【病毒外文文獻(xiàn)】2015 Middle East Respiratory Syndrome Coronavirus Superspreading Event Involving 81 Persons, Korea 2015

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2015 The Korean Academy of Medical Sciences This is an Open Access article distributed under the terms of the Creative Commons Attribution Non Commercial License http creativecommons org licenses by nc 4 0 which permits unrestricted non commercial use distribution and reproduction in any medium provided the original work is properly cited pISSN 1011 8934 eISSN 1598 6357 Middle East Respiratory Syndrome Coronavirus Superspreading Event Involving 81 Persons Korea 2015 Since the first imported case of Middle East respiratory syndrome coronavirus MERS CoV infection was reported on May 20 2015 in Korea there have been 186 laboratory confirmed cases of MERS CoV infection with 36 fatalities Ninety seven percent 181 186 of the cases had exposure to the health care facilities We are reporting a superspreading event that transmitted MERS CoV to 81 persons at a hospital emergency room ER during the Korean outbreak in 2015 The index case was a 35 yr old man who had vigorous coughing while staying at the ER for 58 hr As in severe acute respiratory syndrome outbreaks superspreading events can cause a large outbreak of MERS in healthcare facilities with severe consequences All healthcare facilities should establish and implement infection prevention and control measure as well as triage policies and procedures for early detection and isolation of suspected MERS CoV cases Keywords MERS Coronavirus Superspreading Event Emergency Room Prevention Myoung don Oh 1 Pyoeng Gyun Choe 1 Hong Sang Oh 1 Wan Beom Park 1 Sang Min Lee 1 Jinkyeong Park 2 Sang Kook Lee 3 Jeong Sup Song 4 and Nam Joong Kim 1 1 Department of Internal Medicine Seoul National University College of Medicine Seoul 2 Department of Internal Medicine Sungkyunkwan University School of Medicine Seoul 3 Department of Internal Medicine Good Morning Hospital Pyeongtaek 4 Department of Internal Medicine Pyeongtaek St Mary s Hospital Pyeongtaek Korea Myoung don Oh and Pyoeng Gyun Choe contributed equally to this work Received 3 October 2015 Accepted 5 October 2015 Address for Correspondence Myoung don Oh MD Department of Internal Medicine Seoul National University College of Medicine 103 Daehak ro Jongno gu Seoul 03080 Korea Tel 82 2 2072 2945 Fax 82 2 762 9662 E mail mdohmd snu ac kr Funding This study was supported by research grant 2015 1980 from the Clinical Research Institute Seoul National University Hospital http dx doi org 10 3346 jkms 2015 30 11 1701 J Korean Med Sci 2015 30 1701 1705 Middle East respiratory syndrome coronavirus MERS CoV infection is a severe respiratory disease that has recently emer ged in the Middle East 1 As of September 30 2015 26 coun tries reported 1 589 laboratory confirmed cases of infection with MERS CoV including 567 deaths to the World Health Or ganization 2 Most cases of MERS CoV infection have occurr ed in the Middle East although travel associated MERS cases have been reported by 16 countries outside the Middle East 3 Since the first case of MERS CoV infection in Korea was re ported on May 2015 in a traveler returning from the Middle East 4 there have been 186 laboratory confirmed cases with 36 fa talities It is the largest outbreak outside the Middle East and 97 181 186 of all cases were associated with healthcare fa cilities The largest 4 hospital clusters 91 36 14 11 cases per each hospital account for 82 of all cases 5 Here we report a superspreading event of MERS CoV involving 81 persons at an emergency room ER A 35 yr old Korean man was admitted to Hospital A on May 13 2015 with a seven day history of fever and productive cough He did not have any pre existing diseases Chest radiography and computed tomography on admission showed patchy con solidation in his left lung Empirical antibiotics were introduced and his symptoms improved gradually but fever was rebound ed on scheduled discharge date On May 20 2015 he was dis charged with a body temperature of 38 C During his stay at this hospital he was unknowingly exposed to MERS CoV during May 15 to 17 when the first imported case of MER CoV infec tion in Korea was admitted to the same ward On May 21 he was readmitted to Hospital A with fever of 38 3 C Computed tomography performed on readmission re vealed slight improvement of consolidation in left lung but new ly appearing small ground glass nodules in multiple lung fields Fig 1A B and C His symptoms did not improve despite chang ing the antibiotics As his fever continued and diarrhea devel oped he sought another hospital Hospital B for treatment on May 25 Chest radiography showed faint infiltrates in both lung fields Fig 1D On May 27 chest infiltrates became more prom inent and intermittent tachypnea developed The attending phy BRIEF COMMUNICATION Infectious Diseases Microbiology ParasitologyOh M D et al MERS Co V Superspreading Event 1702 http jkms org http dx doi org 10 3346 jkms 2015 30 11 1701 sician of Hospital B recommended that he visited a tertiary re ferral hospital On May 27 he was admitted to the ER of Hospital C located in Seoul On arrival because he had pneumonia a facemask was placed on the patient Chest radiography showed multiple patchy opacities in both lung fields Fig 1E Twelve hours later as his dyspnea worsened and oxygen saturation decreased to 90 oxygen supplementation at a rate of two liters per minute via nasal cannula was started During his 58 hr stay in the ER the location of his bed was changed several times He walked around the ER and other places nearby while coughing frequent ly and oftentimes removing his facemask He went to the toilet in the ER several times to expectorate in an effort to clear his throat In addition he had watery diarrhea up to seven times per 24 hr On May 29 KCDC notified the attending doctor that the pa tient had been exposed to MERS CoV at Hospital A Chest radi ography showed rapid progression of the infiltrates Fig 1F He was immediately transferred to an isolation room in the medi cal intensive care unit where he was intubated for mechanical ventilation On May 30 real time reverse transcriptase poly merase chain reaction RT PCR assay on a sputum specimen obtained on May 29 was returned as positive for MERS CoV As a result he was transferred on the same day to an isolation unit of a fourth hospital a MERS treatment hospital designated by the government Fig 2A shows the clinical course of the patient After the di agnosis of MERS CoV infection was made pegylated interferon alpha 2a was given by subcutaneous injection at a dose of 180 g per week for 2 weeks and oral ribavirin 1 200 mg loading dose followed by 400 mg every 8 hr for 4 days then 200 mg ev ery 6 hr for 6 days was given He received methylprednisolone 60 mg intravenously daily over 11 days for treatment of acute respiratory distress syndrome The laboratory tests showed mild changes including leukopenia hypoalbuminemia proteinuria and liver enzyme elevation Table 1 His condition improved continuously and mechanical ventilation was discontinued on June 6 On June 21 he was removed from the isolation room af ter the two consecutive sputum specimens collected at 48 hr in terval tested negative for MERS CoV on RT PCR assay He was A May 21 2015 B May 21 2015 C May 21 2015 D May 25 2015 E May 27 2015 F May 29 2015 Fig 1 Abnormalities on chest imaging of the patient Shown are computed tomography scans of the chest of the patient obtained on May 21 2015 A B and C Pre existing pneumonic consolidation in the left lung A and newly appearing ground glass nodules were observed A B and C red lines D is chest radiograph of the patient on May 25 2015 Faint infiltrates were shown in both lung fields E and F are chest radiographs of the patient on May 27 and May 29 2015 respectively when the patient stayed at the emergency room Multiple patchy opacities became more prominent on both lungs on May 27 2015 and 2 days later the opacities became more confluent Oh M D et al MERS Co V Superspreading Event http jkms org 1703 http dx doi org 10 3346 jkms 2015 30 11 1701 discharged the following day The index patient triggered a huge outbreak of MERS CoV at Hospital C resulting in a total of 91 cases of MERS CoV infec tion Of the 90 cases 39 35 90 were family members visiting the ER and 13 12 90 were doctors and nurses Of the cluster of 90 cases at Hospital C 81 cases had been exposed to the in dex patient at ER These 81 cases were tertiary infection in the chain of transmission The days of symptom onset for the 81 cases are shown in Fig 2B The incubation period ranged from 2 to 16 days with a median of 6 days Previous study reported that person to person transmission of MERS CoV can occur in health care settings 6 8 In a hos pital outbreak of MERS CoV in eastern Saudi Arabia 21 cases were infected by person to person transmission in 3 different health care facilities 7 In the 2014 MERS CoV outbreak in Jed dah Saudi Arabia 88 of the 112 symptomatic patients with MERS CoV infection had exposure to a health care facility 8 Neither of these papers reported any superspreading events in Table 1 Laboratory data for the patient Day White blood cells cell L Lymphocytes cell L Hemoglobin g dL Platelets cell L Creatinine mg dL Albumin g dL AST U L ALT U L PT INR Urine albumin in dipstick test May 21 8 280 3 146 18 5 339 000 1 03 4 7 42 74 ND ND May 25 5 200 634 16 6 164 000 1 0 4 1 50 57 1 26 May 27 4 000 688 15 9 122 000 1 0 3 6 55 46 ND ND May 30 5 260 652 15 9 138 000 0 66 3 3 134 70 1 01 2 June 2 6 780 623 13 7 230 000 0 89 2 6 141 61 1 09 2 June 6 8 300 1 307 13 9 392 000 0 69 3 1 64 131 1 15 1 June 10 11 220 2 221 15 5 453 000 0 67 3 7 91 212 1 08 June 14 8 890 3 138 15 2 334 000 0 81 4 0 67 167 1 02 June 18 6 280 1 720 13 1 184 000 0 73 3 6 29 66 1 06 June 22 7 640 2 009 13 2 259 000 0 82 3 8 36 56 1 13 AST aspartate aminotransferase ALT alanine transaminase PT prothrombin time INR international normalized ratio ND not determined Fig 2 Clinical course of the patient and the epidemic curve for the cases of Middle East respiratory syndrome coronavirus infections directly exposed to the patient The patient had productive cough due to pneumonia in his left lung prior to the onset of MERS CoV infection New infiltrates on chest radiograph and dyspnea developed on May 25 2015 and 5 days later respiratory failure developed A Of the cluster of 91 cases related to Hospital C 81 had exposure to the patient at the emergency room Among 81 cases the date of symptoms onset was not available in four cases The incubation period ranged from 2 to 16 days with a median of 6 days B The case had another exposure to a family member with MERS CoV infection between 8 to 10 days prior to onset of symptom GGO ground glass opacity CT computed tomography MERS CoV Middle East re spiratory syndrome coronavirus INF 2a interferon alpha2a 0 2 4 6 8 10 12 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Exposed to the patient at ER 36 38 40 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Temperature C No of Cases 36 38 40 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 ND M ay June Calendar day 24 29 36 28 23 Fig 2 Threshold cycle Value of MERS CoV upEgene Panel A Clinical Course Panel B Epidemic Curve by date of illness onset GGO nodules on CT scans New infiltrates On Chest PA Intubation Extubation Treatment Ribavirin IFN 2a M a y J u n e Calendar day 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 May May June June Calendar day Calendar day 24 28 23 29 36 ND 40 38 36 Exposed at Hospital A Temperature C Treatment Threshold cycle Value of MERS CoV upE gene No of cases Epidemic curve by date of illness onset Clinical course GGO nodules on CT scans New infiltrates On Chest PA Exposed to the patient at ER Intubation Extubation Ribavirin IFN 2a 12 10 8 6 4 2 0 A BOh M D et al MERS Co V Superspreading Event 1704 http jkms org http dx doi org 10 3346 jkms 2015 30 11 1701 contrast to the many severe acute respiratory syndrome SARS superspreading events in hospitals in 2003 9 Thus this is the first report of superspreading event of MERS CoV in health care facilities A superspreading event is likely to be related to the triad of the agent host and environment The preliminary analysis of virus sequencing data did not found any mutations linked to transmissibility or pathogenesis 10 11 However recent com plete genome analysis of the virus showed genetic recombina tion events between group 3 and group 5 of clade B that may have implications for the transmissibility 12 Although the pa tient did not undergo any aerosol generating procedures he had vigorous and frequent coughing that could be related to high viral shedding or increased efficiency of transmission As the ER did not have private rooms with toilet the patient walked through the ER to go to the public toilet several times a day The social tradition of many visitors or family members stay ing with patients created an environment conducive to super spreading events because of allowing close contact Thus the behavior of the patient the environment of ER and social tradi tion contributed a large number of close contacts leading to this superspreading event We found the shortest incubation period was 2 days and half of the 81 cases developed symptoms within 7 days after the ex posure Therefore it is of paramount importance that case iden tification laboratory confirmation and contact tracing should be done within a few days As contact tracing would be the most time consuming task public disclosure of the information on the possible exposure time and place of the index case could facilitate a more rapid and comprehensive contact tracing Our report highlights that all persons staying in the same ER or per haps using the same toilet should be considered and evaluated as having been potentially exposed to MERS CoV It is not al ways possible to early identify patients with MERS Therefore all health care facilities should have infection prevention and control practices in place Sustained human to human transmission did not occur in the Korean outbreak of MERS CoV although at least 23 cases of fourth generation transmission were confirmed 5 As of Sep tember 30 2015 exported cases of MERS CoV infection have been reported by 18 countries outside the Arabian Peninsula 3 but MERS CoV has never been spread to more than a few other people in health care facilities in these countries 13 15 The basic reproduction number R 0 for MERS CoV has been es timated to be less than 1 suggesting that the virus has not yet reached epidemic potential 16 However a recent study sug gested that cluster size over 150 cases should not be unexpected and there is substantial potential for superspreading events 17 Superspreading events have contributed other infectious dis ease outbreaks 18 most notably with the other recent new coronavirus that caused SARS in 2003 One of the defining fea tures of SARS CoV transmission inside and outside hospitals was superspreading events 19 20 Until now the lack of report ed superspreading events due to MERS CoV was a reassuring difference between MERS and SARS This report clearly dem onstrates that as in SARS outbreak superspreading events can cause a large outbreak of MERS in health care facilities To pre vent future international hospital outbreaks of MERS CoV all health care facilities should establish and implement infection prevention and control measures as well as triage policies and procedures for early detection and isolation of suspected MERS CoV cases DISCLOSURE The authors have no conflicts of interest to disclose AUTHOR CONTRIBUTION Conception and design Oh MD Choe PG Park WB Kim NJ Acquisition of data Choe PG Oh HS Lee SM Park JK Lee SK Song JS Analysis and interpretation of data Oh MD Choe PG Park WB Kim NJ Manuscript preparation Oh MD Choe PG Oh HS Manuscript approval all authors ORCID Myoung don Oh http orcid org 0000 0002 2344 7695 Pyoeng Gyun Choe http orcid org 0000 0001 6794 7918 Hong Sang Oh http orcid org 0000 0002 4535 6305 Wan Beom Park http orcid org 0000 0003 0022 9625 Sang Min Lee http orcid org 0000 0002 1388 9318 Jinkyeong Park http orcid org 0000 0002 8833 9062 Sang Kook Lee http orcid org 0000 0003 1993 0374 Jeong Sup Song http orcid org 0000 0002 2205 8655 Nam Joong Kim http orcid org 0000 0001 6793 9467 REFERENCES 1 Lee JK MERS Countermeasures as One of Global Health Security Agen da J Korean Med Sci 2015 30 997 8 2 World Health Organization Disease outbreak news Middle East respi ratory syndrome coronavirus MERS CoV Saudi Arabia Sep 30 2015 WHO 2015 Available at http www who int csr don 30 september 2015 mers saudi arabia en accessed on 1 Oct 2015 3 World Health Organization Middle East Respiratory Syndrome Coro 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