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Results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study

John A. Kellum, MD; Lan Kong, PhD; Mitchell P. Fink, MD; Lisa A. Weissfeld, PhD; Donald M. Yealy, MD; Michael R. Pinsky, MD; Jonathan Fine, MD; Alexander Krichevsky, PhD; Russell L. Delude, PhD; Derek C. Angus, MD, MPH; for the GenIMS Investigators

Arch Intern Med. 2007;167(15):1655-1663.

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.

Author Affiliations: The Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Laboratory (Drs Kellum, Kong, Fink, Weissfeld, Yealy, Pinsky, Krichevsky, Delude, and Angus), Departments of Critical Care Medicine (Drs Kellum, Fink, Delude, and Angus) and Emergency Medicine (Dr Yealy), University of Pittsburgh, and Department of Biostatistics, University of Pittsburgh Graduate School of Public Health (Drs Kang and Weissfeld), Pittsburgh, Pennsylvania; and Beulah Hinds Center for Lung Studies, Section of Pulmonary and Critical Care Medicine, Norwalk Hospital, Norwalk, Connecticut (Dr Fine).
Group Information: A list of the GenIMS Investigators was published in Crit Care Med. 2007;35(4):1061-1067.

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