【病毒外文文獻(xiàn)】2018 Healthcare-associated Infections_ The Hallmark of the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) With

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Accepted Manuscript Healthcare associated Infections The Hallmark of the Middle East Respiratory Syndrome Coronavirus MERS CoV With Review of the Literature Jaffar A Al Tawfiq MD Paul G Auwaerter M B A MD PII S0195 6701 18 30286 X DOI 10 1016 j jhin 2018 05 021 Reference YJHIN 5446 To appear in Journal of Hospital Infection Received Date 2 April 2018 Accepted Date 27 May 2018 Please cite this article as Al Tawfiq JA Auwaerter PG Healthcare associated Infections The Hallmark of the Middle East Respiratory Syndrome Coronavirus MERS CoV With Review of the Literature Journal of Hospital Infection 2018 doi 10 1016 j jhin 2018 05 021 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 Healthcare associated Infections The Hallmark of the Middle East Respiratory Syndrome Coronavirus MERS CoV With Review of the Literature Jaffar A Al Tawfiq MD1 2 3 Paul G Auwaerter M B A MD4 Specialty Internal Medicine Johns Hopkins Aramco Healthcare Dhahran Saudi Arabia1 and Indiana University School of Medicine Indiana USA2 Johns Hopkins University School of Medicine Baltimore MD USA3 and The Sherrilyn and Ken Fisher Center for Environmental Infectious Diseases Johns Hopkins University School of Medicine Baltimore MD USA4 Corresponding author Dr Jaffar A Al Tawfiq P O Box 76 Room A 428 2 Building 61 Dhahran Health Center Saudi Aramco Dhahran 31311 Saudi Arabia E mail address jaffar tawfiq jaltawfi Tel 966 13 877 3524 Fax 966 13 877 3790 Key words Middle East Respiratory Syndrome Coronavirus MERS Healthcare associated outbreaks Financial support all authors have no funding Conflict of interest all authors have no conflict of interest to declare M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 2 Abstract The Middle East Respiratory Syndrome Coronavirus MERS CoV is a coronavirus capable of causing acute respiratory illness Laboratory confirmed MERS CoV cases may be asymptomatic have mild disease or life threatening infection with a high case fatality rate There are three patterns of transmission sporadic community cases from presumed non human exposure family clusters arising from contact with the infected family index case and healthcare acquired infections among patients and from patients to healthcare workers Healthcare acquired MERS infection has become a well known characteristic of the disease and a leading means of spread Contributing factors foremost to such healthcare associated outbreaks include delayed recognition inadequate infection control measures inadequate triaging and isolation of suspected MERS or other respiratory illness patients crowding and patients remaining in the emergency department for many days A review of the literature suggests effective control of these hospital outbreaks was accomplished in most instances by the application of proper infection control procedures Prompt recognition isolation and management of suspected cases are key factors for the prevention of the spread of MERS Repeated assessments of infection control and monitoring of corrective measures contribute to changing the course of an outbreak Limiting the number of contacts and hospital visits are also important factors to decrease the spread of infection M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 3 Introduction The Middle East Respiratory Syndrome Coronavirus MERS CoV is a viral infection capable of causing acute respiratory infection though its spectrum ranges from asymptomatic laboratory confirmed cases or mild infection to a life threatening disease with a high case fatality rate 1 2 Initially described in 2012 in a 60 year old man hospitalized with suspected community acquired pneumonia developed renal and respiratory failure ultimately succumbing to progressive disease 3 The first reported healthcare associated infection was described among multiple facilities in Al Hasa Saudi Arabia 4 However a later retrospective analysis of a respiratory outbreak occurring in a Jordan public hospital determined that this cluster dated back earlier becoming the first recognized healthcare associated MERS CoV infection in April 2012 5 The disease was also recognized internationally in many countries with secondary transmissions The first MERS CoV infection in France caused one secondary transmission among 123 contacts 6 In a study of 51 outbreaks nosocomial transmissions were observed in 80 4 of the clusters 7 Another study found 37 5 of 1797 cases were ascribed to healthcare associated infections 8 The percentage of healthcare workers HCWs involved in different outbreaks is variable and ranges between 14 and 64 9 There seems to be a higher risk of severe disease in people with comorbid diseases and older age 8 As of March 2018 the WHO reported 2189 laboratory confirmed cases from 27 countries including 782 35 7 deaths 10 Among the reported cases peaks occurred in 2014 due to the Jeddah outbreak and 2015 South Korea outbreak figure 1 There are three patterns of MERS CoV transmission 1 sporadic community cases from presumed non human exposure 1 family clusters resulting from contact with an infected M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 4 family index case 11 13 and healthcare acquired infections between patients and from patients to healthcare workers 1 4 5 14 31 Though MERS CoV has a documented ability to transmit between humans even in healthcare settings there does not appear to be sustained human to human transmission This is likely due to the MERS CoV relatively low reproduction number of 0 8 1 3 29 30 The South Korean MERS outbreak was thought to have a low reproduction number of 1 31 However the reproduction number was estimated to be as high as 2 5 in some MERS outbreaks in Saudi Arabia and South Korea 32 The upper reproduction estimates were probably derived from lack of sufficient infection control measures and the estimates were lowered with improved detection and prevention practices over time In this review we review the available literature on healthcare associated infections and transmission of MERS CoV to elucidate the contributing risk factors Search strategy The search was performed according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses PRISMA guidelines http www prismastatement org The search included MEDLINE and Scopus databases for articles published in English as follows 1 MERS OR MERS CoV OR Middle East Respiratory Syndrome Coronavirus 2 Transmission OR Outbreak OR Healthcare associated infection OR Nosocomial or cluster 3 1 AND 2 M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 5 In addition we searched the Saudi Ministry of Health website for updates and the World Health Organization website and ProMed websites for any listed outbreaks We included published papers written in English if the studies described any healthcare associated outbreak and included contributing factors to the outbreak or factors that were used to limit and control the spread of the infection We excluded case reports and reports of clinical presentations We also excluded outbreaks with no specific descriptions of contributing factors to the outbreaks 10 18 26 Of the 40 full text articles assessed for eligibility 18 articles were excluded as these did not describe factors related to outbreaks A total of 22 articles were included in the final analyses for contributing factors for MERS CoV outbreaks in healthcare settings Timeline of Healthcare Associated Infections Many healthcare associated outbreaks have occurred in Saudi Arabia though a large outbreak arose in South Korea in 2015 1 A timeline of these outbreaks is shown in figure 2 the most recent updated figure from the World Health Organization The first outbreak in Saudi Arabia occurred in Al Hasa 4 followed by a significant epidemic in Jeddah in 2014 14 16 Other outbreaks in 2014 were in King Faisal Specialist Hospital 17 King Fahad Medical City in Riyadh 18 and and Al Madinah Al Mounawarh 21 There were no specific factors listed contributing to an outbreak at Prince Sultan Military Medical City Riyadh 18 20 In 2015 there were three outbreaks in Saudi Arabia in three public hospitals in Al Hasa region 22 King Abdulaziz Medical City in Riyadh 23 25 and King Fahad Cardiac Center 26 A multi facility outbreak of MERS CoV infection occurred in September 2014 January 2015 in Taif Saudi Arabia in four healthcare facilities 27 M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 6 Observed Infection Control Practices among Various Outbreaks Jordan Hospital Outbreak April 2012 The outbreak in Zarqa Jordan involved 13 healthcare workers with pneumonia 5 Following the identification of MERS CoV specimens from two fatal cases were retrospectively confirmed to be MERS CoV by real time RT PCR 5 Based on serology and PCR testing the attack rate was 10 among potentially exposed healthcare workers 15 In this outbreak multiple infection control issues were observed and included absence of physical barriers between different beds in intensive care units apart from cloth drapes lack of isolation and negative pressure rooms and non adherence to infection control measures 15 Patients were transferred to two other hospitals with no further evidence of intra hospital transmissions believed due to adequate infection control measures in the accepting institutions 15 Al Hasa 2013 Outbreak April May 2013 The outbreak involved four hospitals with 21 of the 23 cases acquired by person to person transmission within hemodialysis units intensive care units or other in patient areas 4 Contributing factors to this outbreak included the use of aerosol generating procedures and the performance of resuscitations 4 The outbreak abated by emphasizing primary infection control measures hand hygiene droplet and contact precautions for febrile patients testing all febrile patients for MERS CoV surgical mask use for all patients undergoing hemodialysis and N95 respirators for healthcare workers during aerosol generating procedures Additional measures included enhanced environmental cleaning and excluding non essential staff and visitors 4 A super spreading event might also have occurred in the Al Hasa outbreak where one patient infected seven secondary cases 4 M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 7 France Cases May 2013 A French patient contracted MERS CoV while traveling requiring hospitalization Of the 123 contacts of this index patient only one 0 8 hospitalized patient tested positive and 39 contacts of the second patient tested negative 6 Abu Dhabi Outbreak July 2013 A patient developed community acquired infection through camel contact receiving care in two different hospitals Of the 277 healthcare contacts four 1 4 had healthcare associated infections These four patients were exposed to the index case before the MERS CoV diagnosis and institution of any respiratory protection measures 28 Al Madinah Al Munawarrah August 24 to September 3 2013 From August 24 to September 3 2014 18 cases were linked to one cluster involving 11 healthcare associated infections 21 The outbreak was thought to be secondary to under recognition and poor infection control measures 21 Abu Dhabi Outbreak March April 2014 In this cluster the index case arose from camel exposure Only 2 2 2 of 90 hospital contacts were positive for MERS CoV 28 Another cluster was traced to a community member who visited an emergency room three times and was then subsequently admitted to a regular unit Evaluation of 224 contacts identified 15 6 7 positive cases 28 Prince Sultan Military Medical City March and April 2014 M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 8 Among multiple outbreaks in this hospital the largest outbreak came from 15 patients acquiring infection within the emergency room 20 The outbreak abated after application of infection control measures Jeddah 2014 Outbreak March 2 May 10 2014 Involving 14 hospitals and more than 200 cases 60 of infected cases resulted from healthcare associated transmission 14 16 33 Factors contributing to intra hospital transmission included inadequate separation of suspected MERS patients crowding and inconsistent use of infection control precautions 33 There was no triaging or isolation of patients with respiratory illness and patients remained in the emergency department for many days 33 In addition uncontrolled patient movements and high visitor traffic also contributed to the spate 23 Taif Saudi Arabia Outbreak September 2014 January 2015 The outbreak in Taif Saudi Arabia included four healthcare settings with the largest number traced to a hemodialysis unit involving 15 patients 27 The implicated cause was close spacing between patients of less than two meters 27 South Korea Outbreak May July 2015 The most prominent outbreak outside the Arabian Peninsula about 17 000 contacts were quarantined by the summer of 2015 34 The index patient had been in contact with 742 people between May 11 to 20 2015 in one hospital subsequently infecting 28 patients 35 An additional 186 MERS CoV cases were identified in more than 17 healthcare settings 31 36 39 Among the many contributory reasons for MERS CoV advancing within South Korea included healthcare workers unfamiliar with MERS suboptimal infection prevention and control M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 9 measures overcrowded emergency departments multi bed hospital rooms medical shopping by patients presence of visitors to infected patients extensive MERS patient movements and the use of aerosol generating procedures 40 42 Particularly problematic factors in the South Korea outbreak were contributions of overcrowding medical shopping and super spreaders 1 43 35 40 44 45 The first case in the Republic of Korea infected 27 secondary cases and one of the secondary patients then infected 24 tertiary cases and another secondary patient infected 73 tertiary cases 43 Another report from South Korea found 85 28 23 11 and 6 secondary cases arising from individual patients with MERS CoV 40 A secondary patient was described causing 91 tertiary MERS cases of which 39 occurred within the emergency department and 13 of cases were healthcare workers 45 Delayed isolation of suspected patients was an important factor that contributed to the spread of MERS CoV This was higher in super spreaders compared to other patients mean 6 6 vs 2 9 days P 0 061 46 Multi bedded rooms and nebulization treatments may have also contributed to the spread of MERS CoV in South Korea 47 King Abdulaziz Medical City in Riyadh in June August 2015 One of the largest MERS outbreaks occurred in the King Abdulaziz Medical City Riyadh Transmission appeared related to care in the emergency department before a MERS suspicion or diagnosis causing 130 cases 23 25 A major contributing factor was overcrowding in the emergency department 48 Jordan Outbreak August 2015 Amman Jordan during August October 2015 experienced 16 laboratory confirmed cases from nine hospitals 36 There were human to human transmissions in both cardiac care and M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 10 intensive care units of two hospitals 36 Analyzed viral isolates were similar to those recovered in Riyadh except for deletions in open reading frames 4a though its impact on transmissibility or virulence remains unknown 49 Riyadh June 2016 A nosocomial MERS outbreak was reported in Riyadh Saudi Arabia during 19 22 June 2016 This appeared to start with a woman admitted to the vascular surgery ward through the emergency room Her initial symptoms were not characteristic of MERS CoV infection After confirmation of the diagnosis active screening revealed 24 positive contacts HCWs 20 and of all contacts 20 83 3 were asymptomatic 50 Riyadh June 1 July 3 2017 Outbreaks The index case was a 47 year old male who underwent emergency intubation in the emergency room From 220 contacts 33 additional cases were identified as positive including 16 HCWs 10 This cluster was linked to a smaller cluster of five cases in another hospital with the involvement of three household contacts one patient contact and one health care worker 10 A third unrelated outbreak also occurred in Riyadh in June 2017 and involved nine cases with eight HCWs 4 asymptomatic and four had mild disease 10 Discussion The WHO continues to tally laboratory confirmed MERS CoV infections In the recent update from September 2012 to July 2017 there were 2040 cases with health care facility associated infections 40 HCWs patients and visitors representing 31 of cases 10 The initial symptoms of MERS CoV are non specific often thought to be pedestrian respiratory M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 11 infections and thus may go unnoticed Adherence to standard precautions at all times given the unpredictability of MERS CoV infection appears to be the critical factor for the prevention of transmission in health care facilities 10 Additionally environmental contamination may play a role in some transmission of MERS as viral RNA has been detected for up to five days on surfaces 36 A well characterized outbreak in Abu Dhabi United Arab Emirates offers insights into important infection control issues The overwhelming reason for MERS CoV spread centered on the delayed diagnosis of MERS CoV as 93 of infected contacts were exposed before the patient s diagnosis Also use of personal protective equipment PPE use during care was inconsistent among these HCWs especially during aerosol generating procedures Although improved PPE use would benefit a larger preventative impact would be placing patients presenting with respiratory complaints and potential MERS CoV infection in proper isolation with infection control practices until MERS CoV infection is ruled out using the standard PCR diagnostic method Protocols to address such patients in emergency departments or patients developing an apparent viral illness while hospitalized for other conditions should include the ability to rapidly isolate patients and run laboratory testing which would likely mitigate spread within healthcare systems Proper triaging of patients with acute respiratory illness is a fundamental step towards the application of a unified process to deal with such patients as suggested by the World Health Organization and the United States Centers for Disease control and preventions 51 52 Despite such advice not all healthcare systems in regions endemic for MERS CoV or in non endemic regions caring for a potentially infected traveller follow these steps In a simulation of a mystery infectious patient 95 drills including 42 drills specifically for patients with possible M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 12 MERS were conducted in 49 emergency departments in New York City USA Hospitals were variable in the identification of potentially infectious patients and implementation of appropriate infection control measures such as suboptimal adherence to hand hygiene PPE use and isolation signage posting 53 The Saudi Ministry of Health had recently introduced visual triage using a scoring system to aid in the assessment of patients presenting with respiratory symptoms in emergency departments dialysis units and other clinical settings 54 Also the Saudi Ministry of Health had developed a rapid response team that visits hospitals upon the identification of any positive MERS cases to help streamline contact tracing and implementation of infection control measures 55 A similar rapid response team was also formed following the MERS outbreak in South Korea 56