Critically ill patients with Middle East respiratory syndrome coronavirus infection
Identifieur interne : 000377 ( Pmc/Corpus ); précédent : 000376; suivant : 000378Critically ill patients with Middle East respiratory syndrome coronavirus infection
Auteurs : Hasan M. Al-Dorzi ; Sami Alsolamy ; Yaseen M. ArabiSource :
- Critical Care [ 1364-8535 ] ; 2016.
Abstract
This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency medicine 2016. Other selected articles can be found online at
Url:
DOI: 10.1186/s13054-016-1234-4
PubMed: 26984370
PubMed Central: 4794852
Links to Exploration step
PMC:4794852Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Critically ill patients with Middle East respiratory syndrome coronavirus infection</title><author><name sortKey="Al Dorzi, Hasan M" sort="Al Dorzi, Hasan M" uniqKey="Al Dorzi H" first="Hasan M." last="Al-Dorzi">Hasan M. Al-Dorzi</name><affiliation><nlm:aff id="Aff1">King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Intensive Care Department, 11426 Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2">King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Alsolamy, Sami" sort="Alsolamy, Sami" uniqKey="Alsolamy S" first="Sami" last="Alsolamy">Sami Alsolamy</name><affiliation><nlm:aff id="Aff2">King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff3">King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Emergency Medicine and Intensive Care Departments, Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Arabi, Yaseen M" sort="Arabi, Yaseen M" uniqKey="Arabi Y" first="Yaseen M." last="Arabi">Yaseen M. Arabi</name><affiliation><nlm:aff id="Aff1">King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Intensive Care Department, 11426 Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2">King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26984370</idno><idno type="pmc">4794852</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794852</idno><idno type="RBID">PMC:4794852</idno><idno type="doi">10.1186/s13054-016-1234-4</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000377</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000377</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Critically ill patients with Middle East respiratory syndrome coronavirus infection</title><author><name sortKey="Al Dorzi, Hasan M" sort="Al Dorzi, Hasan M" uniqKey="Al Dorzi H" first="Hasan M." last="Al-Dorzi">Hasan M. Al-Dorzi</name><affiliation><nlm:aff id="Aff1">King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Intensive Care Department, 11426 Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2">King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Alsolamy, Sami" sort="Alsolamy, Sami" uniqKey="Alsolamy S" first="Sami" last="Alsolamy">Sami Alsolamy</name><affiliation><nlm:aff id="Aff2">King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff3">King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Emergency Medicine and Intensive Care Departments, Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Arabi, Yaseen M" sort="Arabi, Yaseen M" uniqKey="Arabi Y" first="Yaseen M." last="Arabi">Yaseen M. Arabi</name><affiliation><nlm:aff id="Aff1">King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Intensive Care Department, 11426 Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2">King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia</nlm:aff></affiliation></author></analytic><series><title level="j">Critical Care</title><idno type="ISSN">1364-8535</idno><idno type="eISSN">1466-609X</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency medicine 2016. Other selected articles can be found online at <ext-link ext-link-type="uri" xlink:href="http://www.biomedcentral.com/collections/annualupdate2016">http://www.biomedcentral.com/collections/annualupdate2016</ext-link>. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from <ext-link ext-link-type="uri" xlink:href="http://www.springer.com/series/8901">http://www.springer.com/series/8901</ext-link>.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Zaki, Am" uniqKey="Zaki A">AM Zaki</name></author><author><name sortKey="Van Boheemen, S" uniqKey="Van Boheemen S">S van Boheemen</name></author><author><name sortKey="Bestebroer, Tm" uniqKey="Bestebroer T">TM Bestebroer</name></author><author><name sortKey="Osterhaus, Ad" uniqKey="Osterhaus A">AD Osterhaus</name></author><author><name sortKey="Fouchier, Ra" uniqKey="Fouchier R">RA Fouchier</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hijawi, B" uniqKey="Hijawi B">B Hijawi</name></author><author><name sortKey="Abdallat, M" uniqKey="Abdallat M">M Abdallat</name></author><author><name sortKey="Sayaydeh, A" 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Crit Care</journal-id><journal-title-group><journal-title>Critical Care</journal-title></journal-title-group><issn pub-type="ppub">1364-8535</issn><issn pub-type="epub">1466-609X</issn><publisher><publisher-name>BioMed Central</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26984370</article-id><article-id pub-id-type="pmc">4794852</article-id><article-id pub-id-type="publisher-id">1234</article-id><article-id pub-id-type="doi">10.1186/s13054-016-1234-4</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review</subject></subj-group></article-categories><title-group><article-title>Critically ill patients with Middle East respiratory syndrome coronavirus infection</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Al-Dorzi</surname><given-names>Hasan M.</given-names></name><address><email>aldorzih@yahoo.com</email></address><xref ref-type="aff" rid="Aff1"></xref><xref ref-type="aff" rid="Aff2"></xref></contrib><contrib contrib-type="author"><name><surname>Alsolamy</surname><given-names>Sami</given-names></name><address><email>dr.sami.j@gmail.com</email></address><xref ref-type="aff" rid="Aff2"></xref><xref ref-type="aff" rid="Aff3"></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Arabi</surname><given-names>Yaseen M.</given-names></name><address><email>arabi@ngha.med.sa</email><email>arabi@ngha.med.sa</email></address><xref ref-type="aff" rid="Aff1"></xref><xref ref-type="aff" rid="Aff2"></xref></contrib><aff id="Aff1"><label></label>King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Intensive Care Department, 11426 Riyadh, Saudi Arabia</aff><aff id="Aff2"><label></label>King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia</aff><aff id="Aff3"><label></label>King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Emergency Medicine and Intensive Care Departments, Riyadh, Saudi Arabia</aff></contrib-group><pub-date pub-type="epub"><day>16</day><month>3</month><year>2016</year></pub-date><pub-date pub-type="pmc-release"><day>16</day><month>3</month><year>2016</year></pub-date><pub-date pub-type="ppub"><year>2016</year></pub-date><volume>20</volume><elocation-id>65</elocation-id><permissions><copyright-statement>© Al-Dorzi et al. 2016</copyright-statement></permissions><abstract id="Abs1"><p>This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency medicine 2016. Other selected articles can be found online at <ext-link ext-link-type="uri" xlink:href="http://www.biomedcentral.com/collections/annualupdate2016">http://www.biomedcentral.com/collections/annualupdate2016</ext-link>. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from <ext-link ext-link-type="uri" xlink:href="http://www.springer.com/series/8901">http://www.springer.com/series/8901</ext-link>.</p></abstract><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2016</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="Sec1"><title>Background</title><p>The Middle East respiratory syndrome coronavirus (MERS‐CoV) is an emerging virus that may lead to severe acute respiratory illness frequently associated with multiorgan failure and death. The objective of this chapter is to summarize the current state of knowledge regarding the pathogenesis, clinical manifestations, diagnosis, management and outcomes of MERS‐CoV infection focusing on the critically ill.</p></sec><sec id="Sec2"><title>Epidemiology</title><p>The virus was first isolated from a patient with fatal pneumonia and acute kidney injury in Jeddah, Saudi Arabia in June 2012 [<xref ref-type="bibr" rid="CR1">1</xref>]. After its identification, the virus was linked to a healthcare‐associated cluster of respiratory illnesses in Jordan dating back to March 2012 [<xref ref-type="bibr" rid="CR2">2</xref>]. The disease epidemiology has been characterized by sporadic cases throughout the year with surges of cases occurring because of hospital outbreaks. As of December 27, 2015, the World Health Organization (WHO) had reported 1,621 laboratory‐confirmed cases, including at least 584 (36 %) related deaths [<xref ref-type="bibr" rid="CR3">3</xref>]. Cases of MERS‐CoV have occurred in 26 countries, with all cases linked to residence in or travel to the Arabian Peninsula.</p><p>The majority of cases have occurred in Saudi Arabia (80 %) and South Korea (12 %) [<xref ref-type="bibr" rid="CR3">3</xref>]. In Saudi Arabia, multiple hospital outbreaks occurred in Alahsa (April–May 2013) [<xref ref-type="bibr" rid="CR4">4</xref>], Jeddah (April and May 2014) [<xref ref-type="bibr" rid="CR5">5</xref>], and Riyadh (August–September 2015) [<xref ref-type="bibr" rid="CR3">3</xref>]. The outbreak in the Republic of Korea started in May 2015 and resulted from a case with travel history to the Middle East (Saudi Arabia, Qatar, United Arab Emirates and Bahrain). Subsequently, human‐to‐human transmission occurred to close contacts (family members, patients sharing a room or ward with infected patients and healthcare workers caring for infected patients) and led to 185 cases of MERS‐CoV infection [<xref ref-type="bibr" rid="CR3">3</xref>]. The last laboratory‐confirmed case in Korea was on 4 July 2015 [<xref ref-type="bibr" rid="CR3">3</xref>].</p></sec><sec id="Sec3"><title>Pathogenesis</title><p>Coronaviruses are a family of enveloped, single‐stranded RNA viruses [<xref ref-type="bibr" rid="CR6">6</xref>]. They can infect animals and humans and have the propensity to cross species [<xref ref-type="bibr" rid="CR6">6</xref>]. They cause a variety of illnesses that range from the common cold to severe respiratory illnesses [<xref ref-type="bibr" rid="CR6">6</xref>]. The Severe Acute Respiratory Syndrome coronavirus (SARS‐CoV) was the first coronavirus identified to cause widespread outbreaks of critical illness. It caused a worldwide outbreak during the winter of 2002–2003, eventually leading to 8096 confirmed cases, including 774 deaths [<xref ref-type="bibr" rid="CR7">7</xref>]. The SARS epidemic was contained in 2003 [<xref ref-type="bibr" rid="CR7">7</xref>]. SARS‐CoV belongs to lineage B of the betacoronavirus [<xref ref-type="bibr" rid="CR8">8</xref>], whereas MERS‐CoV belongs to lineage C of the same genus. MERS‐CoV enters cells via a common receptor, the dipeptidyl peptidase‐4 (DPP4), also known as CD26, and replicates in bronchial, bronchiolar and type I and II alveolar epithelial cells [<xref ref-type="bibr" rid="CR9">9</xref>, <xref ref-type="bibr" rid="CR10">10</xref>]. The virus has primarily been detected in respiratory secretions, with the highest viral loads in the lower respiratory tract [<xref ref-type="bibr" rid="CR11">11</xref>]. In MERS‐CoV cases, one study showed that approximately 70 % of patients had continued respiratory shedding for > 30 days [<xref ref-type="bibr" rid="CR12">12</xref>]. MERS‐CoV infection often manifests with acute kidney injury (AKI), the pathogenesis of which remains unknown, although direct viral infection is a possibility since the DPP4 receptor is heavily expressed in human kidneys [<xref ref-type="bibr" rid="CR13">13</xref>]. Viral shedding has also been detected in the urine and stool of infected patients [<xref ref-type="bibr" rid="CR14">14</xref>].</p><p>There is accumulating evidence that camels are the primary source for animal‐to‐human transmission of MERS‐CoV. The virus has been isolated from dromedary camels [<xref ref-type="bibr" rid="CR15">15</xref>]. The high viral loads in the upper respiratory tract of infected camels suggest that transmission to humans occurs through close camel contact [<xref ref-type="bibr" rid="CR15">15</xref>]. Transmission through ingestion of camel products (meat and milk) is possible but has never been confirmed. In a cross‐sectional serosurveillance study of 10,009 individuals in Saudi Arabia, positive serology was documented in only 0.15 % [<xref ref-type="bibr" rid="CR16">16</xref>]. Seropositivity was more common in men than in women, in central than in coastal provinces and in shepherds and slaughterhouse workers than in others [<xref ref-type="bibr" rid="CR16">16</xref>]. This may explain, at least in part, the sporadic community‐acquired cases seen at low rates throughout the year.</p><p>Human‐to‐human transmission of MERS‐CoV has been demonstrated among close household contacts and family members [<xref ref-type="bibr" rid="CR17">17</xref>]. However, sustained community‐based transmission has not been reported. Secondary transmission within healthcare settings has been described with already‐hospitalized patients and healthcare workers acquiring the disease [<xref ref-type="bibr" rid="CR18">18</xref>, <xref ref-type="bibr" rid="CR19">19</xref>]. This has been attributed to overcrowding, movement of infected patients who did not yet have a diagnosis and breaches of infection prevention and control practices [<xref ref-type="bibr" rid="CR3">3</xref>]. A study evaluated the stability of MERS‐CoV under different environmental conditions and found that the virus was more stable at low temperature/low humidity than at higher temperature/higher humidity conditions [<xref ref-type="bibr" rid="CR20">20</xref>]. MERS‐CoV could be recovered after 48 h at a 20 °C/40 % relative humidity condition [<xref ref-type="bibr" rid="CR20">20</xref>]. During MERS‐CoV aerosolization, no decrease in stability was observed at the 20 °C/40 % relative humidity condition [<xref ref-type="bibr" rid="CR20">20</xref>]. The prolonged environmental presence suggests that MERS‐CoV may be transmitted via contact or fomites [<xref ref-type="bibr" rid="CR20">20</xref>], although this has not been confirmed.</p></sec><sec id="Sec4"><title>Clinical manifestations</title><p>The disease spectrum ranges from asymptomatic infection to rapidly progressive severe respiratory failure with multiorgan failure. Symptomatic cases manifest after an incubation period of 2–14 days [<xref ref-type="bibr" rid="CR21">21</xref>]. Most severe cases have been reported in adults with chronic comorbidities, including diabetes mellitus, chronic cardiac disease, chronic lung disease, end‐stage kidney disease, or immunosuppression [<xref ref-type="bibr" rid="CR21">21</xref>, <xref ref-type="bibr" rid="CR22">22</xref>]. However, severe infection may also occur among younger patients, including healthcare workers [<xref ref-type="bibr" rid="CR18">18</xref>]. Compared with SARS‐CoV, MERS‐CoV affects older patients, men more than women, and people with comorbid illnesses. The healthcare‐associated MERS‐CoV infections occurred within the first week of the index case illness, while for SARS they occurred mainly in the second week, likely due to the different timings of peak viral load [<xref ref-type="bibr" rid="CR23">23</xref>]. The current literature suggests that children are rarely affected by MERS‐CoV [<xref ref-type="bibr" rid="CR24">24</xref>].</p><p>The most common clinical features in critically ill patients with MERS‐CoV are fever (71 %), cough (68 %), dyspnea (66 %), and gastrointestinal symptoms (32 %) [<xref ref-type="bibr" rid="CR21">21</xref>]. Common laboratory abnormalities include leukopenia, lymphocytopenia, and thrombocytopenia, elevated serum creatinine and lactate dehydrogenase, and altered liver enzymes [<xref ref-type="bibr" rid="CR21">21</xref>]. Initial chest radiographs are abnormal in most symptomatic patients and findings range from minimal abnormalities to extensive bilateral infiltrates [<xref ref-type="bibr" rid="CR21">21</xref>]. Figure <xref rid="Fig1" ref-type="fig">1</xref> shows the chest radiographs of four patients with MERS‐CoV pneumonia on the first day of intubation and demonstrates different patterns of lung infiltrates. Computed tomography (CT) findings have included bilateral airspace opacities predominantly in the subpleural and basilar lung regions with more extensive ground‐glass opacities than consolidation [<xref ref-type="bibr" rid="CR25">25</xref>].<fig id="Fig1"><label>Fig. 1</label><caption><p>Chest radiographs on the first day of endotracheal intubation of four patients with Middle East respiratory syndrome coronavirus (MERS‐CoV) pneumonia</p></caption><graphic xlink:href="13054_2016_1234_Fig1_HTML" id="MO1"></graphic></fig></p><p>Rapid progression to hypoxemic respiratory failure requiring intubation usually occurs within the first week after symptom onset [<xref ref-type="bibr" rid="CR26">26</xref>]. In one observational study at a single center in Saudi Arabia (October 1, 2012 to May 31, 2014), severe infection requiring ICU admission occurred in 49 (70 %) of 70 cases with 46 (66 %) requiring invasive mechanical ventilation. In the univariate analysis, factors associated with severe infection requiring ICU admission were age ≥ 65 years (odds ratio [OR] 9.47, 95 % confidence interval [CI] 2.45–36.56), male sex (OR 3.05, 95 % CI 1.05–8.84), higher age‐adjusted Charlson comorbidity index (OR 1.35, 95 % CI 1.11–1.65), the presence of bilateral pulmonary infiltrates on chest radiograph (OR 4.89, 95 % CI 1.16–20.47), concomitant infections (OR 12.66, 95 % CI 2.65–60.46), and serum albumin < 35 g/l at MERS‐CoV diagnosis (OR 8.0, 95 % CI 1.97–32.46) [<xref ref-type="bibr" rid="CR19">19</xref>]. Severe neurologic syndrome, including altered level of consciousness, ranging from confusion to coma, ataxia, and focal motor deficit, has been reported in three critically ill MERS‐CoV patients, with brain magnetic resonance imaging (MRI) showing widespread, bilateral hyperintense lesions on T2‐weighted images in the white matter and subcortical areas of different brain areas [<xref ref-type="bibr" rid="CR27">27</xref>].</p></sec><sec id="Sec5"><title>Diagnosis</title><p>The WHO has issued guidance for the definition of MERS‐CoV cases, based on clinical criteria, exposure history and diagnostic findings as shown in Table <xref rid="Tab1" ref-type="table">1</xref> [<xref ref-type="bibr" rid="CR3">3</xref>]. The clinical and radiological manifestations do not differentiate MERS‐CoV infection from other causes of respiratory infection. Diagnosis is, therefore, based on molecular testing by real‐time reverse‐transcription polymerase chain reaction (rRT‐PCR) for two sites in the virus genome: the upstream E protein (upE) for screening and the open reading frame (ORF) 1a or 1b for confirmation [<xref ref-type="bibr" rid="CR28">28</xref>]. Lower respiratory tract specimens have a higher sensitivity than upper respiratory tract specimens for detecting MERS‐CoV [<xref ref-type="bibr" rid="CR29">29</xref>]. The success of rRT‐PCR testing depends on the experience and expertise of laboratory personnel, avoidance of contamination and the type and specimen condition. Gene sequencing targeting <italic>RdRp</italic> (present in all corona viruses) and <italic>N</italic> (specific to MERS‐CoV) gene fragments can be used for confirmation [<xref ref-type="bibr" rid="CR28">28</xref>]. MERS‐CoV can be also diagnosed by seroconversion on two samples two weeks apart. Enzyme‐linked immunosorbent assay can be used for screening and immunofluorescence assay (IFA) or neutralization for confirmation [<xref ref-type="bibr" rid="CR28">28</xref>]. Several MERS‐CoV‐specific serologic assays have been developed but need validation [<xref ref-type="bibr" rid="CR28">28</xref>]. The MERS‐CoV virus can be cultured in commonly available cell lines [<xref ref-type="bibr" rid="CR28">28</xref>]; however, this requires specialized biosafety level 3 laboratories.<table-wrap id="Tab1"><label>Table 1</label><caption><p>Interim case definitions for Middle East respiratory syndrome coronavirus (MERS‐CoV) infection (as of 14 July 2015) [<xref ref-type="bibr" rid="CR3">3</xref>]</p></caption><table frame="hsides" rules="groups"><tbody><tr><td rowspan="3">Probable case</td><td>An acute respiratory illness with fever and clinical, radiological, or histopathological evidence of pulmonary involvement<break></break>AND<break></break>Direct epidemiologic link with a confirmed MERS‐CoV case<break></break>AND<break></break>MERS‐CoV testing is unavailable, negative on a single inadequate specimen or inconclusive</td></tr><tr><td>An acute respiratory illness with fever and clinical, radiological, or histopathological evidence of pulmonary involvement<break></break>AND<break></break>The person lives in or has travelled to Middle Eastern countries or countries where MERS‐CoV is known to be circulating in dromedary camels or where human MERS‐CoV infections have recently occurred<break></break>AND<break></break>MERS‐CoV testing is inconclusive</td></tr><tr><td>An acute febrile respiratory illness of any severity<break></break>AND<break></break>Direct epidemiologic link with a confirmed MERS‐CoV case<break></break>AND<break></break>MERS‐CoV testing is inconclusive</td></tr><tr><td>Confirmed case</td><td>A person with laboratory‐confirmed MERS‐CoV infection irrespective of clinical signs and symptoms</td></tr></tbody></table></table-wrap></p></sec><sec id="Sec6"><title>Management</title><p>At present, there is no proven specific therapy for MERS‐CoV infection. Therefore, the mainstay of management of critically ill patients with MERS‐CoV infection is supportive evidence‐based care. Admission to the ICU is frequently required for close monitoring (e.g., patients with high oxygen requirements) or organ support. The WHO has issued interim guidance for the management of suspected and confirmed MERS‐CoV infection [<xref ref-type="bibr" rid="CR30">30</xref>].</p><sec id="Sec7"><title>Infection prevention and control</title><p>Because of the risk of transmission within the healthcare setting, appropriate patient isolation and strict implementation of infection prevention and control measures are crucial in the management of MERS‐CoV cases. For suspected cases, the WHO recommends droplet and contact precautions [<xref ref-type="bibr" rid="CR30">30</xref>]. When performing an aerosol generating procedure (e.g., aspiration or open suctioning of respiratory tract, intubation, bronchoscopy, cardiopulmonary resuscitation) airborne precautions should be additionally applied [<xref ref-type="bibr" rid="CR30">30</xref>]. The Centers for Disease Control and Prevention (CDC) recommends that droplet precautions should be added to standard precautions when providing care to all patients with symptoms of acute respiratory infection and that a suspected or confirmed MERS‐CoV case should be isolated in an airborne infection isolation room that is constructed and maintained according to current guidelines [<xref ref-type="bibr" rid="CR31">31</xref>]. If such a room is not available, the patient should be transferred as soon as is feasible to a facility where one is available [<xref ref-type="bibr" rid="CR31">31</xref>]. Until transfer, the patient should wear a facemask and should be isolated in a room with the door closed [<xref ref-type="bibr" rid="CR31">31</xref>]. Healthcare workers should adhere to standard contact and airborne precautions. Hand hygiene should be performed appropriately and personal protective equipment, including respirators, should be applied correctly [<xref ref-type="bibr" rid="CR31">31</xref>]. In addition, visitation should be restricted and controlled [<xref ref-type="bibr" rid="CR31">31</xref>]. Hospitals should also develop protocols to be ready for a potential increase in the need to isolate patients with suspected or confirmed MERS‐Cov infection.</p></sec><sec id="Sec8"><title>Management of respiratory failure</title><p>Early supportive management includes supplemental oxygen for hypoxemia, respiratory distress and shock and early invasive mechanical ventilation for significant respiratory distress or persistent hypoxemia [<xref ref-type="bibr" rid="CR30">30</xref>]. Patients with acute respiratory distress syndrome (ARDS) should receive evidence‐based care that includes a lung‐protective ventilation strategy [<xref ref-type="bibr" rid="CR32">32</xref>]: targeting a tidal volume of 6 ml/kg of predicted body weight, a plateau airway pressure ≤ 30 cmH<sub>2</sub>O and SpO<sub>2</sub> 88–93 % or PaO<sub>2</sub> 55–80 mmHg. Moderate to severe ARDS cases (PaO<sub>2</sub>:FiO<sub>2</sub> < 150 mmHg) are candidates for early prone positioning [<xref ref-type="bibr" rid="CR33">33</xref>] and early neuromuscular blockade for 48 h [<xref ref-type="bibr" rid="CR34">34</xref>]. Proning is recommended within 36 h of ARDS onset for at least 16 h, since this approach was associated with reduced mortality compared with managing patients in the supine position [<xref ref-type="bibr" rid="CR33">33</xref>]. A 48‐h infusion of intravenous cisatracurium within 48 h of ARDS onset has also been associated with reduced mortality compared with placebo [<xref ref-type="bibr" rid="CR34">34</xref>]. Extracorporeal membrane oxygenation (ECMO) is an option for patients with refractory hypoxemia [<xref ref-type="bibr" rid="CR35">35</xref>, <xref ref-type="bibr" rid="CR36">36</xref>], and has been successfully used in young patients with severe H1N1 influenza with refractory hypoxemia [<xref ref-type="bibr" rid="CR36">36</xref>] as well as in MERS‐CoV patients [<xref ref-type="bibr" rid="CR11">11</xref>]. Systematic corticosteroids should generally be avoided unless indicated for other established reasons [<xref ref-type="bibr" rid="CR30">30</xref>]. The effect of corticosteroids on the outcome of MERS‐CoV patients is unknown; however, corticosteroid use has been associated with increased morbidity in patients with SARS‐CoV and severe influenza [<xref ref-type="bibr" rid="CR37">37</xref>, <xref ref-type="bibr" rid="CR38">38</xref>].</p><p>High‐flow oxygen, non‐invasive ventilation and high‐frequency oscillatory ventilation should probably be avoided or used with caution in MERS patients because of the potential to generate aerosols and lack of effectiveness in patients with ARDS [<xref ref-type="bibr" rid="CR39">39</xref>]. A systematic review found that the following procedures were associated with an increased risk of acute respiratory infection transmission to healthcare workers through aerosol‐generation: endotracheal intubation, non‐invasive ventilation, tracheotomy, and manual ventilation [<xref ref-type="bibr" rid="CR39">39</xref>]. Strict infection prevention practices should, therefore, be employed when these interventions are performed.</p></sec><sec id="Sec9"><title>Management of acute kidney injury</title><p>Conservative fluid management is advocated especially in the presence of hypoxemia and the absence of shock. When renal replacement therapy (RRT) should be started in patients with AKI is controversial. However, the presence of fluid overload at the start of RRT has been associated with a worse outcome [<xref ref-type="bibr" rid="CR40">40</xref>]. Starting ultrafiltration at lower degrees of fluid overload and early targeting of a negative balance may be beneficial [<xref ref-type="bibr" rid="CR41">41</xref>, <xref ref-type="bibr" rid="CR42">42</xref>].</p></sec><sec id="Sec10"><title>Feeding</title><p>Early trophic feeding for 7 days in ARDS patients [<xref ref-type="bibr" rid="CR43">43</xref>] and permissive underfeeding for up to 14 days in mechanically ventilated patients [<xref ref-type="bibr" rid="CR44">44</xref>] have been shown to be equivalent to target feeding for most outcomes including survival. Underfeeding may be preferred for patients in the prone position.</p></sec><sec id="Sec11"><title>Specific therapies</title><p>To date, there is no effective specific treatment for MERS‐CoV infection. Data on ribavirin, interferon, and convalescent plasma are limited [<xref ref-type="bibr" rid="CR21">21</xref>]. A study in rhesus macaques found that a combination of interferon‐α2b and ribavirin was associated with a reduction in MERS‐CoV replication and improved outcome [<xref ref-type="bibr" rid="CR45">45</xref>]. Clinical studies on combined ribavirin and interferon showed inconsistent results [<xref ref-type="bibr" rid="CR46">46</xref>]. Convalescent sera from patients who have recovered may be useful. A post‐hoc meta‐analysis of 32 studies on SARS‐CoV and severe influenza found reduced mortality after antibody treatment compared with placebo or no treatment (pooled OR 0.25, 95 % CI 0.14–0.45), but the included studies were of low or very low quality [<xref ref-type="bibr" rid="CR47">47</xref>]. Three studies from separate laboratories have reported the development of fully human neutralizing monoclonal antibodies against MERS‐CoV but no clinical data are currently available [<xref ref-type="bibr" rid="CR48">48</xref>]. Repurposed commonly‐used drugs, such as statins, mycophenolic acid, and anti‐tumor necrosis factor agents, which have potential anti‐inflammatory or antiviral effects against MERS‐CoV and at the same time an excellent safety record, may be treatment options. However, these drugs are not recommended for clinical use outside clinical trials [<xref ref-type="bibr" rid="CR49">49</xref>]. There are no currently licensed MERS‐CoV vaccines; however, work is ongoing to develop effective vaccines [<xref ref-type="bibr" rid="CR50">50</xref>].</p></sec></sec><sec id="Sec12"><title>Outcomes</title><p>The overall case fatality rate of MERS‐CoV infection is ~ 35 % [<xref ref-type="bibr" rid="CR3">3</xref>]. However, the mortality rate of patients with severe illness requiring critical care is higher (58–84 %) [<xref ref-type="bibr" rid="CR19">19</xref>, <xref ref-type="bibr" rid="CR22">22</xref>, <xref ref-type="bibr" rid="CR26">26</xref>]. Requirement for ICU admission for hospitalized patients is frequent (45–70 %) [<xref ref-type="bibr" rid="CR19">19</xref>, <xref ref-type="bibr" rid="CR22">22</xref>]. In an observational study, 41 out of 49 (84 %) cases requiring ICU admission died, with 33 (78.6 %) having a progressive disease course until death [<xref ref-type="bibr" rid="CR19">19</xref>]. In a multivariable regression analysis, only the presence of a concomitant infection (OR 14.13, 95 % CI 1.58–126.09) and a low serum albumin (OR 6.31, 95 % CI 1.24–31.90) were associated with the need for ICU admission [<xref ref-type="bibr" rid="CR19">19</xref>]. The multivariable analysis showed age ≥ 65 years to be the only independent risk factor for increased mortality (OR 4.39, 95 % CI 2.13–9.05) [<xref ref-type="bibr" rid="CR19">19</xref>]. AKI (41 %), hepatic dysfunction (31 %) and cardiac arrhythmias (16 %), such as tachyarrhythmias and severe bradycardia requiring temporary pacemaker insertion, were common complications [<xref ref-type="bibr" rid="CR19">19</xref>]. Another observational study of 12 critically ill cases found that barotrauma occurred in 17 %, vasopressors were needed in 92 % and RRT was performed in 58 % [<xref ref-type="bibr" rid="CR26">26</xref>]. The median time from onset of symptoms to intubation was 4.5 days (range 0–33 days). The median ICU and hospital lengths of stay were 30 (7–104) days and 41 (8–96) days, respectively, and 25 % of patients had a tracheostomy [<xref ref-type="bibr" rid="CR26">26</xref>]. The 28‐day and 90‐day mortality rates were 42 and 58 %, respectively [<xref ref-type="bibr" rid="CR26">26</xref>].</p><p>It should be noted that the mortality of MERS‐CoV cases during the Korean outbreak (May–July 2015) was only 19 % compared with ~ 42 % in Saudi Arabia (as at Sept 11, 2015) [<xref ref-type="bibr" rid="CR3">3</xref>]. However, the composition of the two cohorts was different in the relative percentages of asymptomatic and mildly symptomatic cases. The Korean healthcare authorities applied widespread screening and intensified public health measures, such as contact tracing, quarantine and isolation of suspected cases and all contacts for at least 14 days [<xref ref-type="bibr" rid="CR3">3</xref>]. The identification of asymptomatic or mildly symptomatic patients and differences in patient characteristics, such as comorbid conditions, may have led to an overall lower mortality rate in Korea.</p></sec><sec id="Sec13"><title>Conclusions</title><p>More than three years after its identification, MERS‐CoV remains a major global threat. Infection with MERS‐CoV is frequently severe and associated with significant morbidity and mortality. Although our understanding of this virus and its disease continues to evolve, large knowledge gaps remain. The Arabian Peninsula remains the most affected region, but there is concern about the spread of this virus to other countries and globally. Until zoonotic transfer of the virus from animals to humans is stopped, the risk of additional domestic and perhaps international outbreaks persists. Moreover, there is an urgent need for larger epidemiologic and outcome studies and randomized controlled trials examining different therapeutic interventions. Collaboration between international health authorities and research centers is necessary and is crucial to achieve these goals.</p></sec></body><back><fn-group><fn><p><bold>Competing interests</bold></p><p>The authors declare that they have no competing interests.</p></fn><fn><p><bold>Authors’ contributions</bold></p><p>HMA, SA, YMA contributed to the review. 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