A novel protein signature from plasma extracellular vesicles for non-invasive differential diagnosis of idiopathic pulmonary fibrosis
Adduri, Raju SR, Kai Cai, Karen V. Alzate, Ravikiran Vasireddy, Jeffrey W. Miller, Sergio Poli de Frias, Fernando Poli de Frias et al. "A novel protein signature from plasma extracellular vesicles for non-invasive differential diagnosis of idiopathic pulmonary fibrosis." medRxiv (2021).
Background Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial pneumonia of unknown etiology often leading to respiratory failure. Over half of IPF patients present with discordant features of usual interstitial pneumonia on high-resolution computed tomography at diagnosis which warrants surgical lung biopsy to exclude the possibility of other interstitial lung diseases (ILDs). Therefore, there is a need for non-invasive biomarkers for expediting the differential diagnosis of IPF. Methods Using mass spectrometry, we performed proteomic analysis of plasma extracellular vesicles (EVs) in a cohort of subjects with IPF, chronic hypersensitivity pneumonitis, nonspecific interstitial pneumonitis, and healthy subjects (HS). A five-protein signature was identified by lasso regression and was validated in an independent cohort using ELISA. We evaluated the concordance between plasma EV proteome and the lung transcriptome data. Lastly, we compared the molecular pathways overrepresented in IPF by differentially expressed proteins and transcripts from EVs and lung tissues, respectively. Results The five-protein signature derived from mass spectrometry data showed area under the receiver operating characteristic curve of 0.915 (95%CI: 0.819-1.011) and 0.958 (95%CI: 0.882-1.034) for differentiating IPF from other ILDs and from HS, respectively. We also found that the EV protein expression profiles mirrored their corresponding mRNA expressions in IPF lungs. Further, we observed an overlap in the EV proteome- and lung mRNA-associated molecular pathways. Conclusions We discovered a plasma EV-based protein signature for differential diagnosis of IPF and validated this signature in an independent cohort. The signature needs to be tested in large prospective cohorts to establish its clinical utility. Competing Interest Statement AKP is employed with Izon Science US Ltd. The company has no role in design of the study and acquisition of experimental data and interpretation. All other authors have no conflict of interests. Funding Statement This work was supported by UT System Rising STARs award and core funds from UTHSCT, Tyler, Texas, to NVK. DN received funding from NIH (R01 GM083122). Cryo-TEM is supported by Cancer Prevention and Research Institute of Texas grant RR140082 to DN. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by institutional review boards of University of Pittsburgh (IRB STUDY19040326 and STUDY20030223), Brigham and Womens hospital (IRB2012P000840), Hiroshima University (IRBM326) and University of Texas Health Science Center at Tyler (IRB 20-019 & 0000370). All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes