seroprevalence of MERS 146 CoV IgG among HCWs exposed to MERS patients who were asymptomatic or symptomatic 147 with negative MERS CoV PCR was 0 3 Based on the 15 cases of PCR confirmed MERS 148 cases in our study hospitals we assumed that at least 17 healthcare workers were affected by 149 M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 11 MERS and the incidence was at least 1 5 17 1169 Five of these cases were males and 12 150 were females 151 152 Symptoms Reported by Participants and Extent of Exposure 153 Overall 221 30 0 participants out of 737 reported one or more symptoms within 4 154 weeks of contact with PCR confirmed MERS patient Generalized symptoms 177 737 155 24 0 including fever 82 737 11 1 fatigue 82 737 11 1 and myalgia 68 737 156 9 2 were frequently reported Respiratory symptoms were reported in 13 6 and 157 gastrointestinal symptoms in 7 5 of participants 158 Total duration of contact with MERS patients and mean duration of contact with MERS 159 patients in a day were both significantly longer in MERS referral hospitals Two hundred and 160 ninety four participants had been exposed to one or more PCR confirmed MERS patients 161 without at least one form of appropriate PPE Exposure to AGP without PAPR occurred in 162 122 participants Table 3 163 Among the participants who on even one occasion did not use appropriate PPE 0 7 164 2 294 were seropositive compared to 0 among those who used it appropriately every 165 time Among participants who were exposed to AGP 0 8 1 122 were seropositive among 166 those who had been exposed without PAPR even once whereas 0 2 1 615 were 167 seropositive among those who had been exposed only with PAPR Table 4 168 M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 12 Discussion 169 In this study we evaluated the seroprevalence of MERS CoV among HCWs who had 170 had contact with MERS patients We found 2 asymptomatic or subclinical MERS infection in 171 HCWs both of them were exposed without appropriate PPE Overall prevalence of MERS 172 CoV seropositivity was 0 3 2 737 especially among the participants who did not use 173 appropriate PPE 0 7 2 294 was seropositive Considering fifteen PCR confirmed MERS 174 cases among HCWs in study hospital the incidence of MERS affected cases among 1169 175 exposed HCWs was at least 1 5 176 MERS CoV seroprevalence among populations other than confirmed MERS patients are 177 limited Recently it was reported that seroprevalence of MERS CoV IgG among the general 178 population of Saudi Arabia was 0 15 and that of the high risk population was 2 3 3 6 179 17 This suggests that a number of cases of asymptomatic or mild infection may be present 180 in the high risk population However there are not sufficient MERS CoV IgG seroprevalence 181 data among HCWs with which we can compare our results In SARS affected areas in 2003 182 seroprevalence among HCWs by using a confirmatory test ranged from 0 to 1 04 18 183 suggesting that undetected or asymptomatic cases were present after the SARS epidemic Our 184 study found a similar proportion of MERS subclinical infection among HCWs 185 To prevent MERS infection in HCWs use of PPE is emphasized In general isolation 186 gown and gloves are recommended as a contact precaution and su