title: Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Virology, Erasmus Medical Centre, PO Box 1738, 3000 DR, Rotterdam, Netherlands. t.kuiken@erasmusmc.nl <t.kuiken@erasmusmc.nl>
authors.forename: Thijs
authors.initials: T
authors.lastname: Kuiken
authors.forename: Ron A M
authors.initials: RA
authors.lastname: Fouchier
authors.forename: Martin
authors.initials: M
authors.lastname: Schutten
authors.forename: Guus F
authors.initials: GF
authors.lastname: Rimmelzwaan
authors.forename: Geert
authors.initials: G
authors.lastname: van Amerongen
authors.forename: Debby
authors.initials: D
authors.lastname: van Riel
authors.forename: Jon D
authors.initials: JD
authors.lastname: Laman
authors.forename: Ton
authors.initials: T
authors.lastname: de Jong
authors.forename: Gerard
authors.initials: G
authors.lastname: van Doornum
authors.forename: Wilina
authors.initials: W
authors.lastname: Lim
authors.forename: Ai Ee
authors.initials: AE
authors.lastname: Ling
authors.forename: Paul K S
authors.initials: PK
authors.lastname: Chan
authors.forename: John S
authors.initials: JS
authors.lastname: Tam
authors.forename: Maria C
authors.initials: MC
authors.lastname: Zambon
authors.forename: Robin
authors.initials: R
authors.lastname: Gopal
authors.forename: Christian
authors.initials: C
authors.lastname: Drosten
authors.forename: Sylvie
authors.initials: S
authors.lastname: van der Werf
authors.forename: Nicolas
authors.initials: N
authors.lastname: Escriou
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Manuguerra
authors.forename: Klaus
authors.initials: K
authors.lastname: Stöhr
authors.forename: J S Malik
authors.initials: JS
authors.lastname: Peiris
authors.forename: Albert D M E
authors.initials: AD
authors.lastname: Osterhaus
mesh_terms: D000818:Animals; D002681:China / Q000453:epidemiology; D021821:Communicable Diseases, Emerging / Q000453:epidemiology / Q000821:virology; D004195:Disease Models, Animal; D004196:Disease Outbreaks; D014943:Global Health; D006801:Humans; D008252:Macaca fascicularis; D011650:Pulmonary Alveoli / Q000473:pathology / Q000821:virology; D045473:Severe acute respiratory syndrome-related coronavirus / Q000302:isolation & purification* / Q000472:pathogenicity; D045169:Severe Acute Respiratory Syndrome / Q000453:epidemiology / Q000473:pathology / Q000821:virology*