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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Molecular Epidemiology of Hospital Outbreak of Middle East
Respiratory Syndrome, Riyadh, Saudi Arabia, 2014</title>
<author><name sortKey="Fagbo, Shamsudeen F" sort="Fagbo, Shamsudeen F" uniqKey="Fagbo S" first="Shamsudeen F." last="Fagbo">Shamsudeen F. Fagbo</name>
</author>
<author><name sortKey="Skakni, Leila" sort="Skakni, Leila" uniqKey="Skakni L" first="Leila" last="Skakni">Leila Skakni</name>
</author>
<author><name sortKey="Chu, Daniel K W" sort="Chu, Daniel K W" uniqKey="Chu D" first="Daniel K. W." last="Chu">Daniel K. W. Chu</name>
</author>
<author><name sortKey="Garbati, Musa A" sort="Garbati, Musa A" uniqKey="Garbati M" first="Musa A." last="Garbati">Musa A. Garbati</name>
</author>
<author><name sortKey="Joseph, Mercy" sort="Joseph, Mercy" uniqKey="Joseph M" first="Mercy" last="Joseph">Mercy Joseph</name>
</author>
<author><name sortKey="Peiris, Malik" sort="Peiris, Malik" uniqKey="Peiris M" first="Malik" last="Peiris">Malik Peiris</name>
</author>
<author><name sortKey="Hakawi, Ahmed M" sort="Hakawi, Ahmed M" uniqKey="Hakawi A" first="Ahmed M." last="Hakawi">Ahmed M. Hakawi</name>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">26484549</idno>
<idno type="pmc">4622263</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4622263</idno>
<idno type="RBID">PMC:4622263</idno>
<idno type="doi">10.3201/eid2111.150944</idno>
<date when="2015">2015</date>
<idno type="wicri:Area/Pmc/Corpus">000032</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000032</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Molecular Epidemiology of Hospital Outbreak of Middle East
Respiratory Syndrome, Riyadh, Saudi Arabia, 2014</title>
<author><name sortKey="Fagbo, Shamsudeen F" sort="Fagbo, Shamsudeen F" uniqKey="Fagbo S" first="Shamsudeen F." last="Fagbo">Shamsudeen F. Fagbo</name>
</author>
<author><name sortKey="Skakni, Leila" sort="Skakni, Leila" uniqKey="Skakni L" first="Leila" last="Skakni">Leila Skakni</name>
</author>
<author><name sortKey="Chu, Daniel K W" sort="Chu, Daniel K W" uniqKey="Chu D" first="Daniel K. W." last="Chu">Daniel K. W. Chu</name>
</author>
<author><name sortKey="Garbati, Musa A" sort="Garbati, Musa A" uniqKey="Garbati M" first="Musa A." last="Garbati">Musa A. Garbati</name>
</author>
<author><name sortKey="Joseph, Mercy" sort="Joseph, Mercy" uniqKey="Joseph M" first="Mercy" last="Joseph">Mercy Joseph</name>
</author>
<author><name sortKey="Peiris, Malik" sort="Peiris, Malik" uniqKey="Peiris M" first="Malik" last="Peiris">Malik Peiris</name>
</author>
<author><name sortKey="Hakawi, Ahmed M" sort="Hakawi, Ahmed M" uniqKey="Hakawi A" first="Ahmed M." last="Hakawi">Ahmed M. Hakawi</name>
</author>
</analytic>
<series><title level="j">Emerging Infectious Diseases</title>
<idno type="ISSN">1080-6040</idno>
<idno type="eISSN">1080-6059</idno>
<imprint><date when="2015">2015</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>A contiguous outbreak was the result of multiple introductions from outside the
hospital.</p>
</div>
</front>
<back><div1 type="bibliography"><listBibl><biblStruct></biblStruct>
<biblStruct></biblStruct>
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<biblStruct></biblStruct>
<biblStruct></biblStruct>
</listBibl>
</div1>
</back>
</TEI>
<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Emerg Infect Dis</journal-id>
<journal-id journal-id-type="iso-abbrev">Emerging Infect. Dis</journal-id>
<journal-id journal-id-type="publisher-id">EID</journal-id>
<journal-title-group><journal-title>Emerging Infectious Diseases</journal-title>
</journal-title-group>
<issn pub-type="ppub">1080-6040</issn>
<issn pub-type="epub">1080-6059</issn>
<publisher><publisher-name>Centers for Disease Control and Prevention</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">26484549</article-id>
<article-id pub-id-type="pmc">4622263</article-id>
<article-id pub-id-type="publisher-id">15-0944</article-id>
<article-id pub-id-type="doi">10.3201/eid2111.150944</article-id>
<article-categories><subj-group subj-group-type="second-type"><subject>Expedited</subject>
</subj-group>
<subj-group subj-group-type="heading"><subject>Research</subject>
</subj-group>
<subj-group subj-group-type="article-type"><subject>Research</subject>
</subj-group>
<subj-group subj-group-type="TOC-title"><subject>Molecular Epidemiology of Hospital Outbreak of Middle East Respiratory Syndrome, Riyadh, Saudi Arabia, 2014</subject>
</subj-group>
</article-categories>
<title-group><article-title>Molecular Epidemiology of Hospital Outbreak of Middle East
Respiratory Syndrome, Riyadh, Saudi Arabia, 2014</article-title>
<alt-title alt-title-type="running-head">Epidemiology of MERS Outbreak, Saudi
Arabia</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Fagbo</surname>
<given-names>Shamsudeen F.</given-names>
</name>
<xref ref-type="fn" rid="FN1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Skakni</surname>
<given-names>Leila</given-names>
</name>
<xref ref-type="fn" rid="FN1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chu</surname>
<given-names>Daniel K.W.</given-names>
</name>
<xref ref-type="fn" rid="FN1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Garbati</surname>
<given-names>Musa A.</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Joseph</surname>
<given-names>Mercy</given-names>
</name>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Peiris</surname>
<given-names>Malik</given-names>
</name>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Hakawi</surname>
<given-names>Ahmed M.</given-names>
</name>
</contrib>
<aff id="aff1">King Fahad Medical City, Riyadh, Saudi Arabia (S.F. Fagbo, L. Skakni, M.A. Gabrati, M. Joseph, A.M. Hakawi);</aff>
<aff id="aff2">The University of Hong Kong, Hong Kong, China (D.K.W. Chu, M. Peiris)</aff>
</contrib-group>
<author-notes><corresp id="cor1">Address for correspondence: Malik Peiris, School of Public
Health, The University of Hong Kong, 21 Sassoon Rd, Pokfualm, Hong Kong, China;
email: <email xlink:href="malik@hku.hk">malik@hku.hk</email>
, or Ahmed M.
Hakawi, Infection Control and Environmental Health Administration and Infection
Diseases Section, Medical Specialities Department, King Fahad Medical City,
Riyadh, Saudi Arabia; email: <email xlink:href="ahakawi@kfmc.med.sa">ahakawi@kfmc.med.sa</email>
</corresp>
</author-notes>
<pub-date pub-type="ppub"><month>11</month>
<year>2015</year>
</pub-date>
<volume>21</volume>
<issue>11</issue>
<fpage>1981</fpage>
<lpage>1988</lpage>
<abstract abstract-type="toc"><p>A contiguous outbreak was the result of multiple introductions from outside the
hospital.</p>
</abstract>
<abstract><p>We investigated an outbreak of Middle East respiratory syndrome (MERS) at King
Fahad Medical City (KFMC), Riyadh, Saudi Arabia, during March 29–May 21,
2014. This outbreak involved 45 patients: 8 infected outside KFMC, 13 long-term
patients at KFMC, 23 health care workers, and 1 who had an indeterminate source
of infection. Sequences of full-length MERS coronavirus (MERS-CoV) from 10
patients and a partial sequence of MERS-CoV from another patient, when compared
with other MERS-CoV sequences, demonstrated that this outbreak was part of a
larger outbreak that affected multiple health care facilities in Riyadh and
possibly arose from a single zoonotic transmission event that occurred in
December 2013 (95% highest posterior density interval November 8,
2013–February 10, 2014). This finding suggested continued health
care–associated transmission for 5 months. Molecular epidemiology
documented multiple external introductions in a seemingly contiguous outbreak
and helped support or refute transmission pathways suspected through
epidemiologic investigation.</p>
</abstract>
<kwd-group kwd-group-type="author"><title>Keywords: </title>
<kwd>Middle East respiratory syndrome</kwd>
<kwd>MERS</kwd>
<kwd>Middle East respiratory syndrome coronavirus</kwd>
<kwd>MERS-CoV</kwd>
<kwd>coronavirus</kwd>
<kwd>viruses</kwd>
<kwd>transmission</kwd>
<kwd>molecular epidemiology</kwd>
<kwd>nosocomial infection</kwd>
<kwd>health care workers</kwd>
<kwd>phylogeny</kwd>
<kwd>mutation</kwd>
<kwd>respiratory infections</kwd>
<kwd>zoonoses</kwd>
<kwd>Saudi Arabia</kwd>
</kwd-group>
</article-meta>
</front>
<body><p>Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) was first recognized as a
cause of severe human respiratory disease in 2012 (<xref rid="R1" ref-type="bibr"><italic>1</italic>
</xref>
). As of June 19, 2015, a total of 1,338 confirmed
cases of MERS and at least 475 MERS-associated deaths had been reported (<xref rid="R2" ref-type="bibr"><italic>2</italic>
</xref>
). Human zoonotic infections have
largely been acquired in the Middle East. Imported cases in Europe, North America,
Africa, and Asia have been linked to travel to the Middle East, occasionally with local
secondary transmission (<xref rid="R2" ref-type="bibr"><italic>2</italic>
</xref>
).</p>
<p>Although human infections are zoonotic in origin, clusters of human-to-human transmission
have been reported, particularly within households or health care settings (<xref rid="R3" ref-type="bibr"><italic>3</italic>
</xref>
<italic>–</italic>
<xref rid="R6" ref-type="bibr"><italic>6</italic>
</xref>
). In an outbreak in Jeddah, Saudi
Arabia, in 2014 involving multiple health care facilities, 255 laboratory-confirmed MERS
cases were documented during a 2-month period, but intensified infection prevention
measures in hospitals terminated that outbreak (<xref rid="R6" ref-type="bibr"><italic>6</italic>
</xref>
<italic>,</italic>
<xref rid="R7" ref-type="bibr"><italic>7</italic>
</xref>
). Available genetic data for these patients showed
that they were clustered, which suggested widespread transmission of related viruses
(<xref rid="R6" ref-type="bibr"><italic>6</italic>
</xref>
). Of 191 symptomatic
patients, 40 were health care workers (HCWs). For the remaining patients for whom data
were available, most had some form of contact with a health care facility or patients
with suspected MERS. Investigation of outbreaks in health care settings also identified
asymptomatic and milder cases, especially in healthy young adults and HCWs with no
underlying illnesses (<xref rid="R7" ref-type="bibr"><italic>7</italic>
</xref>
).
Dromedary camels have been proposed as a source of human infection; however, the
possibility of other reservoirs and intermediate hosts has not been excluded (<xref rid="R2" ref-type="bibr"><italic>2</italic>
</xref>
<italic>,</italic>
<xref rid="R8" ref-type="bibr"><italic>8</italic>
</xref>
).</p>
<p>Molecular epidemiologic analysis of transmission was attempted for a 2013 MERS outbreak
at multiple health care facilities in the eastern region of Saudi Arabia (<xref rid="R5" ref-type="bibr"><italic>5</italic>
</xref>
). Combined analysis of genomic
and epidemiologic data provided insights into transmission chains that would otherwise
not have been apparent. The study on the 2014 Jeddah outbreak included analysis of viral
sequences from 2 hospitals in Riyadh and identified a cluster of infections at the
Prince Sultan Military Medical City (PSMMC) during March–April 2014 (<xref rid="R6" ref-type="bibr"><italic>6</italic>
</xref>
). In this study, we analyzed
viral genetic data for patients and HCWs with MERS at King Fahad Medical City (KFMC),
Riyadh, Saudi Arabia, during February 1–May 31, 2014, and available epidemiologic
data to better understand transmission within the hospital and place the outbreak in
KFMC in the context of contemporaneous MERS outbreaks in other hospitals in Riyadh.</p>
<sec sec-type="materials|methods"><title>Materials and Methods</title>
<sec><title>Clinical Setting</title>
<p>KFMC is a 1,200-bed tertiary care hospital in Riyadh that comprises 4 hospitals
and 4 medical centers on 1 campus. The main hospital is affiliated with
specialized women’s, children’s, and rehabilitation hospitals. The
4 centers are the National Neuroscience, Heart, Oncology, and Diabetes centers.
The main hospital, affiliated hospitals, and centers provide nationwide referral
services. This study was approved by the Institutional Review Board of KFMC. </p>
<p>The emergency department (ED) is located on the ground floor of KFMC. It accepts
patients from throughout Saudi Arabia; in 2014, there were 139,173 recorded
visits. Time in the ED is usually brief, but some patients might have extended
ED stays depending on availability of isolation rooms in the wards.</p>
<p>Medical wards (MWs) MW-C and MW-D, which have 50 beds combined (<xref ref-type="local-data" rid="SD1">Technical Appendix 1</xref>
Figure 1), are
located in the main hospital and admit patients from the ED, outpatient clinics,
and referrals from elsewhere in Saudi Arabia. Most rooms in these 2 adjacent
wards have 4 beds. However, MW-C has 6 isolation rooms, 2 with negative pressure
ventilation, and MW-D has 4 isolation rooms, none with negative pressure
ventilation. Patients are occasionally moved between the 2 wards, but nurses
work only in their assigned wards.</p>
</sec>
<sec><title>Patients and Specimens</title>
<p>Patients, including HCWs, confirmed to have MERS diagnosed at KFMC during
February 1–May 31, 2014, composed the study population. Nasopharyngeal
swab specimens and tracheal aspirates or bronchoalveolar lavages were collected
for viral diagnosis. A case of MERS, according to the Saudi Arabian Ministry of
Health definition, was fever and acute respiratory illness in a patient who had
a positive test result for MERS-CoV infection. Criteria for investigation of
patients and HCW for MERS-CoV is provided in <xref ref-type="local-data" rid="SD1">Technical Appendix 1</xref>
.</p>
</sec>
<sec><title>Laboratory Diagnosis</title>
<p>A reverse transcription PCR diagnostic kit (MERS-Coronavirus EMC Orf1a and SA1
EMC upstream E-gene, Light Mix Modular Assays; TIB MOLBIOL, Adelphia, NJ, USA,
and Roche, Mannheim, Germany) was used for the screening and confirmation of
MERS-CoV infection. Each sample was also tested simultaneously for 15
respiratory viruses (influenza A and B; parainfluenza viruses 1, 2, 3, and 4;
respiratory syncytial virus; adenovirus; enterovirus; human metapneumovirus;
human coronaviruses 229E, OC43, NL63 and HKU-1; and human bocavirus) by using
the Seeplex RV15 ACE Detection Kit (Seegene Inc., Seoul, South Korea). Samples
from the early phase of the outbreak were tested for MERS-CoV at the Ministry of
Health laboratories; midway into the outbreak, KFMC developed in-house MERS-CoV
testing capability.</p>
</sec>
<sec><title>Epidemiologic Data</title>
<p>Patient demographics and epidemiologic data on study participants were collected
by retrospective chart review, from electronic health records, and from leave or
sick leave records of staff. Patients with confirmed cases of MERS were
spatiotemporally mapped within the hospital. Additional contact histories were
obtained through direct interviews with the infected HCWs or patients. On the
basis of date of hospital attendance or admission, date of onset of illness, and
reported incubation period for MERS (median 5 days, range 2–14 days)
(<xref rid="R9" ref-type="bibr"><italic>9</italic>
</xref>
), the patients
were classified into those acquiring infection outside KFMC (externally
acquired), long-term patients acquiring infection while at KFMC (long-term
patients) and HCWs working at the hospital. HCWs were presumed to have acquired
nosocomial infections at KFMC, although infection outside the hospital could not
be excluded.</p>
<p>Potential transmission links were identified on the basis of patients or HCW
present or working in the same ward or ED concurrently with a MERS patient.
Given the retrospective nature of this study, it was not possible to assess
whether HCW exposures occurred without use of adequate personal protective
equipment (PPE).</p>
</sec>
<sec><title>Genetic Sequencing and Phylogenetic Analysis</title>
<p>cDNA was synthesized by using gene-specific primers for different regions of the
MERS-CoV genome and subsequently subjected to multiple sets of PCR that covered
the entire virus genome (primers available on request). Overlapping PCR products
generated were sequenced by using MERS-CoV–specific primers. Sequences
(without primer sequences) were aligned and assembled by using Geneious version
8.0.5 (<ext-link ext-link-type="uri" xlink:href="http://www.geneious.com">http://www.geneious.com</ext-link>
). Genomes were sequenced with
<underline>></underline>
3–5 times coverage.</p>
<p>A time-resolved phylogenetic tree was estimated from a concatenated gene
alignment of MERS-CoV genome by using BEAST version 1.8 (<ext-link ext-link-type="uri" xlink:href="http://beast.bio.ed.ac.uk/">http://beast.bio.ed.ac.uk/</ext-link>
). Analysis was conducted by using a
general time-reversible model and gamma-distributed sites with separate rates
for the 3 codon positions under a relaxed lognormal clock model.</p>
</sec>
</sec>
<sec sec-type="results"><title>Results</title>
<sec><title>Descriptive Epidemiology</title>
<p>The number of specimen tested for MERS-CoV in March, April, and May 2014, were 3,
222 and 1,731, respectively, increasingly markedly during the course of the
outbreak. During the study period, 45 patients at KFMC had virologically
confirmed MERS. Eight of these patients had externally acquired infections, and
13 long-term hospitalized patients had nosocomial infections; 23 HCWs had
MERS-CoV infections, presumably acquired at KFMC. Patient EA-9 (disease onset
May 5, first ED visit May 1) might have been infected either at KFMC or at an
external source.</p>
<p>Enhanced surveillance identified 4 asymptomatically infected HCWs. Disease onset
dates of different patient groups are shown in <xref ref-type="fig" rid="F1">Figure 1</xref>
. Thirteen patients died of their infections: 3 of 8
patients with externally acquired infections, 9 of 14 long-term hospitalized
patients, and 1 of 23 HCWs. MERS-CoV–infected HCWs had a median age of
35.5 years (range 24–58 years); non-HCWs had a median age of 60 years
(range 12–77 years) (p<0.005). Demographic characteristics of all
patients and work locations of infected HCWs are shown in <xref ref-type="local-data" rid="SD1">Technical Appendix 1</xref>
Table 1.</p>
<fig id="F1" fig-type="figure" position="float"><label>Figure 1</label>
<caption><p>Date of symptom onset for patients with confirmed Middle East respiratory
syndrome coronavirus (MERS-CoV) infection hospitalized at King Fahad
Medical City, Riyadh, Saudi Arabia, 2014. For 4 asymptomatic health care
workers (HCWs) detected by screening, date of virus detection, rather
than symptom onset, is indicated. </p>
</caption>
<graphic xlink:href="15-0944-F1"></graphic>
</fig>
</sec>
<sec><title>Viral Genetic Analysis</title>
<p>To investigate virus introduction and intrahospital transmission pathways,
available archived respiratory specimens from 15 patients who had high viral
loads were obtained and genetically analyzed. Whole-genome sequences were
obtained from 10 patients and a partial genome was obtained from 1 patient
(<xref ref-type="table" rid="T1">Table</xref>
; <xref ref-type="local-data" rid="SD1">Technical Appendix 1</xref>
Table 2) (GenBank accession nos.
KT121572–KT121581 and KT202801).</p>
<table-wrap id="T1" position="float"><label>Table</label>
<caption><title>Characteristics of 21 patients tested for infection with MERS-CoV,
King Fahad Medical City, Saudi Arabia, 2014*</title>
</caption>
<table frame="hsides" rules="groups"><col width="121" span="1"></col>
<col width="49" span="1"></col>
<col width="63" span="1"></col>
<col width="58" span="1"></col>
<col width="67" span="1"></col>
<col width="63" span="1"></col>
<col width="59" span="1"></col>
<thead><tr><th valign="bottom" align="left" scope="col" rowspan="1" colspan="1">Patient</th>
<th valign="bottom" align="center" scope="col" rowspan="1" colspan="1">Age, y/sex</th>
<th valign="bottom" align="center" scope="col" rowspan="1" colspan="1">Date of illness
onset</th>
<th valign="bottom" align="center" scope="col" rowspan="1" colspan="1">Date of first ED
visit</th>
<th valign="bottom" align="center" scope="col" rowspan="1" colspan="1">Date of
hospitalization</th>
<th valign="bottom" align="center" scope="col" rowspan="1" colspan="1">Patient group</th>
<th valign="bottom" align="center" scope="col" rowspan="1" colspan="1">Outcome</th>
</tr>
</thead>
<tbody><tr><td valign="bottom" align="left" scope="col" rowspan="1" colspan="1">Externally acquired
infections</td>
<td valign="bottom" align="left" rowspan="1" colspan="1"></td>
<td valign="bottom" align="left" rowspan="1" colspan="1"></td>
<td valign="bottom" align="left" rowspan="1" colspan="1"></td>
<td valign="bottom" align="left" rowspan="1" colspan="1"></td>
<td valign="bottom" align="left" rowspan="1" colspan="1"></td>
<td valign="bottom" align="left" rowspan="1" colspan="1"></td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> EA-1</td>
<td valign="top" align="center" rowspan="1" colspan="1">32/M</td>
<td valign="top" align="center" rowspan="1" colspan="1">Mar 29</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 5</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 6</td>
<td valign="top" align="center" rowspan="1" colspan="1">Patient</td>
<td valign="top" align="center" rowspan="1" colspan="1">Recovered</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> EA-2</td>
<td valign="top" align="center" rowspan="1" colspan="1">65/F</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 6</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 11</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 12</td>
<td valign="top" align="center" rowspan="1" colspan="1">Patient</td>
<td valign="top" align="center" rowspan="1" colspan="1">Deceased</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> EA-3</td>
<td valign="top" align="center" rowspan="1" colspan="1">46/F</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 13</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 20</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 21</td>
<td valign="top" align="center" rowspan="1" colspan="1">Patient</td>
<td valign="top" align="center" rowspan="1" colspan="1">Recovered</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> EA-4</td>
<td valign="top" align="center" rowspan="1" colspan="1">70/M</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 18</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 22</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 28</td>
<td valign="top" align="center" rowspan="1" colspan="1">Patient</td>
<td valign="top" align="center" rowspan="1" colspan="1">Deceased</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> EA-5</td>
<td valign="top" align="center" rowspan="1" colspan="1">64/M</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 18</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 27</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 28</td>
<td valign="top" align="center" rowspan="1" colspan="1">Patient</td>
<td valign="top" align="center" rowspan="1" colspan="1">Recovered</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> EA-6</td>
<td valign="top" align="center" rowspan="1" colspan="1">22/F</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 20</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 27</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 28</td>
<td valign="top" align="center" rowspan="1" colspan="1">Patient</td>
<td valign="top" align="center" rowspan="1" colspan="1">Recovered</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> EA-7</td>
<td valign="top" align="center" rowspan="1" colspan="1">28/F</td>
<td valign="top" align="center" rowspan="1" colspan="1">May 1</td>
<td valign="top" align="center" rowspan="1" colspan="1">May 2</td>
<td valign="top" align="center" rowspan="1" colspan="1">Transferred</td>
<td valign="top" align="center" rowspan="1" colspan="1">Patient</td>
<td valign="top" align="center" rowspan="1" colspan="1">Transferred</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> EA-8</td>
<td valign="top" align="center" rowspan="1" colspan="1">21/F</td>
<td valign="top" align="center" rowspan="1" colspan="1">May 5</td>
<td valign="top" align="center" rowspan="1" colspan="1">May 8</td>
<td valign="top" align="center" rowspan="1" colspan="1">May 9</td>
<td valign="top" align="center" rowspan="1" colspan="1">Patient</td>
<td valign="top" align="center" rowspan="1" colspan="1">Deceased</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> EA-9†</td>
<td valign="top" align="center" rowspan="1" colspan="1">50/F</td>
<td valign="top" align="center" rowspan="1" colspan="1">May 5</td>
<td valign="top" align="center" rowspan="1" colspan="1">May 1</td>
<td valign="top" align="center" rowspan="1" colspan="1">May 3</td>
<td valign="top" align="center" rowspan="1" colspan="1">Patient</td>
<td valign="top" align="center" rowspan="1" colspan="1">Deceased</td>
</tr>
<tr><td valign="top" align="left" scope="col" rowspan="1" colspan="1">Nosocomial infections</td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
<td valign="top" align="left" rowspan="1" colspan="1"></td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> KFMC-0</td>
<td valign="top" align="center" rowspan="1" colspan="1">34/F</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 9</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 16</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 17</td>
<td valign="top" align="center" rowspan="1" colspan="1">ED nurse</td>
<td valign="top" align="center" rowspan="1" colspan="1">Recovered</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> KFMC-1</td>
<td valign="top" align="center" rowspan="1" colspan="1">45/F</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 20</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 29</td>
<td valign="top" align="center" rowspan="1" colspan="1">May 2</td>
<td valign="top" align="center" rowspan="1" colspan="1">ED nurse</td>
<td valign="top" align="center" rowspan="1" colspan="1">Deceased</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> KFMC-2</td>
<td valign="top" align="center" rowspan="1" colspan="1">60/F</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 25</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 4</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 5</td>
<td valign="top" align="center" rowspan="1" colspan="1">Patient</td>
<td valign="top" align="center" rowspan="1" colspan="1">Deceased</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> KFMC-3</td>
<td valign="top" align="center" rowspan="1" colspan="1">62/F</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 27</td>
<td valign="top" align="center" rowspan="1" colspan="1">Feb 1</td>
<td valign="top" align="center" rowspan="1" colspan="1">Jan 12</td>
<td valign="top" align="center" rowspan="1" colspan="1">Patient</td>
<td valign="top" align="center" rowspan="1" colspan="1">Deceased</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> KFMC-4</td>
<td valign="top" align="center" rowspan="1" colspan="1">63/F</td>
<td valign="top" align="center" rowspan="1" colspan="1">May 1</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 21</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 22</td>
<td valign="top" align="center" rowspan="1" colspan="1">Patient</td>
<td valign="top" align="center" rowspan="1" colspan="1">Deceased</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> KFMC-5</td>
<td valign="top" align="center" rowspan="1" colspan="1">56/F</td>
<td valign="top" align="center" rowspan="1" colspan="1">May 3</td>
<td valign="top" align="center" rowspan="1" colspan="1">May 10</td>
<td valign="top" align="center" rowspan="1" colspan="1">May 12</td>
<td valign="top" align="center" rowspan="1" colspan="1">Nurse, MW-D</td>
<td valign="top" align="center" rowspan="1" colspan="1">Recovered</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> KFMC-6</td>
<td valign="top" align="center" rowspan="1" colspan="1">74/F</td>
<td valign="top" align="center" rowspan="1" colspan="1">May 6</td>
<td valign="top" align="center" rowspan="1" colspan="1">Mar 19</td>
<td valign="top" align="center" rowspan="1" colspan="1">Mar 21</td>
<td valign="top" align="center" rowspan="1" colspan="1">Patient</td>
<td valign="top" align="center" rowspan="1" colspan="1">Transferred</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> KFMC-7</td>
<td valign="top" align="center" rowspan="1" colspan="1">36/F</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 26</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 30</td>
<td valign="top" align="center" rowspan="1" colspan="1">May 3</td>
<td valign="top" align="center" rowspan="1" colspan="1">Nurse, MW-C</td>
<td valign="top" align="center" rowspan="1" colspan="1">Recovered</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> KFMC-8</td>
<td valign="top" align="center" rowspan="1" colspan="1">53/F</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 30</td>
<td valign="top" align="center" rowspan="1" colspan="1">Mar 27</td>
<td valign="top" align="center" rowspan="1" colspan="1">Mar 28</td>
<td valign="top" align="center" rowspan="1" colspan="1">Patient</td>
<td valign="top" align="center" rowspan="1" colspan="1">Recovered</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> KFMC-9</td>
<td valign="top" align="center" rowspan="1" colspan="1">29/M</td>
<td valign="top" align="center" rowspan="1" colspan="1">May 1</td>
<td valign="top" align="center" rowspan="1" colspan="1">May 7</td>
<td valign="top" align="center" rowspan="1" colspan="1">May 9</td>
<td valign="top" align="center" rowspan="1" colspan="1">ED nurse</td>
<td valign="top" align="center" rowspan="1" colspan="1">Recovered</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> KFMC-10</td>
<td valign="top" align="center" rowspan="1" colspan="1">46/F</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 23</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 30</td>
<td valign="top" align="center" rowspan="1" colspan="1">May 5</td>
<td valign="top" align="center" rowspan="1" colspan="1">Nurse, MW-C</td>
<td valign="top" align="center" rowspan="1" colspan="1">Recovered</td>
</tr>
<tr><td valign="top" align="left" scope="row" rowspan="1" colspan="1"> KFMC-11</td>
<td valign="top" align="center" rowspan="1" colspan="1">41/F</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 24</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 27</td>
<td valign="top" align="center" rowspan="1" colspan="1">Apr 30</td>
<td valign="top" align="center" rowspan="1" colspan="1">Nurse, MW-C</td>
<td valign="top" align="center" rowspan="1" colspan="1">Recovered</td>
</tr>
</tbody>
</table>
<table-wrap-foot><p>*MERS-CoV, Middle East respiratory syndrome coronavirus; ED, emergency
department; KFMC, King Fahad Medical City; MW, medical
ward.
†This patient visited the ED on May 1 for another
illness and was hospitalized on May 3. MERS-related symptoms developed
on May 5 while she was hospitalized. The incubation period was
compatible with either externally acquired or nosocomial infection.</p>
</table-wrap-foot>
</table-wrap>
<p>A time-resolved phylogenetic tree (<xref ref-type="fig" rid="F2">Figure 2</xref>
)
shows whole-genome sequences from these 10 patients within the context of other
available MERS-CoV whole-genome sequences. Nodes A, B, and C have strong
statistical support in this time-resolved phylogeny and in a separate
maximum-likelihood phylogenetic tree of these same sequences (aBayes branch
support) (<xref rid="R10" ref-type="bibr"><italic>10</italic>
</xref>
).
Phylogenetic analysis suggests that patients at KFMC were part of a larger
outbreak of MERS that was ongoing in Riyadh at that time, involving, but perhaps
not limited to, other hospitals, such as PSMMC and King Khalid University
Hospital (KKUH). The dated phylogeny suggests that a putative zoonotic event
(node A in <xref ref-type="fig" rid="F2">Figure 2</xref>
) occurred on
approximately December 31, 2013 (95% highest posterior density (HPD) interval
November 8, 2013–February 10, 2014), although the possibility of separate
zoonotic events for closely related viruses cannot be excluded.</p>
<fig id="F2" fig-type="figure" position="float"><label>Figure 2</label>
<caption><p>Time-resolved phylogenetic tree of Middle East respiratory syndrome
coronavirus (MERS-CoV) genomes, Saudi Arabia, 2014, constructed by using
BEAST version 1.8 (<ext-link ext-link-type="uri" xlink:href="http://beast.bio.ed.ac.uk/">http://beast.bio.ed.ac.uk/</ext-link>
). Upper scale bar indicates
nucleotide substitutions per site. Lower scale bar indicates years in
reference to sample KFMC-6 (collected May 18, 2014). Genomes sequenced
in this study are indicated in bold. *Indicates major nodes with
posterior probabilities >0.95. Estimated median dates for nodes A, B,
C, D, and E (95% highest posterior density intervals) are A) Dec 31,
2013 (Nov 8, 2013–Feb 10, 2014), B) Jan 28, 2014 (Dec 16,
2013–Feb 27, 2014), C) Feb 15, 2014 (Jan 10, 2014–Mar 16,
2014), D) Feb 26,2014 (Jan 23, 2014–Mar 25, 2014), E) Apr 4, 2014
(Mar 9, 2014–Apr 25, 2014). KKUH, King Khalid University
Hospital; KFMC, King Fahd Medical City.</p>
</caption>
<graphic xlink:href="15-0944-F2"></graphic>
</fig>
<p>Virus isolate KFMC-9 clusters phylogenetically with viruses from KKUH and
separately with other viruses from KFMC. This isolate has a signature mutation
(C26144T KFMC-9) that is also present in KKUH-90b, KKUH-291, and KKUH-368
isolates, indicating that patient from which this virus was isolated was
infected with a virus related to those in the ongoing outbreak at KKUH (<xref ref-type="fig" rid="F3">Figure 3</xref>
; <xref ref-type="local-data" rid="SD1">Technical Appendix 2</xref>
). The ancestral node B has strong
statistical support (posterior density <underline>></underline>
0.95) and an
estimated date of January 28, 2014 (95% HPD interval December 16,
2013–February 27, 2014), which is long before the date of onset of the
first known case of MERS at KFMC (March 29, 2014) (<xref ref-type="table" rid="T1">Table</xref>
). Node C in the dated phylogeny (<xref ref-type="fig" rid="F2">Figure 2</xref>
) also has strong statistical support, and an
estimated date for this node was February 15 (HPD interval January
10–March 16) which is also before the date of disease onset of the first
known patient in the outbreak at KFMC. Thus, it is likely that there were
multiple introductions of MERS-CoV to KFMC to account for the observed virus
genetic diversity in the patients studied at KFMC.</p>
<fig id="F3" fig-type="figure" position="float"><label>Figure 3</label>
<caption><p>Nucleotide differences from consensus ancestral sequences of Middle East
respiratory syndrome coronavirus (MERS-CoV), Saudi Arabia, 2014,
estimated at nodes C and E in a time-resolved phylogenetic tree (<xref ref-type="fig" rid="F2">Figure 2</xref>
). The region of the genome
sequenced is indicated by the length of each box. Exact genome
polymorphic nucleotide positions, sampling date, and nucleotide
substitutions is shown in <xref ref-type="local-data" rid="SD1">Technical Appendix 2</xref>
. Nucleotide changes are indicated by
red (A), orange (T), blue (C), and green (G) vertical bars. ORF, open
reading frame; KKUH, King Khalid University Hospital; KFMC, King Fahad
Medical City; KSA, Kingdom of Saudi Arabia. </p>
</caption>
<graphic xlink:href="15-0944-F3"></graphic>
</fig>
<p>Viruses in node A in the phylogenetic tree have a nucleotide substitution rate of
6.54 × 10<sup>−4</sup>
nt substitutions/site/year (genome length
analyzed 29,897 kb), which is comparable to a previously reported value of 6.3
× 10<sup>–4</sup>
(<xref rid="R5" ref-type="bibr"><italic>5</italic>
</xref>
). Estimated ancestral sequence at nodes C and
E (identical) in the dated phylogenetic tree and nucleotide substitutions
observed in virus sequences obtained in this study, together with virus
sequences from patients in KKUH and PSMMC hospitals that appear to be related to
this outbreak, are shown in <xref ref-type="fig" rid="F3">Figure 3</xref>
and
<xref ref-type="local-data" rid="SD1">Technical Appendix 2</xref>
.</p>
<p>We tested the hypothesis that KFMC-7, KFMC-8, and KFMC-10 viruses diverged from
the ancestral virus after April 5, 2014, the date that patient EA-1 came to the
ER. Observed nucleotide differences were greater than would be expected if
KFMC-7, KFMC-8, and KFMC-10 diverged at KFMC after April 5, suggesting that
<underline>></underline>
1 of these 3 viruses were transmitted separately
to KFMC (<xref ref-type="local-data" rid="SD1">Technical Appendix 1</xref>
Table
3). Conversely, KFMC-1–6 viruses had expected mutation rates, in
accordance with observed phylogeny. Node E (including viruses KFMC-1–6)
was less robust, but had an estimated date of April 4 (HPD interval March
9–April 25), which as an entry point for transmission at KFMC is more
plausible with observed epidemiologic data. Viruses KFMC 1–6 had
<underline><</underline>
1 nt difference between them for 29,897 nt
sequenced, and the zoonotic time span between the oldest and newest virus
specimens was 20 days (<xref ref-type="local-data" rid="SD1">Technical Appendix
2</xref>
). The partial genome sequence for KFMC-11 is also identical with
that of KFMC-1–6 or KFMC-7. However, this partial sequence, although
5,225 nt, cannot optimally resolve transmission pathways.</p>
</sec>
<sec><title>Epidemiologic Data</title>
<p>Ward locations and patient data are shown in <xref ref-type="local-data" rid="SD1">Technical Appendix 1</xref>
Figure 2, and layout of key wards is
shown in <xref ref-type="local-data" rid="SD1">Technical Appendix 1</xref>
Figure 1. Before admission to KFMC, patient EA-1, the first patient to be
identified during the outbreak at KFMC, had regularly visited his father, who
was hospitalized at PSMMC, where a MERS outbreak was ongoing.</p>
<p>On the basis of known incubation periods, onset of illness, and presence at the
same location (<xref ref-type="local-data" rid="SD1">Technical Appendix 1</xref>
Figure 2), the ER was a plausible venue for MERS-CoV transmission from patient
EA-1 to KFMC-0 and from patient KFMC-0 to patient KFMC-1. Patients KFMC-0 and
KFMC-1 were co-workers in the ER, and patient KFMC-1 provided care for patient
KFMC-0 when she was ill in the ER. Patient KFMC-1 also provided care for patient
KFMC-0 without PPE in the staff quarters when she was on sick leave (April 15).
There were no archived specimens from patients EA-1 and KFMC-0. Patient KFMC-1
was the first patient from this outbreak from whom we have virus genomic
data.</p>
<p>Patient KFMC-0 was subsequently treated in MW-C where long-term patients KFMC-2
(illness onset April 25), KFMC-4 (illness onset May 1), and KFMC-6 (illness
onset May 6) became ill during April 4–May 3 and were hospitalized, and
viruses closely related to the virus from the KFMC-1 cluster (<xref ref-type="local-data" rid="SD1">Technical Appendix 1</xref>
Figure 2) were
isolated. Patient KFMC-3 was a chronically ill long-term patient in MW-C. A
respiratory infection developed, and infection with influenza A(H1N1)pdm09 virus
was detected in respiratory specimens on April 27. She was discharged on April 4
but was readmitted on May 6 because of deteriorating respiratory function and
was subsequently given a diagnosis of MERS-CoV infection. Retesting of a
predischarge respiratory specimen collected on April 30 showed MERS-CoV
infection. Thus, patient KFMC-3 probably had MERS a few days before the testing
date. However, the exact onset of illness could not be determined. Patient
KFMC-3 used the intensive care unit bed previously used by patient EA-1 on April
15.</p>
<p>Nurse KFMC-5, who worked in MW-D, had disease onset on May 3. Virus isolated from
her specimen was closely related to the cluster of viruses isolated in MW-C.
Although this nurse had no duties in MW-C, MW-C and MW-D are adjacent general
medical wards on the same hospital floor (<xref ref-type="local-data" rid="SD1">Technical Appendix 1</xref>
Figure 1).</p>
<p>Genetic analysis suggested that viruses from patient KFMC-9, KFMC-7, KFMC-8, and
KFMC-10 were introduced separately into KFMC. Patient KFMC-9 worked in the ER
and patients EA-6 and EA-3, who acquired MERS outside the hospital, were
admitted to the ER 4 and 11 days, respectively, before onset of disease in
patient KFMC-9, which indicated that patients EA-6 and EA-3 were possible
sources of infection for patient KFMC-9. Patient EA-2 was hospitalized in a
4-bed room in MW-C where nurses KFMC-7 and KFMC-10 worked. In addition, patient
KFMC-8 was a long-term patient in the same ward, which provided opportunities
for introduction of a genetically distinct virus (<xref ref-type="local-data" rid="SD1">Technical Appendix 1</xref>
Figure 2).</p>
</sec>
</sec>
<sec sec-type="discussion"><title>Discussion</title>
<p>We describe a hospital-associated outbreak of <underline>></underline>
45 MERS-CoV
infections that occurred at KFMC, Riyadh, Saudi Arabia, during March–May
2014. There appears to be a periodicity in peaks of transmission ≈7 days
apart, which is compatible with the known incubation period and case-to-case serial
interval reported to be 7.6 days (<xref rid="R4" ref-type="bibr"><italic>4</italic>
</xref>
).</p>
<p>Before this molecular epidemiologic study, the assumption was that the outbreak at
KFMC was self-contained and originated from patient EA-1, independent of other
outbreaks reported in Riyadh. Viral genomic data obtained during this study
generated alternative hypotheses and show that the outbreak of KFMC was linked to
ongoing transmission within health care facilities in Riyadh at that time,
including, but probably not limited to, PSMMC and KKUH. Data suggest a single
zoonotic event that occurred around December 31, 2013 (95% HPD interval November 8,
2013–February 10, 2014), followed by transmission in health care facilities
for ≈5 months. However, an alternative possibility of multiple, independent
spillover events from closely related viruses in a zoonotic reservoir cannot be
excluded. This chain of transmission was spread as far as Indiana in the United
States by an HCW from Riyadh (<xref rid="R11" ref-type="bibr"><italic>11</italic>
</xref>
) and 2 travelers returning to the Netherlands (<xref rid="R12" ref-type="bibr"><italic>12</italic>
</xref>
). Viral sequence data for
viruses from the 2 travelers was fragmentary and excluded from phylogenetic
analysis. However, this cluster of human MERS-CoV in Riyadh was distinct from the
large contemporaneous cluster of human-to-human transmission that occurred in Jeddah
and represents a separate zoonotic transmission event (<xref rid="R6" ref-type="bibr"><italic>6</italic>
</xref>
). Only 1 of the analyzed sequences from the
Riyadh cluster has an amino acid change in the receptor binding domain of the spike
protein (<xref rid="R13" ref-type="bibr"><italic>13</italic>
</xref>
), the C23, 697T
nonsynonymous mutation in KFMC-8, which leads to an R→C amino acid
change.</p>
<p>In this outbreak, 36 cases of MERS-CoV infection were putatively acquired through
nosocomial transmission. However, given ongoing human-to-human transmission in
Riyadh, it cannot be ruled out that some HCWs acquired infection from outside KFMC.
Molecular epidemiology indicates 1 definite cluster of transmission associated with
KFMC-1–like viruses, which are genetically closely related (KFMC-1–6).
There are plausible epidemiologic links for transmission from patient EA-1, the
first known patient admitted to KFMC in 2014, in the ER to patient KFMC-0, then to
patient KFMC-1, and to patients KFMC-2–KFMC-6. Because no virus sequence data
was available patients EA-1 or KFMC-0, the role of these 2 persons in the
transmission chain remains presumptive. The nearly identical virus genetic sequences
for KFMC-1, -2, -3, -4, -5, and -6 and plausible epidemiologic exposures provide
more definite pathways of transmission (<xref ref-type="local-data" rid="SD1">Technical Appendix 1</xref>
Figure 2). Although virus KFMC-2 has 1 unique
nucleotide substitution (T5321C), that sequence derives from a specimen collected
late in the patient’s illness and might have originated in her after she
transmitted infection to patients KFMC-4 and KFMC-6.</p>
<p>Genetic identity of virus KFMC-3 with viruses in the KFMC-1 cluster led to
reassessment of the assumption that infection of patient KFMC-3 was externally
acquired infection. Retesting of 2 archived (April 2014) specimens, 1 of which was
positive for influenza A(H1N1)pdm09 virus, showed that patient KFMC-3 was
nosocomially infected with influenza A(H1N1)pdm09 virus and MERS-CoV before her
discharge on May 4, and this MERS-CoV was closely related to the KFMC-1 virus group.
The source of infection for patient KFMC-3 was unclear. This patient used the
intensive care unit bed used by patient EA-1 on April 15, and patient KFMC-8
occupied the isolation room vacated by patient EA-2, which raised the possibility of
fomite transmission or transmission associated with HCW cases not detected by the
surveillance system.</p>
<p>Although epidemiologic linkages would have led us to deduce that patient KFMC-9 may
have acquired infection from the KFMC-1 virus cluster, viral genetic analysis
conclusively demonstrates that this was a separate introduction into KFMC through a
person with an externally acquired infection with a virus closely related to viruses
at KKUH. Molecular epidemiology also demonstrated that virus KFMC-7, KFMC-8, and
KFMC-10 were not linked to viruses in the KFMC-1 cluster, although there were
plausible epidemiologic links with patients infected with viruses from the KFMC-1
cluster. These 3 infections might have resulted from 1, 2, or 3 independent virus
introductions from outside KFMC.</p>
<p>Our data suggest that the ER and MW-C at KFMC were major foci of transmission.
Although findings are not conclusive, HCWs with mild upper respiratory illness who
continued to work might have contributed to transmission. Many of these issues were
addressed during and after this outbreak, including, but not limited to, enhancing
awareness of MERS through electronic communication, establishing in-house capacity
for rapid MERS-CoV testing, active screening of KFMC staff who had influenza-like
symptoms through a dedicated influenza clinic, establishing a triage area for
patients in the ED, designation of wards for isolation and screening of suspected
MERS cases, and strengthening infection control practices among staff by mandatory
training.</p>
<p>Our study had limitations. Archived respiratory specimens from patients with MERS
acquired outside KFMC (EA-1–EA-9) were unavailable for genomic analysis,
which caused us to make assumptions in our putative chains of transmission. Some of
the retrospectively retrieved epidemiologic data were obtained through interviews
with HCWs and patients 1 year after the outbreak. For example, data on PPE use and
extent of exposure to individual MERS-infected patients was difficult to establish
with confidence. Thus, risk factors or modes of transmission (i.e., roles of large
or small droplets, contact) could not be established. Dates and ward locations of
patients and staff were available from the electronic medical record systems at
KFMC, and we relied on proximity analysis (e.g., patients being co-housed in the
same ward or nursed by the same nursing team members as other known patients with
MERS) to provide epidemiologic context to the molecular epidemiologic data.</p>
<p>In summary, we provide molecular epidemiologic data derived from complete virus
genome genetic analysis that is suggestive of a large MERS outbreak involving
multiple health care facilities in Riyadh, suggesting ongoing human-to-human
transmission over many months. Using molecular analysis supplemented by available
epidemiologic data, we identified MERS-CoV transmission within a large health care
facility and demonstrated the feasibility and value of complete viral genome
sequence analysis in outbreak investigations. We showed that what was seemingly a
contiguous outbreak within KFMC was caused by multiple introductions of virus from
outside the hospital. The small number of mutations observed across the 29,897-nt
genome analyzed during this outbreak emphasizes the need for complete genome
analysis if molecular epidemiology is to be meaningful in such settings. The ongoing
outbreak of MERS in South Korea (<xref rid="R2" ref-type="bibr"><italic>2</italic>
</xref>
), the largest cluster of transmission from a
returning traveler to date, highlights the ongoing threat from MERS and the need for
understanding pathways of transmission. Detailed molecular epidemiology can
contribute to these efforts and thus help minimize transmission.</p>
</sec>
<sec sec-type="supplementary-material"><title></title>
<supplementary-material content-type="local-data" id="SD1"><caption><p><bold>Technical Appendix 1.</bold>
Additional information regarding molecular
epidemiology of hospital outbreak of Middle East respiratory syndrome,
Riyadh, Saudi Arabia, 2014.</p>
</caption>
<media mimetype="application" mime-subtype="pdf" xlink:href="15-0944-Techapp-s1.pdf" xlink:type="simple" id="d35e851" position="anchor"></media>
</supplementary-material>
<supplementary-material content-type="local-data" id="SD2"><caption><p><bold>Technical Appendix 2</bold>
. Nucleotide differences from consensus
ancestral sequences of Middle East respiratory syndrome coronavirus, 2014,
estimated at nodes C and E of the time-resolved phylogenetic tree (<xref ref-type="fig" rid="F2">Figure 2</xref>
). Relevant nucleotides at each
polymorphic nucleotide position, dates of sampling, number of days from
nodes C and E to the time of sampling, and number of nucleotide differences
from consensus sequence are indicated. Dots indicate sequence identity. UTR,
untranslated region; ORF, open reading frame; KKUH, King Khalid University
Hospital; KFMC, King Fahad Medical City; KSA, Kingdom of Saudi Arabia. Days
of diff Node indicates days of difference to nodes C or E. *Partial
sequences.</p>
</caption>
<media mimetype="application" mime-subtype="excel" xlink:href="15-0944-Techapp-s2.xlsx" xlink:type="simple" id="d35e861" position="anchor"></media>
</supplementary-material>
</sec>
</body>
<back><fn-group><fn fn-type="citation"><p><italic>Suggested citation for this article</italic>
: Fagbo SF, Skakni L, Chu
DKW, Garbati MA, Joseph M, Peiris M, et al. Molecular epidemiology of hospital
outbreak of Middle East respiratory syndrome, Riyadh, Saudi Arabia, 2014. Emerg
Infect Dis. 2015 Nov [<italic>date cited</italic>
]. <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.3201/eid2111.150944">http://dx.doi.org/10.3201/eid2111.150944</ext-link>
</p>
</fn>
<fn id="FN1"><label>1</label>
<p>These authors contributed equally to this article.</p>
</fn>
</fn-group>
<ack><title>Acknowledgments</title>
<p>We thank Abdulwahid Al Dehaimi, Rami Hassan, Abdulrahman Mohammed Al Rashaid,
Angelita Des Santos, Trevor Wyngaard, Rizalina Espanola, Rhoda Medina, Tariq Wani,
and Noorazlina Abdulhamid for support and assistance with laboratory, clinical, and
epidemiologic data collection and analysis; and H.Y.E. Lau, B.J. Cowling, and T.T.Y.
Lam for advice on statistical and phylogenetic analysis..</p>
<p>The study was supported by a research grant from the US National Institutes of Health
(contract no. HHSN272201400006C), and a commissioned grant from the Health and
Medical Research fund, Food and Health Bureau, Government of the Hong Kong Special
Administrative Region.</p>
</ack>
<bio id="d35e886"><p>Dr. Fagbo is an epidemiologist at the Clinical and Applied Research Department, King
Fahad Medical City, Riyadh, Saudi Arabia. His research interests are emerging viral
infections and zoonoses at the animal human interface.</p>
</bio>
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