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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Severe Acute Respiratory Syndrome Coronavirus as an Agent of Emerging and Reemerging Infection</title><author><name sortKey="Cheng, Vincent C C" sort="Cheng, Vincent C C" uniqKey="Cheng V" first="Vincent C. C." last="Cheng">Vincent C. C. Cheng</name><affiliation><nlm:aff id="aff0">State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, China</nlm:aff></affiliation></author><author><name sortKey="Lau, Susanna K P" sort="Lau, Susanna K P" uniqKey="Lau S" first="Susanna K. P." last="Lau">Susanna K. P. Lau</name><affiliation><nlm:aff id="aff0">State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, China</nlm:aff></affiliation></author><author><name sortKey="Woo, Patrick C Y" sort="Woo, Patrick C Y" uniqKey="Woo P" first="Patrick C. Y." last="Woo">Patrick C. Y. Woo</name><affiliation><nlm:aff id="aff0">State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, China</nlm:aff></affiliation></author><author><name sortKey="Yuen, Kwok Yung" sort="Yuen, Kwok Yung" uniqKey="Yuen K" first="Kwok Yung" last="Yuen">Kwok Yung Yuen</name><affiliation><nlm:aff id="aff0">State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, China</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">17934078</idno><idno type="pmc">2176051</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2176051</idno><idno type="RBID">PMC:2176051</idno><idno type="doi">10.1128/CMR.00023-07</idno><date when="2007">2007</date><idno type="wicri:Area/Pmc/Corpus">000632</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000632</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Severe Acute Respiratory Syndrome Coronavirus as an Agent of Emerging and Reemerging Infection</title><author><name sortKey="Cheng, Vincent C C" sort="Cheng, Vincent C C" uniqKey="Cheng V" first="Vincent C. C." last="Cheng">Vincent C. C. Cheng</name><affiliation><nlm:aff id="aff0">State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, China</nlm:aff></affiliation></author><author><name sortKey="Lau, Susanna K P" sort="Lau, Susanna K P" uniqKey="Lau S" first="Susanna K. P." last="Lau">Susanna K. P. Lau</name><affiliation><nlm:aff id="aff0">State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, China</nlm:aff></affiliation></author><author><name sortKey="Woo, Patrick C Y" sort="Woo, Patrick C Y" uniqKey="Woo P" first="Patrick C. Y." last="Woo">Patrick C. Y. Woo</name><affiliation><nlm:aff id="aff0">State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, China</nlm:aff></affiliation></author><author><name sortKey="Yuen, Kwok Yung" sort="Yuen, Kwok Yung" uniqKey="Yuen K" first="Kwok Yung" last="Yuen">Kwok Yung Yuen</name><affiliation><nlm:aff id="aff0">State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, China</nlm:aff></affiliation></author></analytic><series><title level="j">Clinical Microbiology Reviews</title><idno type="ISSN">0893-8512</idno><idno type="eISSN">1098-6618</idno><imprint><date when="2007">2007</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Before the emergence of severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) in 2003, only 12 other animal or human coronaviruses were known. The discovery of this virus was soon followed by the discovery of the civet and bat SARS-CoV and the human coronaviruses NL63 and HKU1. Surveillance of coronaviruses in many animal species has increased the number on the list of coronaviruses to at least 36. The explosive nature of the first SARS epidemic, the high mortality, its transient reemergence a year later, and economic disruptions led to a rush on research of the epidemiological, clinical, pathological, immunological, virological, and other basic scientific aspects of the virus and the disease. This research resulted in over 4,000 publications, only some of the most representative works of which could be reviewed in this article. The marked increase in the understanding of the virus and the disease within such a short time has allowed the development of diagnostic tests, animal models, antivirals, vaccines, and epidemiological and infection control measures, which could prove to be useful in randomized control trials if SARS should return. The findings that horseshoe bats are the natural reservoir for SARS-CoV-like virus and that civets are the amplification host highlight the importance of wildlife and biosecurity in farms and wet markets, which can serve as the source and amplification centers for emerging infections.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Clin Microbiol Rev</journal-id><journal-title>Clinical Microbiology Reviews</journal-title><issn pub-type="ppub">0893-8512</issn><issn pub-type="epub">1098-6618</issn><publisher><publisher-name>American Society for Microbiology (ASM)</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">17934078</article-id><article-id pub-id-type="pmc">2176051</article-id><article-id pub-id-type="publisher-id">0023-07</article-id><article-id pub-id-type="doi">10.1128/CMR.00023-07</article-id><article-categories><subj-group subj-group-type="heading"><subject>Reviews</subject></subj-group></article-categories><title-group><article-title>Severe Acute Respiratory Syndrome Coronavirus as an Agent of Emerging and Reemerging Infection</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Cheng</surname><given-names>Vincent C. C.</given-names></name><xref ref-type="aff" rid="aff0"></xref></contrib><contrib contrib-type="author"><name><surname>Lau</surname><given-names>Susanna K. P.</given-names></name><xref ref-type="aff" rid="aff0"></xref></contrib><contrib contrib-type="author"><name><surname>Woo</surname><given-names>Patrick C. Y.</given-names></name><xref ref-type="aff" rid="aff0"></xref></contrib><contrib contrib-type="author"><name><surname>Yuen</surname><given-names>Kwok Yung</given-names></name><xref ref-type="aff" rid="aff0"></xref><xref ref-type="corresp" rid="cor1">*</xref></contrib></contrib-group><aff id="aff0">State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, China</aff><author-notes><fn id="cor1"><label>*</label><p>Corresponding author. Mailing address: State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong Special Administrative Region, China. Phone: (852) 2855 4892. Fax: (852) 2855 1241. E-mail: <email>hkumicro@hkucc.hku.hk</email></p></fn></author-notes><pub-date pub-type="ppub"><month>10</month><year>2007</year></pub-date><volume>20</volume><issue>4</issue><fpage>660</fpage><lpage>694</lpage><permissions><copyright-statement>Copyright © 2007, American Society for Microbiology</copyright-statement></permissions><self-uri xlink:title="pdf" xlink:href="zcm00407000660.pdf"></self-uri><abstract><p>Before the emergence of severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) in 2003, only 12 other animal or human coronaviruses were known. The discovery of this virus was soon followed by the discovery of the civet and bat SARS-CoV and the human coronaviruses NL63 and HKU1. Surveillance of coronaviruses in many animal species has increased the number on the list of coronaviruses to at least 36. The explosive nature of the first SARS epidemic, the high mortality, its transient reemergence a year later, and economic disruptions led to a rush on research of the epidemiological, clinical, pathological, immunological, virological, and other basic scientific aspects of the virus and the disease. This research resulted in over 4,000 publications, only some of the most representative works of which could be reviewed in this article. The marked increase in the understanding of the virus and the disease within such a short time has allowed the development of diagnostic tests, animal models, antivirals, vaccines, and epidemiological and infection control measures, which could prove to be useful in randomized control trials if SARS should return. The findings that horseshoe bats are the natural reservoir for SARS-CoV-like virus and that civets are the amplification host highlight the importance of wildlife and biosecurity in farms and wet markets, which can serve as the source and amplification centers for emerging infections.</p></abstract></article-meta></front><floats-wrap><fig position="float" id="f1"><label>FIG. 1.</label><caption><p>Phylogenetic tree of 28 coronaviruses with complete protein sequences of helicase. Their accession numbers are shown in parentheses. Italic type indicates the complete genome accession numbers since helicase protein sequence accession numbers of these coronaviruses are not available. The helicase of another eight coronaviruses of spotted hyena, cheetah, ferret, puffinosis, rat, pigeon, goose, and duck are not included because no complete protein sequence is available. The classification of Asian leopard cat coronavirus is undefined. The tree was constructed by the neighbor-joining method using clustalX 1.83. The scale bar indicates the estimated number of substitutions per 50 nucleotides. (Data are from references <xref ref-type="bibr" rid="r265">265</xref>, <xref ref-type="bibr" rid="r326">326</xref>, <xref ref-type="bibr" rid="r339">339</xref>, <xref ref-type="bibr" rid="r367">367</xref>, <xref ref-type="bibr" rid="r368">368</xref>, and <xref ref-type="bibr" rid="r375">375</xref>.)</p></caption><graphic xlink:href="zcm0040722200001"></graphic></fig><fig position="float" id="f2"><label>FIG. 2.</label><caption><p>Genome arrangement of SARS-CoV. Gray boxes indicate 3CL protease (3CL<sup>pro</sup>), polymerase (pol), spike (S), envelope (E), membrane (M), and nucleocapsid (N) genes.</p></caption><graphic xlink:href="zcm0040722200002"></graphic></fig><table-wrap position="float" id="t1"><label>TABLE 1.</label><caption><p>Nomenclature and functional characteristics of SARS-CoV gene products and their interactions with host cells in disease pathogenesis</p></caption><table frame="hsides" rules="groups"><thead><tr><th colspan="1" rowspan="1" align="center" valign="bottom">Gene nomenclature (no. of amino acid residues in product)</th><th colspan="1" rowspan="1" align="center" valign="bottom">Gene product and/or characteristic(s) (reference[s])</th><th colspan="1" rowspan="1" align="center" valign="bottom">Effect on cellular response of host (reference[s])</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" align="left" valign="top"><italic>Orf1a/b</italic></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> <italic>nsp1</italic> (180)</td><td colspan="1" rowspan="1" align="left" valign="top">Expression promoted degradation of host endogenous mRNAs, which may inhibit host protein synthesis and prevented endogenous IFN-β mRNA accumulation (<xref ref-type="bibr" rid="r167">167</xref>)</td><td colspan="1" rowspan="1" align="left" valign="top">Induce CCL5, CXCL10 (IP10), and CCL3 expression in human lung epithelial cells via activation of NF-κB; increases cellular RNA degradation, which might facilitate SARS-CoV replication or block immune responses (<xref ref-type="bibr" rid="r81">81</xref>, <xref ref-type="bibr" rid="r192">192</xref>)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> <italic>nsp2</italic> (638)</td><td colspan="1" rowspan="1" align="left" valign="top">Deletion attenuates viral growth and RNA synthesis (<xref ref-type="bibr" rid="r106">106</xref>)</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> <italic>nsp3</italic> (1,922)</td><td colspan="1" rowspan="1" align="left" valign="top">Papain-like protease 2; proteolytic processing of the viral polyprotein at 3 sites and participation in synthesis of subgenomic RNA segment (<xref ref-type="bibr" rid="r15">15</xref>, <xref ref-type="bibr" rid="r121">121</xref>, <xref ref-type="bibr" rid="r224">224</xref>)</td><td colspan="1" rowspan="2" align="center" valign="middle">Putative catalytic triad (Cys1651-His1812-Asp1826) and zinc-binding site have deubiquitinating activity; this unexpected activity in addition to its papain-like protease suggests a novel viral strategy to modulate the host cell ubiquitination machinery to its advantage (<xref ref-type="bibr" rid="r15">15</xref>, <xref ref-type="bibr" rid="r224">224</xref>, <xref ref-type="bibr" rid="r279">279</xref>)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">ADP-ribose 1-phosphatase; dephosphorylates Appr-1‴-p, a side product of cellular tRNA splicing, to ADP-ribose (<xref ref-type="bibr" rid="r271">271</xref>)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> <italic>nsp4</italic> (500)</td><td colspan="1" rowspan="1" align="left" valign="top">Not known</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> <italic>nsp5</italic> (306)</td><td colspan="1" rowspan="1" align="left" valign="top">3C-like protease; proteolytic processing of the replicative polyprotein at 11 specific sites and forming key functional enzymes such as replicase and helicase (<xref ref-type="bibr" rid="r5">5</xref>, <xref ref-type="bibr" rid="r394">394</xref>)</td><td colspan="1" rowspan="1" align="left" valign="top">Growth arrest and apoptosis via caspase-3 and caspase-9 activities demonstrated in SARS-CoV 3CLpro-expressing human promonocyte cells with increased activation of the nuclear factor-κB-dependent reporter (<xref ref-type="bibr" rid="r222">222</xref>)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> <italic>nsp6</italic> (290)</td><td colspan="1" rowspan="1" align="left" valign="top">Not known</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> <italic>nsp7</italic> (83)</td><td colspan="1" rowspan="1" align="left" valign="top">Three-dimensional structure by nuclear magnetic resonance study found potential sites for protein-protein interactions (<xref ref-type="bibr" rid="r261">261</xref>)</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> <italic>nsp8</italic> (198)</td><td colspan="1" rowspan="1" align="left" valign="top">Putative RNA-dependent RNA polymerase; crystal structure of the hexadecameric nsp7-nsp8 possesses a central channel with dimensions and positive electrostatic properties favorable for nucleic acid binding; it is probably another unique RNA-dependent RNA polymerase for its large genome (<xref ref-type="bibr" rid="r158">158</xref>, <xref ref-type="bibr" rid="r414">414</xref>)</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> <italic>nsp9</italic> (113)</td><td colspan="1" rowspan="1" align="left" valign="top">Three-dimensional crystal structure of a dimer which binds viral RNA and interacts with nsp8 (<xref ref-type="bibr" rid="r92">92</xref>, <xref ref-type="bibr" rid="r316">316</xref>)</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> <italic>nsp10</italic> (139)</td><td colspan="1" rowspan="1" align="left" valign="top">Crystal structure suggests a nucleic acid binding function within a larger RNA binding protein complex for viral gene transcription and replication (<xref ref-type="bibr" rid="r166">166</xref>, <xref ref-type="bibr" rid="r309">309</xref>)</td><td colspan="1" rowspan="1" align="left" valign="top">Interacts specifically with the NADH 4L subunit and cytochrome oxidase II with depolarization of inner mitochondrial membrane of transfected human embryo lung fibroblast and extensive cytopathic effect (<xref ref-type="bibr" rid="r210">210</xref>)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> <italic>nsp11</italic> (13)</td><td colspan="1" rowspan="1" align="left" valign="top">Not known</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> <italic>nsp12</italic> (932)</td><td colspan="1" rowspan="1" align="left" valign="top">RNA-dependent RNA polymerase; replication and transcription to produce genome- and subgenome-sized RNAs of both polarities (<xref ref-type="bibr" rid="r158">158</xref>)</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> <italic>nsp13</italic> (601)</td><td colspan="1" rowspan="1" align="left" valign="top">Helicase (dNTPase and RNA 5′-triphosphatase activities) (<xref ref-type="bibr" rid="r95">95</xref>)</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> <italic>nsp14</italic> (527)</td><td colspan="1" rowspan="1" align="left" valign="top">3′→5′-exoribonuclease; this unusual 3′→5′-exoribonuclease activity supplements the endoribonuclease activity in the replication of the giant RNA genome (<xref ref-type="bibr" rid="r242">242</xref>)</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> <italic>nsp15</italic> (346)</td><td colspan="1" rowspan="1" align="left" valign="top">Uridylate-specific endoribonuclease; RNA endonuclease that is critically involved in the coronavirus replication cycle (<xref ref-type="bibr" rid="r284">284</xref>)</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> <italic>nsp16</italic> (298)</td><td colspan="1" rowspan="1" align="left" valign="top">Putative 2′-<italic>O</italic>-ribose methyltransferase (<xref ref-type="bibr" rid="r343">343</xref>)</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"><italic>Orf2</italic> (1,255)</td><td colspan="1" rowspan="1" align="left" valign="top">Spike protein; binds to the host cell receptor ACE2 and other coreceptors, mediates viral entry into host cells as a type 1 viral fusion protein; required acidification of endosomes for efficient S-mediated viral entry; proteolytic cleavage by abundantly expressed infected cell membrane-associated factor Xa into S1 and S2; protease activation required for cell-cell fusion (<xref ref-type="bibr" rid="r159">159</xref>, <xref ref-type="bibr" rid="r162">162</xref>, <xref ref-type="bibr" rid="r206">206</xref>, <xref ref-type="bibr" rid="r214">214</xref>, <xref ref-type="bibr" rid="r227">227</xref>, <xref ref-type="bibr" rid="r301">301</xref>, <xref ref-type="bibr" rid="r334">334</xref>)</td><td colspan="1" rowspan="1" align="left" valign="top">293 T cells transfected with ACE2 can form multinucleated syncytia with cells expressing the spike; intraperitoneal injections of spike protein into mice reduced ACE2 expression in lungs and worsened acute lung failure in vivo that can be attenuated by blocking the renin-angiotensin pathway (<xref ref-type="bibr" rid="r181">181</xref>); recombinant baculovirus expressing different deletion and insertion fragments identified the functional region of S protein from amino acids 324-688, which can induce the release of IL-8 in lung cells (<xref ref-type="bibr" rid="r43">43</xref>); induces unfolded protein response in cultured cells as SARS-CoV with a substantial amt of S protein accumulation in the endoplasmic reticulum, which may modulate viral replication (<xref ref-type="bibr" rid="r30">30</xref>)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"><italic>Orf3a</italic> (274)</td><td colspan="1" rowspan="1" align="left" valign="top">Forms potassium-sensitive ion channel, may promote virus budding and release (<xref ref-type="bibr" rid="r234">234</xref>)</td><td colspan="1" rowspan="1" align="left" valign="top">Overexpression in cell line may trigger apoptosis; its expression in A549 lung epithelial cells up-regulates mRNA and intracellular and secreted levels of all three subunits, alpha, beta, and gamma, of fibrinogen, which is also observed in SARS-CoV-infected Vero E6 cells; it is highly immunogenic and induces neutralizing antibodies (<xref ref-type="bibr" rid="r193">193</xref>, <xref ref-type="bibr" rid="r321">321</xref>); 3a/X1 and 7a/X4 were capable of activating NF-κB and c-Jun N-terminal kinase and significantly enhanced IL-8 promoter activity in A549 cells; enhanced production of inflammatory chemokines that were known to be up-regulated in SARS-CoV infection (<xref ref-type="bibr" rid="r169">169</xref>)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"><italic>Orf3b</italic> (154)</td><td colspan="1" rowspan="1" align="left" valign="top">Predominately localized to the nucleolus in different transfected cells (<xref ref-type="bibr" rid="r409">409</xref>)</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 but not 293T cells transfected with a construct for expressing Orf3b underwent necrosis as early as 6 h after transfection but underwent simultaneous necrosis and apoptosis at later time points; Orf3b inhibits expression of IFN-β at synthesis and signaling (<xref ref-type="bibr" rid="r175">175</xref>, <xref ref-type="bibr" rid="r178">178</xref>)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"><italic>Orf4</italic> (76)</td><td colspan="1" rowspan="1" align="left" valign="top">Envelope protein; synthetic peptides form ion channels in planar lipid bilayers, which are more permeable to monovalent cations than to monovalent anions; putatively involved in viral budding and release (<xref ref-type="bibr" rid="r359">359</xref>)</td><td colspan="1" rowspan="1" align="left" valign="top">Induced apoptosis in transfected Jurkat T cells especially in the absence of growth factors; a novel BH3-like region was located in the C-terminal cytosolic domain of SARS-CoV E protein can bind to Bcl-xL, whose overexpression can antagonize apoptosis; this may explain the consistent lymphopenia found in SARS patients (<xref ref-type="bibr" rid="r397">397</xref>)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"><italic>Orf5</italic> (221)</td><td colspan="1" rowspan="1" align="left" valign="top">Membrane protein; surface protein responsible for viral assembly and budding</td><td colspan="1" rowspan="1" align="left" valign="top">M protein induced apoptosis in HEK293T cells, which could be suppressed by caspase inhibitors (<xref ref-type="bibr" rid="r29">29</xref>)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"><italic>Orf6</italic> (63)</td><td colspan="1" rowspan="1" align="left" valign="top">Novel membrane protein that accelerates replication and virulence of a recombinant mouse coronavirus expressing Orf6; an important virulence factor in vivo demonstrated in a mouse model (<xref ref-type="bibr" rid="r327">327</xref>)</td><td colspan="1" rowspan="1" align="left" valign="top">Inhibits both IFN synthesis and signaling; inhibited nuclear translocation but not phosphorylation of STAT1 (<xref ref-type="bibr" rid="r178">178</xref>); Orf6 is localized to the endoplasmic reticulum/Golgi membrane of infected cells; it binds and disrupts nuclear import complex formation by tethering karyopherin alpha 2 and karyopherin beta 1 to the membrane; this retention of the complex at the endoplasmic reticulum/Golgi membrane leads to a loss of STAT1 transport into the nucleus despite viral RNA-induced IFN signaling; thus, it blocks the expression of STAT1-activated genes, which are essential for establishing an antiviral state (<xref ref-type="bibr" rid="r100">100</xref>)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"><italic>Orf7a</italic> (122)</td><td colspan="1" rowspan="1" align="left" valign="top">Unique type I transmembrane protein; involved in viral assembly by interacting with M and E, which are essential for virus-like particle formation when coexpressed with S and N (<xref ref-type="bibr" rid="r97">97</xref>, <xref ref-type="bibr" rid="r150">150</xref>, <xref ref-type="bibr" rid="r245">245</xref>)</td><td colspan="1" rowspan="1" align="left" valign="top">Expression of <italic>Orf7a</italic> induces apoptosis via a caspase-3-dependent pathway and in cell lines derived from different organs including lung, kidney, and liver (<xref ref-type="bibr" rid="r179">179</xref>, <xref ref-type="bibr" rid="r320">320</xref>, <xref ref-type="bibr" rid="r408">408</xref>)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"><italic>Orf7b</italic> (44)</td><td colspan="1" rowspan="1" align="left" valign="top">Not known</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"><italic>Orf8a</italic> (39)</td><td colspan="1" rowspan="1" align="left" valign="top">Not known</td><td colspan="1" rowspan="1" align="left" valign="top">Orf8a was localized in mitochondria, and overexpression resulted in increases in mitochondrial transmembrane potential, reactive oxygen species production, caspase-3 activity, and cellular apoptosis; Orf8a enhances viral replication and induces apoptosis through a mitochondrion-dependent pathway (<xref ref-type="bibr" rid="r49">49</xref>)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"><italic>Orf8b</italic> (84)</td><td colspan="1" rowspan="1" align="left" valign="top">May modulate viral replication; expression of E was down-regulated by Orf8b but not Orf8a or Orf8ab (<xref ref-type="bibr" rid="r172">172</xref>)</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"><italic>Orf9</italic> (422)</td><td colspan="1" rowspan="1" align="left" valign="top">Nucleocapsid protein; binding and packaging of viral RNA in assembly of the virion (<xref ref-type="bibr" rid="r147">147</xref>)</td><td colspan="1" rowspan="1" align="left" valign="top">N antagonized IFN by inhibiting synthesis of IFN-β (<xref ref-type="bibr" rid="r130">130</xref>); NF-κB activation in Vero E6 cells expressing the N protein is dose dependent (<xref ref-type="bibr" rid="r220">220</xref>); N may cause inflammation of the lungs by activating COX-2 gene expression by binding directly to the promoter, resulting in inflammation through multiple COX-2 signaling cascades (<xref ref-type="bibr" rid="r393">393</xref>); induced apoptosis of COS-1 monkey kidney but not 293T cells in the absence of growth factors; induced actin reorganization in cells devoid of growth factors (<xref ref-type="bibr" rid="r315">315</xref>)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"><italic>Orf9b</italic> (98)</td><td colspan="1" rowspan="1" align="left" valign="top">Crystal structure of <italic>Orf9b</italic>, an alternative ORF within the N gene, may be involved in membrane attachment and associates with intracellular vesicles, consistent with a role in assembly of the virion (<xref ref-type="bibr" rid="r241">241</xref>)</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr></tbody></table></table-wrap><table-wrap position="float" id="t2"><label>TABLE 2.</label><caption><p>Sequence of events and molecular evolution of SARS-CoV throughout the epidemic<xref ref-type="table-fn" rid="t2fn1"><italic>a</italic></xref></p></caption><table frame="hsides" rules="groups"><thead><tr><th colspan="1" rowspan="1" align="center" valign="bottom">Phase and date</th><th colspan="1" rowspan="1" align="center" valign="bottom">Important event, phase of evolution, and genotypic marker(s)<xref ref-type="table-fn" rid="t2fn2"><italic>b</italic></xref></th></tr></thead><tbody><tr><td colspan="1" rowspan="1" align="left" valign="top">Early</td><td colspan="1" rowspan="1" align="left" valign="top">Most isolates had SNV genotypic marker of the GZ02 reference nucleotide at positions 17564, 21721, 22222, 23823, and 27827 of G:A:C:G:C; some initial cases had the 29-bp insertion or 82-bp deletion at <italic>Orf8</italic>; avg <italic>K<sub>a</sub></italic>/<italic>K<sub>s</sub></italic> ratio of >1, which was higher than that of the middle phase, which indicates strong positive selection</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> 16 November 2002</td><td colspan="1" rowspan="1" align="left" valign="top">First case that fulfilled the WHO definition of SARS at Foshan, Guangdong Province, China</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> 17 December 2002</td><td colspan="1" rowspan="1" align="left" valign="top">Chef from Heyuan who worked at a restaurant in Shenzhen had atypical pneumonia</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> 26 December 2002 to 20 January 2003</td><td colspan="1" rowspan="1" align="left" valign="top">Outbreak of similar cases at Zhongshan</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Middle</td><td colspan="1" rowspan="1" align="left" valign="top">SNV genotypic marker of G:A:C:T:C; avg <italic>K<sub>a</sub></italic>/<italic>K<sub>s</sub></italic> ratio was higher than that of the late phase but was <1, which indicates purifying selection</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> 12 January 2003</td><td colspan="1" rowspan="1" align="left" valign="top">Outbreak in Guangzhou resulted in complicated SARS cases transferred to the major hospitals in Guangzhou</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> 31 January 2003</td><td colspan="1" rowspan="1" align="left" valign="top">Outbreak in Guanzhou hospitals involving patients and health care workers</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Late</td><td colspan="1" rowspan="1" align="left" valign="top">SNV marker of T:G:T:T:T; avg <italic>K<sub>a</sub></italic>/<italic>K<sub>s</sub></italic> ratio shows stabilization of nonsynonymous mutation rate; some isolates had 415-bp deletion at <italic>Orf8</italic></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> 21 February 2003</td><td colspan="1" rowspan="1" align="left" valign="top">65-yr-old doctor from Guangdong Province resided at “hotel M” in Hong Kong (index patient); unwell since 15 February and admitted to the hospital on 22 February; infected 17 residents at hotel M, some of whom traveled to Vietnam, Singapore, and Toronto, where they started new local clusters of cases</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> 26 February 2003</td><td colspan="1" rowspan="1" align="left" valign="top">Hotel M contact was admitted to a hospital in Hanoi and started a nosocomial outbreak</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> 4 March 2003</td><td colspan="1" rowspan="1" align="left" valign="top">Another hotel M contact was admitted to Prince of Wales Hospital in Hong Kong and started a nosocomial outbreak</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> 5 March 2003</td><td colspan="1" rowspan="1" align="left" valign="top">Another hotel M contact died in Toronto; five family members were affected</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> 12 March 2003</td><td colspan="1" rowspan="1" align="left" valign="top">WHO issued a global alert</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> 14 March 2003</td><td colspan="1" rowspan="1" align="left" valign="top">Clusters of atypical pneumonia were reported in Singapore and Toronto, which were epidemiologically linked to hotel M outbreak</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> 15 March 2003</td><td colspan="1" rowspan="1" align="left" valign="top">WHO named this new disease SARS after receiving reports of more than 150 cases; WHO issued emergency travel advice in response to SARS</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> 21 March 2003</td><td colspan="1" rowspan="1" align="left" valign="top">A novel coronavirus was identified in two patients with SARS in Hong Kong; the agent, isolated in rhesus monkey kidney cells (fRhk4), produced a cytopathic effect; in an immunofluorescence antibody assay, sera from SARS patients had rising antibody titers against the virus-infected cells</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> 22 to 27 March 2003</td><td colspan="1" rowspan="1" align="left" valign="top">Isolation of a novel coronavirus was confirmed in laboratories of the United States and Germany</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> 12 April 2003</td><td colspan="1" rowspan="1" align="left" valign="top">Sequencing of the full genome of SARS-CoV was completed</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> 16 April 2003</td><td colspan="1" rowspan="1" align="left" valign="top">WHO announces that SARS-CoV is the causative agent of SARS</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> June 2003</td><td colspan="1" rowspan="1" align="left" valign="top">A virus with 99.8% nucleotide identity with SARS-CoV was isolated from palm civets and other game food mammals</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> 5 July 2003</td><td colspan="1" rowspan="1" align="left" valign="top">Absence of further transmission in Taiwan signaled the end of human-to-human transmission</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Aftermath</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> 3 September 2003</td><td colspan="1" rowspan="1" align="left" valign="top">Laboratory-acquired SARS-CoV infection was reported in Singapore</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> 16 December 2003 to 8 January 2004</td><td colspan="1" rowspan="1" align="left" valign="top">4 symptomatic cases and 1 asymptomatic case of SARS due to animal-to-human transmission occurred in the city of Guangzhou, Guangdong Province, China; all isolates had a 29-bp signature sequence insertion for animal SARS-CoV in <italic>Orf8</italic></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> 17 December 2003</td><td colspan="1" rowspan="1" align="left" valign="top">Second laboratory-acquired SARS-CoV infection reported in Taiwan</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> 25 March and 17 April 2004</td><td colspan="1" rowspan="1" align="left" valign="top">Third and fourth laboratory-acquired SARS-CoV infection reported in Beijing, China</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> 16 September 2005</td><td colspan="1" rowspan="1" align="left" valign="top">Finding of SARS-CoV-like virus in horseshoe bats; all isolates sequenced had a 29-bp signature sequence for bat SARS-CoV</td></tr></tbody></table><table-wrap-foot><fn id="t2fn1"><label>a</label><p>See references <xref ref-type="bibr" rid="r27">27</xref>, <xref ref-type="bibr" rid="r89">89</xref>, <xref ref-type="bibr" rid="r117">117</xref>, <xref ref-type="bibr" rid="r182">182</xref>, <xref ref-type="bibr" rid="r190">190</xref>, <xref ref-type="bibr" rid="r197">197</xref>, <xref ref-type="bibr" rid="r215">215</xref>, <xref ref-type="bibr" rid="r218">218</xref>, <xref ref-type="bibr" rid="r221">221</xref>, <xref ref-type="bibr" rid="r236">236</xref>, <xref ref-type="bibr" rid="r251">251</xref>, <xref ref-type="bibr" rid="r252">252</xref>, <xref ref-type="bibr" rid="r259">259</xref>, <xref ref-type="bibr" rid="r277">277</xref>, <xref ref-type="bibr" rid="r304">304</xref>, <xref ref-type="bibr" rid="r377">377</xref>, <xref ref-type="bibr" rid="r378">378</xref>, <xref ref-type="bibr" rid="r422">422</xref>, and <xref ref-type="bibr" rid="r431">431</xref>.</p></fn><fn id="t2fn2"><label>b</label><p><italic>K<sub>a</sub>/K<sub>s</sub></italic> ratio refers to the ratio of nonsynonymous nucleotide substitutions to synonymous nucleotide substitutions during the molecular evolution of SARS-CoV.</p></fn></table-wrap-foot></table-wrap><table-wrap position="float" id="t3"><label>TABLE 3.</label><caption><p>Correlation between clinical, virological, immunological, and histopathological findings</p></caption><table frame="hsides" rules="groups"><thead><tr><th colspan="1" rowspan="1" align="center" valign="bottom">Clinical and laboratory features (% positive isolates [no. of isolates studied/total no.]) (reference)<xref ref-type="table-fn" rid="t3fn1"><italic>a</italic></xref></th><th colspan="1" rowspan="1" align="center" valign="bottom">Viral load for indicated day(s) after onset of symptoms (reference)</th><th colspan="1" rowspan="1" align="center" valign="bottom">Blood immune profile or histopathological feature (reference)</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" align="left" valign="top">Systemic involvement</td><td colspan="1" rowspan="4" align="center" valign="middle">Mean 1.1 log copies/ml between days 10 and 15 in serum (<xref ref-type="bibr" rid="r156">156</xref>)</td><td colspan="1" rowspan="4" align="center" valign="middle">Increased mean serum concentrations of IL-16, TNF-α, and transforming growth factor β1 but decreased IL-18 between days 3 and 27 (<xref ref-type="bibr" rid="r16">16</xref>); increased IFN-γ and inflammatory cytokines IL-1, IL-6, and IL-12 for at least 2 wk; chemokine profile demonstrated increased neutrophil chemokine IL-8, MCP-1, and Th1 chemokine IP-10 (<xref ref-type="bibr" rid="r360">360</xref>); increased serum concn of IP10, MIG, and IL-8 during the first wk was associated with adverse outcome or death (<xref ref-type="bibr" rid="r325">325</xref>)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Fever (99.9 [751/752])</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Chill or rigors (51.5 [377/732])</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Malaise (58.8 [317/539])</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Respiratory involvement</td><td colspan="1" rowspan="5" align="center" valign="middle">Mean 2.4 log copies/ml between days 10 and 15 for NPA (<xref ref-type="bibr" rid="r156">156</xref>), 9.58 × 10<sup>2</sup>-5.93 × 10<sup>6</sup> copies/ml for throat swab and 7.08 × 10<sup>2</sup>-6.38 × 10<sup>8</sup> copies/ml for saliva between days 2 and 9 (<xref ref-type="bibr" rid="r349">349</xref>), and 2 × 10<sup>4</sup>-1 × 10<sup>10</sup> copies/ml between days 5 and 51 for lung tissue (<xref ref-type="bibr" rid="r96">96</xref>)</td><td colspan="1" rowspan="5" align="center" valign="middle">IP10 highly expressed in both lung and lymphoid tissues, with monocyte-macrophage infiltration and depletion of lymphocytes (<xref ref-type="bibr" rid="r163">163</xref>); increased alveolar macrophages and CD8 cells, decreased CD4-to-CD8 ratio, and increased TNF-α, IL-6, IL-8, RANTES, and MCP-1 levels in bronchoalveolar lavage samples (<xref ref-type="bibr" rid="r124">124</xref>, <xref ref-type="bibr" rid="r344">344</xref>); IP10 was increased in lung tissue from patients who died of SARS (<xref ref-type="bibr" rid="r325">325</xref>); increased differential expression of cytokines within these pulmonary tissues, including Stat1, IFN-regulatory factor 1, IL-6, IL-8, and IL-18, often characteristic of patients with acute respiratory distress syndrome (<xref ref-type="bibr" rid="r8">8</xref>)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Rhinorrhea (13.8 [50/362])</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Sore throat (16.5 [91/552])</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Cough (65.5 [460/702])</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Dyspnea (45.9 [282/614])</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Cardiovascular involvement</td><td colspan="1" rowspan="4" align="center" valign="middle">1 × 10<sup>4</sup>-2.8 × 10<sup>7</sup> copies/ml between days 5 and 23 for cardiac tissue (<xref ref-type="bibr" rid="r96">96</xref>)</td><td colspan="1" rowspan="4" align="center" valign="middle">Subclinical diastolic impairment without systolic involvement but no interstitial lymphocytic infiltrate or myocyte necrosis in histology (<xref ref-type="bibr" rid="r211">211</xref>); gross pulmonary thromboemboli and marantic cardiac valvular vegetations in some autopsies (<xref ref-type="bibr" rid="r67">67</xref>)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Tachycardia (46.1 [71/154])</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Bradycardia (14.9 [18/121]) (<xref ref-type="bibr" rid="r403">403</xref>)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Hypotension (50.4 [61/121]) (<xref ref-type="bibr" rid="r403">403</xref>)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Gastrointestinal involvement</td><td colspan="1" rowspan="2" align="center" valign="middle">Mean 6.1 log copies/ml between days 10 and 15 for stool (<xref ref-type="bibr" rid="r156">156</xref>), with higher mean viral load in NPA obtained on day 10 significantly associated with diarrhea (<xref ref-type="bibr" rid="r58">58</xref>); 2.7 × 10<sup>3</sup>-2.7 × 10<sup>9</sup> copies/ml between days 10 and 29 for small intestinal tissue and 5.3 × 10<sup>3</sup>-3.7 × 10<sup>8</sup> copies/ml between days 10 and 43 for large intestinal tissue (<xref ref-type="bibr" rid="r96">96</xref>)</td><td colspan="1" rowspan="2" align="center" valign="middle">Minimal architectural disruption despite active viral replication in enterocytes of both terminal ileum and colonic biopsy specimens; no villous atrophy or inflammation (<xref ref-type="bibr" rid="r205">205</xref>); atrophy of mucosal lymphoid tissue (<xref ref-type="bibr" rid="r298">298</xref>)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Diarrhea (20.1 [130/647])</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Other symptoms</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Myalgia (48.5 [365/752])</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Focal myofiber necrosis with scanty macrophage infiltration may be related to steroid treatment (<xref ref-type="bibr" rid="r204">204</xref>)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Headache (38.8 [292/752])</td><td colspan="1" rowspan="1" align="left" valign="top">RT-PCR positive for some cerebrospinal fluid (<xref ref-type="bibr" rid="r188">188</xref>)</td><td colspan="1" rowspan="1" align="left" valign="top">Necrosis of neuron cells and broad hyperplasia of gliocytes (<xref ref-type="bibr" rid="r389">389</xref>)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Dizziness (27.3 [163/597])</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Hematological involvement</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="4" align="center" valign="middle">Prolonged lymphopenia with nadir during days 7-9 returning to normal after 5 wk; death and severity are associated with profound CD4<sup>+</sup> and CD8<sup>+</sup> lymphopenia; little change in CD4/CD8 ratio (<xref ref-type="bibr" rid="r136">136</xref>)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Anemia (12.6 [17/135])</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Leukopenia (24.2 [114/472])</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Lymphopenia (66.4 [296/446])</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Thrombocytopenia (29.7 [140/472])</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Biochemical involvement</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Increased serum alanine aminotransferase levels (44.1 [208/472])</td><td colspan="1" rowspan="1" align="left" valign="top">Positive RT-PCR for liver tissue (<xref ref-type="bibr" rid="r44">44</xref>), 6 × 10<sup>3</sup>-5 × 10<sup>4</sup> copies/ml between days 2 and 9 for liver tissue (<xref ref-type="bibr" rid="r96">96</xref>)</td><td colspan="1" rowspan="1" align="left" valign="top">Ballooning of hepatocytes and mild to moderate lobular lymphocytic infiltration (<xref ref-type="bibr" rid="r44">44</xref>)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Impaired serum creatinine (6.7 [36/536]) (<xref ref-type="bibr" rid="r76">76</xref>)</td><td colspan="1" rowspan="1" align="left" valign="top">Mean 1.3 log copies/ml between days 10 and 15 for urine (<xref ref-type="bibr" rid="r156">156</xref>) and 4.3 × 10<sup>3</sup>-7.4 × 10<sup>5</sup> copies/ml between days 11 and 27 for kidney tissue (<xref ref-type="bibr" rid="r96">96</xref>)</td><td colspan="1" rowspan="1" align="left" valign="top">Acute tubular necrosis (<xref ref-type="bibr" rid="r76">76</xref>)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Decreased serum tri-iodothyronine and thyroxine</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Extensive cell apoptosis and exfoliation of the follicular epithelium into distorted, dilated, or collapsed follicles (<xref ref-type="bibr" rid="r354">354</xref>)</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Other</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Histological orchitis (<xref ref-type="bibr" rid="r388">388</xref>)</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Widespread germ cell destruction, few or no spermatozoa in the seminiferous tubule, thickened basement membrane, and leukocyte infiltration with T lymphocytes and macrophages in the interstitial tissue (<xref ref-type="bibr" rid="r388">388</xref>)</td></tr></tbody></table><table-wrap-foot><fn id="t3fn1"><label>a</label><p>See references <xref ref-type="bibr" rid="r7">7</xref>, <xref ref-type="bibr" rid="r21">21</xref>, <xref ref-type="bibr" rid="r37">37</xref>, <xref ref-type="bibr" rid="r149">149</xref>, <xref ref-type="bibr" rid="r197">197</xref>, <xref ref-type="bibr" rid="r258">258</xref>, <xref ref-type="bibr" rid="r259">259</xref>, <xref ref-type="bibr" rid="r270">270</xref>, <xref ref-type="bibr" rid="r278">278</xref>, <xref ref-type="bibr" rid="r336">336</xref>, and <xref ref-type="bibr" rid="r425">425</xref> for clinical and laboratory features unless otherwise specified in the table.</p></fn></table-wrap-foot></table-wrap><table-wrap position="float" id="t4"><label>TABLE 4.</label><caption><p>Clinical evaluation of molecular diagnostic tests for SARS-CoV</p></caption><table frame="hsides" rules="groups"><thead><tr><th colspan="1" rowspan="1" align="center" valign="bottom">Diagnostic method and target gene</th><th colspan="1" rowspan="1" align="center" valign="bottom">Clinical specimen</th><th colspan="1" rowspan="1" align="center" valign="bottom">Diagnostic gold standard</th><th colspan="1" rowspan="1" align="center" valign="bottom">Collection time after onset of symptoms (no. of samples)</th><th colspan="1" rowspan="1" align="center" valign="bottom">% Sensitivity (viral load [copies/ml])</th><th colspan="1" rowspan="1" align="center" valign="bottom">Reference</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" align="left" valign="top">In-house RT-PCR</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">RNA pol<xref ref-type="table-fn" rid="t4fn1"><italic>a</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">NPA</td><td colspan="1" rowspan="1" align="left" valign="top">Laboratory confirmed<xref ref-type="table-fn" rid="t4fn2"><italic>b</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Days 1-5<xref ref-type="table-fn" rid="t4fn3"><italic>c</italic></xref> (72)</td><td colspan="1" rowspan="1" align="left" valign="top">59.7<xref ref-type="table-fn" rid="t4fn4"><italic>d</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r391">391</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 1-5 (98)</td><td colspan="1" rowspan="1" align="left" valign="top">29.6</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r32">32</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">RNA pol</td><td colspan="1" rowspan="1" align="left" valign="top">NPA</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Days 0-5 (501)</td><td colspan="1" rowspan="1" align="left" valign="top">41.1</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r56">56</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 6-11 (211)</td><td colspan="1" rowspan="1" align="left" valign="top">58.8</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 12-20 (62)</td><td colspan="1" rowspan="1" align="left" valign="top">37.1</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Day >21 (15)</td><td colspan="1" rowspan="1" align="left" valign="top">13.3</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">RNA pol</td><td colspan="1" rowspan="1" align="left" valign="top">Throat swab</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Days 1-13 (590)</td><td colspan="1" rowspan="1" align="left" valign="top">37.5</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r384">384</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">RNA pol<xref ref-type="table-fn" rid="t4fn1"><italic>a</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Nose and throat swab</td><td colspan="1" rowspan="1" align="left" valign="top">Laboratory confirmed<xref ref-type="table-fn" rid="t4fn2"><italic>b</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Days 1-5<xref ref-type="table-fn" rid="t4fn3"><italic>c</italic></xref> (54)</td><td colspan="1" rowspan="1" align="left" valign="top">61.1<xref ref-type="table-fn" rid="t4fn4"><italic>d</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r391">391</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 1-5 (53)</td><td colspan="1" rowspan="1" align="left" valign="top">28.3</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r32">32</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">RNA pol</td><td colspan="1" rowspan="1" align="left" valign="top">Upper respiratory<xref ref-type="table-fn" rid="t4fn5"><italic>e</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Days 0-5 (212)</td><td colspan="1" rowspan="1" align="left" valign="top">31.1</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r56">56</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 6-11 (73)</td><td colspan="1" rowspan="1" align="left" valign="top">37</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 12-20 (45)</td><td colspan="1" rowspan="1" align="left" valign="top">31.1</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Day >21 (159)</td><td colspan="1" rowspan="1" align="left" valign="top">5.7</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">RNA pol<xref ref-type="table-fn" rid="t4fn1"><italic>a</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Respiratory<xref ref-type="table-fn" rid="t4fn6"><italic>f</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Laboratory confirmed<xref ref-type="table-fn" rid="t4fn2"><italic>b</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">1 wk (243)</td><td colspan="1" rowspan="1" align="left" valign="top">26.3</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r39">39</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">2 wk (134)</td><td colspan="1" rowspan="1" align="left" valign="top">30.6</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">3-4 wk (94)</td><td colspan="1" rowspan="1" align="left" valign="top">18.1</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">RNA pol</td><td colspan="1" rowspan="1" align="left" valign="top">Stool</td><td colspan="1" rowspan="1" align="left" valign="top">Laboratory confirmed<xref ref-type="table-fn" rid="t4fn2"><italic>b</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Days 5-10<xref ref-type="table-fn" rid="t4fn3"><italic>c</italic></xref> (19)</td><td colspan="1" rowspan="1" align="left" valign="top">57.9<xref ref-type="table-fn" rid="t4fn4"><italic>d</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r391">391</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 1-5 (25)</td><td colspan="1" rowspan="1" align="left" valign="top">20</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r32">32</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">1 wk (21)</td><td colspan="1" rowspan="1" align="left" valign="top">42.9</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r39">39</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">2 wk (25)</td><td colspan="1" rowspan="1" align="left" valign="top">68</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">3-4 wk (80)</td><td colspan="1" rowspan="1" align="left" valign="top">42.5</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">RNA pol</td><td colspan="1" rowspan="1" align="left" valign="top">Stool</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Days 0-5 (77)</td><td colspan="1" rowspan="1" align="left" valign="top">23.4</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r56">56</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 6-11 (86)</td><td colspan="1" rowspan="1" align="left" valign="top">57</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 12-20 (72)</td><td colspan="1" rowspan="1" align="left" valign="top">52.8</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Day >21 (297)</td><td colspan="1" rowspan="1" align="left" valign="top">15.2</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">RNA pol</td><td colspan="1" rowspan="1" align="left" valign="top">Urine</td><td colspan="1" rowspan="1" align="left" valign="top">Laboratory confirmed<xref ref-type="table-fn" rid="t4fn2"><italic>b</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Days 5-10<xref ref-type="table-fn" rid="t4fn3"><italic>c</italic></xref> (78)</td><td colspan="1" rowspan="1" align="left" valign="top">50<xref ref-type="table-fn" rid="t4fn4"><italic>d</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r391">391</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 1-5 (15)</td><td colspan="1" rowspan="1" align="left" valign="top">0</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r32">32</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">1 wk (75)</td><td colspan="1" rowspan="1" align="left" valign="top">2.7</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r39">39</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">2 wk (82)</td><td colspan="1" rowspan="1" align="left" valign="top">6.1</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">3-4 wk (54)</td><td colspan="1" rowspan="1" align="left" valign="top">11.1</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> RNA pol</td><td colspan="1" rowspan="1" align="left" valign="top">Urine</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Days 0-11 (16)</td><td colspan="1" rowspan="1" align="left" valign="top">12.5</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r56">56</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 12-20 (21)</td><td colspan="1" rowspan="1" align="left" valign="top">4.8</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days >21-23 (161)</td><td colspan="1" rowspan="1" align="left" valign="top">1.9</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> RNA pol</td><td colspan="1" rowspan="1" align="left" valign="top">Blood (serum)</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Days 0-5 (64)</td><td colspan="1" rowspan="1" align="left" valign="top">17.2</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r56">56</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 6-11 (14)</td><td colspan="1" rowspan="1" align="left" valign="top">35.7</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 12-20 (9)</td><td colspan="1" rowspan="1" align="left" valign="top">11.1</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Nested RNA pol</td><td colspan="1" rowspan="1" align="left" valign="top">Blood (plasma)</td><td colspan="1" rowspan="1" align="left" valign="top">Laboratory confirmed<xref ref-type="table-fn" rid="t4fn2"><italic>b</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Days 1-3 (24)</td><td colspan="1" rowspan="1" align="left" valign="top">79.2</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r108">108</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">In-house quantitative PCR</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> ORF 1b<xref ref-type="table-fn" rid="t4fn1"><italic>a</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">NPA</td><td colspan="1" rowspan="1" align="left" valign="top">Laboratory confirmed<xref ref-type="table-fn" rid="t4fn2"><italic>b</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Days 1-3 (32)</td><td colspan="1" rowspan="1" align="left" valign="top">50</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r263">263</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 4-6 (35)</td><td colspan="1" rowspan="1" align="left" valign="top">31.4</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 7-10 (31)</td><td colspan="1" rowspan="1" align="left" valign="top">51.6</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> ORF 1b<xref ref-type="table-fn" rid="t4fn7"><italic>g</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">NPA</td><td colspan="1" rowspan="1" align="left" valign="top">Laboratory confirmed<xref ref-type="table-fn" rid="t4fn2"><italic>b</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Day 1 (8)</td><td colspan="1" rowspan="1" align="left" valign="top">62.5<xref ref-type="table-fn" rid="t4fn4"><italic>d</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r264">264</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Day 2 (16)</td><td colspan="1" rowspan="1" align="left" valign="top">87.5<xref ref-type="table-fn" rid="t4fn4"><italic>d</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Day 3 (26)</td><td colspan="1" rowspan="1" align="left" valign="top">80.1<xref ref-type="table-fn" rid="t4fn4"><italic>d</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> ORF 1b</td><td colspan="1" rowspan="1" align="left" valign="top">NPA</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS or laboratory confirmed<xref ref-type="table-fn" rid="t4fn2"><italic>b</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Days 10-15 (142)</td><td colspan="1" rowspan="1" align="left" valign="top">42.3 (2.4 log [mean])</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r156">156</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> 1-step ORF 1b<xref ref-type="table-fn" rid="t4fn7"><italic>g</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">NPA</td><td colspan="1" rowspan="1" align="left" valign="top">Laboratory confirmed<xref ref-type="table-fn" rid="t4fn2"><italic>b</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Days 1-3 (29)</td><td colspan="1" rowspan="1" align="left" valign="top">96.6<xref ref-type="table-fn" rid="t4fn4"><italic>d</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r266">266</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 4-9 (57)</td><td colspan="1" rowspan="1" align="left" valign="top">80.7<xref ref-type="table-fn" rid="t4fn4"><italic>d</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> 1-step ORF 1b</td><td colspan="1" rowspan="1" align="left" valign="top">Throat wash</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, laboratory-confirmed SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Days 2-9 (17)</td><td colspan="1" rowspan="1" align="left" valign="top">9.58 × 10<sup>2</sup> (min)-5.93 × 10<sup>6</sup> (max)</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r349">349</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Saliva</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 2-9 (17)</td><td colspan="1" rowspan="1" align="left" valign="top">7.08 × 10<sup>2</sup> (min)-6.38 × 10<sup>8</sup> (max)</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> N</td><td colspan="1" rowspan="1" align="left" valign="top">Respiratory<xref ref-type="table-fn" rid="t4fn8"><italic>h</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, laboratory-confirmed SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Days 2-54 (31)</td><td colspan="1" rowspan="1" align="left" valign="top">74.2</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r88">88</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> N</td><td colspan="1" rowspan="1" align="left" valign="top">NPA and stool</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Days 1-4 (32)</td><td colspan="1" rowspan="1" align="left" valign="top">18.8</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r155">155</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 5-10 (37)</td><td colspan="1" rowspan="1" align="left" valign="top">35.1</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> RNA pol</td><td colspan="1" rowspan="1" align="left" valign="top">Stool</td><td colspan="1" rowspan="1" align="left" valign="top">Laboratory confirmed<xref ref-type="table-fn" rid="t4fn2"><italic>b</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Days 1-10 (8)</td><td colspan="1" rowspan="1" align="left" valign="top">75</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r189">189</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 11-20 (27)</td><td colspan="1" rowspan="1" align="left" valign="top">81.5</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 21-30 (5)</td><td colspan="1" rowspan="1" align="left" valign="top">80</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> ORF 1b</td><td colspan="1" rowspan="1" align="left" valign="top">Stool</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS or laboratory confirmed<xref ref-type="table-fn" rid="t4fn2"><italic>b</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Days 1-3 (6)</td><td colspan="1" rowspan="1" align="left" valign="top">66.7</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r263">263</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 4-6 (15)</td><td colspan="1" rowspan="1" align="left" valign="top">80</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 7-10 (16)</td><td colspan="1" rowspan="1" align="left" valign="top">62.5</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 10-15 (94)</td><td colspan="1" rowspan="1" align="left" valign="top">87.2 (6.1 log [median])</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r156">156</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> N</td><td colspan="1" rowspan="1" align="left" valign="top">Stool</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Days 1-10 (37)</td><td colspan="1" rowspan="1" align="left" valign="top">27</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r413">413</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 11-20 (71)</td><td colspan="1" rowspan="1" align="left" valign="top">26.8</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 21-30 (77)</td><td colspan="1" rowspan="1" align="left" valign="top">15.6</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 31-40 (67)</td><td colspan="1" rowspan="1" align="left" valign="top">17.9</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Day >40 (74)</td><td colspan="1" rowspan="1" align="left" valign="top">9.5</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> N</td><td colspan="1" rowspan="1" align="left" valign="top">Stool</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, laboratory-confirmed SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Days 2-54 (23)</td><td colspan="1" rowspan="1" align="left" valign="top">87 (5.5 × 10<sup>4</sup> [median])</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r88">88</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> RNA pol</td><td colspan="1" rowspan="1" align="left" valign="top">Urine</td><td colspan="1" rowspan="1" align="left" valign="top">Laboratory confirmed<xref ref-type="table-fn" rid="t4fn2"><italic>b</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Days 1-10 (14)</td><td colspan="1" rowspan="1" align="left" valign="top">7.1</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r189">189</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 11-20 (86)</td><td colspan="1" rowspan="1" align="left" valign="top">31.4</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 21-30 (21)</td><td colspan="1" rowspan="1" align="left" valign="top">14.3</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 31-60 (12)</td><td colspan="1" rowspan="1" align="left" valign="top">16.7</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> ORF 1b</td><td colspan="1" rowspan="1" align="left" valign="top">Urine</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS or laboratory confirmed<xref ref-type="table-fn" rid="t4fn2"><italic>b</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Days 10-15 (111)</td><td colspan="1" rowspan="1" align="left" valign="top">28.8 (1.3 log [mean])</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r156">156</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Blood (serum)</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 10-15 (53)</td><td colspan="1" rowspan="1" align="left" valign="top">41.5 (1.1 log [mean])</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> 1-step ORF 1b<xref ref-type="table-fn" rid="t4fn9"><italic>i</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Blood (plasma)</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, laboratory-confirmed SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Days 2-4 (20)</td><td colspan="1" rowspan="1" align="left" valign="top">50 (2.36 × 10<sup>3</sup> [median])<xref ref-type="table-fn" rid="t4fn4"><italic>d</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r349">349</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 5-7 (12)</td><td colspan="1" rowspan="1" align="left" valign="top">75 (6.91 × 10<sup>3</sup> [median])<xref ref-type="table-fn" rid="t4fn4"><italic>d</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 8-11 (11)</td><td colspan="1" rowspan="1" align="left" valign="top">63.6 (1.74 × 10<sup>4</sup> [median])<xref ref-type="table-fn" rid="t4fn4"><italic>d</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 12-16 (8)</td><td colspan="1" rowspan="1" align="left" valign="top">37.5 (3.83 × 10<sup>3</sup> [median])<xref ref-type="table-fn" rid="t4fn4"><italic>d</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> N</td><td colspan="1" rowspan="1" align="left" valign="top">Blood (plasma)</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, laboratory-confirmed SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Days 2-54 (7)</td><td colspan="1" rowspan="1" align="left" valign="top">42.9</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r88">88</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> N</td><td colspan="1" rowspan="1" align="left" valign="top">Blood (whole blood)</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Days 1-10 (62)</td><td colspan="1" rowspan="1" align="left" valign="top">45.2</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r413">413</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 11-20 (41)</td><td colspan="1" rowspan="1" align="left" valign="top">48.8</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 21-30 (165)</td><td colspan="1" rowspan="1" align="left" valign="top">13.3</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 31-40 (158)</td><td colspan="1" rowspan="1" align="left" valign="top">16.5</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">In-house LAMP<xref ref-type="table-fn" rid="t4fn10"><italic>j</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> ORF 1b<xref ref-type="table-fn" rid="t4fn7"><italic>g</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">NPA</td><td colspan="1" rowspan="1" align="left" valign="top">Laboratory confirmed<xref ref-type="table-fn" rid="t4fn2"><italic>b</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Days 1-3 (15)</td><td colspan="1" rowspan="1" align="left" valign="top">60<xref ref-type="table-fn" rid="t4fn4"><italic>d</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r267">267</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 4-7 (37)</td><td colspan="1" rowspan="1" align="left" valign="top">70.3<xref ref-type="table-fn" rid="t4fn4"><italic>d</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Day >7 (7)</td><td colspan="1" rowspan="1" align="left" valign="top">100<xref ref-type="table-fn" rid="t4fn4"><italic>d</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> 1-step replicase</td><td colspan="1" rowspan="1" align="left" valign="top">Respiratory specimens<xref ref-type="table-fn" rid="t4fn11"><italic>k</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Day 3 (49)</td><td colspan="1" rowspan="1" align="left" valign="top">26.5<xref ref-type="table-fn" rid="t4fn4"><italic>d</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r146">146</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Commercial quantitative PCR</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Roche kit<xref ref-type="table-fn" rid="t4fn12"><italic>l</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Respiratory<xref ref-type="table-fn" rid="t4fn8"><italic>h</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, laboratory-confirmed SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Days 2-54 (30)<xref ref-type="table-fn" rid="t4fn13"><italic>m</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">73.3</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r88">88</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Roche kit</td><td colspan="1" rowspan="1" align="left" valign="top">NPA and throat swab</td><td colspan="1" rowspan="1" align="left" valign="top">Laboratory confirmed<xref ref-type="table-fn" rid="t4fn2"><italic>b</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Days 1-5<xref ref-type="table-fn" rid="t4fn3"><italic>c</italic></xref> (47)</td><td colspan="1" rowspan="1" align="left" valign="top">85<xref ref-type="table-fn" rid="t4fn4"><italic>d</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r390">390</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Roche kit</td><td colspan="1" rowspan="1" align="left" valign="top">Stool</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, laboratory-confirmed SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Days 2-54 (23)</td><td colspan="1" rowspan="1" align="left" valign="top">78.3 (4.3 × 10<sup>4</sup> [median])</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r88">88</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Roche kit</td><td colspan="1" rowspan="1" align="left" valign="top">Stool</td><td colspan="1" rowspan="1" align="left" valign="top">Laboratory confirmed<xref ref-type="table-fn" rid="t4fn2"><italic>b</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Days 1-5<xref ref-type="table-fn" rid="t4fn3"><italic>c</italic></xref> (32)</td><td colspan="1" rowspan="1" align="left" valign="top">88<xref ref-type="table-fn" rid="t4fn4"><italic>d</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r390">390</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Commercial kit<xref ref-type="table-fn" rid="t4fn14"><italic>n</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Stool</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Day ≤7 (13)</td><td colspan="1" rowspan="1" align="left" valign="top">46-62<xref ref-type="table-fn" rid="t4fn4"><italic>d</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r230">230</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Days 8-21 (12)</td><td colspan="1" rowspan="1" align="left" valign="top">58-75<xref ref-type="table-fn" rid="t4fn4"><italic>d</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Day >21 (31)</td><td colspan="1" rowspan="1" align="left" valign="top">13-19<xref ref-type="table-fn" rid="t4fn4"><italic>d</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Roche kit</td><td colspan="1" rowspan="1" align="left" valign="top">Urine</td><td colspan="1" rowspan="1" align="left" valign="top">Laboratory confirmed<xref ref-type="table-fn" rid="t4fn2"><italic>b</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Days 1-5<xref ref-type="table-fn" rid="t4fn3"><italic>c</italic></xref> (22)</td><td colspan="1" rowspan="1" align="left" valign="top">82<xref ref-type="table-fn" rid="t4fn4"><italic>d</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r390">390</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Roche kit</td><td colspan="1" rowspan="1" align="left" valign="top">Blood (plasma)</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, laboratory-confirmed SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Days 2-54 (7)</td><td colspan="1" rowspan="1" align="left" valign="top">28.6</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r88">88</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Artus kit<xref ref-type="table-fn" rid="t4fn15"><italic>o</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Respiratory<xref ref-type="table-fn" rid="t4fn8"><italic>h</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, laboratory-confirmed SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Days 2-54 (31)</td><td colspan="1" rowspan="1" align="left" valign="top">74.2</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r88">88</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Artus kit</td><td colspan="1" rowspan="1" align="left" valign="top">NPA and throat swab</td><td colspan="1" rowspan="1" align="left" valign="top">Laboratory confirmed<xref ref-type="table-fn" rid="t4fn2"><italic>b</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Days 1-5<xref ref-type="table-fn" rid="t4fn3"><italic>c</italic></xref> (47)</td><td colspan="1" rowspan="1" align="left" valign="top">87<xref ref-type="table-fn" rid="t4fn4"><italic>d</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r390">390</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Artus kit</td><td colspan="1" rowspan="1" align="left" valign="top">Stool</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, laboratory-confirmed SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Days 2-54 (22)<xref ref-type="table-fn" rid="t4fn7"><italic>g</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">81.8</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r88">88</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Artus kit</td><td colspan="1" rowspan="1" align="left" valign="top">Stool</td><td colspan="1" rowspan="1" align="left" valign="top">Laboratory confirmed<xref ref-type="table-fn" rid="t4fn2"><italic>b</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Days 1-5<xref ref-type="table-fn" rid="t4fn3"><italic>c</italic></xref> (32)</td><td colspan="1" rowspan="1" align="left" valign="top">91<xref ref-type="table-fn" rid="t4fn4"><italic>d</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r390">390</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Artus kit</td><td colspan="1" rowspan="1" align="left" valign="top">Urine</td><td colspan="1" rowspan="1" align="left" valign="top">Laboratory confirmed<xref ref-type="table-fn" rid="t4fn2"><italic>b</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Days 1-5<xref ref-type="table-fn" rid="t4fn3"><italic>c</italic></xref> (22)</td><td colspan="1" rowspan="1" align="left" valign="top">82<xref ref-type="table-fn" rid="t4fn4"><italic>d</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r390">390</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Artus kit</td><td colspan="1" rowspan="1" align="left" valign="top">Blood (plasma)</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, laboratory-confirmed SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Days 2-54 (7)</td><td colspan="1" rowspan="1" align="left" valign="top">14.3</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r88">88</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Artus kit</td><td colspan="1" rowspan="1" align="left" valign="top">Lung tissue</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Days 5-51 (19)</td><td colspan="1" rowspan="1" align="left" valign="top">100 (2 × 10<sup>4</sup> [min]-1 × 10<sup>10</sup> [max])</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r96">96</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Artus kit</td><td colspan="1" rowspan="1" align="left" valign="top">Small bowel tissue</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Days 10-29 (15)</td><td colspan="1" rowspan="1" align="left" valign="top">73 (2.7 × 10<sup>3</sup> [min]-2.7 × 10<sup>9</sup> [max])</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r96">96</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Artus kit</td><td colspan="1" rowspan="1" align="left" valign="top">Large bowel tissue</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Days 10-43 (15)</td><td colspan="1" rowspan="1" align="left" valign="top">73 (5.3 × 10<sup>3</sup> [min]-3.7 × 10<sup>8</sup> [max])</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r96">96</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Artus kit</td><td colspan="1" rowspan="1" align="left" valign="top">Lymph node tissue</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Days 14-34 (13)</td><td colspan="1" rowspan="1" align="left" valign="top">69 (1.5 × 10<sup>4</sup> [min]-8.9 × 10<sup>8</sup> [max])</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r96">96</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Artus kit</td><td colspan="1" rowspan="1" align="left" valign="top">Liver tissue</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Days 10-24 (17)</td><td colspan="1" rowspan="1" align="left" valign="top">41 (6 × 10<sup>3</sup> [min]-5 × 10<sup>4</sup> [max])</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r96">96</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Artus kit</td><td colspan="1" rowspan="1" align="left" valign="top">Cardiac tissue</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Days 5-23 (18)</td><td colspan="1" rowspan="1" align="left" valign="top">40 (1 × 10<sup>4</sup> [min]-2.8 × 10<sup>7</sup> [max])</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r96">96</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Artus kit</td><td colspan="1" rowspan="1" align="left" valign="top">Kidney tissue</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">Days 11-27 (16)</td><td colspan="1" rowspan="1" align="left" valign="top">38 (4.3 × 10<sup>3</sup> [min]-7.4 × 10<sup>5</sup> [max])</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r96">96</xref></td></tr></tbody></table><table-wrap-foot><fn id="t4fn1"><label>a</label><p>For the RNA extraction protocol, 140 μl of nasopharyngeal aspirate (NPA) was used.</p></fn><fn id="t4fn2"><label>b</label><p>A rise of fourfold or more in antibody titer against SARS-CoV.</p></fn><fn id="t4fn3"><label>c</label><p>Day after admission.</p></fn><fn id="t4fn4"><label>d</label><p>Specificity of the test was 100%.</p></fn><fn id="t4fn5"><label>e</label><p>Upper respiratory specimens consisted of throat and nasal swabs (<italic>n</italic> = 216), throat swabs (<italic>n</italic> = 164), nasopharyngeal swabs (<italic>n</italic> = 47), and nasal swabs (<italic>n</italic> = 62).</p></fn><fn id="t4fn6"><label>f</label><p>Respiratory specimens consisted of tracheal aspirate (<italic>n</italic> = 7), pooled throat and nasal swabs (<italic>n</italic> = 25), nasal swabs (<italic>n</italic> = 58), NPA (<italic>n</italic> = 192), throat swabs (<italic>n</italic> = 43), and throat washing (<italic>n</italic> = 146).</p></fn><fn id="t4fn7"><label>g</label><p>For the modified RNA extraction protocol, 560 μl of NPA was used.</p></fn><fn id="t4fn8"><label>h</label><p>Respiratory specimens consisted of saliva (<italic>n</italic> = 3), nasopharyngeal swabs (<italic>n</italic> = 16), sputum (<italic>n</italic> = 8), endotracheal aspirate (<italic>n</italic> = 2), and bronchoalveolar lavage fluid (<italic>n</italic> = 2).</p></fn><fn id="t4fn9"><label>i</label><p>The test adopted the SARS1S_AS TaqMan assay design (Applied Biosystems, Foster City, CA), and 280 μl of plasma was used for RNA extraction.</p></fn><fn id="t4fn10"><label>j</label><p>LAMP, real-time loop-mediated amplification.</p></fn><fn id="t4fn11"><label>k</label><p>Respiratory specimens consisted of throat wash (<italic>n</italic> = 15), throat swabs (<italic>n</italic> = 13), and throat and nasal swabs (<italic>n</italic> = 21).</p></fn><fn id="t4fn12"><label>l</label><p>Roche kit indicates a LightCycler SARS-CoV quantification kit (b-Test_Lot) (Roche Diagnostics, Germany).</p></fn><fn id="t4fn13"><label>m</label><p>There was no result for one sample due to failed internal control. The sample was omitted from the sensitivity evaluation of this assay.</p></fn><fn id="t4fn14"><label>n</label><p>Commercial kit indicates a RealArt HPA-Coronavirus LC RT PCR kit (Artus GmbH, Hamburg, Germany) and a SARS-CoV POL assay (EraGen Biosciences, Madison, WI) with different extraction methods (QIAGEN viral RNA Minikit, bioMerieux miniMg, and Cortex MagaZorb).</p></fn><fn id="t4fn15"><label>o</label><p>Artus kit indicates a RealArt HPA-Coronavirus LC RT-PCR kit (Artus GmbH, Hamburg, Germany).</p></fn></table-wrap-foot></table-wrap><table-wrap position="float" id="t5"><label>TABLE 5.</label><caption><p>Clinical evaluation of antigen detection for SARS-CoV</p></caption><table frame="hsides" rules="groups"><thead><tr><th colspan="1" rowspan="1" align="center" valign="bottom">Diagnostic method and detection target</th><th colspan="1" rowspan="1" align="center" valign="bottom">Diagnostic gold standard</th><th colspan="1" rowspan="1" align="center" valign="bottom">Collection time after onset of symptoms (days)<xref ref-type="table-fn" rid="t5fn1"><italic>a</italic></xref> (no. of samples)</th><th colspan="1" rowspan="1" align="center" valign="bottom">Sensitivity (%)</th><th colspan="1" rowspan="1" align="center" valign="bottom">Overall specificity (%)</th><th colspan="1" rowspan="1" align="center" valign="bottom">Reference</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" align="left" valign="top">EIA</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> N protein</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="center" valign="top">3-5 (8)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">50</td><td colspan="1" rowspan="1" align="char" char="." valign="top">98.5</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r48">48</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top">6-10 (14)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">71.4</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top">11-20 (9)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">44.4</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> N protein</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="center" valign="top">1-5 (84)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">92.9</td><td colspan="1" rowspan="1" align="char" char="." valign="top">100</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r86">86</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top">6-10 (63)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">69.8</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top">11-20 (52)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">30.8</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> N protein</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="center" valign="top">1-5 (85)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">94</td><td colspan="1" rowspan="1" align="char" char="." valign="top">99.9</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r46">46</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top">6-10 (60)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">78</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> N protein</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="center" valign="top">NM (18)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">100</td><td colspan="1" rowspan="1" align="char" char="." valign="top">100</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r127">127</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> N protein</td><td colspan="1" rowspan="1" align="left" valign="top">Laboratory confirmed<xref ref-type="table-fn" rid="t5fn2"><italic>b</italic></xref></td><td colspan="1" rowspan="1" align="center" valign="top">6-24 (66) (NPA)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">52</td><td colspan="1" rowspan="1" align="char" char="." valign="top">96.7</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r191">191</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top">11-31 (94) (urine)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">5</td><td colspan="1" rowspan="1" align="char" char="." valign="top">99</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top">8-32 (65) (stool)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">55</td><td colspan="1" rowspan="1" align="char" char="." valign="top">96</td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Immunofluorescence assay</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> N protein</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="center" valign="top">2-9 (17) (throat wash)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">65</td><td colspan="1" rowspan="1" align="char" char="." valign="top">100</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r226">226</xref></td></tr></tbody></table><table-wrap-foot><fn id="t5fn1"><label>a</label><p>Serum samples collected unless specified. NM, not mentioned.</p></fn><fn id="t5fn2"><label>b</label><p>Positive for IgG antibodies against SARS-CoV by indirect immunofluorescence assay in serum sample during the course of illness.</p></fn></table-wrap-foot></table-wrap><table-wrap position="float" id="t6"><label>TABLE 6.</label><caption><p>Clinical evaluation of antibody detection for SARS-CoV</p></caption><table frame="hsides" rules="groups"><thead><tr><th colspan="1" rowspan="1" align="center" valign="bottom">Diagnostic method and detection target</th><th colspan="1" rowspan="1" align="center" valign="bottom">Diagnostic gold standard</th><th colspan="1" rowspan="1" align="center" valign="bottom">Collection time (days) after onset of symptoms<xref ref-type="table-fn" rid="t6fn1"><italic>a</italic></xref> (no. of samples)</th><th colspan="1" rowspan="1" align="center" valign="bottom">Sensitivity (%)</th><th colspan="1" rowspan="1" align="center" valign="bottom">Overall specificity (%)</th><th colspan="1" rowspan="1" align="center" valign="bottom">Reference</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" align="left" valign="top">EIA</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Anti-N protein antibodies</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">1-5 (27)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">14.8</td><td colspan="1" rowspan="1" align="char" char="." valign="top">100</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r299">299</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">6-10 (38)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">68.4</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">11-61 (135)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">89.6</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Anti-N protein antibodies</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">10 (16)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">81.3</td><td colspan="1" rowspan="1" align="char" char="." valign="top">100</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r330">330</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">20 (16)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">100</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">30 (16)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">100</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Anti-N protein antibodies</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">12-72 (280)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">89.3</td><td colspan="1" rowspan="1" align="center" valign="top">NM</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r273">273</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Anti-N protein antibodies</td><td colspan="1" rowspan="1" align="left" valign="top">Laboratory confirmed<xref ref-type="table-fn" rid="t6fn2"><italic>b</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">12-43 (106)</td><td colspan="1" rowspan="1" align="center" valign="top">95.3/96.6/96.6<xref ref-type="table-fn" rid="t6fn6"><italic>f</italic></xref></td><td colspan="1" rowspan="1" align="center" valign="top">94.3/59.4/60.4<xref ref-type="table-fn" rid="t6fn6"><italic>f</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r373">373</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Anti-N protein antibodies</td><td colspan="1" rowspan="1" align="left" valign="top">Laboratory confirmed<xref ref-type="table-fn" rid="t6fn2"><italic>b</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">NM<xref ref-type="table-fn" rid="t6fn3"><italic>c</italic></xref> (106)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">94.3</td><td colspan="1" rowspan="1" align="char" char="." valign="top">100</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r369">369</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Anti-N protein antibodies</td><td colspan="1" rowspan="1" align="left" valign="top">Laboratory confirmed<xref ref-type="table-fn" rid="t6fn4"><italic>d</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">First wk (36) (IgM)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">33</td><td colspan="1" rowspan="1" align="char" char="." valign="top">100</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r404">404</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Second wk (36) (IgM)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">97</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Third wk (36) (IgM)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">100</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Anti-N protein antibodies</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">NM (407)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">70.2</td><td colspan="1" rowspan="1" align="char" char="." valign="top">99.9</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r54">54</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Anti-N protein antibodies</td><td colspan="1" rowspan="1" align="left" valign="top">Neutralization antibody assay</td><td colspan="1" rowspan="1" align="left" valign="top">NM (276)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">92</td><td colspan="1" rowspan="1" align="char" char="." valign="top">92</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r294">294</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Anti-S protein antibodies</td><td colspan="1" rowspan="1" align="left" valign="top">Laboratory confirmed<xref ref-type="table-fn" rid="t6fn2"><italic>b</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">11-45 (95)</td><td colspan="1" rowspan="1" align="center" valign="top">58.9/74.7<xref ref-type="table-fn" rid="t6fn7"><italic>g</italic></xref></td><td colspan="1" rowspan="1" align="center" valign="top">98.6/93.9<xref ref-type="table-fn" rid="t6fn7"><italic>g</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r374">374</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Anti-S protein antibodies</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">NM (51)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">80.4</td><td colspan="1" rowspan="1" align="char" char="." valign="top">100</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r423">423</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Anti-S2 protein antibodies</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">NM (20)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">85</td><td colspan="1" rowspan="1" align="char" char="." valign="top">100</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r350">350</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Anti-SARS-CoV antibodies</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">NM (56)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">96.4</td><td colspan="1" rowspan="1" align="char" char="." valign="top">100</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r297">297</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Antibodies against Gst-N and Gst-U274</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">16-65 (74)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">100</td><td colspan="1" rowspan="1" align="char" char="." valign="top">99.5</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r115">115</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Antibodies against Gst-N and</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">1-10 (31)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">58</td><td colspan="1" rowspan="1" align="char" char="." valign="top">99.5</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r114">114</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Gst-U274</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">11-20 (120)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">70</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">21-30 (57)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">75.4</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">>30 (19)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">94.7</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Immunochromatography</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Antibodies against Gst-N and Gst-U274</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">1-10 (31)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">54.8</td><td colspan="1" rowspan="1" align="char" char="." valign="top">97.7</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r114">114</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">11-20 (120)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">68.3</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">21-30 (57)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">80.7</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">>30 (19)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">78.9</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Western blot assay</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Anti-N protein antibodies</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">4-76 (44)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">90.9</td><td colspan="1" rowspan="1" align="char" char="." valign="top">98.3</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r126">126</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Immunofluorescence assay</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Anti-SARS-CoV antibodies</td><td colspan="1" rowspan="1" align="left" valign="top">True SARS<xref ref-type="table-fn" rid="t6fn5"><italic>e</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">1-5 (64) (IgG)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">0</td><td colspan="1" rowspan="1" align="char" char="." valign="top">100</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r38">38</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">6-10 (35) (IgG)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">34.3</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">11-15 (23) (IgG)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">78.3</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">16-20 (43) (IgG)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">97.7</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">21-37 (47) (IgG)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">100</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Anti-S protein antibodies</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">7-14 (6)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">100</td><td colspan="1" rowspan="1" align="char" char="." valign="top">100</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r235">235</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">14-76 (15)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">100</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Antibodies against N-S fusion protein</td><td colspan="1" rowspan="1" align="left" valign="top">WHO criteria, probable SARS</td><td colspan="1" rowspan="1" align="left" valign="top">>17 (23)</td><td colspan="1" rowspan="1" align="char" char="." valign="top">95.6</td><td colspan="1" rowspan="1" align="char" char="." valign="top">100</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r128">128</xref></td></tr></tbody></table><table-wrap-foot><fn id="t6fn1"><label>a</label><p>Serum samples were collected.</p></fn><fn id="t6fn2"><label>b</label><p>Positive for IgG antibodies against SARS-CoV by indirect immunofluorescence assay in serum sample during the course of illness.</p></fn><fn id="t6fn3"><label>c</label><p>NM, not mentioned.</p></fn><fn id="t6fn4"><label>d</label><p>Details not specified.</p></fn><fn id="t6fn5"><label>e</label><p>True SARS is defined as WHO criteria for probable cases of SARS and/or at least one specimen positive for SARS-CoV by RT-PCR.</p></fn><fn id="t6fn6"><label>f</label><p>IgG/IgM/IgA.</p></fn><fn id="t6fn7"><label>g</label><p>IgG/IgM.</p></fn></table-wrap-foot></table-wrap><table-wrap position="float" id="t7"><label>TABLE 7.</label><caption><p>Antiviral agents and immunomodulators against SARS-CoV in vivo</p></caption><table frame="hsides" rules="groups"><thead><tr><th colspan="1" rowspan="1" align="center" valign="bottom">Antiviral agent and/or immunomodulator (no. of subjects) (study design)</th><th colspan="1" rowspan="1" align="center" valign="bottom">Main findings<xref ref-type="table-fn" rid="t7fn1"><italic>a</italic></xref></th><th colspan="1" rowspan="1" align="center" valign="bottom">Reference</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" align="left" valign="top">Ribavirin (144 patients) (retrospective case series)</td><td colspan="1" rowspan="1" align="left" valign="top">126 patients (88%) treated; side effects of hemolysis (76%) and lowered hemoglobin of 2 g/dl (49%)</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r21">21</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Ribavirin (229 patients) (retrospective uncontrolled cohort analysis)</td><td colspan="1" rowspan="1" align="left" valign="top">97 patients (42.2%) treated; crude death rate of 10.3% (treatment) vs 12.9% (control) (<italic>P</italic> = 0.679)</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r199">199</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Ribavirin and corticosteroids (75 patients) (prospective case series)</td><td colspan="1" rowspan="1" align="left" valign="top">9 patients (12%) had spontaneous pneumomediastinum; 20% developed ARDS in wk 3</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r258">258</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Ribavirin and MP (31 patients<xref ref-type="table-fn" rid="t7fn2"><italic>b</italic></xref>) (retrospective case series)</td><td colspan="1" rowspan="1" align="left" valign="top">No patient required intubation or mechanical ventilation; no mortality noted in this series</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r303">303</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Ribavirin and corticosteroids<xref ref-type="table-fn" rid="t7fn3"><italic>c</italic></xref> (71 patients<xref ref-type="table-fn" rid="t7fn4"><italic>d</italic></xref>) (prospective cohort study)</td><td colspan="1" rowspan="1" align="left" valign="top">Crude mortality rate of 3.4% (only in patients aged >65 yr); none of the discharged survivors required continuation of oxygen therapy</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r186">186</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Ribavirin and corticosteroids<xref ref-type="table-fn" rid="t7fn5"><italic>e</italic></xref> (138 patients) (prospective uncontrolled study)</td><td colspan="1" rowspan="1" align="left" valign="top">None responded to antibacterials; 25 patients (18.1%) responded to ribavirin and low-dose corticosteroid; 107 patients required high-dose MP, 88.8% of whom responded; 21 patients (15.2%) required mechanical ventilation; mortality rate, 10.9%</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r314">314</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Ribavirin and MP (72 patients<xref ref-type="table-fn" rid="t7fn6"><italic>f</italic></xref>) (retrospective uncontrolled study)</td><td colspan="1" rowspan="1" align="left" valign="top">Patients treated with initial pulse MP therapy had no better rate on mechanical ventilation (5.9% vs 9.1%) (NS) and mortality (5.9% vs 5.5%) (NS)</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r139">139</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Lopinavir-ritonavir and ribavirin (41 patients) (retrospective study with historical control)<xref ref-type="table-fn" rid="t7fn7"><italic>g</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">ARDS and death were lower in treatment group than in historical control (2.4% vs 28.8%) (<italic>P</italic> < 0.001) at day 21 after symptom onset</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r72">72</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Lopinavir-ritonavir as initial therapy (44 patients) (retrospective matched cohort study)<xref ref-type="table-fn" rid="t7fn8"><italic>h</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Intubation rate of 0% vs 11% (<italic>P</italic> < 0.05); mortality rate of 2.3% vs 15.6% (<italic>P</italic> < 0.05)</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r33">33</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Lopinavir-ritonavir as rescue therapy (31 patients) (retrospective matched cohort study)<xref ref-type="table-fn" rid="t7fn9"><italic>i</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Intubation rate of 9.7% vs 18.1% (NS); mortality rate of 12.9% vs 14% (NS)</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r33">33</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">IFN-alfacon-1 and corticosteroids (22 patients) (open-label study)</td><td colspan="1" rowspan="1" align="left" valign="top">9 patients (40.9%) were treated; 1 (11.1%) patient required mechanical ventilation, and no patient died; of 13 patients (59.1%) treated with corticosteroid alone, 3 (23.1%) required mechanical ventilation and 1 (7.7%) died</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r231">231</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Pentaglobin, an IgM-enriched immunoglobulin (12 patients<xref ref-type="table-fn" rid="t7fn10"><italic>j</italic></xref>) (retrospective analysis)</td><td colspan="1" rowspan="1" align="left" valign="top">Improvement in radiographic scores compared with day 1 (median, 9.5) on days 6 (median, 6) (<italic>P</italic> = 0.01) and 7 (median, 6) (<italic>P</italic> = 0.01) and in oxygen requirement compared with day 1 (median, 2.5 liters/min) on days 6 (median, 1 liter/min) (<italic>P</italic> = 0.04) and 7 (median, 0.5 liters/min) (<italic>P</italic> = 0.04) after commencement of pentaglobin treatment</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r140">140</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Convalescent plasma (1 patient<xref ref-type="table-fn" rid="t7fn11"><italic>k</italic></xref>) (case report)</td><td colspan="1" rowspan="1" align="left" valign="top">Convalescent plasma (200 ml) was given at day 15 after onset of illness without adverse reaction; patient recovered uneventfully</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r366">366</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Convalescent plasma (3 patients)</td><td colspan="1" rowspan="1" align="left" valign="top">Viral load decreased from 4.9 × 10<sup>5</sup>-6.5 × 10<sup>5</sup> copies/ml to undetectable 1 day after transfusion</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r401">401</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Convalescent plasma (80 patients)</td><td colspan="1" rowspan="1" align="left" valign="top">A higher day 22 discharge rate was observed in patients treated before day 14 of illness (58.3% vs 15.6%) (<italic>P</italic> < 0.001), and in patients with positive PCR, SARS-CoV antibodies were negative at the time of plasma infusion (66.7% vs 20%) (<italic>P</italic> = 0.001)</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r60">60</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Two herbal formulas (Sang Ju Yin and Yu Ping Feng San) (37 healthy volunteers)</td><td colspan="1" rowspan="1" align="left" valign="top">Given oral traditional Chinese medicine regimen daily for 14 days with transient increase in CD4/CD8 ratio</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r269">269</xref></td></tr></tbody></table><table-wrap-foot><fn id="t7fn1"><label>a</label><p>ARDS, acute respiratory distress syndrome; MP, methylprednisolone; NS, <italic>P</italic> value was not significant.</p></fn><fn id="t7fn2"><label>b</label><p>One patient recovered on antibacterial treatment alone.</p></fn><fn id="t7fn3"><label>c</label><p>A 3-week step-down course of corticosteroids and pulsed methylprednisolone rescue for deterioration.</p></fn><fn id="t7fn4"><label>d</label><p>Three patients recovered on antibacterial treatment alone.</p></fn><fn id="t7fn5"><label>e</label><p>Low-dose corticosteroid and selective use of high-dose methylprednisolone.</p></fn><fn id="t7fn6"><label>f</label><p>Initially treated with high-dose pulse (<italic>n</italic> = 17) versus nonpulse (<italic>n</italic> = 55) methylprednisolone.</p></fn><fn id="t7fn7"><label>g</label><p>One hundred eleven patients treated with ribavirin as a historical control.</p></fn><fn id="t7fn8"><label>h</label><p>Six hundred thirty-four patients selected as matched cohort.</p></fn><fn id="t7fn9"><label>i</label><p>Three hundred forty-three patients selected as matched cohort.</p></fn><fn id="t7fn10"><label>j</label><p>Patients who continued to deteriorate despite ribavirin and corticosteroid therapy.</p></fn><fn id="t7fn11"><label>k</label><p>Patient who continued to deteriorate despite ribavirin and corticosteroid therapy.</p></fn></table-wrap-foot></table-wrap><table-wrap position="float" id="t8"><label>TABLE 8.</label><caption><p>Antiviral agents and immunomodulators tested against SARS-CoV in animals and in vitro</p></caption><table frame="hsides" rules="groups"><thead><tr><th colspan="1" rowspan="1" align="center" valign="bottom">Antiviral agent(s) and/or immunomodulator(s)</th><th colspan="1" rowspan="1" align="center" valign="bottom">Study setting and methods (virus strain)</th><th colspan="1" rowspan="1" align="center" valign="bottom">Main findings<xref ref-type="table-fn" rid="t8fn1"><italic>a</italic></xref></th><th colspan="1" rowspan="1" align="center" valign="bottom">Reference</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" align="left" valign="top">IFN-αB/D (hybrid IFN)</td><td colspan="1" rowspan="1" align="left" valign="top">BALB/c mice (Urbani)</td><td colspan="1" rowspan="1" align="left" valign="top">i.p. IFN-αB/D once daily for 3 days beginning 4 h after virus exposure reduced SARS-CoV replication in lungs by 1 log<sub>10</sub> at 10,000 and 32,000 IU; at the highest dose of 100,000 IU, virus lung titers were not detectable</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r13">13</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Ampligen [poly(I:C124)] (mismatched double-stranded RNA IFN inducer)</td><td colspan="1" rowspan="1" align="left" valign="top">BALB/c mice (Urbani)</td><td colspan="1" rowspan="1" align="left" valign="top">i.p. Ampligen at 10 mg/kg 4 h after virus exposure reduced virus lung titers to undetectable levels</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r13">13</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Pegylated IFN-α as prophylactic treatment</td><td colspan="1" rowspan="1" align="left" valign="top">Cynomolgus macaques (<italic>Macaca fascicularis</italic>) (patient 5668)</td><td colspan="1" rowspan="1" align="left" valign="top">Significantly reduced viral replication and excretion, viral antigen expression by type 1 pneumocytes, and pulmonary damage; postexposure treatment with pegylated IFN-α yielded intermediate results</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r118">118</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">IFN-α2b (Intron A)</td><td colspan="1" rowspan="1" align="left" valign="top">Vero (FFM-1, HK isolate)</td><td colspan="1" rowspan="1" align="left" valign="top">Mean (SD) EC<sub>50</sub> = 4,950 (890) IU/ml (SI of >2) for FFM-1 isolate; mean (SD) EC<sub>50</sub> = 6,500 (980) IU/ml (SI of >105) for HK isolate</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r78">78</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Caco2 (FFM-1, HK isolate)</td><td colspan="1" rowspan="1" align="left" valign="top">Mean (SD) EC<sub>50</sub> = 1,530 (220) IU/ml (SI of >6.5) for FFM-1 isolate; mean (SD) EC<sub>50</sub> = 880 (130) IU/ml (SI of >11.4) for HK isolate</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r78">78</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">IFN-β1b (Betaferon)</td><td colspan="1" rowspan="1" align="left" valign="top">Vero (FFM-1, HK isolate)</td><td colspan="1" rowspan="1" align="left" valign="top">Mean (SD) EC<sub>50</sub> = 95 (17) IU/ml (SI of >105) for FFM-1 isolate; mean (SD) EC<sub>50</sub> = 105 (21) IU/ml (SI of >95) for HK isolate</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r78">78</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Caco2 (FFM-1, HK isolate)</td><td colspan="1" rowspan="1" align="left" valign="top">Mean (SD) EC<sub>50</sub> = 21 (3.9) IU/ml (SI of >476) for FFM-1 isolate; mean (SD) EC<sub>50</sub> = 9.2 (2.1) IU/ml (SI of >1,087) for HK isolate</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r78">78</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">IFN-γ1b (Imukin)</td><td colspan="1" rowspan="1" align="left" valign="top">Vero (FFM-1, HK isolate)</td><td colspan="1" rowspan="1" align="left" valign="top">Mean (SD) EC<sub>50</sub> = 2,500 (340) IU/ml (SI of >4) for FFM-1 isolate; mean (SD) EC<sub>50</sub> = 1,700 (290) IU/ml (SI of >5.9) for HK isolate</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r78">78</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Caco2 (FFM-1, HK isolate)</td><td colspan="1" rowspan="1" align="left" valign="top">Mean (SD) EC<sub>50</sub> = >10,000 IU/ml (SI NA) for FFM-1 isolate; mean (SD) EC<sub>50</sub> = >10,000 IU/ml (SI NA) for HK isolate</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r78">78</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">IFN-β1a</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (Tor2, Tor7, and Urbani)</td><td colspan="1" rowspan="1" align="left" valign="top">IFN with p.i. IC<sub>50</sub> = 50 IU/ml; IFN added postinfection IC<sub>50</sub> = 500 IU/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r137">137</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">IFN-β, IFN-α, IFN-γ</td><td colspan="1" rowspan="1" align="left" valign="top">Vero, MxA-expressing Vero (FFM-1)</td><td colspan="1" rowspan="1" align="left" valign="top">SARS-CoV strongly inhibited by IFN-β (with p.i.) and less so with IFN-α and IFN-γ; MxA does not interfere with viral replication</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r305">305</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">IFN-α, IFN-β</td><td colspan="1" rowspan="1" align="left" valign="top">FRhK-4 (NM<sup>f</sup>)</td><td colspan="1" rowspan="1" align="left" valign="top">↓ intracellular viral RNA copies; IFN-α IC<sub>50</sub> = 25 U/ml; IFN-β IC<sub>50</sub> = 14 U/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r426">426</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">IFN-α2b</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (Tor2, Tor3, Tor7, and Tor684)</td><td colspan="1" rowspan="1" align="left" valign="top">IC<sub>50</sub> = ∼500 IU/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r308">308</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Leu-IFN-α</td><td colspan="1" rowspan="1" align="left" valign="top">FRhK-4 (HKU39849)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> at 48 h = 5,000 μg/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r50">50</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (HKU39849)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> at 48 h = 19.5 μg/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r50">50</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">IFN-α (p.i. for 16 h before viral inoculation)</td><td colspan="1" rowspan="1" align="left" valign="top">FRhK-4 (HKU39849)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> at 48 h = 39 μg/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r50">50</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (HKU39849)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> at 48 h = 19.5 μg/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r50">50</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">IFN-β</td><td colspan="1" rowspan="1" align="left" valign="top">FRhK-4 (HKU39849)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> at 48 h = 200 μg/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r50">50</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (HKU39849)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> at 48 h = 106 μg/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r50">50</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">IFN-β (p.i. for 16 h before viral inoculation)</td><td colspan="1" rowspan="1" align="left" valign="top">FRhK-4 (HKU39849)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> at 48 h = 625 μg/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r50">50</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (HKU39849)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> at 48 h = 19.5 μg/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r50">50</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">IFN-β1b (Betaferon)</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (2003VA2774)</td><td colspan="1" rowspan="1" align="left" valign="top">IC<sub>50</sub> = 0.2 IU/ml; IC<sub>95</sub> = 8 IU ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r318">318</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">IFN-αn3 (Alferon)</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (2003VA2774)</td><td colspan="1" rowspan="1" align="left" valign="top">IC<sub>50</sub> = 0.8 IU/ml; IC<sub>95</sub> = 200 IU/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r318">318</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Human leukocyte IFN-α (Multiferon)</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (2003VA2774)</td><td colspan="1" rowspan="1" align="left" valign="top">IC<sub>50</sub> = 2 IU/ml; IC<sub>95</sub> = 44 IU/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r318">318</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">IFN-β</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (FFM-1)</td><td colspan="1" rowspan="1" align="left" valign="top">IC<sub>50</sub> = 110 IU/ml at 10 TCID<sub>50</sub>; IC<sub>50</sub> = 625 IU/ml at 100 TCID<sub>50</sub></td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r83">83</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Multiferon</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (FFM-1)</td><td colspan="1" rowspan="1" align="left" valign="top">IC<sub>50</sub> = 540 IU/ml at 10 TCID<sub>50</sub>; IC<sub>50</sub> = 2,400 IU/ml at 100 TCID<sub>50</sub></td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r83">83</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">IFN-α2b</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (FFM-1)</td><td colspan="1" rowspan="1" align="left" valign="top">IC<sub>50</sub> = >3,125 IU/ml at 10 TCID<sub>50</sub>; IC<sub>50</sub> = >3,125 IU/ml at 100 TCID<sub>50</sub></td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r83">83</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">IFN-α2a</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (FFM-1)</td><td colspan="1" rowspan="1" align="left" valign="top">IC<sub>50</sub> = >3,125 IU/ml at 10 TCID<sub>50</sub>; IC<sub>50</sub> = >3,125 IU/ml at 100 TCID<sub>50</sub></td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r83">83</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">IFN-alfacon1 (Infergen)</td><td colspan="1" rowspan="1" align="left" valign="top">Vero (Urbani)</td><td colspan="1" rowspan="1" align="left" valign="top">IC<sub>50</sub> = 0.001 μg/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r257">257</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">IL-4 and IFN-γ</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (HKU39849)</td><td colspan="1" rowspan="1" align="left" valign="top">IL-4 and IFN-γ downregulated cell surface expression of ACE2; ACE2 mRNA levels were also decreased after treatment</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r84">84</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">IFN-β and ribavirin</td><td colspan="1" rowspan="1" align="left" valign="top">Caco2 (FFM-1)</td><td colspan="1" rowspan="1" align="left" valign="top">Mean (SD) CI = 0.45 (0.07)</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r243">243</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">HR2-8 (HR2-derived peptide)</td><td colspan="1" rowspan="1" align="left" valign="top">Vero 118 (NM)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> = 17 μM</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r22">22</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">CP-1 (HR2-derived peptide)</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (WHU)</td><td colspan="1" rowspan="1" align="left" valign="top">IC<sub>50</sub> ≈ 19 μmol/liter</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r227">227</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">HR1-1 (HR1-derived peptide)</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (BJ01 and pseudovirus)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> = 3.68 μM for wild-type virus assay; EC<sub>50</sub> = 0.14 μM for pseudotyped virus assay</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r407">407</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">HR2-18 (HR2-derived peptide)</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (BJ01 and pseudovirus)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> = 5.22 μM for wild-type virus assay; EC<sub>50</sub> = 1.19 μM for pseudotyped virus assay</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r407">407</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">HR2</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (WHU)</td><td colspan="1" rowspan="1" align="left" valign="top">CPE inhibition IC<sub>50</sub> = 0.5-5 nM (synthetic HR2 peptide) and 66.2-500 nM (fusion HR2 peptide)</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r432">432</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Peptides representing various regions of ACE2</td><td colspan="1" rowspan="1" align="left" valign="top">TELCeB6, HeLa, and VeroE6 (pseudovirus)</td><td colspan="1" rowspan="1" align="left" valign="top">IC<sub>50</sub> = 50 μM (peptide aa 22-44); IC<sub>50</sub> = 6 μM (peptide aa 22-57); IC<sub>50</sub> = 0.1 μM (peptide aa 22-44 and 351-357) artificially linked by glycine</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r120">120</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Peptides analogous to viral spike protein</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6, L2 (Urbani)</td><td colspan="1" rowspan="1" align="left" valign="top">Inhibit viral plaque formation by 40-70% at 15-30 μM; peptides analogous to regions of the N terminus or the pretransmembrane domain of the S2 subunit; inhibit viral plaque formation by >80% at 15-30 μM (peptides analogous to the SARS-CoV loop region)</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r295">295</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">siRNA, RL004, RL005</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (Y3)</td><td colspan="1" rowspan="1" align="left" valign="top">siRNA (600 pmol/liter) targeting conserved regions of SARS-CoV, ↓ virally induced CPE at 67 h</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r418">418</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">siRNA</td><td colspan="1" rowspan="1" align="left" valign="top">FRhK-4 (HKU66078)</td><td colspan="1" rowspan="1" align="left" valign="top">siRNA duplexes targeting regions in entire viral genome, ↓ virally induced CPE and viral production at 72 h</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r428">428</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">siRNA targeting viral RP</td><td colspan="1" rowspan="1" align="left" valign="top">Vero (NM)</td><td colspan="1" rowspan="1" align="left" valign="top">↓ virally induced CPE, ↓ viral production, ↓ viral protein synthesis at 1.5 or 3 μg of siRNA</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r351">351</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">RNA interference targeting viral RP</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6, 293, HeLa (SARS-CoV-p9)</td><td colspan="1" rowspan="1" align="left" valign="top">↓ expression of RP (293 and HeLa cells); ↓ plaque formation at 1 μg of siRNA</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r232">232</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">siRNA targeting S gene</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6, 293T (BJ01)</td><td colspan="1" rowspan="1" align="left" valign="top">↓ S gene expression in SARS-CoV-infected cells at 2, 3, and 4 μg of siRNA</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r419">419</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">siRNAs targeting S gene and 3′ untranslated region</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (HK strain)</td><td colspan="1" rowspan="1" align="left" valign="top">↓ viral antigen synthesis of 64% (by siSARS-S2), 51% (siSARS-S3), 40% (siSARS 3′ untranslated region) at 100 pmol of siRNA</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r379">379</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Glycyrrhizin</td><td colspan="1" rowspan="1" align="left" valign="top">Vero (FFM-1, FFM-2)</td><td colspan="1" rowspan="1" align="left" valign="top">CPE assay mean (SD) CC<sub>50</sub> = >20,000 mg/liter; EC<sub>50</sub> = 300 (51) mg/liter (SI of >67)</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r77">77</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">FRhK-4 (HKU39849)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> at 48 h = >400 μg/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r50">50</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (HKU39849)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> at 48 h = 100 μg/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r50">50</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Mizoribine</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (FFM-1)</td><td colspan="1" rowspan="1" align="left" valign="top">IC<sub>50</sub> = 3.5 μg/ml; CC<sub>50</sub> = >200 μg/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r293">293</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (HKU39489)</td><td colspan="1" rowspan="1" align="left" valign="top">IC<sub>50</sub> = 16 μg/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r293">293</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Ribavirin</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (FFM-1)</td><td colspan="1" rowspan="1" align="left" valign="top">IC<sub>50</sub> = 20 μg/ml; CC<sub>50</sub> = >200 μg/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r293">293</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (HKU39489)</td><td colspan="1" rowspan="1" align="left" valign="top">IC<sub>50</sub> = 80 μg/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r293">293</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">FRhK-4 (HKU39849)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> at 48 h = 50-100 μg/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r50">50</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (HKU39849)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> at 48 h = >200 μg/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r50">50</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Rimantidine</td><td colspan="1" rowspan="1" align="left" valign="top">FRhK-4 (HKU39849)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> at 48 h = 16 μg/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r50">50</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (HKU39849)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> at 48 h = 8-16 μg/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r50">50</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Lopinavir</td><td colspan="1" rowspan="1" align="left" valign="top">FRhK-4 (HKU39849)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> at 48 h = 16 μg/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r50">50</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (HKU39849)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> at 48 h = 8-16 μg/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r50">50</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Baicalin</td><td colspan="1" rowspan="1" align="left" valign="top">FRhK-4 (HKU39849)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> at 48 h = 12.5 μg/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r50">50</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (HKU39849)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> at 48 h = 100 μg/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r50">50</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Aurintricarboxylic acid</td><td colspan="1" rowspan="1" align="left" valign="top">Vero (NM)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> = 0.2 mg/ml; CC<sub>50</sub> = 37.5 mg/ml; SI = 187</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r129">129</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Reserpine</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (HK strain)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> = 3.4 μM; CC<sub>50</sub> = 25 μM; SI = 7.3</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r381">381</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Aescin</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (HK strain)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> = 6 μM; CC<sub>50</sub> = 15 μM; SI = 2.5</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r381">381</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Valinomycin</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (HK strain)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> = 0.85 μM; CC<sub>50</sub> = 68 μM; SI = 80</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r381">381</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Niclosamide</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (Taiwan strain)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> = 1-3 μM; CC<sub>50</sub> = 250 μM</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r380">380</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Nelfinavir</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (FFM-1)</td><td colspan="1" rowspan="1" align="left" valign="top">Mean (SD) EC<sub>50</sub> = 0.048 (0.024) μM; CC<sub>50</sub> = 14.75 (2.75) μM; SI = 302.1</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r392">392</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Chloroquine</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (FFM-1)</td><td colspan="1" rowspan="1" align="left" valign="top">Mean (SD) IC<sub>50</sub> = 8.8 (1.2) μM; CC<sub>50</sub> = 261.3 (14.5) μM; SI = 30</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r174">174</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (Urbani)</td><td colspan="1" rowspan="1" align="left" valign="top">Mean (SD) EC<sub>50</sub> = 4.4 (1.0) μM; refractory to infection if pretreated with chloroquine (10 μM) for 20 h</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r341">341</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Indomethacin</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (Tor2)</td><td colspan="1" rowspan="1" align="left" valign="top">IC<sub>50</sub> = 50 μM</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r4">4</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">3C-like proteinase inhibitors</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Cinanserin (SQ 10,643)</td><td colspan="1" rowspan="1" align="left" valign="top">Vero (NM)</td><td colspan="1" rowspan="1" align="left" valign="top">IC<sub>50</sub> = 5 μM</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r51">51</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> TG-0205221</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (NM)</td><td colspan="1" rowspan="1" align="left" valign="top">↓ viral load by 4.7 logs at 5 μM</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r396">396</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Octapeptide AVLQSGFR</td><td colspan="1" rowspan="1" align="left" valign="top">Vero (BJ01)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> = 0.027 mg/liter; CC<sub>50</sub> = >100 mg/liter; SI = >3,704</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r101">101</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Peptidomimetic inhibitor</td><td colspan="1" rowspan="1" align="left" valign="top">NM</td><td colspan="1" rowspan="1" align="left" valign="top">IC<sub>50</sub> = 45-70 μM</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r103">103</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Calpain inhibitors, Val-Leu-CHO</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (Urbani)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>90</sub> = 3 μM</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r14">14</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Calpain inhibitors, Z-Val-Phe-Ala-CHO</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (Urbani)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>90</sub> = 15 μM</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r14">14</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Cyclopentenyl carbocyclic nucleosides</td><td colspan="1" rowspan="1" align="left" valign="top">NM</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> = 47 μM for 1,2,3-triazole analogue (17c); EC<sub>50</sub> = 21 μM for 1,2,4-triazole analogue (17a)</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r65">65</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Nucleoside analogue inhibitor, β-<sc>d</sc>-<italic>N</italic><sup>4</sup>-hydroxycytidine</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (Urbani)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>90</sub> = 6 μM</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r14">14</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Nitric oxide, <italic>S</italic>-nitroso-<italic>N</italic>-acetylpenicillamine</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (FFM-1)</td><td colspan="1" rowspan="1" align="left" valign="top">Mean (SD) IC<sub>50</sub> = 222 (83.7) μM; SI = 3</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r173">173</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Pyridine <italic>N</italic>-oxide derivatives</td><td colspan="1" rowspan="1" align="left" valign="top">Crandel feline kidney (CRFK) and Vero (FFM-1)</td><td colspan="1" rowspan="1" align="left" valign="top">Among 192 compounds tested, the oxide part on pyridine moiety was indispensable for antiviral activity with CC<sub>50</sub> of 50-100 mg/liter</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r11">11</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Stilbene derivatives</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (NM)</td><td colspan="1" rowspan="1" align="left" valign="top">Inhibited by compounds 17 and 19 at 0.5 mg/ml, and no significant cytotoxic effects were observed in vitro</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r217">217</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Peptide-conjugated antisense morpholino oligomers (P-PMO)</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (Tor2)</td><td colspan="1" rowspan="1" align="left" valign="top">Several virus-targeted P-PMO (AUG1, AUG2, AUG3, 1AFBS, and 3UTR) consistently reduced CPE at a concn of 20 μM</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r246">246</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">20-mer synthetic peptides (S protein fragments)</td><td colspan="1" rowspan="1" align="left" valign="top">FRhK-4 (GZ50)</td><td colspan="1" rowspan="1" align="left" valign="top">IC<sub>50</sub> = 24.9-113 μg/ml; IC<sub>90</sub> = 0.9-15.9 μg/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r427">427</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Diverse small molecules,<xref ref-type="table-fn" rid="t8fn2"><italic>b</italic></xref> MP576, HE602, and VE607</td><td colspan="1" rowspan="1" align="left" valign="top">Vero (HKU39849)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> = <10 μM</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r170">170</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Adamantane-derived compounds<xref ref-type="table-fn" rid="t8fn3"><italic>c</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">FRhK-4 (NM)</td><td colspan="1" rowspan="1" align="left" valign="top">IC<sub>50</sub> = 0.5-3 μM; CC<sub>50</sub> = >300 μM</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r328">328</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Semisynthetic derivatives of glycopeptide</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Vancomycin</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (FFM-1)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> = 22->100 μM; CC<sub>50</sub> = >80 μM</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r10">10</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Eremomycin</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (FFM-1)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> = 14->100 μM; CC<sub>50</sub> = 45->100 μM</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r10">10</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Teicoplanin, ristocetin A, and DA-40926</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (FFM-1)</td><td colspan="1" rowspan="1" align="left" valign="top">EC<sub>50</sub> = >80 μM; CC<sub>50</sub> = >80 μM</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r10">10</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"><italic>Lycoris radiata</italic> (Chinese medicinal herb)</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (BJ001, BJ006)</td><td colspan="1" rowspan="1" align="left" valign="top">Mean (SD) EC<sub>50</sub> = 2.4 (0.2) μg/ml; CC<sub>50</sub> = 886.6 (35.0) μg/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r212">212</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"><italic>Artemisia annua</italic> (Chinese medicinal herb)</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (BJ001, BJ006)</td><td colspan="1" rowspan="1" align="left" valign="top">Mean (SD) EC<sub>50</sub> = 34.5 (2.6) μg/ml; CC<sub>50</sub> = 1,035 (92.8) μg/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r212">212</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"><italic>Pyrrosia lingua</italic> (Chinese medicinal herb)</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (BJ001, BJ006)</td><td colspan="1" rowspan="1" align="left" valign="top">Mean (SD) EC<sub>50</sub> = 43.2 (14.1) μg/ml; CC<sub>50</sub> = 2,378 (87.3) μg/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r212">212</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"><italic>Lindera</italic> sp. (Chinese medicinal herb)</td><td colspan="1" rowspan="1" align="left" valign="top">Vero E6 (BJ001, BJ006)</td><td colspan="1" rowspan="1" align="left" valign="top">Mean (SD) EC<sub>50</sub> = 88.2 (7.7) μg/ml; CC<sub>50</sub> = 1,374 (39.0) μg/ml</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r212">212</xref></td></tr></tbody></table><table-wrap-foot><fn id="t8fn1"><label>a</label><p>i.p., intraperitoneal; EC<sub>50</sub>, 50% effective concentration; SI, selectivity index; NA, not available; p.i., preincubation; NM, not mentioned; IC<sub>50</sub>, 50% inhibitory concentration; TCID<sub>50</sub>, 50% tissue culture infective dose; CI, combination index (combination index of <1 indicates synergism); CPE, cell culture cytopathic effect; aa, amino acids; RP, RNA polymerase; CC<sub>50</sub>, 50% cytotoxic concentration; ↓, decreased.</p></fn><fn id="t8fn2"><label>b</label><p>MP576, HE602, and VE607 were validated to be inhibitors of SARS-CoV M<sup>pro</sup>, Hel, and viral entry, respectively.</p></fn><fn id="t8fn3"><label>c</label><p>Bananin, iodobananin, vanillinbananin, and eubananin were effective inhibitors of the ATPase activity of the SCV helicase.</p></fn></table-wrap-foot></table-wrap><table-wrap position="float" id="t9"><label>TABLE 9.</label><caption><p>Passive and active immunization against SARS</p></caption><table frame="hsides" rules="groups"><thead><tr><th colspan="1" rowspan="1" align="center" valign="bottom">Type of vaccine</th><th colspan="1" rowspan="1" align="center" valign="bottom">Target (animal model)</th><th colspan="1" rowspan="1" align="center" valign="bottom">Response<xref ref-type="table-fn" rid="t9fn1"><italic>a</italic></xref></th><th colspan="1" rowspan="1" align="center" valign="bottom">Reference(s)</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" align="left" valign="top">Passive immunization</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Human monoclonal antibody</td><td colspan="1" rowspan="1" align="left" valign="top">S protein (ferret)</td><td colspan="1" rowspan="1" align="left" valign="top">Decrease in lung viral titer, decrease in viral shedding, prevention of virally induced tissue pathology</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r329">329</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">S protein (BALB/c mice)</td><td colspan="1" rowspan="1" align="left" valign="top">Decrease in lung/nasal viral titers</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r333">333</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">S protein (BALB/c mice)</td><td colspan="1" rowspan="1" align="left" valign="top">Decrease in lung viral titers</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r313">313</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Human monoclonal antibody from transgenic (HuMantibody) mice</td><td colspan="1" rowspan="1" align="left" valign="top">S protein (BALB/c mice)</td><td colspan="1" rowspan="1" align="left" valign="top">Decrease in lung/nasal viral titers</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r110">110</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Active immunization</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Inactivated whole virus</td><td colspan="1" rowspan="1" align="left" valign="top">Inactivated SARS-CoV (BALB/c mice)</td><td colspan="1" rowspan="1" align="left" valign="top">Neutralizing antibodies</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r323">323</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Inactivated SARS-CoV (BALB/c mice)</td><td colspan="1" rowspan="1" align="left" valign="top">Neutralizing antibodies; specific IgA in tracheal/lung wash fluid with adjuvant-added or PEG-precipitated vaccine only</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r274">274</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Inactivated SARS-CoV (BALB/c mice, rabbits)</td><td colspan="1" rowspan="1" align="left" valign="top">Specific antibodies recognizing RBD of S1; blocked binding of RBD to ACE2; significant decrease in S protein-mediated cell entry in pseudotyped virus assay</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r134">134</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">Inactivated SARS-CoV (BALB/c mice)</td><td colspan="1" rowspan="1" align="left" valign="top">Neutralizing antibodies</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r306">306</xref>,<xref ref-type="bibr" rid="r317">317</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Recombinant protein fragment</td><td colspan="1" rowspan="1" align="left" valign="top">S protein (BALB/c mice)</td><td colspan="1" rowspan="1" align="left" valign="top">Neutralizing antibodies</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r19">19</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">S protein (BALB/c mice, rabbits)</td><td colspan="1" rowspan="1" align="left" valign="top">Neutralizing antibodies</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r415">415</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">S protein (rabbits)</td><td colspan="1" rowspan="1" align="left" valign="top">Neutralizing antibodies against receptor binding domain</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r133">133</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">S protein (BALB/c mice)</td><td colspan="1" rowspan="1" align="left" valign="top">Neutralizing antibodies against receptor binding domain</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r132">132</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Adenoviral vector</td><td colspan="1" rowspan="1" align="left" valign="top">S, M, and N proteins (rhesus macaques)</td><td colspan="1" rowspan="1" align="left" valign="top">Neutralizing antibodies, T-cell responses</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r102">102</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Modified vaccinia virus Ankara</td><td colspan="1" rowspan="1" align="left" valign="top">S protein (BALB/c mice)</td><td colspan="1" rowspan="1" align="left" valign="top">Neutralizing antibodies; decrease in lung/nasal viral titers, passive serum transfer protective</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r18">18</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">S protein (BALB/c mice, rabbits, Chinese rhesus monkeys)</td><td colspan="1" rowspan="1" align="left" valign="top">Neutralizing antibodies; decrease in lung/nasal viral titers</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r55">55</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">S protein (ferrets)</td><td colspan="1" rowspan="1" align="left" valign="top">Neutralizing antibodies; enhanced hepatitis in vaccinated ferrets when challenged with SARS-CoV</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r355">355</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Recombinant attenuated HPIF3</td><td colspan="1" rowspan="1" align="left" valign="top">S protein (African green monkey)</td><td colspan="1" rowspan="1" align="left" valign="top">Neutralizing antibodies, decrease in viral shedding</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r25">25</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Recombinant vesicular stomatitis virus</td><td colspan="1" rowspan="1" align="left" valign="top">S protein (BALB/c mice)</td><td colspan="1" rowspan="1" align="left" valign="top">Neutralizing antibodies, decrease in lung viral titer</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r171">171</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Attenuated rabies virus</td><td colspan="1" rowspan="1" align="left" valign="top">S or N protein (BALB/c mice)</td><td colspan="1" rowspan="1" align="left" valign="top">Neutralizing antibodies specific to S but not with N protein</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r94">94</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Recombinant Venezuelan equine encephalitis virus replicon particle</td><td colspan="1" rowspan="1" align="left" valign="top">S or N protein (young and senescent BALB/c mice)</td><td colspan="1" rowspan="1" align="left" valign="top">Good protection in young but partial protection in senescent mice with S vaccine; enhanced immunopathology with N vaccine</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r85">85</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> DNA vaccine</td><td colspan="1" rowspan="1" align="left" valign="top">S protein (BALB/c mice)</td><td colspan="1" rowspan="1" align="left" valign="top">Neutralizing antibodies, T-cell responses; decrease in lung/nasal viral titers; serum transfer protective</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r399">399</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">S protein (BALB/c mice)</td><td colspan="1" rowspan="1" align="left" valign="top">Neutralizing antibodies, T-cell responses</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r123">123</xref>,<xref ref-type="bibr" rid="r412">412</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">E, M, and N proteins (BALB/c mice)</td><td colspan="1" rowspan="1" align="left" valign="top">DNA encoding N induced highest neutralizing antibodies and T-cell responses</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r164">164</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">N protein (C3H/He mice)</td><td colspan="1" rowspan="1" align="left" valign="top">Specific antibodies, T-cell responses</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r433">433</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">N protein (C57BL/6 mice)</td><td colspan="1" rowspan="1" align="left" valign="top">T-cell responses; decrease in surrogate viral titer in lungs</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r176">176</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">S protein (rabbits)</td><td colspan="1" rowspan="1" align="left" valign="top">Neutralizing antibodies</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r348">348</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top">N protein (mice)</td><td colspan="1" rowspan="1" align="left" valign="top">Specific antibodies, N-specific splenocyte proliferation responses, DTH and CD8<sup>+</sup> CTL responses</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r424">424</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> DNA vaccine boosted by recombinant protein produced in <italic>E. coli</italic></td><td colspan="1" rowspan="1" align="left" valign="top">S protein (BALB/c mice)</td><td colspan="1" rowspan="1" align="left" valign="top">Very high S-specific neutralizing antibodies</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r370">370</xref></td></tr></tbody></table><table-wrap-foot><fn id="t9fn1"><label>a</label><p>PEG, polyethylene glycol; RBD, receptor-binding domain; DTH, delayed-type hypersensitivity; CTL, cytotoxic T cell.</p></fn></table-wrap-foot></table-wrap><table-wrap position="float" id="t10"><label>TABLE 10.</label><caption><p>Animals tested for susceptibility to SARS-CoV in experimental and natural infection<xref ref-type="table-fn" rid="t10fn1"><italic>a</italic></xref></p></caption><table frame="hsides" rules="groups"><thead><tr><th colspan="1" rowspan="1" align="center" valign="bottom">Animal species and age</th><th colspan="1" rowspan="1" align="center" valign="bottom">Dose and route of inoculation (virus strain)</th><th colspan="1" rowspan="1" align="center" valign="bottom">Point of evaluation (days)</th><th colspan="1" rowspan="1" align="center" valign="bottom">Main findings</th><th colspan="1" rowspan="1" align="center" valign="bottom">Reference</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" align="left" valign="top">Cynomolgus macaques (<italic>Macaca fascicularis</italic>)</td><td colspan="1" rowspan="1" align="left" valign="top">10<sup>3</sup> to 10<sup>6</sup> TCID<sub>50</sub>; i.n., i.v., conjunctival (NM)</td><td colspan="1" rowspan="1" align="left" valign="top">Up to 16</td><td colspan="1" rowspan="1" align="left" valign="top">Lethargy from 3 dpi, respiratory distress from 4 dpi, died with severe multifocal pulmonary consolidation and histologically interstitial pneumonia, diffuse alveolar damage, necrosis of alveolar and bronchiolar epithelium, and alveolar edema with proteinaceous fluid admixed with fibrin, erythrocytes, alveolar macrophages, and neutrophils</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r98">98</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Cynomolgus macaques (<italic>Macaca fascicularis</italic>); adult</td><td colspan="1" rowspan="1" align="left" valign="top">10<sup>6</sup> TCID<sub>50</sub>; i.n., IT, conjunctiva (strain from patient 5688)</td><td colspan="1" rowspan="1" align="left" valign="top">6</td><td colspan="1" rowspan="1" align="left" valign="top">Excreted SARS-CoV from nose, mouth, and pharynx from 2 dpi; diffuse alveolar damage with epithelial necrosis, serosanguineous exudate, hyaline membrane formation, type 2 pneumocyte hyperplasia, and syncytium formation</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r182">182</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Cynomolgus macaques and rhesus macaques</td><td colspan="1" rowspan="1" align="left" valign="top">10<sup>7</sup> PFU; IT, i.v. (Tor2)</td><td colspan="1" rowspan="1" align="left" valign="top">12</td><td colspan="1" rowspan="1" align="left" valign="top">Mild self-limited respiratory infection</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r291">291</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">African green, rhesus, and cynomolgus monkeys; juvenile</td><td colspan="1" rowspan="1" align="left" valign="top">10<sup>6</sup> TCID<sub>50</sub>; i.n., IT (Urbani)</td><td colspan="1" rowspan="1" align="left" valign="top">Up to 28</td><td colspan="1" rowspan="1" align="left" valign="top">SARS-CoV replicated in the respiratory tract but did not induce illness; moderate to high titers of SARS-CoV excretion with associated interstitial pneumonitis detected in lungs of African green monkeys on 2 dpi and resolved by 4 dpi</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r239">239</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Rhesus macaques (<italic>Macaca mulatta</italic>); 1-3 yr</td><td colspan="1" rowspan="1" align="left" valign="top">10<sup>3</sup>, 10<sup>5</sup>, 10<sup>7</sup> TCID<sub>50</sub>; i.n. (PUMC01)</td><td colspan="1" rowspan="1" align="left" valign="top">Up to 60</td><td colspan="1" rowspan="1" align="left" valign="top">Transient fever occurred 2-3 dpi; SARS-CoV-specific IgGs detected in sera of macaques from 11 to 60 dpi; SARS-CoV RNA detected in pharyngeal swab samples 5 dpi; histopathological changes of interstitial pneumonia during the 60 dpi</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r272">272</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Cynomolgus macaques (<italic>Macaca fascicularis</italic>); adult</td><td colspan="1" rowspan="1" align="left" valign="top">1.25 × 10<sup>6</sup> PFU; i.n., i.v., conjunctiva (Urbani)</td><td colspan="1" rowspan="1" align="left" valign="top">Up to 20</td><td colspan="1" rowspan="1" align="left" valign="top">Mild to moderate symptomatic illness; evidence of viral replication and neutralizing antibodies; chest X-ray unifocal or multifocal pneumonia peaked between 8 and 10 dpi; inoculation by mucosal route produced more prominent disease than that with i.v. inoculation</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r194">194</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">BALB/c mice; 4 wk</td><td colspan="1" rowspan="1" align="left" valign="top">2 × 10<sup>5</sup> TCID<sub>50</sub>; i.n., oral (Urbani)</td><td colspan="1" rowspan="1" align="left" valign="top">3, 5, 7, 10, and 28</td><td colspan="1" rowspan="1" align="left" valign="top">Viral replication in lung and intestinal tissue but caused subclinical infection or very mild disease</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r357">357</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">BALB/c mice; 4-6 wk</td><td colspan="1" rowspan="1" align="left" valign="top">10<sup>5</sup> TCID<sub>50</sub>; i.n. (Urbani)</td><td colspan="1" rowspan="1" align="left" valign="top">1, 2, 3, 5, 7, 9, and 11</td><td colspan="1" rowspan="1" align="left" valign="top">Peak replication in the absence of disease on 1 or 2 dpi; viral clearance within a wk; viral antigen and nucleic acid detected in bronchiolar epithelial cells during peak viral replication</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r311">311</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">C57BL/6 mice; 5-6 wk</td><td colspan="1" rowspan="1" align="left" valign="top">10<sup>4</sup> TCID<sub>50</sub>; i.n. (Urbani)</td><td colspan="1" rowspan="1" align="left" valign="top">Up to 15</td><td colspan="1" rowspan="1" align="left" valign="top">Infected mice had transient infection with relative failure to thrive; viral replication to high levels in lungs of these mice, which peaked on 3 dpi and cleared by day 9 dpi</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r105">105</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">BALB/c mice; 12-14 mo</td><td colspan="1" rowspan="1" align="left" valign="top">10<sup>5</sup> TCID<sub>50</sub>; i.n. (Urbani)</td><td colspan="1" rowspan="1" align="left" valign="top">1, 2, 5, 9, and 13</td><td colspan="1" rowspan="1" align="left" valign="top">Viral replication in aged mice was associated with clinical illness and pneumonia demonstrating an age-related susceptibility to SARS disease</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r287">287</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">129SvEv mice (Stat1<sup>+/−</sup>)</td><td colspan="1" rowspan="1" align="left" valign="top">10<sup>6</sup> PFU; i.n. (Tor2)</td><td colspan="1" rowspan="1" align="left" valign="top">1, 3, 5, 8, 11, 15, and 22</td><td colspan="1" rowspan="1" align="left" valign="top">Stat1-deficient mice had viral replication of virus in lungs and progressively worsening pulmonary disease with inflammation of small airways and alveoli and systemic viral spread to livers and spleens</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r143">143</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">BALB/c mice; 6-8 wk</td><td colspan="1" rowspan="1" align="left" valign="top">10<sup>5</sup> TCID<sub>50</sub>; i.n. (Urbani of 15 passages [MA15] in BALB/c mice)</td><td colspan="1" rowspan="1" align="left" valign="top">6</td><td colspan="1" rowspan="1" align="left" valign="top">Lethality preceded by high-titer viral replication in lungs, viremia, and dissemination to extrapulmonary sites accompanied by lymphopenia, neutrophilia, and pathological changes in lungs; death from an overwhelming viral infection with extensive virally mediated destruction of pneumocytes and ciliated epithelial cells; the MA15 virus has six coding mutations (in <italic>Orf1a</italic>, <italic>Orf1b</italic>, S gene, and M gene) associated with adaptation and increased virulence</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r286">286</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Transgenic mice expressing hACE2 (K18-hACE2)</td><td colspan="1" rowspan="1" align="left" valign="top">2.3 × 10<sup>2</sup>-2.3 × 10<sup>4</sup> PFU; i.n. (Urbani)</td><td colspan="1" rowspan="1" align="left" valign="top">7<xref ref-type="table-fn" rid="t10fn2"><italic>b</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">Weight loss by 3-5 dpi and died by 7 dpi; infection begins in airway epithelia with subsequent alveolar involvement and extrapulmonary virus spread to the brain; infection results in macrophage and lymphocyte infiltration in the lungs and up-regulation of proinflammatory cytokines and chemokines in both the lung and the brain</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r240">240</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Transgenic mice expressing hACE2 (AC70)</td><td colspan="1" rowspan="1" align="left" valign="top">10<sup>3</sup> or 2 × 10<sup>5</sup> TCID<sub>50</sub>; i.n. (Urbani)</td><td colspan="1" rowspan="1" align="left" valign="top">8</td><td colspan="1" rowspan="1" align="left" valign="top">Developed acute wasting syndrome and died within 4-8 dpi; high levels of virus replication detected in lungs and brain; pathological examination suggests that the extensive involvement of the central nervous system likely contributed to the death of mice, even though viral pneumonia was present</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r337">337</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">F344 rat; adult</td><td colspan="1" rowspan="1" align="left" valign="top">100 μl<xref ref-type="table-fn" rid="t10fn3"><italic>c</italic></xref>; i.n. (Frankfurt 1 after 10 passages)<xref ref-type="table-fn" rid="t10fn4"><italic>d</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">3, 5, 7, and 21</td><td colspan="1" rowspan="1" align="left" valign="top">Adult rats showed respiratory symptoms and severe pathological lung lesions; inflammatory cytokine levels in sera and lung tissues were significantly higher in adult than in young rats</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r244">244</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Golden Syrian hamsters; 5 wk</td><td colspan="1" rowspan="1" align="left" valign="top">10<sup>3</sup> TCID<sub>50</sub>; i.n. (Urbani)</td><td colspan="1" rowspan="1" align="left" valign="top">2, 3, 5, 7, 10, and 14</td><td colspan="1" rowspan="1" align="left" valign="top">Little clinical evidence of disease; viral replication in epithelial cells of the respiratory tract with early cellular necrosis, followed by an inflammatory response coincident with viral clearance; focal consolidation in lung; viremia and extrapulmonary spread of SARS-CoV to liver and spleen despite high levels of virus replication and associated pathology</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r288">288</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Common marmosets (<italic>Callithrix jacchus</italic>), small nonhuman primate; juvenile or young adult</td><td colspan="1" rowspan="1" align="left" valign="top">10<sup>6</sup> TCID<sub>50</sub>; IT (Urbani)</td><td colspan="1" rowspan="1" align="left" valign="top">2, 4, and 7</td><td colspan="1" rowspan="1" align="left" valign="top">Mild clinical disease; multifocal mononuclear cell interstitial pneumonitis, multinucleated syncytial cells, edema, and bronchiolitis; viral antigen localized to infected alveolar macrophages and type 1 pneumocytes; viral RNA detected in all animals from pulmonary tissue and in some cases from tracheobronchial lymph node and myocardium with inflammatory changes; multifocal lymphocytic hepatitis with piecemeal necrosis</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r111">111</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Cats</td><td colspan="1" rowspan="1" align="left" valign="top">10<sup>6</sup> TCID<sub>50</sub>; IT (patient 5688)</td><td colspan="1" rowspan="1" align="left" valign="top">4</td><td colspan="1" rowspan="1" align="left" valign="top">Asymptomatic shedding of virus from pharynx</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r237">237</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Ferrets</td><td colspan="1" rowspan="1" align="left" valign="top">10<sup>6</sup> TCID<sub>50</sub>; IT (patient 5688)</td><td colspan="1" rowspan="1" align="left" valign="top">4</td><td colspan="1" rowspan="1" align="left" valign="top">3 out of 6 ferrets became lethargic from 2-4 dpi with viral replication and pneumonitis</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r237">237</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Ferrets (<italic>Mustela putorius furo</italic>)</td><td colspan="1" rowspan="1" align="left" valign="top">10<sup>6</sup> TCID<sub>50</sub>; i.n. (Tor2)</td><td colspan="1" rowspan="1" align="left" valign="top">Up to 29</td><td colspan="1" rowspan="1" align="left" valign="top">Asymptomatic viral replication but significant hepatitis occurred only after vaccination with modified vaccinia virus Ankara carrying SARS-CoV spike protein</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r355">355</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Masked palm civets (<italic>Paguma larvata</italic>); 1 yr</td><td colspan="1" rowspan="1" align="left" valign="top">3 × 10<sup>6</sup> TCID<sub>50</sub>; i.n., IT (BJ01<xref ref-type="table-fn" rid="t10fn5"><italic>e</italic></xref> and GZ01<xref ref-type="table-fn" rid="t10fn6"><italic>f</italic></xref>)</td><td colspan="1" rowspan="1" align="left" valign="top">0, 3, 8, 13, 18, 23, 28, and 33</td><td colspan="1" rowspan="1" align="left" valign="top">Fever, lethargy, and loss of aggressiveness; infection was confirmed by virus isolation, detection of viral genomic RNA, and serum neutralizing antibodies</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r382">382</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Guinea pigs</td><td colspan="1" rowspan="1" align="left" valign="top">Up to 10<sup>4.7</sup> TCID<sub>50</sub>; i.p. (coinfected with SARS-CoV and reovirus)</td><td colspan="1" rowspan="1" align="left" valign="top">NM</td><td colspan="1" rowspan="1" align="left" valign="top">Guinea pigs infected with SARS-CoV developed only interstitial pneumonitis without clinical diseases; death and severe pulmonary pathology were seen in those coinfected with reovirus</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r219">219</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Chicken; 6 wk</td><td colspan="1" rowspan="1" align="left" valign="top">10<sup>6</sup> PFU; i.n., i.v., oral, ocular (Tor3)</td><td colspan="1" rowspan="1" align="left" valign="top">6, 7, 13, 14, 15, and 16</td><td colspan="1" rowspan="1" align="left" valign="top">No disease, pathology, or viral shedding; no antibody response</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r356">356</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Pigs; 6 wk</td><td colspan="1" rowspan="1" align="left" valign="top">2 × 10<sup>6</sup> PFU; i.n., i.v., oral, ocular (Tor3)</td><td colspan="1" rowspan="1" align="left" valign="top">6, 7, 13, 14, 15, and 16</td><td colspan="1" rowspan="1" align="left" valign="top">No disease, pathology, or viral shedding; neutralizing antibodies present</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r356">356</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Himalayan palm civet</td><td colspan="1" rowspan="1" align="left" valign="top">Natural infection</td><td colspan="1" rowspan="1" align="left" valign="top">NA</td><td colspan="1" rowspan="1" align="left" valign="top">Viral shedding demonstrated by culture and RT-PCR in nasal and fecal samples; sequence analysis showed that all animal isolates retain a 29-nucleotide sequence not found in most human isolates</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r117">117</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Raccoon dog (<italic>Nyctereutes procyonoides</italic>)</td><td colspan="1" rowspan="1" align="left" valign="top">Natural infection</td><td colspan="1" rowspan="1" align="left" valign="top">NA</td><td colspan="1" rowspan="1" align="left" valign="top">Viral shedding demonstrated by culture and RT-PCR in nasal and fecal samples; sequence analysis showed that all animal isolates retain a 29-nucleotide sequence not found in most human isolates</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r117">117</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Bats (<italic>Rhinolophus sinicus</italic>)</td><td colspan="1" rowspan="1" align="left" valign="top">Natural infection</td><td colspan="1" rowspan="1" align="left" valign="top">NA</td><td colspan="1" rowspan="1" align="left" valign="top">Coronavirus closely related to SARS-CoV (bat SARS-CoV) in 39% of anal swabs by using RT-PCR with a viral load of 3.89 × 10<sup>2</sup>-2.21 × 10<sup>7</sup>; bat SARS-CoV genome is closely related to SARS-CoV from humans and civets; antibody against recombinant bat SARS-CoV nucleocapsid protein was detected in 84% of Chinese horseshoe bats</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r190">190</xref></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Bats (family Rhinolophidae)</td><td colspan="1" rowspan="1" align="left" valign="top">Natural infection</td><td colspan="1" rowspan="1" align="left" valign="top">NA</td><td colspan="1" rowspan="1" align="left" valign="top">SARS-CoV antibody in 28.3% of <italic>Rhinolophus pearsoni</italic> and 33.3% of <italic>Rhinolophus pussilus</italic> isolates from Guangxi and 71% of <italic>Rhinolophus macrotis</italic> isolates from Hubei; RT-PCR positive for a SARS-like virus in 12.5% of <italic>Rhinolophus ferrumequinum</italic> and 12.5% of <italic>R. macrotis</italic> isolates from Hubei and 10% of <italic>R. pearsoni</italic> isolates from Guangxi</td><td colspan="1" rowspan="1" align="left" valign="top"><xref ref-type="bibr" rid="r215">215</xref></td></tr></tbody></table><table-wrap-foot><fn id="t10fn1"><label>a</label><p>TCID<sub>50</sub>, 50% tissue culture infective dose; i.n., intranasal; i.v., intravenous; NM, not mentioned; dpi, day postinfection; IT, intratracheal. i.p., intraperitoneal; NA, not applicable.</p></fn><fn id="t10fn2"><label>b</label><p>All mice died that day after infection.</p></fn><fn id="t10fn3"><label>c</label><p>Concentration of virus inoculation was not mentioned.</p></fn><fn id="t10fn4"><label>d</label><p>SARS-CoV Frankfurt 1 isolate was serially passaged in young F344 rats (4 weeks) 10 times before experimental inoculation.</p></fn><fn id="t10fn5"><label>e</label><p>BJ01, with a 29-nucleotide deletion.</p></fn><fn id="t10fn6"><label>f</label><p>GZ01, without the 29-nucleotide deletion.</p></fn></table-wrap-foot></table-wrap></floats-wrap></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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