Abstract
RationaleBiomarkers in easily accessible compartments like peripheral blood that can predict disease progression in idiopathic pulmonary fibrosis (IPF) would be clinically useful regarding clinical trial participation or treatment decisions for patients. In this study, we used unbiased proteomics to identify relevant disease progression biomarkers in IPF.MethodsPlasma from IPF patients was measured using an 1129 analyte slow off-rate modified aptamer (SOMAmer) array, and patient outcomes were followed over the next 80 weeks. Receiver operating characteristic (ROC) curves evaluated sensitivity and specificity for levels of each biomarker and estimated area under the curve (AUC) when prognostic biomarker thresholds were used to predict disease progression. Both logistic and Cox regression models advised biomarker selection for a composite disease progression index; index biomarkers were weighted via expected progression-free days lost during follow-up with a biomarker on the unfavorable side of the threshold.ResultsA six-analyte index, scaled 0 to 11, composed of markers of immune function, proteolysis and angiogenesis [high levels of ficolin-2 (FCN2), cathepsin-S (Cath-S), legumain (LGMN) and soluble vascular endothelial growth factor receptor 2 (VEGFsR2), but low levels of inducible T cell costimulator (ICOS) or trypsin 3 (TRY3)] predicted better progression-free survival in IPF with a ROC AUC of 0.91. An index score ≥ 3 (group ≥ 2) was strongly associated with IPF progression after adjustment for age, gender, smoking status, immunomodulation, forced vital capacity % predicted and diffusing capacity for carbon monoxide % predicted (HR 16.8, 95% CI 2.2–126.7, P = 0.006).ConclusionThis index, derived from the largest proteomic analysis of IPF plasma samples to date, could be useful for clinical decision making in IPF, and the identified analytes suggest biological processes that may promote disease progression.
Highlights
The classification of idiopathic interstitial pneumonia is given to a heterogenous group of interstitial lung diseases that are differentiated on the basis of their clinical, radiographic and pathologic features [1, 2]
Mary’s Hospital, personal fees from UpToDate, personal fees from GSK, personal fees from Boehringer Ingelheim, personal fees from GSK, personal fees from Nycomed/Takeda, personal fees from Informa, personal fees from Annenberg, personal fees from California Society for Allergy and Immunology, personal fees from Haymarket Communications, personal fees from Integritas, personal fees from InThought, personal fees from Western Society of Allergy and Immunology, personal fees from AstraZeneca, personal fees from Theravance, immunomodulation, forced vital capacity % predicted and diffusing capacity for carbon monoxide % predicted (HR 16.8, 95% CI 2.2–126.7, P = 0.006)
Well-validated biomarkers from peripheral blood could have tremendous impact if they could help to differentiate a diagnosis of idiopathic pulmonary fibrosis (IPF) from other forms of interstitial lung disease (e.g hypersensitivity pneumonitis) that may respond to therapy or if they could provide accurate prognostic information about the IPF disease course to aid patients in deciding on medication options or clinical trial participation [6, 8, 9]
Summary
The classification of idiopathic interstitial pneumonia is given to a heterogenous group of interstitial lung diseases that are differentiated on the basis of their clinical, radiographic and pathologic features [1, 2]. Markers of lymphocyte activation carry worse prognosis in IPF, while in other cases, deficiencies in immune activation are noted These data, coupled with recent studies showing worse outcomes in IPF patients treated with the immunosuppressive regimen of prednisone, azathioprine and N-acetylcysteine [20] have led to the speculation that occult immune insults (e.g. infections) may drive at least some cases of IPF progression [21, 22]. This is underscored by recent studies showing that progressive disease in IPF is associated with overall bacterial burden as well as certain classes of organisms [12, 13]. Such biomarker analyses have provided potential insight into the pathogenic mechanisms which may account for IPF disease progression
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