Understanding the inflammatory cytokine response in pneumonia and sepsis

Results of the genetic and inflammatory markers of sepsis (GenIMS) study

John A. Kellum, Lan Kong, Mitchell P. Fink, Lisa A. Weissfeld, Donald M. Yealy, Michael R. Pinsky, Jonathan Fine, Alexander Krichevsky, Russell L. Delude, Derek C. Angus

Research output: Contribution to journalArticle

439 Citations (Scopus)

Abstract

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 antiinflammatory cytokine levels are high.

Original languageEnglish (US)
Pages (from-to)1655-1663
Number of pages9
JournalArchives of Internal Medicine
Volume167
Issue number15
DOIs
StatePublished - Aug 13 2007

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Genetic Markers
Sepsis
Pneumonia
Cytokines
Anti-Inflammatory Agents
Interleukin-10
Interleukin-6
Mortality
Community Hospital
Infection
Hospital Emergency Service
Cohort Studies
Tumor Necrosis Factor-alpha
Outcome Assessment (Health Care)
Confidence Intervals
Inflammation
Survival

All Science Journal Classification (ASJC) codes

  • Internal Medicine

Cite this

Kellum, John A. ; Kong, Lan ; Fink, Mitchell P. ; Weissfeld, Lisa A. ; Yealy, Donald M. ; Pinsky, Michael R. ; Fine, Jonathan ; Krichevsky, Alexander ; Delude, Russell L. ; Angus, Derek C. / Understanding the inflammatory cytokine response in pneumonia and sepsis : Results of the genetic and inflammatory markers of sepsis (GenIMS) study. In: Archives of Internal Medicine. 2007 ; Vol. 167, No. 15. pp. 1655-1663.
@article{81ef93c01c624ef2a783fc77e9e099fb,
title = "Understanding the inflammatory cytokine response in pneumonia and sepsis: Results of the genetic and inflammatory markers of sepsis (GenIMS) study",
abstract = "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 antiinflammatory cytokine levels are high.",
author = "Kellum, {John A.} and Lan Kong and Fink, {Mitchell P.} and Weissfeld, {Lisa A.} and Yealy, {Donald M.} and Pinsky, {Michael R.} and Jonathan Fine and Alexander Krichevsky and Delude, {Russell L.} and Angus, {Derek C.}",
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Kellum, JA, Kong, L, Fink, MP, Weissfeld, LA, Yealy, DM, Pinsky, MR, Fine, J, Krichevsky, A, Delude, RL & Angus, DC 2007, 'Understanding the inflammatory cytokine response in pneumonia and sepsis: Results of the genetic and inflammatory markers of sepsis (GenIMS) study', Archives of Internal Medicine, vol. 167, no. 15, pp. 1655-1663. https://doi.org/10.1001/archinte.167.15.1655

Understanding the inflammatory cytokine response in pneumonia and sepsis : Results of the genetic and inflammatory markers of sepsis (GenIMS) study. / Kellum, John A.; Kong, Lan; Fink, Mitchell P.; Weissfeld, Lisa A.; Yealy, Donald M.; Pinsky, Michael R.; Fine, Jonathan; Krichevsky, Alexander; Delude, Russell L.; Angus, Derek C.

In: Archives of Internal Medicine, Vol. 167, No. 15, 13.08.2007, p. 1655-1663.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Understanding the inflammatory cytokine response in pneumonia and sepsis

T2 - Results of the genetic and inflammatory markers of sepsis (GenIMS) study

AU - Kellum, John A.

AU - Kong, Lan

AU - Fink, Mitchell P.

AU - Weissfeld, Lisa A.

AU - Yealy, Donald M.

AU - Pinsky, Michael R.

AU - Fine, Jonathan

AU - Krichevsky, Alexander

AU - Delude, Russell L.

AU - Angus, Derek C.

PY - 2007/8/13

Y1 - 2007/8/13

N2 - 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 antiinflammatory cytokine levels are high.

AB - 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 antiinflammatory cytokine levels are high.

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