The role of interleukin-6 as a prognostic biomarker for predicting acute exacerbation in interstitial lung diseases

PLOS ONE RESEARCH ARTICLE The role of interleukin-6 as a prognostic biomarker for predicting acute exacerbation in interstitial lung diseases Jae Ha Lee ID1, Ji Hoon Jang ID1, Jin Han Park1, Hang-Jea Jang1, Chan Sun Park2, Sunggun Lee3, Seong-Ho Kim3, Ji Yeon Kim4, Hyun Kuk Kim1* a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 1 Division of Pulmonology, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea, 2 Division of Allergy, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea, 3 Division of Rheumatology, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea, 4 Division of Pathology, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea * Abstract OPEN ACCESS Citation: Lee JH, Jang JH, Park JH, Jang H-J, Park CS, Lee S, et al. (2021) The role of interleukin-6 as a prognostic biomarker for predicting acute exacerbation in interstitial lung diseases. PLoS ONE 16(7): e0255365. https://doi.org/10.1371/journal. pone.0255365 Editor: Minghua Wu, University of Texas McGowan Medical School at Houston, UNITED STATES Received: February 6, 2021 Accepted: July 14, 2021 Published: July 27, 2021 Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here: https://doi.org/10.1371/journal.pone.0255365 Copyright: © 2021 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the manuscript and its Supporting information files. Background Interstitial lung diseases (ILDs) are chronic, parenchymal lung diseases with a variable clinical course and a poor prognosis. Within various clinical courses, acute exacerbation (AE) is a devastating condition with significant morbidity and high mortality. The aim of this study was to investigate the role of interleukin-6 (IL-6) to predict AE and prognosis in patients with ILD. Methods Eighty-three patients who were diagnosed with ILD from 2016 to 2019 at the Haeundae Paik Hospital, Busan, South Korea, were included and their clinical data were retrospectively analyzed. Results The median follow-up period was 20 months. The mean age was 68.1 years and 65.1% of the patients were men with 60.2% of patients being ever-smokers. Among ILDs, idiopathic pulmonary fibrosis was the most common disease (68.7%), followed by connective tissue disease-associated ILD (14.5%), cryptogenic organizing pneumonia (9.6%), and nonspecific interstitial pneumonia (6.0%). The serum levels of IL-6 were measured at diagnosis with ILD and sequentially at follow-up visits. During the follow-ups, 15 (18.1%) patients experienced an acute exacerbation (AE) of ILD and among them, four (26.7%) patients died. In the multivariable analysis, high levels of IL-6 (OR 1.014, 95% CI: 1.001–1.027, p = 0.036) along with lower baseline saturations of peripheral oxygen (SpO2) were independent risk factors for AE. In the receiver operating characteristic curve analysis, the area under the curve was 0.815 (p < 0.001) and the optimal cut-off value of serum IL-6 to predict AE was 25.20 pg/mL with a sensitivity of 66.7% and specificity of 80.6%. In the multivariable Cox PLOS ONE | https://doi.org/10.1371/journal.pone.0255365 July 27, 2021 1 / 13 PLOS ONE The role of IL-6 for predicting acute exacerbation of interstitial lung disease Funding: This work was supported by 2019 Inje university research grant (20190041). The grant did not have any influence on the research results and was a support to promote the research activities. analysis, a high level of serum IL-6 (HR 1.007, 95% CI: 1.001–1.014, p = 0.018) was only an independent risk factor for mortality in ILD patients. Competing interests: The authors have declared that no competing interests exist. In our study, a high level of serum IL-6 is a useful biomarker to predict AE and poor prognosis in patients with ILD. Conclusions Introduction Interstitial lung diseases (ILD) are a heterogeneous group of diffuse parenchymal lung disorders with highly variable clinical courses and poor outcomes [1]. Within variable clinical courses, acute exacerbation (AE) is well-known as a life threatening condition with significant morbidity and high mortality [2, 3]. In terms of AE, the incidence in patients with idiopathic pulmonary fibrosis (IPF) is 5–10% per year with a median survival of less than 3 months [4–6]. Previous studies reported that old age, lower lung function including forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLco), and distances or de-saturation during the six minute walk test (6MWT) were risk factors for AE IPF [7, 8]. However, because of limitations of physiologic parameters such as dependency on patient efforts or interobserver variability, predicting AE remains difficult [9]. Serum biomarkers are relatively easy to measure independently of patient effort or observer ability. Within the pathogenesis of AE-IPF, there have been several reports that cytokines may play an important role [10, 11]. Among cytokines, IL-6 is a soluble mediator with pleiotropic effects on inflammation, immune responses, and fibrosis [12, 13]. In a recent study, Shochet et al. reported in experimental research between IPF patients and normal healthy donors that IL-6 trans-signaling components lead to indirect TGF-β, which is well-known as a pro-fibrotic growth factor with an influence on pathway activation and disease progression, suggesting the importance of IL-6 in IPF pathogenesis [14]. Therefore, our aim in this study was to evaluate the role of IL-6 as a biomarker for predicting AE and prognosis in patients with ILD. Materials and methods Study subjects Eighty-three patients who were diagnosed with ILD at the Haeundae-Paik Hospital, Busan, Republic of Korea, from December 2016 to September 2019, were included in this study. Among the patients with ILD, patients who had serum IL-6 levels measured at diagnosis with ILD and at follow-up visits consecutively every 2–3 months were included. All the patients met the diagnostic criteria in the international guidelines set by the American Thoracic Society (ATS) and European Respiratory Society (ERS) [15, 16]. This study was approved by the Institutional Review Board of the Haeundae-Paik Hospital (approval number: 2019-12-036), and the requirement for written informed consent was waived due to the (...truncated)