Biomarker-based exclusion of ventilator-associated pneumonia: a multicentre validation study

Introduction

Ventilator-associated pneumonia (VAP) remains a leading cause of nosocomial infection in the ICU [1]. VAP is confirmed by positive microbiology in approximately one-third of patients with suspected VAP [2], implying that there is scope to improve antibiotic stewardship. In a single-centre study, bronchoalveolar lavage fluid (BALF) inflammatory mediators (in particular interleukin-1 beta (IL-1β)) [3] and neutrophil proteases [4] demonstrated potential as biomarkers to exclude VAP. We aimed to validate these findings in a multicentre study.

Methods

We conducted a prospective, multicentre observational study of 167 patients with clinically suspected VAP from 12 ICUs across the UK. VAP was confirmed by growth of a potential pathogen in BALF at >10⁴ colony-forming units/ml. IL-1β, IL-8, matrix metalloproteinase-8 (MMP-8), MMP-9 and human neutrophil elastase (HNE) were measured in BALF by cytometric bead array. IL-6, IL-8, MMP-8, MMP-9 and HNE were measured in serum. Patients were dichotomised into VAP and non-VAP groups and receiver operating characteristics (ROC) curves were constructed for individual biomarkers and combinations of markers before optimum cutoff points were determined.

Results

A total of 150 patients had paired semi-quantitative culture and biomarker results. Fifty-three (35%) patients had VAP and 97 (65%) patients formed the non-VAP group. All BALF biomarkers were significantly higher in the VAP group (P < 0.001). The area under the ROC curve for IL-1β was 0.81, for IL-8 was 0.736, for MMP-8 was 0.758, for MMP-9 was 0.785 and for HNE was 0.777. Using a cutoff value of 17 pg/ ml, IL-1β had a sensitivity of 96.2%, a specificity of 43.3%, a negative predictive value (NPV) of 95.5% and a post-test probability of 4.5% (95 CI: 1 to 16%). A combination of IL-1β and IL-8 excluded VAP with a sensitivity of 100%, a specificity of 44.3% and a NPV of 1. There was no significant difference in serum biomarkers between the VAP and non-VAP groups.

Conclusion

This study demonstrates that IL-1β effectively excludes VAP when validated in a multicentre study. The performance is further improved by the addition of IL-8, and the combination could form a rapid diagnostic assay to exclude VAP. Biomarker analysis appears to have the potential to improve antibiotic stewardship, and this concept should be formally tested in the setting of a randomised controlled trial.