BACKGROUND: Severe sepsis is common and frequently fatal, and community-acquired pneumonia (CAP) is the leading cause. Although severe sepsis is often attributed to uncontrolled and unbalanced inflammation, evidence from humans with infection syndromes across the breadth of disease is lacking. In this study we describe the systemic cytokine response to pneumonia and determine if specific patterns, including the balance of proinflammatory and anti-inflammatory markers, are associated with severe sepsis and death. METHODS: This is a cohort study of 1886 subjects hospitalized with CAP through the emergency departments in 28 US academic and community hospitals. We defined severe sepsis as CAP complicated by new-onset organ dysfunction, following international consensus conference criteria. We measured plasma tumor necrosis factor, IL-6 (interleukin 6), and IL-10 levels daily for the first week and weekly thereafter. Our main outcome measures were severe sepsis and 90-day mortality. RESULTS: A total of 583 patients developed severe sepsis (31%), of whom 149 died (26%). Systemic cytokine level elevation occurred in 82% of all subjects with CAP. Mean cytokine concentrations were highest at presentation, declined rapidly over the first few days, but remained elevated throughout the first week, beyond resolution of clinical signs of infection. Cytokine levels were highest in fatal severe sepsis and lowest in CAP with no severe sepsis. Unbalanced (high/low) cytokine patterns were unusual (4.6%) and not associated with decreased survival. Highest risk of death was with combined high levels of the proinflammatory IL-6 and anti-inflammatory IL-10 cytokine activity (hazard ratio, 20.5; 95% confidence interval, 10.8-39.0) (P<.001). CONCLUSIONS: The circulating cytokine response to pneumonia is heterogeneous and continues for more than a week after presentation, with considerable overlap between those who do and do not develop severe sepsis. Unbalanced activation is uncommon, and mortality is highest when both proinflammatory and anti-inflammatory cytokine levels are high.
BACKGROUND: Severe sepsis is common and frequently fatal, and community-acquired pneumonia (CAP) is the leading cause. Although severe sepsis is often attributed to uncontrolled and unbalanced inflammation, evidence from humans with infection syndromes across the breadth of disease is lacking. In this study we describe the systemic cytokine response to pneumonia and determine if specific patterns, including the balance of proinflammatory and anti-inflammatory markers, are associated with severe sepsis and death. METHODS: This is a cohort study of 1886 subjects hospitalized with CAP through the emergency departments in 28 US academic and community hospitals. We defined severe sepsis as CAP complicated by new-onset organ dysfunction, following international consensus conference criteria. We measured plasma tumornecrosis factor, IL-6 (interleukin 6), and IL-10 levels daily for the first week and weekly thereafter. Our main outcome measures were severe sepsis and 90-day mortality. RESULTS: A total of 583 patients developed severe sepsis (31%), of whom 149 died (26%). Systemic cytokine level elevation occurred in 82% of all subjects with CAP. Mean cytokine concentrations were highest at presentation, declined rapidly over the first few days, but remained elevated throughout the first week, beyond resolution of clinical signs of infection. Cytokine levels were highest in fatal severe sepsis and lowest in CAP with no severe sepsis. Unbalanced (high/low) cytokine patterns were unusual (4.6%) and not associated with decreased survival. Highest risk of death was with combined high levels of the proinflammatory IL-6 and anti-inflammatory IL-10 cytokine activity (hazard ratio, 20.5; 95% confidence interval, 10.8-39.0) (P<.001). CONCLUSIONS: The circulating cytokine response to pneumonia is heterogeneous and continues for more than a week after presentation, with considerable overlap between those who do and do not develop severe sepsis. Unbalanced activation is uncommon, and mortality is highest when both proinflammatory and anti-inflammatory cytokine levels are high.
Authors: J Cohen; G Guyatt; G R Bernard; T Calandra; D Cook; D Elbourne; J Marshall; A Nunn; S Opal Journal: Crit Care Med Date: 2001-04 Impact factor: 7.598
Authors: Ganesh Suntharalingam; Meghan R Perry; Stephen Ward; Stephen J Brett; Andrew Castello-Cortes; Michael D Brunner; Nicki Panoskaltsis Journal: N Engl J Med Date: 2006-08-14 Impact factor: 91.245
Authors: Mitchell M Levy; Mitchell P Fink; John C Marshall; Edward Abraham; Derek Angus; Deborah Cook; Jonathan Cohen; Steven M Opal; Jean-Louis Vincent; Graham Ramsay Journal: Crit Care Med Date: 2003-04 Impact factor: 7.598
Authors: S M Opal; C J Fisher; J F Dhainaut; J L Vincent; R Brase; S F Lowry; J C Sadoff; G J Slotman; H Levy; R A Balk; M P Shelly; J P Pribble; J F LaBrecque; J Lookabaugh; H Donovan; H Dubin; R Baughman; J Norman; E DeMaria; K Matzel; E Abraham; M Seneff Journal: Crit Care Med Date: 1997-07 Impact factor: 7.598
Authors: Sachin Yende; Eric B Milbrandt; John A Kellum; Lan Kong; Russell L Delude; Lisa A Weissfeld; Derek C Angus Journal: Crit Care Med Date: 2011-08 Impact factor: 7.598
Authors: G Umberto Meduri; Lisa Bridges; Mei-Chiung Shih; Paul E Marik; Reed A C Siemieniuk; Mehmet Kocak Journal: Intensive Care Med Date: 2015-10-27 Impact factor: 17.440
Authors: Silvia Gómez-Zorrilla; Francisco Morandeira; María José Castro; Fe Tubau; Elisabet Periche; Rosario Cañizares; María Angeles Dominguez; Javier Ariza; Carmen Peña Journal: Microb Drug Resist Date: 2016-10-18 Impact factor: 3.431
Authors: Florian B Mayr; Sachin Yende; Gina D'Angelo; Amber E Barnato; John A Kellum; Lisa Weissfeld; Donald M Yealy; Michael C Reade; Eric B Milbrandt; Derek C Angus Journal: Crit Care Med Date: 2010-03 Impact factor: 7.598
Authors: Dimitry S Davydow; Catherine L Hough; Deborah A Levine; Kenneth M Langa; Theodore J Iwashyna Journal: Am J Med Date: 2013-03-14 Impact factor: 4.965