title: Circulating high-mobility group box 1 (HMGB1) concentrations are elevated in both uncomplicated pneumonia and pneumonia with severe sepsis.
abstract: OBJECTIVE
  High-mobility group box 1 (HMGB1) has been proposed as a late mediator of sepsis, but human data are sparse and conflicting. We describe plasma HMGB1 concentrations in humans with community-acquired pneumonia (CAP), the most common cause of severe sepsis, and test the hypotheses that HMGB1 levels are higher in CAP than healthy controls, higher in CAP with severe sepsis than CAP without severe sepsis, and higher in severe sepsis nonsurvivors than survivors.
  
  
  METHODS
  Random, outcome-stratified sample from a prospective study of 1,895 subjects hospitalized with CAP.
  
  
  METHODS
  Twenty-eight U.S. teaching and community hospitals.
  
  
  METHODS
  There were 122 CAP subjects (43 never developed severe sepsis, 49 developed severe sepsis and survived hospitalization, and 30 developed severe sepsis and died) and 38 healthy controls.
  
  
  METHODS
  None.
  
  
  RESULTS
  Median day of onset of severe sepsis was day of admission. HMGB1 was measured daily for the first week and analyzed using repeated-measures models with and without multivariable adjustment for baseline characteristics. HMGB1 concentrations were higher in CAP subjects compared with controls (median concentration on day of admission vs. controls, 190 vs. 0 ng/mL, p = .0001; 93.7% of all CAP measurements were elevated). HMGB1 remained elevated throughout the hospital course with no significant trend (p = .64) and did not differ between those with and without severe sepsis (p = .30). HMGB1 concentrations were higher in severe sepsis nonsurvivors than survivors (p = .001). HMGB1 concentrations remained elevated at discharge (median final HMGB1 measure, 176 ng/mL). Findings persisted in multivariable models and were robust to sensitivity analyses using alternative definitions of severe sepsis.
  
  
  CONCLUSIONS
  HMGB1 is elevated in almost all CAP subjects, and higher circulating HMGB1 is associated with mortality. But immunodetectable HMGB1 levels were also persistently elevated in those patients who fared well. Thus, additional work is needed to understand the biological activities of serum HMGB1 in sepsis.
authors.affiliation: Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Laboratory, University of Pittsburgh, Pittsburgh, PA, USA. angusdc@upmc.edu
authors.forename: Derek C
authors.initials: DC
authors.lastname: Angus
authors.forename: Lihong
authors.initials: L
authors.lastname: Yang
authors.forename: Lan
authors.initials: L
authors.lastname: Kong
authors.forename: John A
authors.initials: JA
authors.lastname: Kellum
authors.forename: Russell L
authors.initials: RL
authors.lastname: Delude
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tracey
authors.forename: Lisa
authors.initials: L
authors.lastname: Weissfeld
mesh_terms: D000368:Aged; D017714:Community-Acquired Infections / Q000097:blood / Q000150:complications; D005260:Female; D024243:HMGB1 Protein / Q000097:blood*; D006801:Humans; D015151:Immunoblotting; D007362:Intensive Care Units; D008297:Male; D011014:Pneumonia / Q000097:blood* / Q000150:complications* / Q000503:physiopathology; D011446:Prospective Studies; D018805:Sepsis / Q000097:blood* / Q000150:complications* / Q000503:physiopathology; D012720:Severity of Illness Index
chemical_list: D024243:HMGB1 Protein