Respiratory Tract Samples, Viral Load, and Genome Fraction Yield in Patients With Middle East Respiratory Syndrome
Identifieur interne : 000E21 ( Pmc/Corpus ); précédent : 000E20; suivant : 000E22Respiratory Tract Samples, Viral Load, and Genome Fraction Yield in Patients With Middle East Respiratory Syndrome
Auteurs : Ziad A. Memish ; Jaffar A. Al-Tawfiq ; Hatem Q. Makhdoom ; Abdullah Assiri ; Raafat F. Alhakeem ; Ali Albarrak ; Sarah Alsubaie ; Abdullah A. Al-Rabeeah ; Waleed H. Hajomar ; Raheela Hussain ; Ali M. Kheyami ; Abdullah Almutairi ; Esam I. Azhar ; Christian Drosten ; Simon J. Watson ; Paul Kellam ; Matthew Cotten ; Alimuddin ZumlaSource :
- The Journal of Infectious Diseases [ 0022-1899 ] ; 2014.
Abstract
Url:
DOI: 10.1093/infdis/jiu292
PubMed: 24837403
PubMed Central: 7107391
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PMC:7107391Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Respiratory Tract Samples, Viral Load, and Genome Fraction Yield in Patients With Middle East Respiratory Syndrome</title><author><name sortKey="Memish, Ziad A" sort="Memish, Ziad A" uniqKey="Memish Z" first="Ziad A." last="Memish">Ziad A. Memish</name><affiliation><nlm:aff id="af1"><institution>Global Centre for Mass Gatherings Medicine and Ministry of Health, Riyadh, Kingdom of Saudi Arabia and College of Medicine, Alfaisal University,</institution></nlm:aff></affiliation></author><author><name sortKey="Al Tawfiq, Jaffar A" sort="Al Tawfiq, Jaffar A" uniqKey="Al Tawfiq J" first="Jaffar A." last="Al-Tawfiq">Jaffar A. Al-Tawfiq</name><affiliation><nlm:aff id="af5"><addr-line>Saudi Aramco Medical Services Organization</addr-line>,<country>Dhahran</country></nlm:aff></affiliation><affiliation><nlm:aff id="af10"><institution>Indiana University School of Medicine</institution>,<addr-line>Indianapolis</addr-line></nlm:aff></affiliation></author><author><name sortKey="Makhdoom, Hatem Q" sort="Makhdoom, Hatem Q" uniqKey="Makhdoom H" first="Hatem Q." last="Makhdoom">Hatem Q. Makhdoom</name><affiliation><nlm:aff id="af2"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution></nlm:aff></affiliation><affiliation><nlm:aff id="af6"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution></nlm:aff></affiliation><affiliation><nlm:aff id="af8"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution>,<addr-line>Madinah</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af9"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution>,<addr-line>Dammam</addr-line>,<country>Kingdom of Saudi Arabia</country></nlm:aff></affiliation></author><author><name sortKey="Assiri, Abdullah" sort="Assiri, Abdullah" uniqKey="Assiri A" first="Abdullah" last="Assiri">Abdullah Assiri</name><affiliation><nlm:aff id="af1"><institution>Global Centre for Mass Gatherings Medicine and Ministry of Health, Riyadh, Kingdom of Saudi Arabia and College of Medicine, Alfaisal University,</institution></nlm:aff></affiliation></author><author><name sortKey="Alhakeem, Raafat F" sort="Alhakeem, Raafat F" uniqKey="Alhakeem R" first="Raafat F." last="Alhakeem">Raafat F. Alhakeem</name><affiliation><nlm:aff id="af1"><institution>Global Centre for Mass Gatherings Medicine and Ministry of Health, Riyadh, Kingdom of Saudi Arabia and College of Medicine, Alfaisal University,</institution></nlm:aff></affiliation></author><author><name sortKey="Albarrak, Ali" sort="Albarrak, Ali" uniqKey="Albarrak A" first="Ali" last="Albarrak">Ali Albarrak</name><affiliation><nlm:aff id="af3"><institution>Prince Sultan Military Medical City</institution></nlm:aff></affiliation></author><author><name sortKey="Alsubaie, Sarah" sort="Alsubaie, Sarah" uniqKey="Alsubaie S" first="Sarah" last="Alsubaie">Sarah Alsubaie</name><affiliation><nlm:aff id="af4"><addr-line>Pediatric Infectious Diseases</addr-line>,<institution>King Saud University</institution>,<addr-line>Riyadh</addr-line></nlm:aff></affiliation></author><author><name sortKey="Al Rabeeah, Abdullah A" sort="Al Rabeeah, Abdullah A" uniqKey="Al Rabeeah A" first="Abdullah A." last="Al-Rabeeah">Abdullah A. Al-Rabeeah</name><affiliation><nlm:aff id="af1"><institution>Global Centre for Mass Gatherings Medicine and Ministry of Health, Riyadh, Kingdom of Saudi Arabia and College of Medicine, Alfaisal University,</institution></nlm:aff></affiliation></author><author><name sortKey="Hajomar, Waleed H" sort="Hajomar, Waleed H" uniqKey="Hajomar W" first="Waleed H." last="Hajomar">Waleed H. Hajomar</name><affiliation><nlm:aff id="af2"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution></nlm:aff></affiliation><affiliation><nlm:aff id="af6"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution></nlm:aff></affiliation><affiliation><nlm:aff id="af8"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution>,<addr-line>Madinah</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af9"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution>,<addr-line>Dammam</addr-line>,<country>Kingdom of Saudi Arabia</country></nlm:aff></affiliation></author><author><name sortKey="Hussain, Raheela" sort="Hussain, Raheela" uniqKey="Hussain R" first="Raheela" last="Hussain">Raheela Hussain</name><affiliation><nlm:aff id="af2"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution></nlm:aff></affiliation><affiliation><nlm:aff id="af6"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution></nlm:aff></affiliation><affiliation><nlm:aff id="af8"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution>,<addr-line>Madinah</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af9"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution>,<addr-line>Dammam</addr-line>,<country>Kingdom of Saudi Arabia</country></nlm:aff></affiliation></author><author><name sortKey="Kheyami, Ali M" sort="Kheyami, Ali M" uniqKey="Kheyami A" first="Ali M." last="Kheyami">Ali M. Kheyami</name><affiliation><nlm:aff id="af2"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution></nlm:aff></affiliation><affiliation><nlm:aff id="af6"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution></nlm:aff></affiliation><affiliation><nlm:aff id="af8"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution>,<addr-line>Madinah</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af9"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution>,<addr-line>Dammam</addr-line>,<country>Kingdom of Saudi Arabia</country></nlm:aff></affiliation></author><author><name sortKey="Almutairi, Abdullah" sort="Almutairi, Abdullah" uniqKey="Almutairi A" first="Abdullah" last="Almutairi">Abdullah Almutairi</name><affiliation><nlm:aff id="af2"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution></nlm:aff></affiliation><affiliation><nlm:aff id="af6"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution></nlm:aff></affiliation><affiliation><nlm:aff id="af8"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution>,<addr-line>Madinah</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af9"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution>,<addr-line>Dammam</addr-line>,<country>Kingdom of Saudi Arabia</country></nlm:aff></affiliation></author><author><name sortKey="Azhar, Esam I" sort="Azhar, Esam I" uniqKey="Azhar E" first="Esam I." last="Azhar">Esam I. Azhar</name><affiliation><nlm:aff id="af7"><addr-line>Special Infectious Diseases Agents Unit, King Fahad Medical Research Center</addr-line>,<institution>King Abdualziz University</institution>,<addr-line>Jeddah</addr-line></nlm:aff></affiliation></author><author><name sortKey="Drosten, Christian" sort="Drosten, Christian" uniqKey="Drosten C" first="Christian" last="Drosten">Christian Drosten</name><affiliation><nlm:aff id="af11"><institution>Institute of Virology, University of Bonn Medical Center</institution>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Watson, Simon J" sort="Watson, Simon J" uniqKey="Watson S" first="Simon J." last="Watson">Simon J. Watson</name><affiliation><nlm:aff id="af12"><institution>Wellcome Trust Sanger Institute</institution>,<addr-line>Hinxton</addr-line>,</nlm:aff></affiliation></author><author><name sortKey="Kellam, Paul" sort="Kellam, Paul" uniqKey="Kellam P" first="Paul" last="Kellam">Paul Kellam</name><affiliation><nlm:aff id="af12"><institution>Wellcome Trust Sanger Institute</institution>,<addr-line>Hinxton</addr-line>,</nlm:aff></affiliation></author><author><name sortKey="Cotten, Matthew" sort="Cotten, Matthew" uniqKey="Cotten M" first="Matthew" last="Cotten">Matthew Cotten</name><affiliation><nlm:aff id="af12"><institution>Wellcome Trust Sanger Institute</institution>,<addr-line>Hinxton</addr-line>,</nlm:aff></affiliation></author><author><name sortKey="Zumla, Alimuddin" sort="Zumla, Alimuddin" uniqKey="Zumla A" first="Alimuddin" last="Zumla">Alimuddin Zumla</name><affiliation><nlm:aff id="af1"><institution>Global Centre for Mass Gatherings Medicine and Ministry of Health, Riyadh, Kingdom of Saudi Arabia and College of Medicine, Alfaisal University,</institution></nlm:aff></affiliation><affiliation><nlm:aff id="af13"><addr-line>Division of Infection and Immunity</addr-line>,<institution>University College London (UCL), and UCL Hospitals National Health Service Foundation Trust</institution>,<country>United Kingdom</country></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24837403</idno><idno type="pmc">7107391</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7107391</idno><idno type="RBID">PMC:7107391</idno><idno type="doi">10.1093/infdis/jiu292</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">000E21</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000E21</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Respiratory Tract Samples, Viral Load, and Genome Fraction Yield in Patients With Middle East Respiratory Syndrome</title><author><name sortKey="Memish, Ziad A" sort="Memish, Ziad A" uniqKey="Memish Z" first="Ziad A." last="Memish">Ziad A. Memish</name><affiliation><nlm:aff id="af1"><institution>Global Centre for Mass Gatherings Medicine and Ministry of Health, Riyadh, Kingdom of Saudi Arabia and College of Medicine, Alfaisal University,</institution></nlm:aff></affiliation></author><author><name sortKey="Al Tawfiq, Jaffar A" sort="Al Tawfiq, Jaffar A" uniqKey="Al Tawfiq J" first="Jaffar A." last="Al-Tawfiq">Jaffar A. Al-Tawfiq</name><affiliation><nlm:aff id="af5"><addr-line>Saudi Aramco Medical Services Organization</addr-line>,<country>Dhahran</country></nlm:aff></affiliation><affiliation><nlm:aff id="af10"><institution>Indiana University School of Medicine</institution>,<addr-line>Indianapolis</addr-line></nlm:aff></affiliation></author><author><name sortKey="Makhdoom, Hatem Q" sort="Makhdoom, Hatem Q" uniqKey="Makhdoom H" first="Hatem Q." last="Makhdoom">Hatem Q. Makhdoom</name><affiliation><nlm:aff id="af2"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution></nlm:aff></affiliation><affiliation><nlm:aff id="af6"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution></nlm:aff></affiliation><affiliation><nlm:aff id="af8"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution>,<addr-line>Madinah</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af9"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution>,<addr-line>Dammam</addr-line>,<country>Kingdom of Saudi Arabia</country></nlm:aff></affiliation></author><author><name sortKey="Assiri, Abdullah" sort="Assiri, Abdullah" uniqKey="Assiri A" first="Abdullah" last="Assiri">Abdullah Assiri</name><affiliation><nlm:aff id="af1"><institution>Global Centre for Mass Gatherings Medicine and Ministry of Health, Riyadh, Kingdom of Saudi Arabia and College of Medicine, Alfaisal University,</institution></nlm:aff></affiliation></author><author><name sortKey="Alhakeem, Raafat F" sort="Alhakeem, Raafat F" uniqKey="Alhakeem R" first="Raafat F." last="Alhakeem">Raafat F. Alhakeem</name><affiliation><nlm:aff id="af1"><institution>Global Centre for Mass Gatherings Medicine and Ministry of Health, Riyadh, Kingdom of Saudi Arabia and College of Medicine, Alfaisal University,</institution></nlm:aff></affiliation></author><author><name sortKey="Albarrak, Ali" sort="Albarrak, Ali" uniqKey="Albarrak A" first="Ali" last="Albarrak">Ali Albarrak</name><affiliation><nlm:aff id="af3"><institution>Prince Sultan Military Medical City</institution></nlm:aff></affiliation></author><author><name sortKey="Alsubaie, Sarah" sort="Alsubaie, Sarah" uniqKey="Alsubaie S" first="Sarah" last="Alsubaie">Sarah Alsubaie</name><affiliation><nlm:aff id="af4"><addr-line>Pediatric Infectious Diseases</addr-line>,<institution>King Saud University</institution>,<addr-line>Riyadh</addr-line></nlm:aff></affiliation></author><author><name sortKey="Al Rabeeah, Abdullah A" sort="Al Rabeeah, Abdullah A" uniqKey="Al Rabeeah A" first="Abdullah A." last="Al-Rabeeah">Abdullah A. Al-Rabeeah</name><affiliation><nlm:aff id="af1"><institution>Global Centre for Mass Gatherings Medicine and Ministry of Health, Riyadh, Kingdom of Saudi Arabia and College of Medicine, Alfaisal University,</institution></nlm:aff></affiliation></author><author><name sortKey="Hajomar, Waleed H" sort="Hajomar, Waleed H" uniqKey="Hajomar W" first="Waleed H." last="Hajomar">Waleed H. Hajomar</name><affiliation><nlm:aff id="af2"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution></nlm:aff></affiliation><affiliation><nlm:aff id="af6"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution></nlm:aff></affiliation><affiliation><nlm:aff id="af8"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution>,<addr-line>Madinah</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af9"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution>,<addr-line>Dammam</addr-line>,<country>Kingdom of Saudi Arabia</country></nlm:aff></affiliation></author><author><name sortKey="Hussain, Raheela" sort="Hussain, Raheela" uniqKey="Hussain R" first="Raheela" last="Hussain">Raheela Hussain</name><affiliation><nlm:aff id="af2"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution></nlm:aff></affiliation><affiliation><nlm:aff id="af6"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution></nlm:aff></affiliation><affiliation><nlm:aff id="af8"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution>,<addr-line>Madinah</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af9"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution>,<addr-line>Dammam</addr-line>,<country>Kingdom of Saudi Arabia</country></nlm:aff></affiliation></author><author><name sortKey="Kheyami, Ali M" sort="Kheyami, Ali M" uniqKey="Kheyami A" first="Ali M." last="Kheyami">Ali M. Kheyami</name><affiliation><nlm:aff id="af2"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution></nlm:aff></affiliation><affiliation><nlm:aff id="af6"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution></nlm:aff></affiliation><affiliation><nlm:aff id="af8"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution>,<addr-line>Madinah</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af9"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution>,<addr-line>Dammam</addr-line>,<country>Kingdom of Saudi Arabia</country></nlm:aff></affiliation></author><author><name sortKey="Almutairi, Abdullah" sort="Almutairi, Abdullah" uniqKey="Almutairi A" first="Abdullah" last="Almutairi">Abdullah Almutairi</name><affiliation><nlm:aff id="af2"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution></nlm:aff></affiliation><affiliation><nlm:aff id="af6"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution></nlm:aff></affiliation><affiliation><nlm:aff id="af8"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution>,<addr-line>Madinah</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="af9"><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution>,<addr-line>Dammam</addr-line>,<country>Kingdom of Saudi Arabia</country></nlm:aff></affiliation></author><author><name sortKey="Azhar, Esam I" sort="Azhar, Esam I" uniqKey="Azhar E" first="Esam I." last="Azhar">Esam I. Azhar</name><affiliation><nlm:aff id="af7"><addr-line>Special Infectious Diseases Agents Unit, King Fahad Medical Research Center</addr-line>,<institution>King Abdualziz University</institution>,<addr-line>Jeddah</addr-line></nlm:aff></affiliation></author><author><name sortKey="Drosten, Christian" sort="Drosten, Christian" uniqKey="Drosten C" first="Christian" last="Drosten">Christian Drosten</name><affiliation><nlm:aff id="af11"><institution>Institute of Virology, University of Bonn Medical Center</institution>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Watson, Simon J" sort="Watson, Simon J" uniqKey="Watson S" first="Simon J." last="Watson">Simon J. Watson</name><affiliation><nlm:aff id="af12"><institution>Wellcome Trust Sanger Institute</institution>,<addr-line>Hinxton</addr-line>,</nlm:aff></affiliation></author><author><name sortKey="Kellam, Paul" sort="Kellam, Paul" uniqKey="Kellam P" first="Paul" last="Kellam">Paul Kellam</name><affiliation><nlm:aff id="af12"><institution>Wellcome Trust Sanger Institute</institution>,<addr-line>Hinxton</addr-line>,</nlm:aff></affiliation></author><author><name sortKey="Cotten, Matthew" sort="Cotten, Matthew" uniqKey="Cotten M" first="Matthew" last="Cotten">Matthew Cotten</name><affiliation><nlm:aff id="af12"><institution>Wellcome Trust Sanger Institute</institution>,<addr-line>Hinxton</addr-line>,</nlm:aff></affiliation></author><author><name sortKey="Zumla, Alimuddin" sort="Zumla, Alimuddin" uniqKey="Zumla A" first="Alimuddin" last="Zumla">Alimuddin Zumla</name><affiliation><nlm:aff id="af1"><institution>Global Centre for Mass Gatherings Medicine and Ministry of Health, Riyadh, Kingdom of Saudi Arabia and College of Medicine, Alfaisal University,</institution></nlm:aff></affiliation><affiliation><nlm:aff id="af13"><addr-line>Division of Infection and Immunity</addr-line>,<institution>University College London (UCL), and UCL Hospitals National Health Service Foundation Trust</institution>,<country>United Kingdom</country></nlm:aff></affiliation></author></analytic><series><title level="j">The Journal of Infectious Diseases</title><idno type="ISSN">0022-1899</idno><idno type="eISSN">1537-6613</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Abstract</title><p><bold><italic>Background.</italic></bold> Analysis of clinical samples from patients with new viral infections is critical to confirm the diagnosis, to specify the viral load, and to sequence data necessary for characterizing the viral kinetics, transmission, and evolution. We analyzed samples from 112 patients infected with the recently discovered Middle East respiratory syndrome coronavirus (MERS-CoV).</p><p><bold><italic>Methods.</italic></bold> Respiratory tract samples from cases of MERS-CoV infection confirmed by polymerase chain reaction (PCR) were investigated to determine the MERS-CoV load and fraction of the MERS-CoV genome. These values were analyzed to determine associations with clinical sample type.</p><p><bold><italic>Results.</italic></bold> Samples from 112 individuals in which MERS-CoV was detected by PCR were analyzed, of which 13 were sputum samples, 64 were nasopharyngeal swab specimens, 30 were tracheal aspirates, and 3 were bronchoalveolar lavage specimens; 2 samples were of unknown origin. Tracheal aspirates yielded significantly higher MERS-CoV loads, compared with nasopharyngeal swab specimens (<italic>P</italic> = .005) and sputum specimens (<italic>P</italic> = .0001). Tracheal aspirates had viral loads similar to those in bronchoalveolar lavage samples (<italic>P</italic> = .3079). Bronchoalveolar lavage samples and tracheal aspirates had significantly higher genome fraction than nasopharyngeal swab specimens (<italic>P</italic> = .0095 and <italic>P</italic> = .0002, respectively) and sputum samples (<italic>P</italic> = .0009 and <italic>P</italic> = .0001, respectively). The genome yield from tracheal aspirates and bronchoalveolar lavage samples were similar (<italic>P</italic> = .1174).</p><p><bold><italic>Conclusions.</italic></bold> Lower respiratory tract samples yield significantly higher MERS-CoV loads and genome fractions than upper respiratory tract samples.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Lieberman, D" uniqKey="Lieberman D">D Lieberman</name></author><author><name sortKey="Shimoni, A" uniqKey="Shimoni A">A Shimoni</name></author><author><name sortKey="Keren Naus, R" uniqKey="Keren Naus R">R Keren-Naus</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Loens, K" uniqKey="Loens K">K Loens</name></author><author><name sortKey="Van Heirstraeten, L" uniqKey="Van Heirstraeten L">L Van Heirstraeten</name></author><author><name sortKey="Malhotra Kumar, S" uniqKey="Malhotra Kumar S">S 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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Infect Dis</journal-id><journal-id journal-id-type="iso-abbrev">J. Infect. Dis</journal-id><journal-id journal-id-type="publisher-id">jid</journal-id><journal-id journal-id-type="hwp">jinfdis</journal-id><journal-title-group><journal-title>The Journal of Infectious Diseases</journal-title></journal-title-group><issn pub-type="ppub">0022-1899</issn><issn pub-type="epub">1537-6613</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24837403</article-id><article-id pub-id-type="pmc">7107391</article-id><article-id pub-id-type="doi">10.1093/infdis/jiu292</article-id><article-id pub-id-type="publisher-id">jiu292</article-id><article-categories><subj-group subj-group-type="heading"><subject>Major Articles and Brief Reports</subject><subj-group subj-group-type="category-toc-heading"><subject>Viruses</subject></subj-group></subj-group></article-categories><title-group><article-title>Respiratory Tract Samples, Viral Load, and Genome Fraction Yield in Patients With Middle East Respiratory Syndrome</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Memish</surname><given-names>Ziad A.</given-names></name><xref ref-type="aff" rid="af1">1</xref><pmc-comment>zmemish@yahoo.com </pmc-comment>
<xref ref-type="corresp" rid="d808894e450"></xref></contrib><contrib contrib-type="author"><name><surname>Al-Tawfiq</surname><given-names>Jaffar A.</given-names></name><xref ref-type="aff" rid="af5">5</xref><xref ref-type="aff" rid="af10">10</xref></contrib><contrib contrib-type="author"><name><surname>Makhdoom</surname><given-names>Hatem Q.</given-names></name><xref ref-type="aff" rid="af2">2</xref><xref ref-type="aff" rid="af6">6</xref><xref ref-type="aff" rid="af8">8</xref><xref ref-type="aff" rid="af9">9</xref></contrib><contrib contrib-type="author"><name><surname>Assiri</surname><given-names>Abdullah</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Alhakeem</surname><given-names>Raafat F.</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Albarrak</surname><given-names>Ali</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Alsubaie</surname><given-names>Sarah</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Al-Rabeeah</surname><given-names>Abdullah A.</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Hajomar</surname><given-names>Waleed H.</given-names></name><xref ref-type="aff" rid="af2">2</xref><xref ref-type="aff" rid="af6">6</xref><xref ref-type="aff" rid="af8">8</xref><xref ref-type="aff" rid="af9">9</xref></contrib><contrib contrib-type="author"><name><surname>Hussain</surname><given-names>Raheela</given-names></name><xref ref-type="aff" rid="af2">2</xref><xref ref-type="aff" rid="af6">6</xref><xref ref-type="aff" rid="af8">8</xref><xref ref-type="aff" rid="af9">9</xref></contrib><contrib contrib-type="author"><name><surname>Kheyami</surname><given-names>Ali M.</given-names></name><xref ref-type="aff" rid="af2">2</xref><xref ref-type="aff" rid="af6">6</xref><xref ref-type="aff" rid="af8">8</xref><xref ref-type="aff" rid="af9">9</xref></contrib><contrib contrib-type="author"><name><surname>Almutairi</surname><given-names>Abdullah</given-names></name><xref ref-type="aff" rid="af2">2</xref><xref ref-type="aff" rid="af6">6</xref><xref ref-type="aff" rid="af8">8</xref><xref ref-type="aff" rid="af9">9</xref></contrib><contrib contrib-type="author"><name><surname>Azhar</surname><given-names>Esam I.</given-names></name><xref ref-type="aff" rid="af7">7</xref></contrib><contrib contrib-type="author"><name><surname>Drosten</surname><given-names>Christian</given-names></name><xref ref-type="aff" rid="af11">11</xref></contrib><contrib contrib-type="author"><name><surname>Watson</surname><given-names>Simon J.</given-names></name><xref ref-type="aff" rid="af12">12</xref></contrib><contrib contrib-type="author"><name><surname>Kellam</surname><given-names>Paul</given-names></name><xref ref-type="aff" rid="af12">12</xref></contrib><contrib contrib-type="author"><name><surname>Cotten</surname><given-names>Matthew</given-names></name><xref ref-type="aff" rid="af12">12</xref></contrib><contrib contrib-type="author"><name><surname>Zumla</surname><given-names>Alimuddin</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af13">13</xref></contrib></contrib-group><aff id="af1"><label>1</label><institution>Global Centre for Mass Gatherings Medicine and Ministry of Health, Riyadh, Kingdom of Saudi Arabia and College of Medicine, Alfaisal University,</institution></aff><aff id="af2"><label>2</label><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution></aff><aff id="af3"><label>3</label><institution>Prince Sultan Military Medical City</institution></aff><aff id="af4"><label>4</label><addr-line>Pediatric Infectious Diseases</addr-line>,<institution>King Saud University</institution>,<addr-line>Riyadh</addr-line></aff><aff id="af5"><label>5</label><addr-line>Saudi Aramco Medical Services Organization</addr-line>,<country>Dhahran</country></aff><aff id="af6"><label>6</label><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution></aff><aff id="af7"><label>7</label><addr-line>Special Infectious Diseases Agents Unit, King Fahad Medical Research Center</addr-line>,<institution>King Abdualziz University</institution>,<addr-line>Jeddah</addr-line></aff><aff id="af8"><label>8</label><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution>,<addr-line>Madinah</addr-line></aff><aff id="af9"><label>9</label><addr-line>Regional Laboratory</addr-line>,<institution>Ministry of Health</institution>,<addr-line>Dammam</addr-line>,<country>Kingdom of Saudi Arabia</country></aff><aff id="af10"><label>10</label><institution>Indiana University School of Medicine</institution>,<addr-line>Indianapolis</addr-line></aff><aff id="af11"><label>11</label><institution>Institute of Virology, University of Bonn Medical Center</institution>,<country>Germany</country></aff><aff id="af12"><label>12</label><institution>Wellcome Trust Sanger Institute</institution>,<addr-line>Hinxton</addr-line>,</aff><aff id="af13"><label>13</label><addr-line>Division of Infection and Immunity</addr-line>,<institution>University College London (UCL), and UCL Hospitals National Health Service Foundation Trust</institution>,<country>United Kingdom</country></aff><author-notes><corresp id="d808894e450">Correspondence: Ziad A. Memish, MD, FRCP(Can), FRCP(Edin), FRCP(Lond), FACP, WHO Collaborating Center for Mass Gathering Medicine, Ministry of Health, Riyadh 11176, Kingdom of Saudi Arabia (<email>zmemish@yahoo.com</email>).</corresp></author-notes><pub-date pub-type="ppub"><day>15</day><month>11</month><year>2014</year></pub-date><pub-date pub-type="epub"><day>15</day><month>5</month><year>2014</year></pub-date><volume>210</volume><issue>10</issue><fpage>1590</fpage><lpage>1594</lpage><history><date date-type="received"><day>28</day><month>3</month><year>2014</year></date><date date-type="accepted"><day>6</day><month>5</month><year>2014</year></date></history><permissions><copyright-statement>© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: <email>journals.permissions@oup.com</email>.</copyright-statement><copyright-year>2014</copyright-year><license><license-p>This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.</license-p></license></permissions><self-uri xlink:href="jiu292.pdf"></self-uri><abstract><title>Abstract</title><p><bold><italic>Background.</italic></bold> Analysis of clinical samples from patients with new viral infections is critical to confirm the diagnosis, to specify the viral load, and to sequence data necessary for characterizing the viral kinetics, transmission, and evolution. We analyzed samples from 112 patients infected with the recently discovered Middle East respiratory syndrome coronavirus (MERS-CoV).</p><p><bold><italic>Methods.</italic></bold> Respiratory tract samples from cases of MERS-CoV infection confirmed by polymerase chain reaction (PCR) were investigated to determine the MERS-CoV load and fraction of the MERS-CoV genome. These values were analyzed to determine associations with clinical sample type.</p><p><bold><italic>Results.</italic></bold> Samples from 112 individuals in which MERS-CoV was detected by PCR were analyzed, of which 13 were sputum samples, 64 were nasopharyngeal swab specimens, 30 were tracheal aspirates, and 3 were bronchoalveolar lavage specimens; 2 samples were of unknown origin. Tracheal aspirates yielded significantly higher MERS-CoV loads, compared with nasopharyngeal swab specimens (<italic>P</italic> = .005) and sputum specimens (<italic>P</italic> = .0001). Tracheal aspirates had viral loads similar to those in bronchoalveolar lavage samples (<italic>P</italic> = .3079). Bronchoalveolar lavage samples and tracheal aspirates had significantly higher genome fraction than nasopharyngeal swab specimens (<italic>P</italic> = .0095 and <italic>P</italic> = .0002, respectively) and sputum samples (<italic>P</italic> = .0009 and <italic>P</italic> = .0001, respectively). The genome yield from tracheal aspirates and bronchoalveolar lavage samples were similar (<italic>P</italic> = .1174).</p><p><bold><italic>Conclusions.</italic></bold> Lower respiratory tract samples yield significantly higher MERS-CoV loads and genome fractions than upper respiratory tract samples.</p></abstract><kwd-group><kwd>Middle East</kwd><kwd>MERS-CoV</kwd><kwd>RT-PCR</kwd><kwd>molecular</kwd><kwd>diagnosis</kwd><kwd>coronavirus</kwd><kwd>clinical</kwd><kwd>screening</kwd><kwd>viral load</kwd><kwd>Ct value</kwd><kwd>genome fraction</kwd></kwd-group></article-meta></front><body><p>A range of clinical specimens from patients with respiratory tract infections (RTIs) [<xref rid="JIU292C1" ref-type="bibr">1–3</xref>] are sent to the laboratory by clinicians for making a diagnosis and monitoring disease activity. Sputum and nasopharyngeal swab specimens are commonly used for patients who are seen as outpatients or at points of care, and deeper respiratory tract samples, such as tracheal aspirates and bronchoalveolar lavage samples, are frequently obtained from patients who are seriously ill and require admission to the intensive care unit [<xref rid="JIU292C1" ref-type="bibr">1–3</xref>]. Analysis of clinical samples of patients with new viral infections is critical to confirm the diagnosis, undertake genome sequence analysis, and study the transmission dynamics and evolution of the virus [<xref rid="JIU292C4" ref-type="bibr">4–9</xref>].</p><p>The proportion of the virus genome sequence obtained is dependent on collection of good-quality clinical specimens from relevant disease sites that can yield higher levels of the virus. Measuring the concentration of viral genome in the patients' clinical samples (ie, the viral load) during the course of the illness is also important for estimating the period of infectiousness and for defining guidelines on the duration of isolation precautions. Viral load measurements can also reflect active replication and are used in severe viral RTIs for monitoring disease activity, clinical progress, response to therapy, cure, and relapse. Studies of diverse viral RTIs have found that maximal viral shedding occurs in the first few days after onset of symptoms and then declines with time [<xref rid="JIU292C3" ref-type="bibr">3</xref>, <xref rid="JIU292C4" ref-type="bibr">4</xref>, <xref rid="JIU292C7" ref-type="bibr">7</xref>, <xref rid="JIU292C9" ref-type="bibr">9</xref>]. Thus, depending on the site of pathology and viral replication, the most appropriate clinical sample for obtaining the maximal viral genome yield can be ascertained.</p><p>Several community- and hospital-based studies of the recently discovered novel Middle East respiratory syndrome coronavirus (MERS-CoV), a novel species of the genus Betacoronavirus with positive-sense, single-stranded RNA [<xref rid="JIU292C10" ref-type="bibr">10</xref>, <xref rid="JIU292C11" ref-type="bibr">11</xref>], have shown that infection with this virus is associated with respiratory tract disease ranging in severity from mild to severe, rapidly fulminant disease in patients with comorbid medical conditions [<xref rid="JIU292C11" ref-type="bibr">11–19</xref>]. Although a real-time reverse-transcription polymerase chain reaction (RT-PCR) technique for detecting MERS-CoV was developed [<xref rid="JIU292C20" ref-type="bibr">20</xref>, <xref rid="JIU292C21" ref-type="bibr">21</xref>] and approved by the World Health Organization soon after the first case of MERS-CoV infection was reported from the Kingdom of Saudi Arabia (KSA), in September 2012, there are scant data on the yield of MERS-CoV genome sequences from various respiratory tract specimens. Molecular studies of viral infections are crucially dependent on obtaining good-quality clinical specimens yielding adequate quantities of intact viral nucleic acid for sequence analysis.</p><p>We conducted a study of the relationship between respiratory tract sample type, MERS-CoV genome load, the proportion of the virus genome sequence obtained using a range of respiratory tract samples obtained from laboratory-confirmed cases of MERS-CoV infection reported from the KSA.</p><sec sec-type="methods" id="s2"><title>METHODS</title><sec id="s2a"><title>Collection of Clinical Specimens</title><p>The following respiratory tract samples were analyzed for MERS-CoV load (by determining threshold cycle [Ct] values) and the proportion of MERS-CoV genome obtained: sputum samples, nasopharyngeal swab samples, tracheal aspirates, and bronchoalveolar lavage specimens. Sputum specimens were collected directly into a sterile, leak-proof, screw cap container; nasopharyngeal swabs specimens were collected using sterile, synthetic (Dacron)–tipped flocked swabs. Swabs were inserted through the nostril, parallel to the palate, into the nasopharynx, and left in place for a few seconds to absorb secretions. All swabs were placed immediately into sterile tubes containing 2–3 mL of viral transport medium. For lower respiratory tract samples, 2–3 mL of tracheal aspirates or bronchoalveolar lavage fluid were obtained and placed into a dry sterile, leak-proof, screw cap container.</p></sec><sec id="s2b"><title>Storage and Transport of Specimens</title><p>Transport of specimens was performed as previously described [<xref rid="JIU292C19" ref-type="bibr">19</xref>]. In brief, for short periods (≤48 hours) of transport, specimens were kept at 2°C–8°C. If the transport duration was >48 hours, specimens were shipped frozen on dry ice as soon as possible after collection. Each specimen container was labeled with the patient identifier, specimen type, and the sample collection date. Packaging was performed to prevent breakage and spillage, containers were sealed with parafilm and placed in ziplock bags with sufficient absorbent material to absorb the entire contents if spillage occurred, and the primary container was placed inside a secondary container [<xref rid="JIU292C19" ref-type="bibr">19</xref>].</p></sec><sec id="s2c"><title>RNA Extraction</title><p>RNA extraction was performed as described previously [<xref rid="JIU292C19" ref-type="bibr">19</xref>], using the Roche Magna Pure LC (RNA Viral isolation Kit). Sputum samples were pretreated with 2× lysis buffer for 30 minutes in a shaking incubator. Swabs were placed in lysis buffer. A total of 200 µL of each sample was added to a MagNA pure LC plate, which contains 96 wells. Reaction reagents were then loaded and checked before running the samples according to the manufacturer's instructions for nucleic acid extraction in a specimen preparation area.</p></sec><sec id="s2d"><title>MERS-CoV PCR Testing</title><p>Clinical samples were screened by a real-time RT-PCR amplification test as previously described [<xref rid="JIU292C20" ref-type="bibr">20</xref>, <xref rid="JIU292C21" ref-type="bibr">21</xref>], with amplification targeting the upstream E region (upE) and the ORF1a for confirmation. Results were considered positive only if both assays were positive. When the first and second assays were discordant or if the real-time RT-PCR result was ambiguous, an additional clinical sample was requested and analyzed.</p></sec><sec id="s2e"><title>Genome Extraction and Sequence Generation</title><p>MERS-CoV deep sequencing was conducted as previously described [<xref rid="JIU292C22" ref-type="bibr">22</xref>, <xref rid="JIU292C23" ref-type="bibr">23</xref>]. The MERS-CoV genome sequences that have been analyzed have all been published and described previously [<xref rid="JIU292C13" ref-type="bibr">13</xref>, <xref rid="JIU292C22" ref-type="bibr">22–24</xref>].</p></sec><sec id="s2f"><title>Statistical Analyses</title><p>MERS-CoV load and genome fraction were recorded for each set of sputum specimens, nasopharyngeal swab specimens, tracheal aspirates, or bronchoalveolar lavage samples. Standard box and whisker plots with a median value for each set were calculated for MERS-CoV load and fraction of MERS-CoV genome obtained. The fraction of MERS-CoV genome obtained was plotted by sample viral Ct value against sample type. Mann–Whitney <italic>U</italic> tests were performed for all comparisons; a <italic>P</italic> value of <.05 was considered to be statistically significant.</p></sec></sec><sec sec-type="results" id="s3"><title>RESULTS</title><p>Respiratory tract samples obtained from 112 individuals with positive results of real-time RT-PCR for MERS-CoV were analyzed. This set includes 13 sputum samples, 64 nasopharyngeal swabs, 30 tracheal aspirates, and 3 bronchoalveolar lavage samples. Two samples received by the laboratory had no sample type indication and were not included in the analysis.</p><sec id="s3a"><title>Viral Load Ct Values</title><p>A comparison of the MERS-CoV real-time RT-PCR Ct values as a function of sample type was performed (Figure <xref ref-type="fig" rid="JIU292F1">1</xref>, upper panel). Table <xref rid="JIU292TB1" ref-type="table">1</xref> shows the <italic>P</italic> values for the comparison of sample type to Ct value. Tracheal aspirates yielded significantly lower MERS-CoV Ct values (ie, a higher viral load) than nasopharyngeal swab specimens (<italic>P</italic> = .0005) and sputum specimens (<italic>P</italic> = .0001). There was no significant difference in viral load Ct values when tracheal aspirates were compared to bronchoalveolar lavage specimens (<italic>P</italic> = .3079).
</p><table-wrap id="JIU292TB1" orientation="portrait" position="float"><label>Table 1.</label><caption><p>Statistical Analyses of Clinical Sample Type Comparisons for Yield of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Load and of the MERS-CoV Genome Fraction</p></caption><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="char" char="." span="1"></col><col align="char" char="." span="1"></col></colgroup><thead><tr><th align="left" colspan="1" rowspan="1">Comparison</th><th align="center" colspan="1" rowspan="1"><italic>P,</italic> Viral Load<sup>a</sup></th><th align="center" colspan="1" rowspan="1"><italic>P,</italic> Genome Fraction<sup>b</sup></th></tr></thead><tbody><tr><td colspan="1" rowspan="1">TA vs NP</td><td colspan="1" rowspan="1">.0005</td><td colspan="1" rowspan="1">.0002</td></tr><tr><td colspan="1" rowspan="1">TA vs Sputum</td><td colspan="1" rowspan="1">.0001</td><td colspan="1" rowspan="1">.0001</td></tr><tr><td colspan="1" rowspan="1">TA vs BAL</td><td colspan="1" rowspan="1">.3079</td><td colspan="1" rowspan="1">.1174</td></tr><tr><td colspan="1" rowspan="1">NP vs Sputum</td><td colspan="1" rowspan="1">.0113</td><td colspan="1" rowspan="1">.0092</td></tr><tr><td colspan="1" rowspan="1">NP vs BAL</td><td colspan="1" rowspan="1">.0298</td><td colspan="1" rowspan="1">.0095</td></tr><tr><td colspan="1" rowspan="1">Sputum vs BAL</td><td colspan="1" rowspan="1">.0074</td><td colspan="1" rowspan="1">.0009</td></tr></tbody></table><table-wrap-foot><fn id="TN1"><p>Abbreviations: BAL, bronchoalveolar lavage fluid; Ct, threshold cycle; NP, nasopharyngeal swab specimen; TA, tracheal aspirate.</p></fn><fn id="TN2"><p><sup>a</sup> Values denote results of the comparison of Ct real-time reverse-transcription polymerase chain reaction findings, using the Mann–Whitney <italic>U</italic> test.</p></fn><fn id="TN3"><p><sup>b</sup> Values denote results of the comparison of deep sequencing findings, using the Mann–Whitney <italic>U</italic> test.</p></fn></table-wrap-foot></table-wrap><fig id="JIU292F1" orientation="portrait" position="float"><label>Figure 1.</label><caption><p>Clinical sample type and Middle East respiratory syndrome coronavirus (MERS-CoV) threshold cycle (Ct) values. The Ct of real-time reverse-transcription polymerase chain reaction, a measurement of MES-CoV viral load (upper panel) or fraction of MERS-CoV genome obtained by deep sequencing (lower panel) were plotted by clinical sample type (tracheal aspirates [TAs], nasopharyngeal swab specimens [NPs], sputum specimens, and bronchoalveolar lavage specimens [BALs]). Box and whisker plots were prepared using the Python/Matplotlib box plot module (<uri xlink:type="simple" xlink:href="http://matplotlib.org/examples/pylab_examples/boxplot_demo.html">http://matplotlib.org/examples/pylab_examples/boxplot_demo.html</uri>). Data are for 110 specimens collected through 14 November 2014. Gray boxes indicate the lower to upper quartile values of each subset, blue lines indicate median values, and whiskers indicate ranges, with outlier points falling above or below 1.5 times the interquartile range indicated individually.</p></caption><graphic xlink:href="jiu29201"></graphic></fig></sec><sec id="s3b"><title>Genome Fraction Values</title><p>Figure <xref ref-type="fig" rid="JIU292F1">1</xref> (lower panel) shows the MERS-CoV genome fraction obtained from each sample type. Figure <xref ref-type="fig" rid="JIU292F2">2</xref> shows the correlation of the fraction of the MERS-CoV genome obtained with the sample Ct value relative to the sample type. Higher MERS-CoV genome fractions were obtained from bronchoalveolar lavage samples and tracheal aspirates than from nasopharyngeal swab specimens (<italic>P</italic> = .0095 and <italic>P</italic> = .0002, respectively) and sputum samples (<italic>P</italic> = .0009 and <italic>P</italic> = .0001, respectively; Table <xref rid="JIU292TB1" ref-type="table">1</xref>). There was no significant difference in genome yield between tracheal aspirates and bronchoalveolar lavage samples (<italic>P</italic> = .1174; Table <xref rid="JIU292TB1" ref-type="table">1</xref>).
</p><fig id="JIU292F2" orientation="portrait" position="float"><label>Figure 2.</label><caption><p>Fraction of the sequenced Middle East respiratory syndrome coronavirus (MERS-CoV) genome obtained as a function of MERS-CoV load. Samples were stratified by clinical sample type and the fraction of MERS-CoV genome obtained by deep sequencing was plotted as a function of the MERS-CoV load (presented in terms of the threshold cycle [Ct] value). Data are for 110 specimens collected through 14 November 2014. Tracheal aspirates (TAs) are indicated by red circles, nasopharyngeal swab samples (NPs) are indicated with black Xs, sputum samples are indicated with gray circles, bronchoalveolar lavage samples (BAL) are indicated with green circles, and samples with an unknown type (n = 2) are indicated with black crosses.</p></caption><graphic xlink:href="jiu29202"></graphic></fig></sec></sec><sec sec-type="discussion" id="s4"><title>DISCUSSION</title><p>This study presents the largest data set available to date on molecular analyses of several types of respiratory tract samples and describes the distribution of the MERS-CoV genome load and fraction of the virus genome sequence obtained from these samples. Varying amounts of MERS-CoV load and fractions of MERS-CoV genomes were obtained from all clinical sample types received from 110 Saudi Arabian patients with MERS-CoV infection. When stratified by site of sample origin, samples from deeper in the respiratory tract (ie, tracheal aspirates and bronchoalveolar lavage specimens) yielded significantly higher MERS-CoV genome loads and genome sequenced fractions than samples from other respiratory tract (ie, sputum and nasopharyngeal swab specimens), although samples from all anatomical sites appear to be suitable for viral load determination and virus genome sequencing studies.</p><p>Conventionally, tests to detect viral infections in the respiratory tract are performed on sputum or nasopharyngeal swab specimens from patients not requiring admission to the intensive care unit [<xref rid="JIU292C1" ref-type="bibr">1</xref>, <xref rid="JIU292C2" ref-type="bibr">2</xref>, <xref rid="JIU292C19" ref-type="bibr">19</xref>] and on tracheal aspirates and bronchoalveolar lavage samples from patients in the intensive care unit [<xref rid="JIU292C3" ref-type="bibr">3</xref>, <xref rid="JIU292C4" ref-type="bibr">4</xref>, <xref rid="JIU292C7" ref-type="bibr">7</xref>, <xref rid="JIU292C13" ref-type="bibr">13</xref>], and the samples are therefore accessible. A limitation of this study is the lack of multiple samples from multiple compartments of a single patient. However, given this limitation, it appears that viral load is good predictor of MERS-CoV sequencing success.</p><p>The viral load in a clinical sample at any given time reflects the dynamic interaction between MERS-CoV replication and the ability of the host's immune system to eliminate the virus. Thus, MERS-CoV load measurements can be clinically useful for monitoring disease activity, clinical progress, response to therapy, and cure, and they can also be used as a marker of prognosis [<xref rid="JIU292C7" ref-type="bibr">7–11</xref>]. The ideal approach to determining the most appropriate clinical sample for making a diagnosis, ascertaining the viral load, and obtaining the optimal genome fraction requires understanding of the natural history of the viral infection [<xref rid="JIU292C9" ref-type="bibr">9–11</xref>]. Data from the severe acute respiratory syndrome (SARS) epidemic showed low SARS-CoV loads in the upper respiratory tract and high viral loads in the lower respiratory tract [<xref rid="JIU292C9" ref-type="bibr">9–11</xref>]. The natural history of SARS-CoV infection was unique in that test results for nasopharyngeal specimens were often negative during the first week of infection, and the highest positivity rates occurred during the second week of illness, peaking at approximately day 10. This allowed definition of which and when during the course of infection clinical specimens will test positive [<xref rid="JIU292C5" ref-type="bibr">5</xref>, <xref rid="JIU292C11" ref-type="bibr">11</xref>]. The low virus detection rate in nasopharyngeal specimens early in the course of SARS-CoV infection illustrates the importance of optimal timing of specimen collection and the optimal specimen type for diagnosis.</p><p>Definition of the natural history of the virus may indicate possible sites in the respiratory tract and other parts of the body where the virus causes inflammation and damage. In other common respiratory viral infections, such as influenza, the viral load peaks soon after the onset of symptoms [<xref rid="JIU292C4" ref-type="bibr">4</xref>]. There were several features of SARS that distinguished it from other viral causes of RTIs [<xref rid="JIU292C7" ref-type="bibr">7</xref>, <xref rid="JIU292C11" ref-type="bibr">11</xref>]. The pathogenic potential, natural history, and transmission dynamics of MERS-CoV require definition before the optimal sample type can be ascertained. Dipeptidyl peptidase 4 was identified as the receptor for MERS-CoV [<xref rid="JIU292C25" ref-type="bibr">25</xref>], and these receptors are expressed on primary human bronchiolar lung tissue; thus, the virus is able to infect lower respiratory tract tissues. Gastrointestinal symptoms are also present in patients infected with MERS-CoV [<xref rid="JIU292C13" ref-type="bibr">13</xref>].</p><p>Diagnostic tests for respiratory viral infections or screening of close contacts have traditionally been performed on upper respiratory tract samples, particularly nasopharyngeal swab specimens, and it is no different for MERS-CoV. For detecting MERS-CoV, the choice of the most appropriate respiratory tract specimen for diagnostic purposes remains to be determined and requires further study of several respiratory tract sample types obtained at the same time from the same patient. Further studies are required to (1) define the natural history of MERS-CoV infection in humans and the viral load kinetics over time in various respiratory tract samples; 2) determine MERS-CoV shedding in various nonrespiratory clinical sample types, such as urine, stool, blood, or effusions from the time of infection to recovery or death; and 3) correlate viral load with intensive care unit admission and death as a composite end point. These data are required to shed further light on MERS-CoV pathogenesis, ascertain the optimal clinical samples for diagnosis, and guide optimal infection control measures. Viral load measurements could also serve as biomarkers for monitoring response to therapy, disease activity, and predict prognosis.</p></sec></body><back><ack><title>Notes</title><p><bold><italic>Acknowledgments.</italic></bold> We are grateful to all staff of the Ministry of Health, Kingdom of Saudi Arabia (KSA); and to Mr Adam Zumla, University College London School of Pharmacy, for kindly providing technical and administrative support.</p><p>This study was initiated, designed, and conducted as a major priority issue under the auspices of The Global Center for Mass Gatherings Medicine (GCMGM), Ministry of Health, KSA. Board members of the GCMGM, Abdullah Al-Rabeeah (chair), Ziad A Memish (vice chair), Alimuddin Zumla, Jaffar A. Al-Tawfiq, Abdullah Assiri, Ali Albarrak, and Rafaat Al-Hakeen, initiated a range of MERS-CoV studies.</p><p>H. Q. M., A. Z., J. Al-T., and M. C. collected data on viral load and genome fraction and finalized the database. All KSA authors were involved in sample collection and patient management. M. C., P. K., and S. J. W. were responsible for generating the MERS-CoV genome sequences analyzed, and M. C. developed the figures and tables. Z. A. M., A. Z., H. Q. M., J. Al-T., and M. C. wrote the first and final drafts of the manuscript. All authors contributed to the finalization of the manuscript.</p><p><bold><italic>Financial support.</italic></bold> This work was supported by the Saudi Ministry of Health. The following authors acknowledge the University College London Hospitals NHS Foundation Trust (to A. Z.); the National Institute of Health Research, Biomedical Research Centre, UCL Hospitals (to A. Z.); the EDCTP (to A. Z.); the EC-FW7 (RiD-RTI to A. Z.); the Wellcome Trust (to P. K., M. C., and S. W.); the European Community Seventh Framework Programme (FP7/2007-2013), under the projects EMPERIE (grant 223 498 to P. K., M. C., and S. W. and contract 223 498 to C. D.) and ANTIGONE (contract 278 976 to C. D.); the German Centre for Infection Research (to C. D.); the German Ministry for Research and Education (to C. D.); and the German Research Council (grants 01KIO701 and DR 772/3-1 to C. D.).</p><p><bold><italic>Potential conflicts of interest.</italic></bold> All authors: No reported conflicts.</p><p>All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. 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