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Editor's Correspondence
July 14, 2008

Mortality in Humans With Pneumonia and Sepsis Is Related to an Uncompensated Anti-inflammatory Response to Infection—Reply

Arch Intern Med. 2008;168(13):1469. doi:10.1001/archinte.168.13.1469

In reply

We appreciate the comments of White and colleagues re garding our study characterizing the inflammatory cytokine response in pneumonia and sepsis.1 We certainly agree that classifying any cytokine as proinflammatory or anti-inflammatory is fraught with a degree of ambiguity. For example, although TNF is a prototypical proinflammatory cytokine, it has well known anti-inflammatory effects, such as inducing apoptosis.2 Likewise, IL-6 has some properties that could be classified as anti-inflammatory. However, it would be an oversimplification to consider it to be an anti-inflammatory cytokine.3 Recent studies have shown that IL-6 is essential for the development of gut barrier dysfunction after hemorrhagic shock and resuscitation in mice,4 and IL-6 may serve as the link between inflammation and thrombosis in sepsis. Isolated human umbilical vein cells treated with IL-6/IL-6 receptor complex produce thrombogenic ultralarge von Willebrand factor fragments and IL-6 also inhibits the cleaving protease, thus further increasing the plasma concentrations of these fragments.5 The release of IL-6 is stimulated by TNF and IL-1 but persists in the plasma for much longer than these other proinflammatory cytokines. As such, IL-6 is a useful marker of proinflammatory cytokine activation. Finally, as shown in Figure 3 of our article,1 both by absolute plasma concentrations of TNF and by the proportion of patients with increased plasma levels, the same pattern we observed with IL-6 is also seen with TNF. Substituting TNF for IL-6 in our analysis does not materially change our results. Thus, we stand by our conclusions that unbalanced activation is uncommon and mortality is highest when both proinflammatory and anti-inflammatory cytokine levels are high.