{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T11:39:31Z","timestamp":1793360371509,"version":"4.5.0"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2020,12,1]],"date-time":"2020-12-01T00:00:00Z","timestamp":1606780800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":["www.atsjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Host inflammatory responses have been strongly associated with adverse outcomes in critically ill patients, but the biologic underpinnings of such heterogeneous responses have not been defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>We examined whether respiratory tract microbiome profiles are associated with host inflammation and clinical outcomes of acute respiratory failure.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We collected oral swabs, endotracheal aspirates (ETAs), and plasma samples from mechanically ventilated patients. We performed 16S ribosomal RNA gene sequencing to characterize upper and lower respiratory tract microbiota and classified patients into host-response subphenotypes on the basis of clinical variables and plasma biomarkers of innate immunity and inflammation. We derived diversity metrics and composition clusters with Dirichlet multinomial models and examined our data for associations with subphenotypes and clinical outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>Oral and ETA microbial communities from 301 mechanically ventilated subjects had substantial heterogeneity in \u03b1 and \u03b2 diversity. Dirichlet multinomial models revealed a cluster with low \u03b1 diversity and enrichment for pathogens (e.g., high Staphylococcus or Pseudomonadaceae relative abundance) in 35% of ETA samples, associated with a hyperinflammatory subphenotype, worse 30-day survival, and longer time to liberation from mechanical ventilation (adjusted P\u2009&amp;lt;\u20090.05), compared with patients with higher \u03b1 diversity and relative abundance of typical oral microbiota. Patients with evidence of dysbiosis (low \u03b1 diversity and low relative abundance of \u201cprotective\u201d oral-origin commensal bacteria) in both oral and ETA samples (17%, combined dysbiosis) had significantly worse 30-day survival and longer time to liberation from mechanical ventilation than patients without dysbiosis (55%; adjusted P\u2009&amp;lt;\u20090.05).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Respiratory tract dysbiosis may represent an important, modifiable contributor to patient-level heterogeneity in systemic inflammatory responses and clinical outcomes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201912-2441oc","type":"journal-article","created":{"date-parts":[[2020,7,27]],"date-time":"2020-07-27T18:13:18Z","timestamp":1595873598000},"page":"1666-1677","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":117,"title":["Respiratory Tract Dysbiosis Is Associated with Worse Outcomes in Mechanically Ventilated Patients"],"prefix":"10.1093","volume":"202","author":[{"given":"Georgios D.","family":"Kitsios","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, School of Medicine and University of Pittsburgh Medical Center"},{"name":"Center for Medicine and the Microbiome"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haopu","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, School of Medicine and University of Pittsburgh Medical Center"},{"name":"Department of Computational and Systems Biology, and"},{"name":"Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Libing","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, School of Medicine and University of Pittsburgh Medical Center"},{"name":"Center for Medicine and the Microbiome"},{"name":"Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shulin","family":"Qin","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, School of Medicine and University of Pittsburgh Medical Center"},{"name":"Center for Medicine and the Microbiome"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Fitch","sequence":"additional","affiliation":[{"name":"Center for Medicine and the Microbiome"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Hong","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, School of Medicine and University of Pittsburgh Medical Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Fair","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, School of Medicine and University of Pittsburgh Medical Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Evankovich","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, School of Medicine and University of Pittsburgh Medical Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Bain","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, School of Medicine and University of Pittsburgh Medical Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faraaz","family":"Shah","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, School of Medicine and University of Pittsburgh Medical Center"},{"name":"School of Medicine, Tsinghua University, Beijing, China; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelvin","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Medicine and the Microbiome"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Meth\u00e9","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, School of Medicine and University of Pittsburgh Medical Center"},{"name":"Center for Medicine and the Microbiome"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panayiotis V.","family":"Benos","sequence":"additional","affiliation":[{"name":"Department of Computational and Systems Biology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Morris","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, School of Medicine and University of Pittsburgh Medical Center"},{"name":"Center for Medicine and the Microbiome"},{"name":"Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan J.","family":"McVerry","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, School of Medicine and University of Pittsburgh Medical Center"},{"name":"Center for Medicine and the Microbiome"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,12,1]]},"reference":[{"key":"2026030321522035300_bib1","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/S2213-2600(17)30188-1","article-title":"Clinical trials in acute respiratory distress syndrome: challenges and opportunities","volume":"5","author":"Matthay","year":"2017","journal-title":"Lancet Respir Med"},{"key":"2026030321522035300_bib2","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/S2213-2600(17)30187-X","article-title":"Novel translational approaches to the search for precision therapies for acute respiratory distress syndrome","volume":"5","author":"Meyer","year":"2017","journal-title":"Lancet Respir Med"},{"key":"2026030321522035300_bib3","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/S2213-2600(14)70097-9","article-title":"Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials","volume":"2","author":"Calfee","year":"2014","journal-title":"Lancet Respir Med"},{"key":"2026030321522035300_bib4","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1136\/thoraxjnl-2016-209719","article-title":"Identification and validation of distinct biological phenotypes in patients with acute respiratory distress syndrome by cluster analysis","volume":"72","author":"Bos","year":"2017","journal-title":"Thorax"},{"key":"2026030321522035300_bib5","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1164\/rccm.201603-0645OC","article-title":"Acute respiratory distress syndrome subphenotypes respond differently to randomized fluid management strategy","volume":"195","author":"Famous","year":"2017","journal-title":"Am J Respir Crit Care Med"},{"key":"2026030321522035300_bib6","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.1097\/CCM.0000000000004018","article-title":"Host-response subphenotypes offer prognostic enrichment in patients with or at risk for acute respiratory distress syndrome","volume":"47","author":"Kitsios","year":"2019","journal-title":"Crit Care Med"},{"key":"2026030321522035300_bib7","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/S0140-6736(14)61136-3","article-title":"The role of the microbiome in exacerbations of chronic lung diseases","volume":"384","author":"Dickson","year":"2014","journal-title":"Lancet"},{"key":"2026030321522035300_bib8","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1164\/rccm.201303-0488WS","article-title":"The role of the lung microbiome in health and disease: a National Heart, Lung, and Blood Institute workshop report","volume":"187","author":"Huang","year":"2013","journal-title":"Am J Respir Crit Care Med"},{"key":"2026030321522035300_bib9","doi-asserted-by":"crossref","first-page":"16031","DOI":"10.1038\/nmicrobiol.2016.31","article-title":"Enrichment of the lung microbiome with oral taxa is associated with lung inflammation of a Th17 phenotype","volume":"1","author":"Segal","year":"2016","journal-title":"Nat Microbiol"},{"key":"2026030321522035300_bib10","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1165\/rcmb.2019-0273TR","article-title":"Methods in lung microbiome research","volume":"62","author":"Carney","year":"2020","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026030321522035300_bib11","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.jcrc.2016.09.029","article-title":"Dysbiosis in the intensive care unit: microbiome science coming to the bedside","volume":"38","author":"Kitsios","year":"2017","journal-title":"J Crit Care"},{"key":"2026030321522035300_bib12","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/S2213-2600(15)00427-0","article-title":"The microbiome and critical illness","volume":"4","author":"Dickson","year":"2016","journal-title":"Lancet Respir Med"},{"key":"2026030321522035300_bib13","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1136\/thoraxjnl-2016-209158","article-title":"The dynamics of the pulmonary microbiome during mechanical ventilation in the intensive care unit and the association with occurrence of pneumonia","volume":"72","author":"Zakharkina","year":"2017","journal-title":"Thorax"},{"key":"2026030321522035300_bib14","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s40168-016-0151-8","article-title":"Composition and dynamics of the respiratory tract microbiome in intubated patients","volume":"4","author":"Kelly","year":"2016","journal-title":"Microbiome"},{"key":"2026030321522035300_bib15","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1164\/rccm.201702-0441OC","article-title":"Lung microbiota is related to smoking status and to development of acute respiratory distress syndrome in critically ill trauma patients","volume":"197","author":"Panzer","year":"2018","journal-title":"Am J Respir Crit Care Med"},{"key":"2026030321522035300_bib16","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.3389\/fmicb.2018.01413","article-title":"Respiratory microbiome profiling for etiologic diagnosis of pneumonia in mechanically ventilated patients","volume":"9","author":"Kitsios","year":"2018","journal-title":"Front Microbiol"},{"key":"2026030321522035300_bib17","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1186\/s12931-019-1203-y","article-title":"Unique patterns of lower respiratory tract microbiota are associated with inflammation and hospital mortality in acute respiratory distress syndrome","volume":"20","author":"Kyo","year":"2019","journal-title":"Respir Res"},{"key":"2026030321522035300_bib18","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1186\/s12931-018-0950-5","article-title":"Microbial dysbiosis and mortality during mechanical ventilation: a prospective observational study","volume":"19","author":"Lamarche","year":"2018","journal-title":"Respir Res"},{"key":"2026030321522035300_bib19","doi-asserted-by":"crossref","first-page":"16113","DOI":"10.1038\/nmicrobiol.2016.113","article-title":"Enrichment of the lung microbiome with gut bacteria in sepsis and the acute respiratory distress syndrome","volume":"1","author":"Dickson","year":"2016","journal-title":"Nat Microbiol"},{"key":"2026030321522035300_bib20","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1164\/rccm.201907-1487OC","article-title":"Lung microbiota predict clinical outcomes in critically ill patients","volume":"201","author":"Dickson","year":"2020","journal-title":"Am J Respir Crit Care Med"},{"key":"2026030321522035300_bib21","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/1471-2180-12-56","article-title":"BactQuant: an enhanced broad-coverage bacterial quantitative real-time PCR assay","volume":"12","author":"Liu","year":"2012","journal-title":"BMC Microbiol"},{"key":"2026030321522035300_bib22","first-page":"2526","article-title":"Acute respiratory distress syndrome: the Berlin definition","volume":"307","author":"Ranieri","year":"2012","journal-title":"JAMA"},{"key":"2026030321522035300_bib23","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1016\/S2213-2600(16)30305-8","article-title":"Epidemiological characteristics, practice of ventilation, and clinical outcome in patients at risk of acute respiratory distress syndrome in intensive care units from 16 countries (PRoVENT): an international, multicentre, prospective study","volume":"4","author":"Neto","year":"2016","journal-title":"Lancet Respir Med"},{"key":"2026030321522035300_bib24","doi-asserted-by":"crossref","first-page":"4345","DOI":"10.1038\/srep04345","article-title":"Modeling the impact of antibiotic exposure on human microbiota","volume":"4","author":"Zhao","year":"2014","journal-title":"Sci Rep"},{"key":"2026030321522035300_bib25","doi-asserted-by":"crossref","first-page":"e00358-19","DOI":"10.1128\/mSphere.00358-19","article-title":"Rectal swabs from critically ill patients provide discordant representations of the gut microbiome compared to stool samples","volume":"4","author":"Fair","year":"2019","journal-title":"mSphere"},{"key":"2026030321522035300_bib26","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1164\/rccm.201210-1913OC","article-title":"Comparison of the respiratory microbiome in healthy nonsmokers and smokers","volume":"187","author":"Morris","year":"2013","journal-title":"Am J Respir Crit Care Med"},{"key":"2026030321522035300_bib27","doi-asserted-by":"crossref","first-page":"e30126","DOI":"10.1371\/journal.pone.0030126","article-title":"Dirichlet multinomial mixtures: generative models for microbial metagenomics","volume":"7","author":"Holmes","year":"2012","journal-title":"PLoS One"},{"key":"2026030321522035300_bib28","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1007\/s00134-018-5480-6","article-title":"Acute respiratory distress syndrome (ARDS) phenotyping","volume":"45","author":"Shankar-Hari","year":"2019","journal-title":"Intensive Care Med"},{"key":"2026030321522035300_bib29","doi-asserted-by":"crossref","first-page":"2003","DOI":"10.1001\/jama.2019.5791","article-title":"Derivation, validation, and potential treatment implications of novel clinical phenotypes for sepsis","volume":"321","author":"Seymour","year":"2019","journal-title":"JAMA"},{"key":"2026030321522035300_bib30","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1164\/rccm.201809-1808OC","article-title":"Understanding heterogeneity in biologic phenotypes of acute respiratory distress syndrome by leukocyte expression profiles","volume":"200","author":"Bos","year":"2019","journal-title":"Am J Respir Crit Care Med"},{"key":"2026030321522035300_bib31","doi-asserted-by":"crossref","first-page":"L76","DOI":"10.1152\/ajplung.00061.2014","article-title":"Alterations of lung microbiota in a mouse model of LPS-induced lung injury","volume":"309","author":"Poroyko","year":"2015","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026030321522035300_bib32","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1164\/rccm.201502-0326LE","article-title":"Intraalveolar catecholamines and the human lung microbiome","volume":"192","author":"Dickson","year":"2015","journal-title":"Am J Respir Crit Care Med"},{"key":"2026030321522035300_bib33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/intimm\/dxh186","article-title":"Toll-like receptors in innate immunity","volume":"17","author":"Takeda","year":"2005","journal-title":"Int Immunol"},{"key":"2026030321522035300_bib34","doi-asserted-by":"crossref","first-page":"e00153-17","DOI":"10.1128\/mSystems.00153-17","article-title":"Translating lung microbiome profiles into the next-generation diagnostic gold standard for pneumonia: a clinical investigator\u2019s perspective","volume":"3","author":"Kitsios","year":"2018","journal-title":"mSystems"},{"key":"2026030321522035300_bib35","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.chom.2009.06.007","article-title":"Patterns of pathogenesis: discrimination of pathogenic and nonpathogenic microbes by the innate immune system","volume":"6","author":"Vance","year":"2009","journal-title":"Cell Host Microbe"},{"key":"2026030321522035300_bib36","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1038\/nature10072","article-title":"Detection of prokaryotic mRNA signifies microbial viability and promotes immunity","volume":"474","author":"Sander","year":"2011","journal-title":"Nature"},{"key":"2026030321522035300_bib37","doi-asserted-by":"crossref","first-page":"E12353","DOI":"10.1073\/pnas.1809700115","article-title":"Integrating host response and unbiased microbe detection for lower respiratory tract infection diagnosis in critically ill adults","volume":"115","author":"Langelier","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026030321522035300_bib38","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1186\/s12931-019-1218-4","article-title":"Metagenomic identification of severe pneumonia pathogens in mechanically-ventilated patients: a feasibility and clinical validity study","volume":"20","author":"Yang","year":"2019","journal-title":"Respir Res"},{"key":"2026030321522035300_bib39","doi-asserted-by":"crossref","first-page":"e61","DOI":"10.1093\/cid\/ciw353","article-title":"Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the infectious diseases society of America and the American thoracic society","volume":"63","author":"Kalil","year":"2016","journal-title":"Clin Infect Dis"},{"key":"2026030321522035300_bib40","doi-asserted-by":"crossref","first-page":"L578","DOI":"10.1152\/ajplung.00476.2018","article-title":"Metagenomic comparison of tracheal aspirate and mini-bronchial alveolar lavage for assessment of respiratory microbiota","volume":"316","author":"Kalantar","year":"2019","journal-title":"Am J Physiol Lung Cell Mol Physiol"}],"container-title":["American Journal of Respiratory and Critical Care Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/202\/12\/1666\/67176265\/ajrccm_202_12_1666.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/202\/12\/1666\/67176265\/ajrccm_202_12_1666.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T02:52:33Z","timestamp":1772592753000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrccm\/article\/202\/12\/1666\/8495293"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,1]]},"references-count":40,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,12,1]]},"published-print":{"date-parts":[[2020,12,15]]}},"URL":"https:\/\/doi.org\/10.1164\/rccm.201912-2441oc","relation":{},"ISSN":["1073-449X","1535-4970"],"issn-type":[{"value":"1073-449X","type":"print"},{"value":"1535-4970","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,12]]},"published":{"date-parts":[[2020,12,1]]},"assertion":[{"value":"2019-12-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-07-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-12-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}