Evaluation of the Diagnostic Efficacies of Serological Markers KL-6, SP-A, SP-D, CCL2, and CXCL13 in Idiopathic Interstitial Pneumonia

Abstract

<b><i>Background:</i></b> The objective of this study was to evaluate the diagnostic value of serological markers Krebs von den Lungen-6 (KL-6), surfactant protein-A (SP-A), SP-D, chemokine ligand 2 (CCL2), and chemokine 13 (CXCL13) in idiopathic interstitial pneumonia (IIP). <b><i>Methods:</i></b> Patients with IIP aged 18–80 years from the First Affiliated Hospital of Guangzhou Medical University were enrolled in this retrospective case-control study. Data on the general patient characteristics, laboratory test results, chest high-resolution CT, and pulmonary function test results were collected. The diagnosis of idiopathic pulmonary fibrosis (IPF) was based on the international practice guidelines for the diagnosis and treatment of IPF, a collaborative effort published by the American Thoracic Society (ATS)/European Respiratory Association (ERS), Japanese Respiratory Society, and Latin American Thoracic Society. The diagnostic criteria of non-IPF (N-IPF) followed the consensus classification of the IIPs, which was jointly issued by the ATS and ERS in 2002. The diagnosis of interstitial pneumonia with autoimmune features (IPAF) was based on the official research statement on IPAF, which was jointly issued by the ATS and ERS in 2015. Serum levels of KL-6, SP-A, SP-D, CCL2, and CXCL13 were measured. The differences in the expression of these biomarkers and their correlation with the severity of the disease were analyzed. The sensitivity, specificity, cutoff value, and area under the curve (AUC) value for each of the indices were determined using the receiver operating characteristic (ROC) curve analysis. <b><i>Findings:</i></b> Between September 2015 and October 2017, 69 patients with IIP. Of these patients, 19 had IPF, 23 had N-IPF, and 27 had IPAF. We also enrolled 20 age- and gender-matched patients with pneumonia and 15 uninfected individuals as normal control. The serum levels of KL-6, SP-A, ­SP-D, CCL2, and CXCL13 were significantly higher in patients with IIP than in patients with pneumonia and the normal controls. The detection of these markers was found to have better diagnostic efficacy in patients with IIP than in those with pneumonia. Of these markers above, KL-6 had the highest diagnostic value (AUC 0.96, 95% CI 0.93–0.99). Based on a logistics regression analysis, the combination of KL-6, CCL2, and CXCL13 had an improved diagnostic efficacy for IIP. In patients with IIP, the serum levels of KL-6, SP-A, CCL2, and CXCL13 all showed a significant negative correlation with the diffusing capacity of the lungs for carbon monoxide (DLCO; <i>r</i> = –0.36, –0.37, –0.36, –0.30, respectively; all <i>p</i> < 0.05). Although their expression levels along with that of SP-D were elevated in patients with IPF, N-IPF, and IPAF, it was difficult to distinguish between these 3 conditions by detecting the 5 serum biomarkers together. Our findings indicate that the serum levels of KL-6, SP-A, SP-D, CCL2, and CXCL13 are notably elevated in patients with IIP and show significant correlation with the severity of interstitial lung lesions. Additionally, we further explore the diagnostic efficacy of 5 biomarkers in different types of IIP. It is the first time that the level of serum marker CXCL13 of N-IPF and IPAF patients was higher than IPF patients, which further enriched the study on serum markers for IIPs. Between September 2015 and October 2017, 69 patients with IIP. Of these patients, 19 had IPF, 23 had N-IPF, and 27 had IPAF. We also enrolled 20 age- and gender-matched patients with pneumonia and 15 uninfected individuals as normal control. The serum levels of KL-6, SP-A, SP-D, CCL2, and CXCL13 were significantly higher in patients with IIP than in patients with pneumonia and the normal controls. Of these markers above, KL-6 had the highest diagnostic value (AUC 0.96, 95% CI 0.93–0.99). Based on a logistics regression analysis, the combination of KL-6, CCL2, and CXCL13 had an improved diagnostic efficacy for IIP. In patients with IIP, the serum levels of KL-6, SP-A, CCL2, and CXCL13 all showed a significant negative correlation with the DLCO (<i>r</i> = –0.36, –0.37, –0.36, –0.30, respectively; all <i>p</i> < 0.05). Our findings indicate that the serum levels of KL-6, ­SP-A, SP-D, CCL2, and CXCL13 are notably elevated in patients with IIP and show significant correlation with the severity of interstitial lung lesions. Additionally, we further explore the diagnostic efficacy of 5 biomarkers in different types of IIP. It is the first time that the level of serum marker CXCL13 of N-IPF and IPAF patients was higher than IPF patients, which further enrich the study on serum markers in IIPs. <b><i>Interpretation:</i></b> Although the combined detection of KL-6, CCL3, and CXCL13 significantly improves the diagnosis of IIP, detection of all the 5 markers together is unable to distinguish between IPF, N-IPF, and IPAF.

Lung in chronic autoimmune diseases and hypersensitivity – how to separate these from idiopathic pulmonary fibrosis

“…Not much reports have focused on AID /connective tissue diseases, although patterns seen in chronic AID are very similar to IPF [40]. Even genetic alterations of surfactant and telomerase genes have been reported in AID similar to IPF [41,42]. Whereas an NSIP pattern almost exclusively is associated with AID or HP, an UIP pattern has a wider range of differentials.…”

Co-trimoxazole to reduce mortality, transplant, or unplanned hospitalisation in people with moderate to very severe idiopathic pulmonary fibrosis: the EME-TIPAC RCT

“…Monocyte chemotactic protein 1 (MCP-1; also known as CCL2) is another monocyte activity marker and its levels are increased in people with IIP. 75 MCP-1 is significantly correlated with interstitial lung lesions. In addition, a monoclonal antibody that neutralises the fibrotic activities of MCP-1 has been used in a clinical trial.…”

Biomarkers in Idiopathic Pulmonary Fibrosis

“…Hamai et al [201] found that a combination of MMP-7 and KL-6 potentially support the diagnosis of IPF and might improve survival prediction in patients with IPF. Recently published study Xue et al [202], found that KL-6, CCL3, and CXCL13 significantly improves the diagnosis of idiopathic interstitial pneumonia. IPF patients with a high level of SP-D but low KL-6 in their serum had a better prognosis [203].…”