Elevated serum human epididymis protein 4 is associated with disease severity and worse survival in idiopathic pulmonary fibrosis: a cohort study.

Elevated expression of human epididymis protein 4 (HE4) was previously described in connective tissue disease-associated interstitial lung diseases (CTD-ILDs) and cystic fibrosis (CF), but the clinical significance of HE4 has remained unknown in idiopathic pulmonary fibrosis (IPF), which is a progressive fibrosing ILD with a heterogeneous course that is in urgent need of reliable biomarkers in its clinical practice. A total of 27 IPF patients with acute exacerbation status (AE-IPF), 32 IPF patients with stable status (S-IPF), and 29 sex-age matched healthy controls were retrospectively included. The levels of serum HE4 and Krebs von den Lungen-6 (KL-6) of the 3 cohorts were measured. In addition, the pulmonary expression of HE4 was evaluated in lung transplant specimens of IPF using immunohistochemistry and Western blot, and noncancerous lung tissue resected from early-stage lung cancer patients as controls. The endpoint of follow-up was March 1st, 2022, and the Cox regression model was used to analyze the prognostic value of HE4. The levels of HE4 and KL-6 were obviously elevated in AE-IPF patients compared to S-IPF (296.4 vs. 178.1 pmol/L for HE4, P<0.001; 2,007.0 vs. 990.5 IU/mL for KL-6, P<0.001) or healthy controls (296.4 vs. 51.8 pmol/L for HE4, P<0.001; 2,007.0 vs. 181.0 IU/mL for KL-6, P<0.001). Significant correlations were observed between serum HE4 levels and percent predicted diffusing capacity of the lung for carbon monoxide (DLCO%) (r=-0.526, P<0.001), percent predicted forced vital capacity (FVC%) (r=-0.344, P=0.024), gender-age-physiology (GAP) index (r=0.535, P<0.001), and oxygenation index (r=-0.550, P<0.001) in IPF patients. In histological analysis, overexpression of HE4 in mucosal epithelium of dilated bronchi was observed in IPF patients compared with controls. Multivariate cox regression revealed that serum levels of HE4 [hazard ratio (HR) =1.004, P=0.042] and GAP index (HR =1.374, P=0.010) were associated with worse survival in IPF patients. The expression of serum HE4 was obviously elevated in IPF patients, especially in AE-IPF patients. In addition, serum HE4 could be utilized as a biomarker of disease severity and poor prognosis of IPF patients. These findings warrant further validation in larger, multi-center, and longitudinal cohorts.

Tian M ，Meng K ，Gao Y ，Zhang J ，Xie M ，Tian Y ，Liu X ，Ma M ，Cai Y ，Wu H ，Ding J ，Chen J ，Cai H ... -  《-》

Human epididymis protein 4 is associated with severity and poor prognosis of connective tissue disease-associated interstitial lung disease with usual interstitial pneumonia pattern.

Overexpression of human epididymis protein 4 (HE4) was previously described in idiopathic pulmonary fibrosis (IPF), but whether serum HE4 can be considered as a potential biomarker in connective tissue disease-associated interstitial lung disease (CTD-ILD) with usual interstitial pneumonia (UIP) pattern was still unknown. A total of 55 CTD-ILD patients with UIP pattern (UIP-CTD) and 52 healthy controls were enrolled in this study. The serum levels of HE4 and Krebs von den Lungen-6 (KL-6) were evaluated in both cohorts. In addition, immunohistochemistry analysis for HE4 was performed on the lung sections of 6 patients with rheumatoid arthritis-associated UIP (UIP-RA) and 6 patients with early-stage lung cancer as normal control. The levels of serum HE4 and KL-6 were higher in patients with UIP-CTD than in healthy controls (292.3 pmol/L versus 79.5 pmol/L for HE4, p < 0.001; 1091.0 IU/mL versus 171.5 IU/mL for KL-6, p < 0.001). Significant correlations between serum HE4 levels and percentpredicted forced vital capacity (FVC%) (r = -0.425, p = 0.004), percent predicted diffusing capacity of the lung for carbon monoxide (DLCO%) (r = -0.447, p = 0.003), and Gender-Age-Physiology (GAP) index (r = 0.494, p < 0.001) were observed in UIP-CTD patients. In immunohistochemistry analysis, elevated expression of HE4 in bronchiolar epithelium and mesenchyme was observed in patients with UIP-RA compared with controls. The serum levels of HE4 (≥277.5 pmol/L) and GAP index were related to an increased risk of mortality (HR = 3.884, p = 0.034; HR = 1.480, p = 0.028, respectively). The expression of HE4 in serum and lung specimens was significantly elevated in UIP-CTD patients. Moreover, serum HE4 may be utilized as a biomarker to evaluate the severity of disease and predict the prognosis of UIP-CTD patients.

Meng K ，Tian M ，Gui X ，Xie M ，Gao Y ，Shi S ，Zhao T ，Xiao Y ，Cai H ，Ding J ... -  《-》

[Characteristics and clinical significance of pulmonary function test and KL-6 in ASSD-ILD and IPF].

Sun D ，Cheng Z ，Jiang TC ，Li PF ，Jia LQ ，Wang TT ，Zheng CP ，Li Y ，Duo MJ ... -  《-》

Human epididymis protein 4 is a new biomarker to predict the prognosis of progressive fibrosing interstitial lung disease.

The clinical course and prognosis of progressive fibrosing interstitial lung diseases (PF-ILDs) vary between individuals. Notably, predictive serum biomarkers for disease management are needed. Serum human epididymis protein 4 (HE4) is reportedly elevated in patients with idiopathic pulmonary fibrosis (IPF); however, its clinical utility remains unknown. We evaluated the potential of serum HE4 as a biomarker for patients with PF-ILD. Serum HE4 was measured in a retrospective study consisting of 34 patients with PF-ILD and 40 healthy volunteers. The relationship between serum HE4 levels and clinical parameters or prognosis was investigated. To validate the significance of results obtained, a prospective observational study was performed in 37 patients presenting PF-ILD and 40 control patients without PF-ILD. Serum HE4 levels were higher in patients with PF-ILD than in healthy volunteers (P < 0.01). Moreover, serum HE4 levels correlated with the extent of honeycombing on chest high-resolution computed tomography (r = 0.41, P = 0.015). In multivariate analysis using the Cox proportional hazard model, higher HE4 levels (>238 pmol/L) were associated with an elevated mortality risk; hazard ratio (HR) 7.27, 95% CI 1.56-34.0, P = 0.01 in the derivation cohort; HR 44.3, 95% CI 4.19-468, P < 0.01 in validation cohort. Serum HE4 levels may serve as a new diagnostic and prognostic biomarker for patients with PF-ILD.

Nishiyama N ，Masuo M ，Nukui Y ，Tateishi T ，Kishino M ，Tateishi U ，Morota K ，Ohbo K ，Miyazaki Y ... -  《-》

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

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). 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. 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; r = -0.36, -0.37, -0.36, -0.30, respectively; all p < 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 (r = -0.36, -0.37, -0.36, -0.30, respectively; all p < 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. 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.

Xue M ，Guo Z ，Cai C ，Sun B ，Wang H ... -  《-》