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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Nucleocapsid Protein as Early Diagnostic Marker for SARS</title><author><name sortKey="Che, Xiao Yan" sort="Che, Xiao Yan" uniqKey="Che X" first="Xiao-Yan" last="Che">Xiao-Yan Che</name><affiliation><nlm:aff id="aff1">First Military Medical University, Guangzhou, People's Republic of China;</nlm:aff></affiliation></author><author><name sortKey="Hao, Wei" sort="Hao, Wei" uniqKey="Hao W" first="Wei" last="Hao">Wei Hao</name><affiliation><nlm:aff id="aff1">First Military Medical University, Guangzhou, People's Republic of China;</nlm:aff></affiliation></author><author><name sortKey="Wang, Yadi" sort="Wang, Yadi" uniqKey="Wang Y" first="Yadi" last="Wang">Yadi Wang</name><affiliation><nlm:aff id="aff1">First Military Medical University, Guangzhou, People's Republic of China;</nlm:aff></affiliation></author><author><name sortKey="Di, Biao" sort="Di, Biao" uniqKey="Di B" first="Biao" last="Di">Biao Di</name><affiliation><nlm:aff id="aff2">Center for Disease Control and Prevention of Guangzhou, Guangzhou, People's Republic of China;</nlm:aff></affiliation></author><author><name sortKey="Yin, Kai" sort="Yin, Kai" uniqKey="Yin K" first="Kai" last="Yin">Kai Yin</name><affiliation><nlm:aff id="aff1">First Military Medical University, Guangzhou, People's Republic of China;</nlm:aff></affiliation></author><author><name sortKey="Xu, Yin Chao" sort="Xu, Yin Chao" uniqKey="Xu Y" first="Yin-Chao" last="Xu">Yin-Chao Xu</name><affiliation><nlm:aff id="aff1">First Military Medical University, Guangzhou, People's Republic of China;</nlm:aff></affiliation></author><author><name sortKey="Feng, Chang Sen" sort="Feng, Chang Sen" uniqKey="Feng C" first="Chang-Sen" last="Feng">Chang-Sen Feng</name><affiliation><nlm:aff id="aff1">First Military Medical University, Guangzhou, People's Republic of China;</nlm:aff></affiliation></author><author><name sortKey="Wan, Zhuo Yue" sort="Wan, Zhuo Yue" uniqKey="Wan Z" first="Zhuo-Yue" last="Wan">Zhuo-Yue Wan</name><affiliation><nlm:aff id="aff3">Center for Disease Control and Prevention of Guangdong Province, Guangzhou, People's Republic of China;</nlm:aff></affiliation></author><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="aff4">The University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of 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="aff4">The University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">15550204</idno><idno type="pmc">3329003</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3329003</idno><idno type="RBID">PMC:3329003</idno><idno type="doi">10.3201/eid1011.040516</idno><date when="2004">2004</date><idno type="wicri:Area/Pmc/Corpus">000860</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000860</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Nucleocapsid Protein as Early Diagnostic Marker for SARS</title><author><name sortKey="Che, Xiao Yan" sort="Che, Xiao Yan" uniqKey="Che X" first="Xiao-Yan" last="Che">Xiao-Yan Che</name><affiliation><nlm:aff id="aff1">First Military Medical University, Guangzhou, People's Republic of China;</nlm:aff></affiliation></author><author><name sortKey="Hao, Wei" sort="Hao, Wei" uniqKey="Hao W" first="Wei" last="Hao">Wei Hao</name><affiliation><nlm:aff id="aff1">First Military Medical University, Guangzhou, People's Republic of China;</nlm:aff></affiliation></author><author><name sortKey="Wang, Yadi" sort="Wang, Yadi" uniqKey="Wang Y" first="Yadi" last="Wang">Yadi Wang</name><affiliation><nlm:aff id="aff1">First Military Medical University, Guangzhou, People's Republic of China;</nlm:aff></affiliation></author><author><name sortKey="Di, Biao" sort="Di, Biao" uniqKey="Di B" first="Biao" last="Di">Biao Di</name><affiliation><nlm:aff id="aff2">Center for Disease Control and Prevention of Guangzhou, Guangzhou, People's Republic of China;</nlm:aff></affiliation></author><author><name sortKey="Yin, Kai" sort="Yin, Kai" uniqKey="Yin K" first="Kai" last="Yin">Kai Yin</name><affiliation><nlm:aff id="aff1">First Military Medical University, Guangzhou, People's Republic of China;</nlm:aff></affiliation></author><author><name sortKey="Xu, Yin Chao" sort="Xu, Yin Chao" uniqKey="Xu Y" first="Yin-Chao" last="Xu">Yin-Chao Xu</name><affiliation><nlm:aff id="aff1">First Military Medical University, Guangzhou, People's Republic of China;</nlm:aff></affiliation></author><author><name sortKey="Feng, Chang Sen" sort="Feng, Chang Sen" uniqKey="Feng C" first="Chang-Sen" last="Feng">Chang-Sen Feng</name><affiliation><nlm:aff id="aff1">First Military Medical University, Guangzhou, People's Republic of China;</nlm:aff></affiliation></author><author><name sortKey="Wan, Zhuo Yue" sort="Wan, Zhuo Yue" uniqKey="Wan Z" first="Zhuo-Yue" last="Wan">Zhuo-Yue Wan</name><affiliation><nlm:aff id="aff3">Center for Disease Control and Prevention of Guangdong Province, Guangzhou, People's Republic of China;</nlm:aff></affiliation></author><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="aff4">The University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of 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="aff4">The University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China</nlm:aff></affiliation></author></analytic><series><title level="j">Emerging Infectious Diseases</title><idno type="ISSN">1080-6040</idno><idno type="eISSN">1080-6059</idno><imprint><date when="2004">2004</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Serum samples from 317 patients with patients with severe acute respiratory syndrome (SARS) were tested for the nucleocapsid (N) protein of SARS-associated coronavirus, with sensitivities of 94% and 78% for the first 5 days and 6–10 days after onset, respectively. The specificity was 99.9%. N protein can be used as an early diagnostic maker for SARS.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><pmc article-type="brief-report"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Emerg Infect Dis</journal-id><journal-id journal-id-type="iso-abbrev">Emerging Infect. Dis</journal-id><journal-id journal-id-type="publisher-id">EID</journal-id><journal-title-group><journal-title>Emerging Infectious Diseases</journal-title></journal-title-group><issn pub-type="ppub">1080-6040</issn><issn pub-type="epub">1080-6059</issn><publisher><publisher-name>Centers for Disease Control and Prevention</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">15550204</article-id><article-id pub-id-type="pmc">3329003</article-id><article-id pub-id-type="publisher-id">04-0516</article-id><article-id pub-id-type="doi">10.3201/eid1011.040516</article-id><article-categories><subj-group subj-group-type="heading"><subject>Dispatch</subject></subj-group><subj-group subj-group-type="article-type"><subject>Dispatch</subject></subj-group></article-categories><title-group><article-title>Nucleocapsid Protein as Early Diagnostic Marker for SARS</article-title><alt-title alt-title-type="running-head">Nucleocapsid Protein as Early Diagnostic Marker for SARS</alt-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Che</surname><given-names>Xiao-Yan</given-names></name><xref ref-type="aff" rid="aff1">*</xref></contrib><contrib contrib-type="author"><name><surname>Hao</surname><given-names>Wei</given-names></name><xref ref-type="aff" rid="aff1">*</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Yadi</given-names></name><xref ref-type="aff" rid="aff1">*</xref></contrib><contrib contrib-type="author"><name><surname>Di</surname><given-names>Biao</given-names></name><xref ref-type="aff" rid="aff2">†</xref></contrib><contrib contrib-type="author"><name><surname>Yin</surname><given-names>Kai</given-names></name><xref ref-type="aff" rid="aff1">*</xref></contrib><contrib contrib-type="author"><name><surname>Xu</surname><given-names>Yin-Chao</given-names></name><xref ref-type="aff" rid="aff1">*</xref></contrib><contrib contrib-type="author"><name><surname>Feng</surname><given-names>Chang-Sen</given-names></name><xref ref-type="aff" rid="aff1">*</xref></contrib><contrib contrib-type="author"><name><surname>Wan</surname><given-names>Zhuo-Yue</given-names></name><xref ref-type="aff" rid="aff3">‡</xref></contrib><contrib contrib-type="author"><name><surname>Cheng</surname><given-names>Vincent C.C.</given-names></name><xref ref-type="aff" rid="aff4">§</xref></contrib><contrib contrib-type="author"><name><surname>Yuen</surname><given-names>Kwok-Yung</given-names></name><xref ref-type="aff" rid="aff4">§</xref></contrib><aff id="aff1"><label>*</label>First Military Medical University, Guangzhou, People's Republic of China;</aff><aff id="aff2"><label>†</label>Center for Disease Control and Prevention of Guangzhou, Guangzhou, People's Republic of China;</aff><aff id="aff3"><label>‡</label>Center for Disease Control and Prevention of Guangdong Province, Guangzhou, People's Republic of China;</aff><aff id="aff4"><label>§</label>The University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China</aff></contrib-group><author-notes><corresp id="cor1">Address for correspondence: Xiao-Yan Che, Center of Laboratory, Zhujiang Hospital, First Military Medical University, Guangzhou 510282, People’s Republic of China; fax: 86-2061643592; email: <email xlink:href="linche@pub.guangzhou.gd.cn">linche@pub.guangzhou.gd.cn</email></corresp></author-notes><pub-date pub-type="ppub"><month>11</month><year>2004</year></pub-date><volume>10</volume><issue>11</issue><fpage>1947</fpage><lpage>1949</lpage><abstract><p>Serum samples from 317 patients with patients with severe acute respiratory syndrome (SARS) were tested for the nucleocapsid (N) protein of SARS-associated coronavirus, with sensitivities of 94% and 78% for the first 5 days and 6–10 days after onset, respectively. The specificity was 99.9%. N protein can be used as an early diagnostic maker for SARS.</p></abstract><kwd-group kwd-group-type="author"><title>Keywords: </title><kwd>SARS-CoV</kwd><kwd>nucleocapsid protein, monoclonal antibody, enzyme-linked immunosorbent assay, early diagnosis, severe acute respiratory syndrome, dispatch</kwd></kwd-group></article-meta></front><body><p>Early laboratory diagnosis of the severe acute respiratory syndrome–associated coronavirus (SARS-CoV) is one step in preventing recurrence of a global outbreak. The availability of the complete genomic sequence of SARS-CoV has facilitated the development of a variety of diagnostic tests for SARS (<xref ref-type="bibr" rid="R1"><italic>1</italic></xref>). Reverse transcription–polymerase chain reaction (RT-PCR) has been used as a rapid diagnostic test in most of the research centers during the last epidemic (<xref ref-type="bibr" rid="R2"><italic>2</italic></xref><italic>–</italic><xref ref-type="bibr" rid="R6"><italic>6</italic></xref>). However, early diagnosis of SARS remains a problem for nonresearch laboratories with little experience in molecular testing. We have developed an antigen-capture enzyme-linked immunosorbent assay (ELISA) based on monoclonal antibodies against the nucleocapsid (N) protein of SARS-CoV (<xref ref-type="bibr" rid="R7"><italic>7</italic></xref>), a predominant antigen produced in the infected cell-culture filtrate. High levels of circulating N protein can be detected in the serum samples of patients with SARS. We attempt to demonstrate the temporal profile of the N protein and antibodies in serum samples from a large cohort of patients with SARS during the acute and convalescent phases of the disease. Our findings suggest that detecting N protein in serum can be used as an early diagnostic marker for SARS.</p><sec><title>The Study</title><p>During the 2003 SARS epidemic in Guangzhou, 420 serum specimens were collected from 317 patients 1–90 days after the onset of symptoms. The condition of all patients was diagnosed according to the World Health Organization criteria and confirmed by seroconversion or a fourfold increase in antibody titer against SARS-CoV by means of immunofluorescent testing. The N protein–capture ELISA was performed (<xref ref-type="bibr" rid="R7"><italic>7</italic></xref>). Briefly, 100 µL of serum was added to the wells of a microtiter plate coated with a mixture of three anti-N protein monoclonal antibodies, and the plates were incubated at 37°C for 60 min. After the plates were washed, 100 µL of anti-N rabbit antiserum was added to the wells, and the plates were incubated at 37°C for 60 min. The wells were washed again and incubated for 1 h at 37°C with 100 µL of peroxidase-conjugated goat anti-rabbit immunoglobulin G (IgG). After the plates were washed, 100 µL of tetramethylbenzidine solution was added to each well. The experiments involving the use of serum samples from patients with SARS were performed within the safety cabinet of a biosafety level 2 laboratory.</p><p>The results for the 420 serum specimens tested by the N protein–capture ELISA are shown in <xref ref-type="fig" rid="F1">Figure 1</xref>. The N protein could be detected as early as day 1 and until day 18. In the 146 serum samples positive for N protein, the optical density (OD) value was highly variable from one sample to another on the same day. The sensitivity of detection was 94% (80 of 85 patients) with blood samples taken during the first 5 days and 78% (47 of 60 patients) for samples taken 6–10 days after onset of symptoms. The detection rate of N protein decreased to 27% on days 11–20 after onset of symptoms. Serum N protein was never detected beyond day 21. Using the same panel of the patient serum samples, we measured the N protein–specific IgG (SARS-CoV N-IgG) and SARS-CoV–specific IgG (SARS-CoV IgG) in serum samples by indirect ELISA, which progressively increased from day 7 onward (<xref ref-type="fig" rid="F2">Figure 2</xref>). With the appearance of antibodies, the N protein detection rate decreased from day 10 after the onset of symptoms. However, from day 7 to day 18, a high level of N protein was still detectable in the serum samples from 11 patients with a mean of OD values of 1.65 when the SARS-CoV N-IgG had already increased to a level with a mean OD value of 1.18.</p><fig id="F1" fig-type="figure" position="float"><label>Figure 1</label><caption><p>N protein detection in 420 serum samples from 317 patients with severe acute respiratory syndrome (SARS). Data represent the optical density at 450 nm (OD<sub>450</sub>) of undiluted serum samples. To establish the normal range of the N protein–capture enzyme-linked immunosorbent assay, serum specimens from 400 healthy blood donors were analyzed. The mean OD<sub>450</sub> for these specimens, as determined by the assay, was 0.078, with a standard deviation of 0.023. The cutoff OD<sub>450</sub> of the assay was then calculated as follows: cutoff = mean of OD<sub>450</sub> from 400 normal serum + 5 x standard deviations = 0.19. Solid line represents cutoff value. The result was considered positive if a sample yielded OD<sub>450</sub> above the cutoff.</p></caption><graphic xlink:href="04-0516-F1"></graphic></fig><fig id="F2" fig-type="figure" position="float"><label>Figure 2</label><caption><p>The profile of N protein detection in blood and antibody response to severe acute respiratory syndrome-associated coronavirus (SARS-CoV) from onset of symptoms to the convalescent phase. IgG, immunoglobulin G.</p></caption><graphic xlink:href="04-0516-F2"></graphic></fig><p>Serum samples from patients collected 4 years previously were used as negative controls. Patients thought to have cases of SARS on admission and later found to be uninfected by serologic testing, and healthcare workers who had close contact with SARS patients were tested for circulating N protein. Of the serum samples from non-SARS patients collected 4 years previously (n = 400), only one was weakly positive for N protein (OD = 0.288). We tested a total of 110 acute-phase serum samples from 105 patients, initially considered to have suspected SARS and later proven to be negative for SARS-CoV by serologic testing of convalescent-phase serum samples taken >28 days after onset of symptoms, and 315 serum samples from healthcare workers. All were negative for the N protein by capture ELISA. This finding resulted in a test specificity of 99.9% (1 of 825).</p></sec><sec sec-type="conclusions"><title>Conclusions</title><p>Our results suggest that N protein in the serum samples of SARS patients can be detected as early as day 1 after disease onset. Although the level of circulating N protein was highly variable from one person to another from day 1 to day 18, development of SARS-CoV N-IgG appears not to be affected by N protein during the acute phase of the infection, 7 days after the onset of symptoms. The positive detection rate of N protein in serum samples within the first 10 days of infection is higher than that detected by RT-PCR (<xref ref-type="bibr" rid="R8"><italic>8</italic></xref><italic>,</italic><xref ref-type="bibr" rid="R9"><italic>9</italic></xref>). Furthermore, the variation in the reported sensitivity and specificity of RT-PCR may be related to the lack of standardization of the assay and the specimen collection (<xref ref-type="bibr" rid="R6"><italic>6</italic></xref>). Therefore, this viral antigen-capture ELISA may have greater sensitivity, specificity, and ease and reliability of in-use performance than the nucleic acid amplification assay. Further comparative studies with nucleic acid amplification tests should be undertaken at clinical laboratories serving acute-care hospitals where rapid SARS diagnosis is vital.</p></sec></body><back><fn-group><fn fn-type="citation"><p><italic>Suggested citation for this article</italic>: Che X-Y, Hao W, Wang Y, Di B, Yin K, Xu Y-C, et al. Nucleocapsid protein as early diagnostic marker for SARS. Emerg Infect Dis. [serial on the Internet]. 2004 Nov [<italic>date cited</italic>]. <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.3201/eid1011.040516">http://dx.doi.org/10.3201/eid1011.040516</ext-link></p></fn></fn-group><ack><title>Acknowledgments</title><p>We thank Rongchang Chen and Yuanda Xu for providing the clinical data for analysis.</p><p>This work was supported by the special programs of SARS from the Ministry of Science and Technology of the People's Republic of China and the Research Project of Guangdong Province for SARS Prevention and Treatment.</p></ack><bio><p>Dr. Che is an immunologist and professor at First Military Medical University, Guangzhou, China. 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