Diagnostic importance of pulmonary interleukin-1beta and interleukin-8 in ventilator-associated pneumonia

Abstract

Background: Ventilator-associated pneumonia (VAP) is the most commonly fatal nosocomial infection. Clinical diagnosis of VAP remains notoriously inaccurate. The hypothesis was tested that significantly augmented inflammatory markers distinguish VAP from conditions closely mimicking VAP.

Methods: A prospective, observational cohort study was carried out in two university hospital intensive care units recruiting 73 patients with clinically suspected VAP, and a semi-urban primary care practice recruiting a reference group of 21 age- and sex-matched volunteers. Growth of pathogens at >10(4) colony-forming units (cfu)/ml of bronchoalveolar lavage fluid (BALF) distinguished VAP from "non-VAP". Inflammatory mediators were quantified in BALF and serum. Mediators showing significant differences between patients with and without VAP were analysed for diagnostic utility by receiver operator characteristic (ROC) curves.

Results: Seventy-two patients had recoverable lavage-24% had VAP. BALF interleukin-1beta (IL-1beta), IL-8, granulocyte colony-stimulating factor and macrophage inflammatory protein-1alpha were significantly higher in the VAP group (all p<0.005). Using a cut-off of 10 pg/ml, BALF IL-1beta generated negative likelihood ratios for VAP of 0.09. In patients with BALF IL-1beta <10 pg/ml the post-test probability of VAP was 2.8%. Using a cut-off value for IL-8 of 2 ng/ml, the positive likelihood ratio was 5.03. There was no difference in cytokine levels between patients with sterile BALF and those with growth of <10(4) cfu/ml.

Conclusions: BALF IL-1beta and IL-8 are amongst the strongest markers yet identified for accurately demarcating VAP within the larger population of patients with suspected VAP. These findings have potential implications for reduction in unnecessary antibiotic use but require further validation in larger populations.

Figure 1

Receiver operating characteristic (ROC) curves and optimal sensitivity, specificity, positive predictive values (PPVs) and negative predictive values (NPVs) for bronchoalveolar lavage fluid (BALF) cytokines (n=72, 55 non-ventilator-associated pneumonia (VAP) and 17 VAP). Data are derived from the patients with clinically suspected VAP. The broken line shows identity. G-CSF, granulocyte colony-stimulating factor; IL, interleukin; +LR, positive likelihood ratio; −LR, negative likelihood ratio; MIP 1-α, macrophage inflammatory protein-1α; sTREM-1; type 1 soluble triggering receptor expressed on myeloid cells.

Figure 2

Scatter plots of pulmonary cytokine levels (n=72, 55 non-ventilator-associated pneumonia (VAP) and 17 VAP). Each dot represents a single observation. The solid lines mark the median values; the hashed line marks the optimal diagnostic cut-off. A log scale is used due to the skewed nature of cytokine levels. G-CSF, granulocyte colony-stimulating factor; IL, interleukin; MIP1-α, macrophage inflammatory protein-1α;

Figure 3

Comparison of pulmonary cytokine levels between patients with ventilator-associated pneumonia (VAP) (n=17), patients with growth of pathogens in bronchoalveolar lavage fluid (BALF) below the diagnostic 10⁴ cfu/ml cut-off (n=22), and patients with no growth in BALF (n=33). (A) Interleukin-8 (IL-8) levels. Data are presented as the median and IQRs, p<0.0001 by Kruskal–Wallis; NS (non-significant), p>0.05, **p<0.01,***p<0.0001 by the Dunn posthoc test. (B) IL-1β levels. Data are presented as the median and IQRs, p=0.0006 by Kruskal–Wallis; NS, p>0.05, **p<0.01,***p<0.0001 by the Dunn posthoc test.