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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">The Middle East Respiratory Syndrome Coronavirus – A Continuing Risk to Global Health Security</title></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27966107</idno><idno type="pmc">7119928</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7119928</idno><idno type="RBID">PMC:7119928</idno><idno type="doi">10.1007/5584_2016_133</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000211</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000211</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The Middle East Respiratory Syndrome Coronavirus – A Continuing Risk to Global Health Security</title></analytic><series><title level="j">Emerging and Re-emerging Viral Infections</title><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="Par1">Two new zoonotic coronaviruses causing disease in humans (Zumla et al. 2015a; Hui and Zumla 2015; Peiris et al. 2003; Yu et al. 2014) have been the focus of international attention for the past 14 years due to their epidemic potential; (1) The Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) (Peiris et al. 2003) first discovered in China in 2001 caused a major global epidemic of the Severe Acute Respiratory Syndrome (SARS). (2) The Middle East respiratory syndrome coronavirus (MERS-CoV) is a new corona virus isolated for the first time in a patients who died of severe lower respiratory tract infection in Jeddah (Saudi Arabia) in June 2012 (Zaki et al. 2012). The disease has been named Middle East Respiratory Syndrome (MERS) and it has remained on the radar of global public health authorities because of recurrent nosocomial and community outbreaks, and its association with severe disease and high mortality rates (Assiri et al. 2013a; Al-Abdallat et al. 2014; Memish et al. 2013a; Oboho et al. 2015; The WHO MERS-CoV Research Group 2013; Cotten et al. 2013a; Assiri et al. 2013b; Memish et al. 2013b; Azhar et al. 2014; Kim et al. 2015; Wang et al. 2015; Hui et al. 2015a). Cases of MERS have been reported from all continents and have been linked with travel to the Middle East (Hui et al. 2015a; WHO 2015c). The World Health Organization (WHO) have held nine meetings of the Emergency Committee (EC) convened by the Director-General under the International Health Regulations (IHR 2005) regarding MERS-CoV (WHO 2015c). There is wishful anticipation in the political and scientific communities that MERS-CoV like SARS-CoV will disappear with time. However it’s been nearly 4 years since the first discovery of MERS-CoV, and MERS cases continue to be reported throughout the year from the Middle East (WHO 2015c). There is a large MERS-CoV camel reservoir, and there is no specific treatment or vaccine (Zumla et al. 2015a). With 10 million people visiting Saudi Arabia every year for Umrah and/or Hajj, the potential risk of global spread is ever present (Memish et al. 2014a; McCloskey et al. 2014; Al-Tawfiq et al. 2014a).</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Al Abdallat, Mm" uniqKey="Al Abdallat M">MM Al-Abdallat</name></author><author><name sortKey="Payne, Dc" uniqKey="Payne D">DC Payne</name></author><author><name sortKey="Alqasrawi, S" uniqKey="Alqasrawi S">S Alqasrawi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Al Tawfiq, Ja" uniqKey="Al Tawfiq J">JA Al-Tawfiq</name></author><author><name sortKey="Zumla, A" uniqKey="Zumla A">A Zumla</name></author><author><name sortKey="Gautret, P" uniqKey="Gautret P">P Gautret</name></author><author><name sortKey="Gray, Gc" uniqKey="Gray G">GC Gray</name></author><author><name sortKey="Hui, Ds" uniqKey="Hui D">DS Hui</name></author><author><name sortKey="Al 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<front><journal-meta><journal-id journal-id-type="publisher-id">978-3-319-52485-6</journal-id><journal-id journal-id-type="doi">10.1007/978-3-319-52485-6</journal-id><journal-id journal-id-type="nlm-ta">Emerging and Re-emerging Viral Infections</journal-id><journal-title-group><journal-title>Emerging and Re-emerging Viral Infections</journal-title><journal-subtitle>Advances in Microbiology, Infectious Diseases and Public Health Volume 6</journal-subtitle></journal-title-group><isbn publication-format="print">978-3-319-52484-9</isbn><isbn publication-format="electronic">978-3-319-52485-6</isbn></journal-meta><article-meta><article-id pub-id-type="pmid">27966107</article-id><article-id pub-id-type="pmc">7119928</article-id><article-id pub-id-type="publisher-id">133</article-id><article-id pub-id-type="doi">10.1007/5584_2016_133</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>The Middle East Respiratory Syndrome Coronavirus – A Continuing Risk to Global Health Security</article-title></title-group><contrib-group content-type="book editors"><contrib contrib-type="editor"><name><surname>Rezza</surname><given-names>Giovanni</given-names></name><address><email>giovanni.rezza@iss.it</email></address><xref ref-type="aff" rid="Aff5">5</xref></contrib><contrib contrib-type="editor"><name><surname>Ippolito</surname><given-names>Giuseppe</given-names></name><address><email>giuseppe.ippolito@inmi.it</email></address><xref ref-type="aff" rid="Aff6">6</xref></contrib><aff id="Aff5"><label>5</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9120 6856</institution-id><institution-id institution-id-type="GRID">grid.416651.1</institution-id><institution>Istituto Superiore di Sanità IRCCS,</institution></institution-wrap>Roma, Italy</aff><aff id="Aff6"><label>6</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1760 4142</institution-id><institution-id institution-id-type="GRID">grid.419423.9</institution-id><institution>IRCCS,</institution><institution>National Institute for Infectious Diseases,</institution></institution-wrap>Roma, Italy</aff></contrib-group><contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Azhar</surname><given-names>Esam I.</given-names></name><address><email>eazhar@kau.edu.sa</email></address><xref ref-type="aff" rid="Aff7">7</xref><xref ref-type="aff" rid="Aff8">8</xref></contrib><contrib contrib-type="author"><name><surname>Lanini</surname><given-names>Simone</given-names></name><address><email>simone.lanini@inmi.it</email></address><xref ref-type="aff" rid="Aff9">9</xref></contrib><contrib contrib-type="author"><name><surname>Ippolito</surname><given-names>Giuseppe</given-names></name><address><email>giuseppe.ippolito@inmi.it</email></address><xref ref-type="aff" rid="Aff10">10</xref></contrib><contrib contrib-type="author"><name><surname>Zumla</surname><given-names>Alimuddin</given-names></name><address><email>a.zumla@ucl.ac.uk</email></address><xref ref-type="aff" rid="Aff11">11</xref><xref ref-type="aff" rid="Aff12">12</xref></contrib><aff id="Aff7"><label>7</label>Special Infectious Agents Unit, King Fahd Medical Research Centre, Jeddah, Saudi Arabia</aff><aff id="Aff8"><label>8</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0619 1117</institution-id><institution-id institution-id-type="GRID">grid.412125.1</institution-id><institution>Medical Laboratory Technology Department, Faculty of Applied Medical Sciences,</institution><institution>King Abdulaziz University,</institution></institution-wrap>Jeddah, Saudi Arabia</aff><aff id="Aff9"><label>9</label>Epidemiology and Preclinical Research Department, INMI Lazzaro Spallanzani, Via Portuense 292, 00149 Rome, Italy</aff><aff id="Aff10"><label>10</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1760 4142</institution-id><institution-id institution-id-type="GRID">grid.419423.9</institution-id><institution>National Institute for Infectious Diseases Lazzaro Spallanzani,</institution></institution-wrap>Via Portuense, 292, 00149 Rome, Italy</aff><aff id="Aff11"><label>11</label><institution-wrap><institution-id institution-id-type="ISNI">0000000121901201</institution-id><institution-id institution-id-type="GRID">grid.83440.3b</institution-id><institution>Division of Infection and Immunity,</institution><institution>University College London,</institution></institution-wrap>London, UK</aff><aff id="Aff12"><label>12</label><institution-wrap><institution-id institution-id-type="ISNI">0000000121901201</institution-id><institution-id institution-id-type="GRID">grid.83440.3b</institution-id><institution>NIHR Biomedical Research Centre,</institution><institution>UCL Hospitals NHS Foundation Trust,</institution></institution-wrap>London, UK</aff></contrib-group><pub-date pub-type="epub"><day>14</day><month>12</month><year>2016</year></pub-date><volume>972</volume><fpage>49</fpage><lpage>60</lpage><permissions><copyright-statement>© Springer International Publishing Switzerland 2016</copyright-statement><license><license-p>This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.</license-p></license></permissions><abstract id="Abs1"><p id="Par1">Two new zoonotic coronaviruses causing disease in humans (Zumla et al. 2015a; Hui and Zumla 2015; Peiris et al. 2003; Yu et al. 2014) have been the focus of international attention for the past 14 years due to their epidemic potential; (1) The Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) (Peiris et al. 2003) first discovered in China in 2001 caused a major global epidemic of the Severe Acute Respiratory Syndrome (SARS). (2) The Middle East respiratory syndrome coronavirus (MERS-CoV) is a new corona virus isolated for the first time in a patients who died of severe lower respiratory tract infection in Jeddah (Saudi Arabia) in June 2012 (Zaki et al. 2012). The disease has been named Middle East Respiratory Syndrome (MERS) and it has remained on the radar of global public health authorities because of recurrent nosocomial and community outbreaks, and its association with severe disease and high mortality rates (Assiri et al. 2013a; Al-Abdallat et al. 2014; Memish et al. 2013a; Oboho et al. 2015; The WHO MERS-CoV Research Group 2013; Cotten et al. 2013a; Assiri et al. 2013b; Memish et al. 2013b; Azhar et al. 2014; Kim et al. 2015; Wang et al. 2015; Hui et al. 2015a). Cases of MERS have been reported from all continents and have been linked with travel to the Middle East (Hui et al. 2015a; WHO 2015c). The World Health Organization (WHO) have held nine meetings of the Emergency Committee (EC) convened by the Director-General under the International Health Regulations (IHR 2005) regarding MERS-CoV (WHO 2015c). There is wishful anticipation in the political and scientific communities that MERS-CoV like SARS-CoV will disappear with time. However it’s been nearly 4 years since the first discovery of MERS-CoV, and MERS cases continue to be reported throughout the year from the Middle East (WHO 2015c). There is a large MERS-CoV camel reservoir, and there is no specific treatment or vaccine (Zumla et al. 2015a). With 10 million people visiting Saudi Arabia every year for Umrah and/or Hajj, the potential risk of global spread is ever present (Memish et al. 2014a; McCloskey et al. 2014; Al-Tawfiq et al. 2014a).</p></abstract><kwd-group xml:lang="en"><title>Keywords</title><kwd>Coronavirus</kwd><kwd>MERS</kwd><kwd>MERS-CoV</kwd><kwd>Middle East</kwd><kwd>Drugs</kwd><kwd>Infection control</kwd><kwd>Treatment</kwd><kwd>Risk</kwd><kwd>Camels</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© Springer International Publishing AG 2017</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="Sec1" sec-type="introduction"><title>Introduction</title><p id="Par2">Two new zoonotic coronaviruses causing disease in humans (Zumla et al. <xref ref-type="bibr" rid="CR69">2015a</xref>; Hui and Zumla <xref ref-type="bibr" rid="CR26">2015</xref>; Peiris et al. <xref ref-type="bibr" rid="CR49">2003</xref>; Yu et al. <xref ref-type="bibr" rid="CR65">2014</xref>) have been the focus of international attention for the past 14 years due to their epidemic potential; (1) the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) (Peiris et al. <xref ref-type="bibr" rid="CR49">2003</xref>) first discovered in China in 2001 which caused a major global epidemic of the Severe Acute Respiratory Syndrome (SARS); and (2) the Middle East respiratory syndrome coronavirus (MERS-CoV) first isolated from a patient who died of severe lower respiratory tract infection in Jeddah (Saudi Arabia) in June 2012 (Zaki et al. <xref ref-type="bibr" rid="CR66">2012</xref>). The disease has been named Middle East Respiratory Syndrome (MERS) and it has remained on the radar of global public health authorities because of recurrent nosocomial and community outbreaks, and its association with severe disease and high mortality rates (Assiri et al. <xref ref-type="bibr" rid="CR5">2013a</xref>; Al-Abdallat et al. <xref ref-type="bibr" rid="CR1">2014</xref>; Memish et al. <xref ref-type="bibr" rid="CR37">2013a</xref>; Oboho et al. <xref ref-type="bibr" rid="CR46">2015</xref>; The WHO MERS-CoV Research Group <xref ref-type="bibr" rid="CR59">2013</xref>; Cotten et al. <xref ref-type="bibr" rid="CR13">2013a</xref>; Assiri et al. <xref ref-type="bibr" rid="CR6">2013b</xref>; Memish et al. <xref ref-type="bibr" rid="CR38">2013b</xref>; Azhar et al. <xref ref-type="bibr" rid="CR7">2014</xref>; Kim et al. <xref ref-type="bibr" rid="CR30">2015</xref>; Wang et al. <xref ref-type="bibr" rid="CR61">2015</xref>; <xref ref-type="bibr" rid="CR27">Hui et al. 2015a</xref>). Cases of MERS have been reported from all continents and have been linked with travel to the Middle East (<xref ref-type="bibr" rid="CR27">Hui et al. 2015a</xref>; WHO <xref ref-type="bibr" rid="CR75">2015c</xref>). The World Health Organization (WHO) have held nine meetings of the Emergency Committee (EC) convened by the Director-General under the International Health Regulations (IHR 2005) regarding MERS-CoV (WHO <xref ref-type="bibr" rid="CR75">2015c</xref>). There is wishful anticipation in the political and scientific communities that MERS-CoV like SARS-CoV will disappear with time. However it’s been nearly 4 years since the first discovery of MERS-CoV, and MERS cases continue to be reported throughout the year from the Middle East (WHO <xref ref-type="bibr" rid="CR75">2015c</xref>). There is a large MERS-CoV camel reservoir, and there is no specific treatment or vaccine (Zumla et al. <xref ref-type="bibr" rid="CR69">2015a</xref>). With 10 million people visiting Saudi Arabia every year for Umrah and/or Hajj, the potential risk of global spread is ever present (Memish et al. <xref ref-type="bibr" rid="CR40">2014a</xref>; McCloskey et al. <xref ref-type="bibr" rid="CR36">2014</xref>; Al-Tawfiq et al. <xref ref-type="bibr" rid="CR2">2014a</xref>).</p><p id="Par3">This chapter gives a succinct overview of MERS-CoV epidemiology, clinical features, and highlights the knowledge gaps and its epidemic risk potential.</p></sec><sec id="Sec2"><title>Epidemiological Features of MERS-CoV</title><sec id="Sec3"><title>Discovery and Evolution</title><p id="Par4">At first identification and publication of the isolation of a novel β CoV coronavirus in September 2012 (Zaki et al. <xref ref-type="bibr" rid="CR66">2012</xref>), the name EMC/2012 was given to it after the laboratory at the Erasmus Medical Centre (EMC) in the Netherlands. The EMC laboratory had sequenced the virus from clinical samples shipped from a hospital in Jeddah, Saudi Arabia where a patient had died of respiratory failure in June 2012. The virus was renamed MERS-CoV after international consensus and the clinical disease it caused was called Middle East Respiratory Syndrome (MERS) (de Groot et al. <xref ref-type="bibr" rid="CR16">2013</xref>). In order to ascertain whether it was a new disease of humans, several retrospective and historical studies were performed on stored biobanks of patient samples in the Middle East. In particular one study showed that in April 2012 there was a hospital MERS cluster of infections in Jordan (Hijawi et al. <xref ref-type="bibr" rid="CR24">2013</xref>), predating the Jeddah case. Recent evolutionary studies based on whole-genome sequences and temporal analysis of infection clusters suggested that MERS-CoV most probably emerged between November 2009 and April 2012 (Cotten et al. <xref ref-type="bibr" rid="CR14">2013b</xref>, <xref ref-type="bibr" rid="CR15">2014</xref>; Penttinen et al. <xref ref-type="bibr" rid="CR50">2013</xref>). Ever since its first discovery, intermittent endemic cases of MERS cases are being reported throughout the year from Saudi Arabia as single cases, clusters in the community or hospital outbreaks (WHO <xref ref-type="bibr" rid="CR75">2015c</xref>). Furthermore there have been MERS cases reported from all continents and these have been linked to travel to the Middle East (Zumla et al. <xref ref-type="bibr" rid="CR69">2015a</xref>; WHO <xref ref-type="bibr" rid="CR75">2015c</xref>).</p></sec><sec id="Sec4"><title>Geographical Distribution</title><p id="Par5">As of 25th November, 2016, WHO reports that globally there have been 1,832 laboratory-confirmed cases of MERS-CoV with 651 deaths reported (case fatality rate 35 %) (WHO <xref ref-type="bibr" rid="CR75">2015c</xref>). Twenty seven countries have reported cases of MERS to the WHO (Fig. <xref rid="Fig1" ref-type="fig">1</xref>): Baharain, Iran, Jordan, Kuwait, Lebanon, Oman, Qatar, Saudi Arabia, the United Arab Emirates, and Yemen (Middle East); Austria, France, Germany, Greece, Italy, Netherlands, Turkey, and the United Kingdom (UK) (Europe); Algeria, Tunisia and Egypt (Africa); China, Malaysia, Republic of Korea, the Philippines and Thailand (Asia); and the United States of America (Americas) (WHO <xref ref-type="bibr" rid="CR64">2016</xref>). A large proportion of MERS cases have been reported from Saudi Arabia. The largest MERS outbreak outside Saudi Arabia occurred in hospitals in the Republic Korea in mid-2015 where MERS-CoV was imported by a traveler to the Middle East. Poor infection control measures led to spread of MERS-CoV resulting in 184 MERS cases with 33 deaths (WHO <xref ref-type="bibr" rid="CR75">2015c</xref>).<fig id="Fig1"><label>Fig. 1</label><caption><p>Global cases of MERS-CoV infection reported to WHO (2012–2015)</p></caption><graphic xlink:href="432480_1_En_133_Fig1_HTML" id="MO1"></graphic></fig></p></sec><sec id="Sec5"><title>Origin and Transmission of MERS-CoV</title><p id="Par6">Several studies have sought to ascertain the natural reservoir of MERS-CoV. Studies on bat feces from Middle East, Africa and several European countries have reported CoV in Nycteris and Pipistrellus bats (Annan et al. <xref ref-type="bibr" rid="CR4">2013</xref>; Memish et al. <xref ref-type="bibr" rid="CR39">2013c</xref>). From Saudi Arabia, over a thousand bat samples were tested and only one fragment of MERS-CoV was found in one Taphozous bat which was related to MERS-CoV isolated from humans (Memish et al. <xref ref-type="bibr" rid="CR39">2013c</xref>). Several studies have subsequently indicated that MERS‐CoV is a zoonotic virus and human infections have been associated with direct or indirect contact with infected dromedary camels (Reusken et al. <xref ref-type="bibr" rid="CR54">2013</xref>, <xref ref-type="bibr" rid="CR55">2014</xref>; Haagmans et al. <xref ref-type="bibr" rid="CR22">2014</xref>; Hemida et al. <xref ref-type="bibr" rid="CR23">2014</xref>; Meyer et al. <xref ref-type="bibr" rid="CR43">2014</xref>; Muller et al. <xref ref-type="bibr" rid="CR44">2014</xref>; Gossner et al. <xref ref-type="bibr" rid="CR21">2016</xref>). Strains of MERS-CoV have been identified in camels in several countries, including Saudi Arabia, Egypt, Oman, and Qatar. MERS-CoV antibodies have been found in camels in Africa and throughout the Middle East. Recently at least five lineages of MERS-CoV in Saudi Arabian camels have been found (Sabir et al. <xref ref-type="bibr" rid="CR56">2016</xref>; Du and Han <xref ref-type="bibr" rid="CR18">2016</xref>). Human to human transmission of MERS-CoV has been documented only for close contacts of infected subjects including transmission among family members and between patients and healthcare worker (Assiri et al. <xref ref-type="bibr" rid="CR5">2013a</xref>, <xref ref-type="bibr" rid="CR6">b</xref>; Cotten et al. <xref ref-type="bibr" rid="CR13">2013a</xref>; Memish et al. <xref ref-type="bibr" rid="CR38">2013b</xref>; Kim et al. <xref ref-type="bibr" rid="CR31">2016a</xref>; Younan et al. <xref ref-type="bibr" rid="CR76">2016</xref>). Convincing evidence support the hypothesis that dromedary camel are a natural reservoir of the infection and that this animal species can have a primary role for the transmission of MERS-CoV to human beings. However, only a small proportion of the primary cases have reported contact with camels. The apparent rarity of MERS-CoV transmission from primary MERS cases apart from hospital settings indicates that the transmission potential and infectivity of such cases is low. The occasional sporadic occurrence of MERS-CoV infection in MERS cases who have any reported animal contact or exposure to MERS cases may be explained by low level infectivity of sub-clinical or asymptomatic cases of MERS-CoV infection (Lessler et al. <xref ref-type="bibr" rid="CR34">2016</xref>).</p></sec><sec id="Sec6"><title>Natural History and Pathogenesis</title><p id="Par7">The sporadic nature of MERS-CoV infection with new cases or clusters distributed over a wide geographic area and rather heterogeneous social settings, represents a significant issue for designing and for implementing solid prospective studies. Thus, the main questions about the epidemiology, source of infection, natural history of the disease, the transmission patterns and pathogenesis remain largely unanswered, as yet (Hui and Zumla <xref ref-type="bibr" rid="CR25">2014</xref>). Furthermore, the appearance of MERS-CoV, in human populations soon after the SARS-CoV pandemic emphasizes the importance of a One Health approach (Rabozzi et al. <xref ref-type="bibr" rid="CR53">2012</xref>) to surveillance of zoonotic infections through integration of human, animal, and environmental health programs. Strengthening surveillance and laboratory networks, as well as training of an effective surveillance workforce is required and needs commitment by all stakeholders, particularly Health Authorities in Middle Eastern Countries.</p></sec></sec><sec id="Sec7"><title>Clinical Presentation</title><p id="Par8">There have been several reviews on the clinical aspects of MERS-CoV (Zumla et al. <xref ref-type="bibr" rid="CR69">2015a</xref>; Hui and Zumla <xref ref-type="bibr" rid="CR26">2015</xref>; The WHO MERS-CoV Research Group <xref ref-type="bibr" rid="CR59">2013</xref>; Assiri et al. <xref ref-type="bibr" rid="CR6">2013b</xref>; Al-Tawfiq et al. <xref ref-type="bibr" rid="CR3">2014b</xref>; ISARIC and Public Health <xref ref-type="bibr" rid="CR29">2014</xref>). MERS presents as a clinical spectrum from the asymptomatic, mild, moderate to severe fulminant multisystem disease. There is limited data on pathogenesis due to lack of autopsy or histological studies. MERS-CoV is known to bind to dipeptidyl peptidase 4 (DPP4) receptors (Lu et al. <xref ref-type="bibr" rid="CR35">2013</xref>) that are widespread in the body but are primarily located in the lower respiratory tract and thus a typical case of MERS presents with fever, cough, and/or shortness of breath and pneumonia (detailed in Table <xref rid="Tab1" ref-type="table">1</xref>). Severe illness can occur in both immunocompetent and immunocompromised host. In general progression to respiratory and/or renal failure requires intensive care support. Some patients have multi-organ failure and secondary infections leading to septic shock. Mortality rates are high in older people, immunosuppressed patients and in those with co-morbities such as diabetes, cancer, chronic obstructive pulmonary and heart disease.<table-wrap id="Tab1"><label>Table 1</label><caption><p>Clinical and laboratory features of patient with MERS</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Clinical/laboratory feature(s)</th><th></th></tr></thead><tbody><tr><td rowspan="2"><bold>Date of first case (place)</bold></td><td>April 2012 (Zarqa, Jordan)</td></tr><tr><td>June 2012 (Jeddah, KSA)</td></tr><tr><td rowspan="2"><bold>Incubation period</bold></td><td>Mean: 5.2 days (95%CI:1.9–14.7)</td></tr><tr><td>Range: 2–14 days</td></tr><tr><td><bold>Serial interval</bold></td><td>7.6 days</td></tr><tr><td><bold>Basic reproduction number</bold></td><td><1</td></tr><tr><td><bold>Age group</bold></td><td></td></tr><tr><td>Adults</td><td>Adults (98 %)</td></tr><tr><td>Children</td><td>Children (2 %)</td></tr><tr><td><bold>Age (years):</bold></td><td>Range:1–94;</td></tr><tr><td><bold>Range, Median</bold></td><td>Median: 50</td></tr><tr><td><bold>Gender (M,F)</bold></td><td>M: 64.5 %, F: 35.5 %</td></tr><tr><td><bold>Mortality</bold></td><td></td></tr><tr><td>Case fatality rate (CFR)-overall</td><td>40 %*</td></tr><tr><td>CFR in patients with co-morbidities</td><td>60 %</td></tr><tr><td><bold>Disease progression</bold></td><td></td></tr><tr><td>Time from onset to ventilatory support</td><td>Median 7 days</td></tr><tr><td>Time from onset to death</td><td>Median 11.5 days</td></tr><tr><td><bold>Presenting symptoms</bold></td><td></td></tr><tr><td>Fever > 38C</td><td>98 %</td></tr><tr><td>Chills/rigors</td><td>87 %</td></tr><tr><td rowspan="3">Cough</td><td>83 %</td></tr><tr><td>56 %</td></tr><tr><td rowspan="3">44 %</td></tr><tr><td>Dry</td></tr><tr><td>Productive</td></tr><tr><td>Haemoptysis</td><td>17 %</td></tr><tr><td>Headache</td><td>11 %</td></tr><tr><td>Myalgia</td><td>32 %</td></tr><tr><td>Malaise</td><td>38 %</td></tr><tr><td>Shortness of breath</td><td>72 %</td></tr><tr><td>Nausea</td><td>21 %</td></tr><tr><td>Vomiting</td><td>21 %</td></tr><tr><td>Diarrhoea</td><td>26 %</td></tr><tr><td>Sore throat</td><td>14 %</td></tr><tr><td>Rhinorrhoea</td><td>6 %</td></tr><tr><td><bold>Co-morbidities (eg obesity, diabetes, cardiac disease and lung disease)</bold></td><td>76 %</td></tr><tr><td><bold>Laboratory results</bold></td><td></td></tr><tr><td>CXR abnormalities</td><td>90–100 %</td></tr><tr><td>Leukopenia (<4.0 × 10<sup>9</sup>/L)</td><td>14 %</td></tr><tr><td>Lymphopenia (<1.5 × 10<sup>9</sup>/L)</td><td>32 %</td></tr><tr><td>Thrombocytopenia (<140 × 10<sup>9</sup>/L)</td><td>36 %</td></tr><tr><td>Elevated LDH</td><td>48 %</td></tr><tr><td>Elevated ALT</td><td>11 %</td></tr><tr><td>Elevated AST</td><td>14 %</td></tr><tr><td><bold>Risk factors associated with poor outcome (severe disease or death)</bold></td><td>Any immunocompromised state, comorbid illness, concomitant infections, low albumin, age ≥ 65 years</td></tr></tbody></table><table-wrap-foot><p>Compiled from references Zumla et al. (<xref ref-type="bibr" rid="CR69">2015</xref>), Assiri et al. (<xref ref-type="bibr" rid="CR5">2013a</xref>, <xref ref-type="bibr" rid="CR6">b</xref>), Al-Abdallat et al. (<xref ref-type="bibr" rid="CR1">2014</xref>), Memish et al. (<xref ref-type="bibr" rid="CR37">2013a</xref>, <xref ref-type="bibr" rid="CR38">b</xref>), Oboho et al. (<xref ref-type="bibr" rid="CR46">2015</xref>), The WHO MERS-CoV Research Group (<xref ref-type="bibr" rid="CR59">2013</xref>), Cotten et al. (2013), Azhar et al. (<xref ref-type="bibr" rid="CR7">2014</xref>)</p></table-wrap-foot></table-wrap></p></sec><sec id="Sec8"><title>Laboratory Diagnosis and Diagnostics</title><p id="Par9">Many cases of MERS-CoV can be easily missed since the presentation is that of any community acquired pneumonia (Zumla et al. <xref ref-type="bibr" rid="CR69">2015a</xref>; WHO <xref ref-type="bibr" rid="CR75">2015c</xref>; Lessler et al. <xref ref-type="bibr" rid="CR34">2016</xref>; Al-Tawfiq et al. <xref ref-type="bibr" rid="CR3">2014b</xref>; ISARIC and Public Health <xref ref-type="bibr" rid="CR29">2014</xref>). Rapid and accurate diagnosis of MERS-CoV infection is important for the clinical management and epidemiological control of MERS-CoV infections. Thus a high degree of clinical awareness of the possibility of MERS-CoV infection is required in all healthcare settings in the Middle East so that an accurate diagnosis can be made and adequate infections control measures promptly implemented (WHO <xref ref-type="bibr" rid="CR62">2015a</xref>; ISARIC and Public Health <xref ref-type="bibr" rid="CR29">2014</xref>; Zumla and Hui <xref ref-type="bibr" rid="CR67">2014</xref>). A history of travel to the Middle East is important for patients presenting in non-Middle Eastern countries (WHO <xref ref-type="bibr" rid="CR75">2015c</xref>; ISARIC and Public Health <xref ref-type="bibr" rid="CR29">2014</xref>; Zumla and Hui <xref ref-type="bibr" rid="CR67">2014</xref>).</p><p id="Par10">Laboratory confirmation of MERS-CoV infection can be obtained by: (a) MERS-CoV specific nucleic acid amplification test (NAAT) with up to two separate targets and/or sequencing; or (b) virus isolation in tissue culture; or (c) serology on serum tested in a WHO collaborating center with established testing methods. Real-time reverse-transcriptase polymerase chain reaction (rRT-PCR) is used (Zumla et al. <xref ref-type="bibr" rid="CR69">2015a</xref>; ISARIC and Public Health <xref ref-type="bibr" rid="CR29">2014</xref>; Corman et al. <xref ref-type="bibr" rid="CR11">2012</xref>, <xref ref-type="bibr" rid="CR12">2014</xref>) for specimens collected from the respiratory tract of suspected cases. CDC recommends the collection of three specimen types, lower respiratory, upper respiratory and serum specimens, for testing using the MERS rRT-PCR assay Accurate laboratory molecular diagnostic tests are available (MERS CDC Laboratory testing for MERS-CoV <xref ref-type="bibr" rid="CR42">2016</xref>) using highly sensitive and specific Real-time reverse transcription (RT-PCR) assays targeting unique gene regions such as the upE region (gene region upstream to E gene). These assays have been used for viral load quantitation in studies on viral shedding patterns, optimization of treatment and infection control strategies. Serological tests have been developed for surveillance purposes although they require evaluation in field studies (Park et al. <xref ref-type="bibr" rid="CR48">2015</xref>).</p></sec><sec id="Sec9"><title>Management of Mers Patients</title><p id="Par11">The clinical management of patients with MERS is largely symptomatic and aimed to reduce the risk of most severe complications, such as secondary infections, and to support renal and respiratory function (Reviewed in Zumla et al. <xref ref-type="bibr" rid="CR69">2015a</xref>; WHO <xref ref-type="bibr" rid="CR63">2015b</xref>, <xref ref-type="bibr" rid="CR64">c</xref>; Lessler et al. <xref ref-type="bibr" rid="CR34">2016</xref>; Rabozzi et al. <xref ref-type="bibr" rid="CR53">2012</xref>; <xref ref-type="bibr" rid="CR3">Al-Tawfiq et al. 2014</xref>; ISARIC and Public Health England <xref ref-type="bibr" rid="CR29">2014</xref>; CDC <xref ref-type="bibr" rid="CR9">2016</xref>). Seriously ill patients should receive intensive care. Moreover, the implementation of appropriate infection control measures as soon is possible, is critical for preventing spread of the infection especially in hospitals. Whilst a range of treatments (CDC <xref ref-type="bibr" rid="CR9">2016</xref>; WHO <xref ref-type="bibr" rid="CR63">2015b</xref>; de Wilde et al. <xref ref-type="bibr" rid="CR17">2013</xref>; Falzarano et al. <xref ref-type="bibr" rid="CR19">2013a</xref>, <xref ref-type="bibr" rid="CR20">b</xref>; Chan et al. <xref ref-type="bibr" rid="CR10">2013</xref>; Omrani et al. <xref ref-type="bibr" rid="CR47">2014</xref>; Shalhoub et al. <xref ref-type="bibr" rid="CR57">2015</xref>; Zumla et al. <xref ref-type="bibr" rid="CR74">2016</xref>) may be useful (Table <xref rid="Tab2" ref-type="table">2</xref>), currently there are no specific treatments for MERS-CoV infections and no controlled randomized clinical trials of any therapeutic have been conducted to date. A whole range of treatments have been used empirically for serious cases of MERS but there is no solid evidence that any of them can improve the clinical outcome. A range of anti-MERS-CoV drugs and host-directed therapies are in the pipeline (Zumla et al. <xref ref-type="bibr" rid="CR68">2014</xref>, <xref ref-type="bibr" rid="CR74">2016</xref>; [61]), properly designed, randomized, controlled clinical trials are required to be performed.<table-wrap id="Tab2"><label>Table 2</label><caption><p>Potentially useful antiviral agents for Middle East respiratory syndrome Coronavirus (MERS-CoV) infection</p></caption><table frame="hsides" rules="groups"><tbody><tr><td><italic>Neutralizing Antibodies</italic><sup>a</sup>:</td></tr><tr><td>Convalescent plasma</td></tr><tr><td>Polyclonal human immunoglobulin from transgenic cows,</td></tr><tr><td>Equine F(ab’)2 antibody fragments,</td></tr><tr><td>Camel antibodies,</td></tr><tr><td>Anti-S monoclonal antibodies</td></tr><tr><td><italic>Interferons</italic><sup>a</sup>:</td></tr><tr><td>Interferon alfa,</td></tr><tr><td>Interferon beta</td></tr><tr><td><italic>Repurposed drugs</italic>:</td></tr><tr><td>Ribavirin monotherapy<sup>b</sup> (±interferon),</td></tr><tr><td>HIV protease inhibitors (lopinavir<sup>a</sup>, nelfinavir),</td></tr><tr><td>Cyclophilin inhibitors (ciclosporin, alisporivir),</td></tr><tr><td>Chloroquine (active in vitro),</td></tr><tr><td>Mycophenolic acid,</td></tr><tr><td>Nitazoxanide</td></tr><tr><td><italic>Recombinant human mannose-binding lectin</italic></td></tr><tr><td><italic>siRNA to key MERS-CoV genes</italic></td></tr></tbody></table><table-wrap-foot><p>Compiled from references Zumla et al. (<xref ref-type="bibr" rid="CR69">2015a</xref>), Hui and Zumla (<xref ref-type="bibr" rid="CR26">2015</xref>)</p><p><sup>a</sup>Treatment benefits likely to exceed risks</p><p><sup>b</sup>Risks likely to exceed benefits</p></table-wrap-foot></table-wrap></p></sec><sec id="Sec10"><title>Infection Control and Transmission Risk</title><p id="Par12">There have been several nosocomial outbreaks of MERS-CoV infection within Saudi Arabia (Assiri et al. <xref ref-type="bibr" rid="CR5">2013a</xref>; Oboho et al. <xref ref-type="bibr" rid="CR46">2015</xref>; Memish et al. <xref ref-type="bibr" rid="CR38">2013b</xref>). The largest nosocomial outbreak outside Saudi Arabia occurred in mid-2015 in the Republic of Korea (Petersen et al. <xref ref-type="bibr" rid="CR51">2015</xref>; <xref ref-type="bibr" rid="CR28">Hui et al. 2015b</xref>; Zumla et al. <xref ref-type="bibr" rid="CR71">2015c</xref>; Kim et al. <xref ref-type="bibr" rid="CR32">2016b</xref>) where the index case was 68-year-old male from Korea who visited several Middle Eastern countries (Saudi Arabia, UAE, Bahrain and Qatar) and developed symptoms upon return to Korea and due to lack of isolation and patient consulting several hospitals, a major outbreak ensued involving several hospitals.</p><p id="Par13">Early recognition of MERS cases and rapid implementation of infection control guidance is necessary to prevent nosocomial outbreaks of MERS-CoV. Implementation of effective infection control measures at the first consideration of the diagnosis of MERS-CoV is crucial for prevention of MERS-CoV outbreaks. The first major nosocomial outbreak of MER-CoV in 2013 occurred at Al-Hasa, Saudi Arabia in four hospitals where 21 cases of hospital acquired MERS-CoV infection were confirmed by sequence analyses (Assiri et al. <xref ref-type="bibr" rid="CR5">2013a</xref>).</p><p id="Par14">Global public health authorities guidelines (CDC <xref ref-type="bibr" rid="CR9">2016</xref>; WHO <xref ref-type="bibr" rid="CR63">2015b</xref>) recommend to use, whenever it is possible airborne infection control measures for all patients with suspected or confirmed MERS-CoV infection. Moreover airborne infection control measures are mandatory for healthcare workers dealing with patients who undergo aerosol-generating procedures. Several outbreaks of MERS-CoV in Saudi Hospitals in Jeddah, Al-Hasa, and Riyadh were attributed to overcrowding in the emergency departments, uncontrolled patient movement, and high traffic of visitors, lack of infection control stewardship. Effective triage is required at the first suspicion of MERS-CoV and in ill patients with a history of travel to the Middle East. Tracing, screening for symptoms and MERS-CoV, and follow up of all contacts, (family, workmates, patients and visitors) is important in preventing further spread. The implementation of extensive contact tracing in order to rapidly diagnose suspected MERS cases and isolate infectious individuals to break the chain of infections is important.</p></sec><sec id="Sec11"><title>Surveillance, Prevention and Control</title><p id="Par15">There is currently no licensed vaccine available, although several experimental candidate MERS-CoV vaccines are being developed. For example, researchers at the National Institute of Health in collaboration with other investigators, including the Public Health Agency of Canada, developed an experimental synthetic DNA based vaccine that can generate protective MERS-CoV antibodies in mice, monkeys, and camels (Muthumani et al. <xref ref-type="bibr" rid="CR45">2015</xref>). Whilst we await the development of effective MERS-CoV vaccines, public health systems in Western and Middle Eastern countries have put in place surveillance systems for the prompt detection and investigation of new cases and contact tracing. The MERS outbreak in South Korea highlights the potential of MERS-CoV to spread across the globe and cause local outbreaks (Petersen et al. <xref ref-type="bibr" rid="CR51">2015</xref>; Hui et al. <xref ref-type="bibr" rid="CR28">2015b</xref>). Whilst cases of MERS related to travel to the Middle East have been reported from a wide geographical area, of note is the absence of any significant number of MERS cases (primary or travel related) reported from sub-Saharan African (SSA) countries (WHO <xref ref-type="bibr" rid="CR75">2015c</xref>; Zumla et al. <xref ref-type="bibr" rid="CR71">2015c</xref>). The reasons why MERS-CoV predominantly affects humans in the Middle East and is not endemic in Africa or Asia where MERS-CoV infected camels and bats are present requires further study (Zumla et al. <xref ref-type="bibr" rid="CR72">2015d</xref>). However this observation may reflect the lack of clinical awareness of MERS and that diagnosis and treatment of respiratory tract infections largely remains empiric, without laboratory confirmation.</p><p id="Par16">An estimated 10 million visitors from over 184 countries travel to Saudi Arabia to participate in Hajj pilgrimage, the mini-pilgrimage Umrah or during the month of Ramadan, the vast majority come from developing countries (Memish et al. <xref ref-type="bibr" rid="CR40">2014a</xref>). If MERS-CoV was a major public health risk, 4 years after its first discover one would have expected cases of MERS-CoV infection in pilgrims. There were no cases of MERS reported during the 2012, 2013, 2014 and 2015 among Hajj pilgrimages (Waldron and Doherty <xref ref-type="bibr" rid="CR60">2015</xref>; Lessler et al. <xref ref-type="bibr" rid="CR33">2014</xref>). It is possible that like SARS-CoV, MERS-CoV will die out with time. Conversely it is also possible that MERS-CoV will mutate and increase its transmission potential and the risk of MERS-CoV spreading globally remains. Coker and colleagues (Soliman et al. <xref ref-type="bibr" rid="CR58">2015</xref>) estimated the potential risk of MERS-CoV infection to pilgrims who visit Saudi Arabia from different regions of the world based on the most likely scenario using recent pilgrim numbers for sub-Saharan Africa. They predict that there will be at most ten returning pilgrims each year with MERS-CoV infections. As the recent Ebola Virus Disease epidemic in West Africa illustrates, African and Asian countries are vulnerable to a Korea-like MERS-CoV outbreak (Zumla et al. <xref ref-type="bibr" rid="CR73">2015e</xref>).</p><p id="Par17">A recent study published in Science by Sabir and colleagues (Sabir et al. <xref ref-type="bibr" rid="CR56">2016</xref>) found that at least five lineages of MERS-CoV are circulating in Saudi Arabian camels. These results suggest that multiple lineages of MERS-CoV have been co-circulating in Saudi Arabia confirming what was suspected before (Cotten et al. <xref ref-type="bibr" rid="CR14">2013b</xref>, <xref ref-type="bibr" rid="CR15">2014</xref>). This is a pre-requisite for recombination to occur and it is no surprise that Sabir et al. identified at least six recombination events, showing that recombination is frequent in MERS-CoV. Of interest was that one lineage sequenced by Sabir et al (Sabir et al. <xref ref-type="bibr" rid="CR56">2016</xref>) was associated with the 2015 Riyadh nosocomial outbreak (Balkhy et al. <xref ref-type="bibr" rid="CR8">2016</xref>), and the MERS-CoV sequenced from the Republic of Korean outbreak also had a recombinant origin. It’s been suggested that the recombinant lineage originated between December 2013 and June 2014, and has rapidly become the predominant lineage in Saudi Arabian camels since November 2014.</p><p id="Par18">MERS-CoV remains a major threat for global health. With recent outbreaks of Ebola virus and Zika virus a coordinated global response is needed to tackle emerging and re-emerging infectious diseases with epidemic potential (Zumla et al. <xref ref-type="bibr" rid="CR73">2015e</xref>; Petersen et al. <xref ref-type="bibr" rid="CR52">2016</xref>; Memish et al. <xref ref-type="bibr" rid="CR41">2014b</xref>). 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