To assess further IL-27 as a sepsis diagnostic biomarker in critically ill patients with a nonlung source of infection, we derived a decision tree incorporating both IL-27 and PCT. Figure 1 shows the derived decision tree, consisting of a very low sepsis probability terminal node (terminal node 1), two high sepsis probability terminal nodes (terminal nodes 5 and 6), and three intermediate sepsis probability nodes (nodes 2–4). Of the 41 cases in the very low sepsis probability node, none (0%) had sepsis. Of the 47 cases in the high sepsis probability nodes, 41 (87%) had sepsis. The proportion with sepsis in the remaining terminal nodes varied from about 9% to about 40%. The diagnostic test characteristics of the decision tree are as follows: sensitivity of 85% (95% CI, 72%–92%), specificity of 86% (95% CI, 78%–91%), positive predictive value (PPV) of 73% (95% CI, 61%–83%), negative predictive value (NPV) of 92% (95% CI, 85–96), positive likelihood ratio (+LR) of 5.9 (95% CI, 3.8–9.1), and negative likelihood ratio (−LR) of 0.2 (95% CI, 0.1–0.3).
This study represents the first test of IL-27 as a sepsis diagnostic biomarker in critically ill adults. In both the overall sepsis cohort and in the sepsis subgroup with a lung source of infection, the AUC for IL-27 was below 0.7, and the diagnostic test characteristics of IL-27 were inferior to that of PCT. When differentiating between a nonlung source of infection and those without sepsis, however, the AUC for IL-27 approached 0.8. Although the diagnostic test characteristics of IL-27 were also inferior to those of PCT in this subgroup, a decision tree incorporating both IL-27 and PCT suggested an improvement of the overall diagnostic accuracy relative to PCT alone. Compared with PCT alone, when a low IL-27 was measured in conjunction with a low PCT, the negative predictive value for sepsis was correctly increased, and when a high IL-27 was added to a high PCT, the PPV for sepsis was correctly increased. Further support that adding IL-27 to PCT improved discrimination is provided by the NRI. In particular, when differentiating between sepsis patients with a nonlung source of infection and patients without sepsis, a low IL-27 helped to identify more reliably the patients without sepsis when compared with PCT alone. We do note that the NRI has been criticized as having the potential to inflate the incremental prognostic impact of a new biomarker when used in isolation (20). The NRI is this study, however, was consistent with changes in traditional diagnostic test statistics, including the AUC.
The decision tree based on IL-27 and PCT has potential to provide a clinically relevant sepsis probability range, which is otherwise not captured by a single biomarker with a single cut point yielding a dichotomous risk estimate for sepsis. For example, patients in terminal node 1 have extremely low probability for sepsis (0.0%), whereas patients in terminal node 6 have extremely high probability for sepsis (94.1%), thus potentially allowing for biomarker data to directly inform clinical decision making. Alternatively, patients in the remaining terminal nodes have variable, intermediate probabilities for sepsis, thus requiring interpretation and integration of biomarker data with the clinical context for decision making. These assertions require prospective validation.
Our results contrast with our prior study involving critically ill children that demonstrated IL-27 was not only additive, but also outperformed PCT with a specificity and PPV for sepsis of more than 90% (9). Several factors may account for the differences between the pediatric and adult studies. Differences in sample storage conditions could affect the stability of IL-27 and therefore the measurement of IL-27 between the two studies. It is also possible that the IL-27 response of children is different than that of adults, as there are clinical and experimental data demonstrating significantly different responses to inflammatory challenges between developing, pediatric hosts and mature, adult hosts (21–24). We are not aware of any existing data demonstrating a developmental influence on IL-27 expression during infection, and so the potential relationship between developmental age and IL-27 expression is worthy of further investigation. Ultimately, IL-27 may prove to be a more effective sepsis diagnostic biomarker in children than in adults.
It is possible that differences in enrollment criteria for the pediatric and adult cohorts may account for the observed differences in the performance of IL-27 between these two groups. Pediatric patients were required to meet criteria for systemic inflammatory response syndrome (SIRS) and were classified as having sepsis based on laboratory confirmation of a positive culture for known bacterial pathogens, and the majority of these positive cultures were from the blood compartment (9, 25, 26). In contrast, the adult cohort did not require meeting criteria for SIRS (5). Patients in the adult cohort were enrolled consecutively, upon admission to the intensive care unit, irrespective of SIRS criteria, and were subsequently classified as having sepsis based on laboratory and clinical criteria. In addition, a majority of the patients in the adult cohort had a primary lung source of infection. This is an important limitation of our study because it may not be representative of all critically ill populations. For example, it is possible that surgical patients or patients suffering from major trauma may have a lower prevalence of lung infections. Thus, although the pediatric and adult cohorts are both clinically representative, they also reflect different clinical contexts that could influence biomarker performance. This further supports our contention that different biomarkers may have more or less utility in different populations with this highly heterogeneous condition.
In post hoc analyses, we noted that the AUC for IL-27 was 0.768 in subjects with sepsis secondary to a gram-negative organism, whereas the AUC was 0.639 in subjects with sepsis secondary to a gram-positive organism. Thus, future studies of IL-27 as a sepsis diagnostic biomarker should consider the bacterial etiology of sepsis. In addition, future studies may also consider the ability of IL-27 to discriminate between different levels of sepsis severity.
In conclusion, as a general sepsis diagnostic biomarker, IL-27 may not be as effective in critically ill adults as in critically ill children. However, in critically ill adults with sepsis secondary to a nonlung source of infection, IL-27 may add to the sepsis diagnostic accuracy of PCT. Further study of IL-27 as a candidate sepsis biomarker is warranted.
The authors thank the investigators who took part in the original prospective study that generated the database used in the current study.
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