Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome
Thijs Kuiken, Ron A M Fouchier, Martin Schutten, Guus F Rimmelzwaan, Geert van Amerongen, Debby van Riel, Jon D Laman, Ton de Jong, Gerard van Doornum, Wilina Lim, Ai Ee Ling, Paul K S Chan, John S Tam, Maria C Zambon, Robin Gopal, Christian Drosten, Sylvie van der Werf, Nicolas Escriou, Jean-Claude Manuguerra, Klaus Stöhr, J S Malik Peiris, Albert D M E Osterhaus, Thijs Kuiken, Ron A M Fouchier, Martin Schutten, Guus F Rimmelzwaan, Geert van Amerongen, Debby van Riel, Jon D Laman, Ton de Jong, Gerard van Doornum, Wilina Lim, Ai Ee Ling, Paul K S Chan, John S Tam, Maria C Zambon, Robin Gopal, Christian Drosten, Sylvie van der Werf, Nicolas Escriou, Jean-Claude Manuguerra, Klaus Stöhr, J S Malik Peiris, Albert D M E Osterhaus
Abstract
Background: The worldwide outbreak of severe acute respiratory syndrome (SARS) is associated with a newly discovered coronavirus, SARS-associated coronavirus (SARS-CoV). We did clinical and experimental studies to assess the role of this virus in the cause of SARS.
Methods: We tested clinical and postmortem samples from 436 SARS patients in six countries for infection with SARS-CoV, human metapneumovirus, and other respiratory pathogens. We infected four cynomolgus macaques (Macaca fascicularis) with SARS-CoV in an attempt to replicate SARS and did necropsies on day 6 after infection.
Findings: SARS-CoV infection was diagnosed in 329 (75%) of 436 patients fitting the case definition of SARS; human metapneumovirus was diagnosed in 41 (12%) of 335, and other respiratory pathogens were diagnosed only sporadically. SARS-CoV was, therefore, the most likely causal agent of SARS. The four SARS-CoV-infected macaques excreted SARS-CoV from nose, mouth, and pharynx from 2 days after infection. Three of four macaques developed diffuse alveolar damage, similar to that in SARS patients, and characterised by epithelial necrosis, serosanguineous exudate, formation of hyaline membranes, type 2 pneumocyte hyperplasia, and the presence of syncytia. SARS-CoV was detected in pneumonic areas by virus isolation and RT-PCR, and was localised to alveolar epithelial cells and syncytia by immunohistochemistry and transmission electron microscopy.
Interpretation: Replication in SARS-CoV-infected macaques of pneumonia similar to that in human beings with SARS, combined with the high prevalence of SARS-CoV infection in SARS patients, fulfill the criteria required to prove that SARS-CoV is the primary cause of SARS.
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