title: Trimethylamine-N-oxide (TMAO) predicts fatal outcomes in community-acquired pneumonia patients without evident coronary artery disease.
abstract: BACKGROUND
  The pro-atherosclerotic metabolite trimethylamine-N-oxide (TMAO) is a risk factor for incident cardiovascular events and a potentially modifiable mediator of chronic inflammation through broad-spectrum antibiotic treatment by changing the microbiome. Whether TMAO is associated with adverse clinical outcomes in acute inflammatory community-acquired pneumonia (CAP) patients is unknown.
  
  
  METHODS
  A total of 317 CAP patients from a previous Swiss multicenter trial were prospectively followed for a median of 6.1years. TMAO plasma levels were measured by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). We used Cox regression models to investigate associations between baseline TMAO levels and all-cause mortality.
  
  
  RESULTS
  Six-year mortality was 45.1%, and 18.9% of the patients had coronary artery disease (CAD). Median admission TMAO (μmolL-1) levels were significantly higher in non-survivors compared to survivors (4.1 [interquartile range (IQR), 2.2-7.2] vs. 2.5 [IQR, 1.5-4.1]; p<0.001). A strong association between TMAO and 6-year all-cause mortality was found for patients without CAD (adjusted hazard ratio (HR) 1.9 ([95% CI 1.2-3.1]; p<0.05). In patients with known CAD, no such association was found (adjusted HR 0.6 (0.2-1.6); p=0.309, interaction p=0.009). In patients without antibiotic pretreatment receiving antibiotic treatment, TMAO significantly decreased from admission to day seven (median, 3.9 [IQR, 2.1-7.5] vs. 3.1 [IQR, 1.4-6.6]; p<0.01).
  
  
  CONCLUSIONS
  TMAO is associated with long-term fatal outcomes in CAP patients without evident CAD and modifiable through antibiotic treatment. Whether chronic modulation of TMAO by targeting the microbiome reduces mortality risk needs to be evaluated in future interventional trials.
authors: University Department of Internal Medicine, Kantonsspital Aarau, Switzerland. Electronic address: manuel.ottiger@gmx.net.
authors: Manuel
authors: M
authors: Ottiger
authors: University Department of Internal Medicine, Kantonsspital Aarau, Switzerland. Electronic address: manuela.nickler@ksa.ch.
authors: Manuela
authors: M
authors: Nickler
authors: Department of Laboratory Medicine, Kantonsspital Aarau, Switzerland. Electronic address: christian.steuer@pharma.ethz.ch.
authors: Christian
authors: C
authors: Steuer
authors: University Department of Internal Medicine, Kantonsspital Aarau, Switzerland. Electronic address: jonas.odermatt@ksa.ch.
authors: Jonas
authors: J
authors: Odermatt
authors: Department of Laboratory Medicine, Kantonsspital Aarau, Switzerland. Electronic address: andreas.huber@ksa.ch.
authors: Andreas
authors: A
authors: Huber
authors: Endocrinology, Diabetology and Metabolism, University Hospital Basel, Switzerland. Electronic address: mirjam.christ@usb.ch.
authors: Mirjam
authors: M
authors: Christ-Crain
authors: Department of Internal Medicine, Kantonsspital Luzern, Switzerland. Electronic address: christoph.henzen@luks.ch.
authors: Christoph
authors: C
authors: Henzen
authors: Department of Internal Medicine, Kantonsspital Münsterlingen, Switzerland. Electronic address: claus.hoess@stgag.ch.
authors: Claus
authors: C
authors: Hoess
authors: Department of Internal Medicine, Bürgerspital Solothurn, Switzerland. Electronic address: endodiab.bss@bluewin.ch.
authors: Robert
authors: R
authors: Thomann
authors: Department of Internal Medicine, Kantonsspital Liestal, Switzerland. Electronic address: werner.zimmerli@unibas.ch.
authors: Werner
authors: W
authors: Zimmerli
authors: University Department of Internal Medicine, Kantonsspital Aarau, Switzerland. Electronic address: happy.mueller@unibas.ch.
authors: Beat
authors: B
authors: Mueller
authors: University Department of Internal Medicine, Kantonsspital Aarau, Switzerland. Electronic address: schuetzph@gmail.com.
authors: Philipp
authors: P
authors: Schuetz
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D002423:Cause of Death; D002561:Cerebrovascular Disorders / Q000453:epidemiology; D002853:Chromatography, Liquid; D017714:Community-Acquired Infections / Q000097:blood* / Q000188:drug therapy / Q000401:mortality; D003324:Coronary Artery Disease / Q000453:epidemiology; D005260:Female; D005334:Fever / Q000453:epidemiology; D006333:Heart Failure / Q000453:epidemiology; D006760:Hospitalization; D006801:Humans; D007902:Length of Stay / Q000706:statistics & numerical data; D008137:Longitudinal Studies; D008297:Male; D008744:Methylamines / Q000097:blood*; D008875:Middle Aged; D009026:Mortality; D009369:Neoplasms / Q000453:epidemiology; D011014:Pneumonia / Q000097:blood* / Q000188:drug therapy / Q000401:mortality; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D051436:Renal Insufficiency, Chronic / Q000453:epidemiology; D012307:Risk Factors; D013557:Switzerland / Q000453:epidemiology; D053719:Tandem Mass Spectrometry
chemical_list: D000900:Anti-Bacterial Agents; D008744:Methylamines; C005855:trimethyloxamine
keywords: Biomarker; Community-acquired pneumonia; Coronary artery disease; Mortality prediction; Trimethylamine-N-oxide