Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance
Identifieur interne : 001B54 ( PascalFrancis/Curation ); précédent : 001B53; suivant : 001B55Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance
Auteurs : YUNWEN HU [République populaire de Chine] ; SHUIHUA LU [République populaire de Chine] ; ZHIGANG SONG [République populaire de Chine] ; WEI WANG [République populaire de Chine] ; PEI HAO [République populaire de Chine] ; JIANHUA LI [République populaire de Chine] ; XIAONAN ZHANG [République populaire de Chine] ; Hui-Ling Yen [Hong Kong] ; BISHENG SHI [République populaire de Chine] ; TAO LI [République populaire de Chine] ; WENCAI GUAN [République populaire de Chine] ; LEI XU [République populaire de Chine] ; YI LIU [République populaire de Chine] ; SEN WANG [République populaire de Chine] ; XIAOLING ZHANG [République populaire de Chine] ; DI TIAN [République populaire de Chine] ; ZHAOQIN ZHU [République populaire de Chine] ; JING HE [République populaire de Chine] ; KAI HUANG [République populaire de Chine] ; HUIJIE CHEN [République populaire de Chine] ; LULU ZHENG [République populaire de Chine] ; XUAN LI [République populaire de Chine] ; JIE PING [République populaire de Chine] ; BIN KANG [République populaire de Chine] ; XIUHONG XI [République populaire de Chine] ; LIJUN ZHA [République populaire de Chine] ; YIXUE LI [République populaire de Chine] ; ZHIYONG ZHANG [République populaire de Chine] ; Malik Peiris [Hong Kong] ; ZHENGHONG YUAN [République populaire de Chine]Source :
- Lancet : (British edition) [ 0140-6736 ] ; 2013.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Association, Homme, Maladie, Médecine.
English descriptors
- KwdEn :
Abstract
Background On March 30, a novel influenza A subtype H7N9 virus (A/H7N9) was detected in patients with severe respiratory disease in eastern China. Virological factors associated with a poor clinical outcome for this virus remain unclear. We quantified the viral load and analysed antiviral resistance mutations in specimens from patients with A/H7N9. Methods We studied 14 patients with A/H7N9 disease admitted to the Shanghai Public Health Clinical Centre (SPHCC), China, between April 4, and April 20, 2013, who were given antiviral treatment (oseltamivir or peramivir) for less than 2 days before admission. We investigated the viral load in throat, stool, serum, and urine specimens obtained sequentially from these patients. We also sequenced viral RNA from these specimens to study the mutations associated with resistance to neuraminidase inhibitors and their association with disease outcome. Findings All patients developed pneumonia, seven of them required mechanical ventilation, and three of them further deteriorated to become dependent on extracorporeal membrane oxygenation (ECMO), two of whom died. Antiviral treatment was associated with a reduction of viral load in throat swab specimens in 11 surviving patients. Three patients with persistently high viral load in the throat in spite of antiviral therapy became ECMO dependent. An Arg292Lys mutation in the virus neuraminidase (NA) gene known to confer resistance to both zanamivir and oseltamivir was identified in two of these patients, both also received corticosteroid treatment. In one of them, wild-type sequence Arg292 was noted 2 days after start of antiviral treatment, and the resistant mutant Lys292 dominated 9 days after start of treatment. Interpretation Reduction of viral load following antiviral treatment correlated with improved outcome. Emergence of NA Arg292Lys mutation in two patients who also received corticosteroid treatment led to treatment failure and a poor clinical outcome. The emergence of antiviral resistance in A/H7N9 viruses, especially in patients receiving corticosteroid therapy, is concerning, needs to be closely monitored, and considered in pandemic preparedness planning. Funding National Megaprojects of China for Infectious Diseases, Shanghai Municipal Health and Family Planning Commission, the National Key Basic Research Program of China, Ministry of Science and Technology, and National Natural Science Foundation of China.
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<author><name sortKey="Sen Wang" sort="Sen Wang" uniqKey="Sen Wang" last="Sen Wang">SEN WANG</name>
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<author><name sortKey="Di Tian" sort="Di Tian" uniqKey="Di Tian" last="Di Tian">DI TIAN</name>
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<author><name sortKey="Zhaoqin Zhu" sort="Zhaoqin Zhu" uniqKey="Zhaoqin Zhu" last="Zhaoqin Zhu">ZHAOQIN ZHU</name>
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<author><name sortKey="Jing He" sort="Jing He" uniqKey="Jing He" last="Jing He">JING HE</name>
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<author><name sortKey="Kai Huang" sort="Kai Huang" uniqKey="Kai Huang" last="Kai Huang">KAI HUANG</name>
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<author><name sortKey="Huijie Chen" sort="Huijie Chen" uniqKey="Huijie Chen" last="Huijie Chen">HUIJIE CHEN</name>
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<author><name sortKey="Lulu Zheng" sort="Lulu Zheng" uniqKey="Lulu Zheng" last="Lulu Zheng">LULU ZHENG</name>
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<author><name sortKey="Xuan Li" sort="Xuan Li" uniqKey="Xuan Li" last="Xuan Li">XUAN LI</name>
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<author><name sortKey="Jie Ping" sort="Jie Ping" uniqKey="Jie Ping" last="Jie Ping">JIE PING</name>
<affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Shanghai Medical College of Fudan University, Shanghai, China; Pathogen Diagnostic Centre, Institute Pasteur of Shanghai, Chinese Academy of Sciences</s1>
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<author><name sortKey="Bin Kang" sort="Bin Kang" uniqKey="Bin Kang" last="Bin Kang">BIN KANG</name>
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<author><name sortKey="Xiuhong Xi" sort="Xiuhong Xi" uniqKey="Xiuhong Xi" last="Xiuhong Xi">XIUHONG XI</name>
<affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Department of Infectious Diseases, Shanghai Public Health Clinical Center</s1>
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<author><name sortKey="Lijun Zha" sort="Lijun Zha" uniqKey="Lijun Zha" last="Lijun Zha">LIJUN ZHA</name>
<affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Department of Infectious Diseases, Shanghai Public Health Clinical Center</s1>
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<author><name sortKey="Yixue Li" sort="Yixue Li" uniqKey="Yixue Li" last="Yixue Li">YIXUE LI</name>
<affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Shanghai Centre for Bioinformation Technology</s1>
<s2>Shanghai</s2>
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<author><name sortKey="Zhiyong Zhang" sort="Zhiyong Zhang" uniqKey="Zhiyong Zhang" last="Zhiyong Zhang">ZHIYONG ZHANG</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Key Lab of Medical Molecular Virology, Department of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center</s1>
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</affiliation>
</author>
<author><name sortKey="Peiris, Malik" sort="Peiris, Malik" uniqKey="Peiris M" first="Malik" last="Peiris">Malik Peiris</name>
<affiliation wicri:level="1"><inist:fA14 i1="06"><s1>State Key Laboratory of Emerging Infectious Disease, School of Public Health, University of Hong Kong</s1>
<s3>HKG</s3>
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</inist:fA14>
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</affiliation>
</author>
<author><name sortKey="Zhenghong Yuan" sort="Zhenghong Yuan" uniqKey="Zhenghong Yuan" last="Zhenghong Yuan">ZHENGHONG YUAN</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Key Lab of Medical Molecular Virology, School of Basic Medical Science</s1>
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</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">INIST</idno>
<idno type="inist">13-0220415</idno>
<date when="2013">2013</date>
<idno type="stanalyst">PASCAL 13-0220415 INIST</idno>
<idno type="RBID">Pascal:13-0220415</idno>
<idno type="wicri:Area/PascalFrancis/Corpus">000273</idno>
<idno type="wicri:Area/PascalFrancis/Curation">001B54</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance</title>
<author><name sortKey="Yunwen Hu" sort="Yunwen Hu" uniqKey="Yunwen Hu" last="Yunwen Hu">YUNWEN HU</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Key Lab of Medical Molecular Virology, Department of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center</s1>
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</affiliation>
</author>
<author><name sortKey="Shuihua Lu" sort="Shuihua Lu" uniqKey="Shuihua Lu" last="Shuihua Lu">SHUIHUA LU</name>
<affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Department of Infectious Diseases, Shanghai Public Health Clinical Center</s1>
<s3>CHN</s3>
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</affiliation>
</author>
<author><name sortKey="Zhigang Song" sort="Zhigang Song" uniqKey="Zhigang Song" last="Zhigang Song">ZHIGANG SONG</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Key Lab of Medical Molecular Virology, Department of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center</s1>
<s3>CHN</s3>
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</affiliation>
</author>
<author><name sortKey="Wei Wang" sort="Wei Wang" uniqKey="Wei Wang" last="Wei Wang">WEI WANG</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Key Lab of Medical Molecular Virology, Department of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center</s1>
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</affiliation>
</author>
<author><name sortKey="Pei Hao" sort="Pei Hao" uniqKey="Pei Hao" last="Pei Hao">PEI HAO</name>
<affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Shanghai Medical College of Fudan University, Shanghai, China; Pathogen Diagnostic Centre, Institute Pasteur of Shanghai, Chinese Academy of Sciences</s1>
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</affiliation>
</author>
<author><name sortKey="Jianhua Li" sort="Jianhua Li" uniqKey="Jianhua Li" last="Jianhua Li">JIANHUA LI</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Key Lab of Medical Molecular Virology, School of Basic Medical Science</s1>
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</affiliation>
</author>
<author><name sortKey="Xiaonan Zhang" sort="Xiaonan Zhang" uniqKey="Xiaonan Zhang" last="Xiaonan Zhang">XIAONAN ZHANG</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Key Lab of Medical Molecular Virology, Department of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center</s1>
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</affiliation>
</author>
<author><name sortKey="Yen, Hui Ling" sort="Yen, Hui Ling" uniqKey="Yen H" first="Hui-Ling" last="Yen">Hui-Ling Yen</name>
<affiliation wicri:level="1"><inist:fA14 i1="06"><s1>State Key Laboratory of Emerging Infectious Disease, School of Public Health, University of Hong Kong</s1>
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<sZ>8 aut.</sZ>
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</affiliation>
</author>
<author><name sortKey="Bisheng Shi" sort="Bisheng Shi" uniqKey="Bisheng Shi" last="Bisheng Shi">BISHENG SHI</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Key Lab of Medical Molecular Virology, Department of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center</s1>
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</affiliation>
</author>
<author><name sortKey="Tao Li" sort="Tao Li" uniqKey="Tao Li" last="Tao Li">TAO LI</name>
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<sZ>2 aut.</sZ>
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<country>République populaire de Chine</country>
</affiliation>
</author>
<author><name sortKey="Wencai Guan" sort="Wencai Guan" uniqKey="Wencai Guan" last="Wencai Guan">WENCAI GUAN</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Key Lab of Medical Molecular Virology, Department of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center</s1>
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</affiliation>
</author>
<author><name sortKey="Lei Xu" sort="Lei Xu" uniqKey="Lei Xu" last="Lei Xu">LEI XU</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Key Lab of Medical Molecular Virology, Department of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center</s1>
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</affiliation>
</author>
<author><name sortKey="Yi Liu" sort="Yi Liu" uniqKey="Yi Liu" last="Yi Liu">YI LIU</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Key Lab of Medical Molecular Virology, Department of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center</s1>
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</affiliation>
</author>
<author><name sortKey="Sen Wang" sort="Sen Wang" uniqKey="Sen Wang" last="Sen Wang">SEN WANG</name>
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<country>République populaire de Chine</country>
</affiliation>
</author>
<author><name sortKey="Xiaoling Zhang" sort="Xiaoling Zhang" uniqKey="Xiaoling Zhang" last="Xiaoling Zhang">XIAOLING ZHANG</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Key Lab of Medical Molecular Virology, Department of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center</s1>
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<country>République populaire de Chine</country>
</affiliation>
</author>
<author><name sortKey="Di Tian" sort="Di Tian" uniqKey="Di Tian" last="Di Tian">DI TIAN</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Key Lab of Medical Molecular Virology, Department of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center</s1>
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</affiliation>
</author>
<author><name sortKey="Zhaoqin Zhu" sort="Zhaoqin Zhu" uniqKey="Zhaoqin Zhu" last="Zhaoqin Zhu">ZHAOQIN ZHU</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Key Lab of Medical Molecular Virology, Department of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center</s1>
<s3>CHN</s3>
<sZ>1 aut.</sZ>
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</affiliation>
</author>
<author><name sortKey="Jing He" sort="Jing He" uniqKey="Jing He" last="Jing He">JING HE</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Key Lab of Medical Molecular Virology, Department of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center</s1>
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</affiliation>
</author>
<author><name sortKey="Kai Huang" sort="Kai Huang" uniqKey="Kai Huang" last="Kai Huang">KAI HUANG</name>
<affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Shanghai Centre for Bioinformation Technology</s1>
<s2>Shanghai</s2>
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<sZ>19 aut.</sZ>
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</affiliation>
</author>
<author><name sortKey="Huijie Chen" sort="Huijie Chen" uniqKey="Huijie Chen" last="Huijie Chen">HUIJIE CHEN</name>
<affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Shanghai Centre for Bioinformation Technology</s1>
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<sZ>19 aut.</sZ>
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<country>République populaire de Chine</country>
</affiliation>
</author>
<author><name sortKey="Lulu Zheng" sort="Lulu Zheng" uniqKey="Lulu Zheng" last="Lulu Zheng">LULU ZHENG</name>
<affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Shanghai Centre for Bioinformation Technology</s1>
<s2>Shanghai</s2>
<s3>CHN</s3>
<sZ>19 aut.</sZ>
<sZ>20 aut.</sZ>
<sZ>21 aut.</sZ>
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<country>République populaire de Chine</country>
</affiliation>
</author>
<author><name sortKey="Xuan Li" sort="Xuan Li" uniqKey="Xuan Li" last="Xuan Li">XUAN LI</name>
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<sZ>19 aut.</sZ>
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<sZ>21 aut.</sZ>
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<country>République populaire de Chine</country>
</affiliation>
</author>
<author><name sortKey="Jie Ping" sort="Jie Ping" uniqKey="Jie Ping" last="Jie Ping">JIE PING</name>
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<s3>CHN</s3>
<sZ>5 aut.</sZ>
<sZ>23 aut.</sZ>
</inist:fA14>
<country>République populaire de Chine</country>
</affiliation>
</author>
<author><name sortKey="Bin Kang" sort="Bin Kang" uniqKey="Bin Kang" last="Bin Kang">BIN KANG</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Key Lab of Medical Molecular Virology, Department of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center</s1>
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</affiliation>
</author>
<author><name sortKey="Xiuhong Xi" sort="Xiuhong Xi" uniqKey="Xiuhong Xi" last="Xiuhong Xi">XIUHONG XI</name>
<affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Department of Infectious Diseases, Shanghai Public Health Clinical Center</s1>
<s3>CHN</s3>
<sZ>2 aut.</sZ>
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<sZ>25 aut.</sZ>
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<country>République populaire de Chine</country>
</affiliation>
</author>
<author><name sortKey="Lijun Zha" sort="Lijun Zha" uniqKey="Lijun Zha" last="Lijun Zha">LIJUN ZHA</name>
<affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Department of Infectious Diseases, Shanghai Public Health Clinical Center</s1>
<s3>CHN</s3>
<sZ>2 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>25 aut.</sZ>
<sZ>26 aut.</sZ>
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<country>République populaire de Chine</country>
</affiliation>
</author>
<author><name sortKey="Yixue Li" sort="Yixue Li" uniqKey="Yixue Li" last="Yixue Li">YIXUE LI</name>
<affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Shanghai Centre for Bioinformation Technology</s1>
<s2>Shanghai</s2>
<s3>CHN</s3>
<sZ>19 aut.</sZ>
<sZ>20 aut.</sZ>
<sZ>21 aut.</sZ>
<sZ>22 aut.</sZ>
<sZ>27 aut.</sZ>
</inist:fA14>
<country>République populaire de Chine</country>
</affiliation>
</author>
<author><name sortKey="Zhiyong Zhang" sort="Zhiyong Zhang" uniqKey="Zhiyong Zhang" last="Zhiyong Zhang">ZHIYONG ZHANG</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Key Lab of Medical Molecular Virology, Department of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center</s1>
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<sZ>1 aut.</sZ>
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<country>République populaire de Chine</country>
</affiliation>
</author>
<author><name sortKey="Peiris, Malik" sort="Peiris, Malik" uniqKey="Peiris M" first="Malik" last="Peiris">Malik Peiris</name>
<affiliation wicri:level="1"><inist:fA14 i1="06"><s1>State Key Laboratory of Emerging Infectious Disease, School of Public Health, University of Hong Kong</s1>
<s3>HKG</s3>
<sZ>8 aut.</sZ>
<sZ>29 aut.</sZ>
</inist:fA14>
<country>Hong Kong</country>
</affiliation>
</author>
<author><name sortKey="Zhenghong Yuan" sort="Zhenghong Yuan" uniqKey="Zhenghong Yuan" last="Zhenghong Yuan">ZHENGHONG YUAN</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Key Lab of Medical Molecular Virology, School of Basic Medical Science</s1>
<s3>CHN</s3>
<sZ>6 aut.</sZ>
<sZ>14 aut.</sZ>
<sZ>30 aut.</sZ>
</inist:fA14>
<country>République populaire de Chine</country>
</affiliation>
</author>
</analytic>
<series><title level="j" type="main">Lancet : (British edition)</title>
<title level="j" type="abbreviated">Lancet : (Br. ed.)</title>
<idno type="ISSN">0140-6736</idno>
<imprint><date when="2013">2013</date>
</imprint>
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<title level="j" type="abbreviated">Lancet : (Br. ed.)</title>
<idno type="ISSN">0140-6736</idno>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiviral</term>
<term>Association</term>
<term>Complication</term>
<term>Disease</term>
<term>Emergence</term>
<term>Epidemiology</term>
<term>Human</term>
<term>Influenza A virus</term>
<term>Medicine</term>
<term>Resistance</term>
<term>Viral load</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr"><term>Association</term>
<term>Complication</term>
<term>Homme</term>
<term>Maladie</term>
<term>Virus grippal A</term>
<term>Charge virale</term>
<term>Emergence</term>
<term>Epidémiologie</term>
<term>Antiviral</term>
<term>Résistance</term>
<term>Médecine</term>
</keywords>
<keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Association</term>
<term>Homme</term>
<term>Maladie</term>
<term>Médecine</term>
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<front><div type="abstract" xml:lang="en">Background On March 30, a novel influenza A subtype H7N9 virus (A/H7N9) was detected in patients with severe respiratory disease in eastern China. Virological factors associated with a poor clinical outcome for this virus remain unclear. We quantified the viral load and analysed antiviral resistance mutations in specimens from patients with A/H7N9. Methods We studied 14 patients with A/H7N9 disease admitted to the Shanghai Public Health Clinical Centre (SPHCC), China, between April 4, and April 20, 2013, who were given antiviral treatment (oseltamivir or peramivir) for less than 2 days before admission. We investigated the viral load in throat, stool, serum, and urine specimens obtained sequentially from these patients. We also sequenced viral RNA from these specimens to study the mutations associated with resistance to neuraminidase inhibitors and their association with disease outcome. Findings All patients developed pneumonia, seven of them required mechanical ventilation, and three of them further deteriorated to become dependent on extracorporeal membrane oxygenation (ECMO), two of whom died. Antiviral treatment was associated with a reduction of viral load in throat swab specimens in 11 surviving patients. Three patients with persistently high viral load in the throat in spite of antiviral therapy became ECMO dependent. An Arg292Lys mutation in the virus neuraminidase (NA) gene known to confer resistance to both zanamivir and oseltamivir was identified in two of these patients, both also received corticosteroid treatment. In one of them, wild-type sequence Arg292 was noted 2 days after start of antiviral treatment, and the resistant mutant Lys292 dominated 9 days after start of treatment. Interpretation Reduction of viral load following antiviral treatment correlated with improved outcome. Emergence of NA Arg292Lys mutation in two patients who also received corticosteroid treatment led to treatment failure and a poor clinical outcome. The emergence of antiviral resistance in A/H7N9 viruses, especially in patients receiving corticosteroid therapy, is concerning, needs to be closely monitored, and considered in pandemic preparedness planning. Funding National Megaprojects of China for Infectious Diseases, Shanghai Municipal Health and Family Planning Commission, the National Key Basic Research Program of China, Ministry of Science and Technology, and National Natural Science Foundation of China.</div>
</front>
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<fA06><s2>9885</s2>
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<fA08 i1="01" i2="1" l="ENG"><s1>Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance</s1>
</fA08>
<fA11 i1="01" i2="1"><s1>YUNWEN HU</s1>
</fA11>
<fA11 i1="02" i2="1"><s1>SHUIHUA LU</s1>
</fA11>
<fA11 i1="03" i2="1"><s1>ZHIGANG SONG</s1>
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<fA11 i1="04" i2="1"><s1>WEI WANG</s1>
</fA11>
<fA11 i1="05" i2="1"><s1>PEI HAO</s1>
</fA11>
<fA11 i1="06" i2="1"><s1>JIANHUA LI</s1>
</fA11>
<fA11 i1="07" i2="1"><s1>XIAONAN ZHANG</s1>
</fA11>
<fA11 i1="08" i2="1"><s1>YEN (Hui-Ling)</s1>
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<fA11 i1="09" i2="1"><s1>BISHENG SHI</s1>
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<fA11 i1="10" i2="1"><s1>TAO LI</s1>
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<fA11 i1="11" i2="1"><s1>WENCAI GUAN</s1>
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<fA11 i1="13" i2="1"><s1>YI LIU</s1>
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<fA11 i1="14" i2="1"><s1>SEN WANG</s1>
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<fA11 i1="15" i2="1"><s1>XIAOLING ZHANG</s1>
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<fA11 i1="16" i2="1"><s1>DI TIAN</s1>
</fA11>
<fA11 i1="17" i2="1"><s1>ZHAOQIN ZHU</s1>
</fA11>
<fA11 i1="18" i2="1"><s1>JING HE</s1>
</fA11>
<fA11 i1="19" i2="1"><s1>KAI HUANG</s1>
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<fA11 i1="20" i2="1"><s1>HUIJIE CHEN</s1>
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<fA11 i1="21" i2="1"><s1>LULU ZHENG</s1>
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<fA11 i1="22" i2="1"><s1>XUAN LI</s1>
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<fA11 i1="24" i2="1"><s1>BIN KANG</s1>
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<fA11 i1="25" i2="1"><s1>XIUHONG XI</s1>
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<fA11 i1="26" i2="1"><s1>LIJUN ZHA</s1>
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<fA11 i1="27" i2="1"><s1>YIXUE LI</s1>
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<fA11 i1="28" i2="1"><s1>ZHIYONG ZHANG</s1>
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<fA11 i1="30" i2="1"><s1>ZHENGHONG YUAN</s1>
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<fA14 i1="01"><s1>Key Lab of Medical Molecular Virology, Department of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center</s1>
<s3>CHN</s3>
<sZ>1 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>4 aut.</sZ>
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<sZ>24 aut.</sZ>
<sZ>28 aut.</sZ>
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<fA14 i1="02"><s1>Key Lab of Medical Molecular Virology, School of Basic Medical Science</s1>
<s3>CHN</s3>
<sZ>6 aut.</sZ>
<sZ>14 aut.</sZ>
<sZ>30 aut.</sZ>
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<fA14 i1="03"><s1>Department of Infectious Diseases, Shanghai Public Health Clinical Center</s1>
<s3>CHN</s3>
<sZ>2 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>25 aut.</sZ>
<sZ>26 aut.</sZ>
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<fA14 i1="04"><s1>Shanghai Medical College of Fudan University, Shanghai, China; Pathogen Diagnostic Centre, Institute Pasteur of Shanghai, Chinese Academy of Sciences</s1>
<s2>Shanghai</s2>
<s3>CHN</s3>
<sZ>5 aut.</sZ>
<sZ>23 aut.</sZ>
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<fA14 i1="05"><s1>Shanghai Centre for Bioinformation Technology</s1>
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<sZ>20 aut.</sZ>
<sZ>21 aut.</sZ>
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<fA14 i1="06"><s1>State Key Laboratory of Emerging Infectious Disease, School of Public Health, University of Hong Kong</s1>
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<fC01 i1="01" l="ENG"><s0>Background On March 30, a novel influenza A subtype H7N9 virus (A/H7N9) was detected in patients with severe respiratory disease in eastern China. Virological factors associated with a poor clinical outcome for this virus remain unclear. We quantified the viral load and analysed antiviral resistance mutations in specimens from patients with A/H7N9. Methods We studied 14 patients with A/H7N9 disease admitted to the Shanghai Public Health Clinical Centre (SPHCC), China, between April 4, and April 20, 2013, who were given antiviral treatment (oseltamivir or peramivir) for less than 2 days before admission. We investigated the viral load in throat, stool, serum, and urine specimens obtained sequentially from these patients. We also sequenced viral RNA from these specimens to study the mutations associated with resistance to neuraminidase inhibitors and their association with disease outcome. Findings All patients developed pneumonia, seven of them required mechanical ventilation, and three of them further deteriorated to become dependent on extracorporeal membrane oxygenation (ECMO), two of whom died. Antiviral treatment was associated with a reduction of viral load in throat swab specimens in 11 surviving patients. Three patients with persistently high viral load in the throat in spite of antiviral therapy became ECMO dependent. An Arg292Lys mutation in the virus neuraminidase (NA) gene known to confer resistance to both zanamivir and oseltamivir was identified in two of these patients, both also received corticosteroid treatment. In one of them, wild-type sequence Arg292 was noted 2 days after start of antiviral treatment, and the resistant mutant Lys292 dominated 9 days after start of treatment. Interpretation Reduction of viral load following antiviral treatment correlated with improved outcome. Emergence of NA Arg292Lys mutation in two patients who also received corticosteroid treatment led to treatment failure and a poor clinical outcome. The emergence of antiviral resistance in A/H7N9 viruses, especially in patients receiving corticosteroid therapy, is concerning, needs to be closely monitored, and considered in pandemic preparedness planning. Funding National Megaprojects of China for Infectious Diseases, Shanghai Municipal Health and Family Planning Commission, the National Key Basic Research Program of China, Ministry of Science and Technology, and National Natural Science Foundation of China.</s0>
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