Research in context
Evidence before this study
We searched PubMed without language restrictions for reports published up to July 20, 2017, using the search terms “idiopathic pulmonary fibrosis”, “biomarkers”, “surfactant protein D”, “matrix metalloproteinase”, “CA-125”, and “CA19-9”. At the time of the search, we found no biomarker studies that had used a two-stage hypothesis-free discovery and targeted validation design. Only one study (our previous report from the PROFILE study) had assessed longitudinal change of biomarkers in a treatment-naive cohort of patients with idiopathic pulmonary fibrosis (IPF). Although tumour markers have been assessed in patients with IPF, no studies had identified CA-125 as a dynamic biomarker or CA19-9 as a biomarker of disease progression for IPF.
Added value of this study
To our knowledge, this is the largest study to prospectively and systematically assess the role of known and potentially novel serum biomarkers in patients with IPF. Furthermore, the two-stage discovery and validation design; the use of two distinct assays (one multiplex and four individual ELISAs); prospective, systematic longitudinal sample measurement; assessment of more than 300 patients with long-term follow-up data; appropriately powered sample size for an a-priori-defined outcome; and the thorough assessment of four epithelial-derived biomarkers represent a step-change over the currently available literature in terms of both the methodological approach and the findings. Thus, our results help to clarify the roles of known biomarkers and highlight the importance of two previously unvalidated biomarkers for IPF.
These data represent the largest prospective analysis of serum biomarkers in IPF. The two-stage design permitted us to adopt an unbiased approach to identifying the most promising biomarkers on the basis of their ability to distinguish individuals with disease from matched healthy controls, identify individuals with IPF who have progressive disease, and identify changes in biomarkers over time to predict death as an outcome (potentially acting as theranostic biomarkers). The most promising biomarkers in the discovery set were independently validated using individual ELISAs, including those available in routine clinical practice.
Implications of all the available evidence
These results identified epithelium-derived proteins as promising biomarkers in all three of our categories. Validation analysis supported the finding that high concentrations of baseline surfactant protein D and matrix metalloproteinase 7 can be used to distinguish individuals with disease from controls and predict outcome. By contrast, high concentrations of CA19-9 were able to predict 12-month disease progression, whereas rising concentrations of CA-125 after 3 months were predictive of 12 month disease progression and overall mortality. Changes in these markers were independent of baseline physiological parameters. These data identify biomarkers of IPF that could potentially be used to streamline clinical trial designs, identify individuals at high risk of progression, and even assess clinical response to therapy.