Evaluation of wound fluid biomarkers to determine healing in adults with venous leg ulcers: A prospective study

Abstract

To the Editor: We appreciate Dr. Kawada’s interest in our recent publication of evaluating wound fluid biomarkers to determine healing of venous leg ulcers in adults. The first point the author has raised is correct that the analysis using the logistic regression model was underpowered to draw definitive conclusion. In fact, we have acknowledged this in the discussion as one of the limitations of our study in relation to this analysis in particular. It is worth to note that this limitation also applies to the tests (chi-square and McNemar tests) proposed by the authors. The purpose of this study was not to compare the sensitivity and specificity of the test. The use of chi-square or McNemar tests does not provide meaningful information on the accuracy of these tests. The objective of this study was to assess the ability of the biomarkers to discriminate between the healing wounds and non-healing wounds. The receiver operating characteristic (ROC) curve adequately provides this information. We did not compare the areas under the curves (AUCs) of the granulocyte-macrophage colony-stimulating factor (GM-CSF) and matrix metallopeptidase-13 (MMP-13) ROC curves and the author’s comments on the statistical approach differing according to the null hypothesis does not apply to the manner in which the ROC curves were utilized in this study. We note with interest the reference in this letter to the role of granzyme K in inflammation. Granzymes are serine proteases that have been shown to be involved in killing tumor cells and cells infected by viruses. They have also been shown to be up-regulated in inflammatory conditions and to contribute to cytokine release. The quoted references relate to models that are different to the healing of chronic wounds and do not assess this molecule in wound fluid. Specifically, the studies relate to human burn tissue, cells in culture, and burns in mice; plasma levels in humans with viral illness and severe systemic sepsis; and plasma levels in human volunteers injected with lipopolysaccharide. The role of granzyme K appears to be associated with the up-regulation of inflammatory cytokines. This would certainly be a molecule of interest to evaluate within chronic wounds, but the studies referenced in this letter do not relate to chronic cutaneous wounds in humans. Hence, at this present time there are no data to suggest that it may have a role as a biomarker of healing when measured in wound fluid from wounds in humans.