Cytokine Levels in Sepsis Defy Conventional Wisdom

PITTSBURGH, Aug. 13 -- Fatal sepsis in hospitalized pneumonia patients is most likely to occur in the presence of high levels of certain proinflammatory and anti-inflammatory cytokines, investigators here found.
Overall, patients who died of severe sepsis had the highest cytokine levels, and patients without severe sepsis had the lowest levels, found Derek C. Angus, M.D., of the University of Pittsburgh, and colleagues, reported in the Aug. 13 issue of the Archives of Internal Medicine.
In particular, combined elevated levels of proinflammatory interleukin-6 and anti-inflammatory interleukin-10 conferred the highest mortality risk.
"We have, for the first time to our knowledge, described the systemic cytokine response to infection and severe sepsis in a large, multicenter inception cohort of subjects presenting to the [emergency department] with [community-acquired pneumonia]," said Dr. Angus, and colleagues.
"Our results show that this response is much longer in duration and much more heterogeneous than suggested by previous studies. Nevertheless, individuals with high circulating levels of both proinflammatory and anti-inflammatory cytokines had markedly increased risk of severe sepsis and death."
The authors noted that the results call into question previous interpretations of the inflammatory response to sepsis, at least as it applies to community-acquired pneumonia:
Systemic cytokine activation is common but not universal.
Cytokine concentrations had already peaked by the time patients presented to emergency departments, suggesting the classic cytokine cascade was already fully activated.
Cytokine activation did not increase with the onset of organ dysfunction.
Although cytokine concentrations were highest in patients who fared worse, differences between groups with different outcomes were modest.
For many patients, cytokine activation persisted throughout hospitalization, far longer than traditional models would suggest.
The findings' departure from those of prior investigations have "important implications for the development of future therapies," the authors concluded.
Severe sepsis is common and frequently fatal, and community-acquired pneumonia is the leading cause, the authors noted. Severe sepsis is often attributed to uncontrolled and unbalanced inflammation, but clinical data to support that viewpoint are scanty.
The researchers retrospectively reviewed records on 1,886 patients hospitalized with a diagnosis of community-acquired pneumonia through emergency departments at 28 academic and community hospitals. They defined severe sepsis as community-acquired pneumonia complicated by new-onset organ dysfunction, consistent with international consensus conference criteria.
Investigators measured plasma levels of tumor necrosis factor, IL-6, and IL-10 daily for the first week and weekly thereafter. The primary outcome measures were severe sepsis and 90-day mortality.
Hospital records showed that 583 (31%) patients developed severe sepsis, and 149 (26%) of these died. Systemic cytokine elevation occurred in 82% of all the patients with community-acquired pneumonia. The mean cytokine concentrations were highest at presentation. Levels declined rapidly over the first few days, but remained elevated throughout the first week, beyond resolution of the clinical signs of infection.
Patients with severe sepsis at presentation had significantly higher mean levels of IL-6, IL-10, and TNF compared with patients who did not have severe sepsis on day one (P<0.001). Additionally, septic patients with elevated cytokine levels had significantly higher levels compared with non-septic patients who had elevated cytokine levels at presentation (P=0.01 to P<0.001).
Among patients who had severe sepsis at any time during hospitalization, those who died within 90 days had significantly higher mean levels of IL-6 and IL-10 compared with levels among patients who were alive at 90 days (P=0.01). A separate analysis limited to patients with elevated cytokine levels showed that patients who died had significantly higher levels of IL-6 (P<0.001) and IL-10 (P=0.03).
IL-6 concentrations decreased rapidly from day one through day three but remained elevated throughout the first week. TNF levels were lower than those for IL-6 on day one and declined sharply over the next two days but remained elevated throughout the first week. More than half of all patients had normal levels throughout hospitalization. IL-10 concentrations also were lower at the outset compared with IL-6 and decreased even more precipitously from day one through day three. The authors reported that 64% of survivors and 42% of non-survivors had normal IL-10 levels throughout their hospitalization.
Although normal cytokine levels were common, only four fatal cases of severe sepsis (2.7%) were associated with undetectable cytokine concentrations. On the other hand, patients who fared well had some concentration of cytokines.
The authors reported no conflicts. The study was supported by the national Institute of General Medical Sciences, GlaxoSmithKline, and Diagnostic Products Corporation.Additional source: Archives of Internal MedicineSource reference: Kellum JA et al. "Understanding the inflammatory cytokine response in pneumonia and sepsis. Results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study." Arch Intern Med 2007;167:1655-1663