Clustering analysis of HRCT parameters measured using a texture-based automated system: relationship with clinical outcomes of IPF.

PURPOSE: The extent of honeycombing and reticulation predict the clinical prognosis of IPF. Emphysema, consolidation, and ground glass opacity are visible in HRCT scans. To date, there have been few comprehensive studies that have used these parameters. We conducted automated quantitative analysis to identify predictive parameters for clinical outcomes and then grouped the subjects accordingly. METHODS: CT images were obtained while patients held their breath at full inspiration. Parameters were analyzed using an automated lung texture quantification system. Cluster analysis was conducted on 159 IPF patients and clinical profiles were compared between clusters in terms of survival. RESULTS: Kaplan-Meier analysis revealed that survival rates declined as fibrosis, reticulation, honeycombing, consolidation, and emphysema scores increased. Cox regression analysis revealed that reticulation had the most significant impact on survival rate, followed by honeycombing, consolidation, and emphysema scores. Hierarchical and K-means cluster analyses revealed 3 clusters. Cluster 1 (n = 126) with the lowest values for all parameters had the longest survival duration, and relatively-well preserved FVC and DLCO. Cluster 2 (n = 15) with high reticulation and consolidation scores had the lowest FVC and DLCO values with a predominance of female, while cluster 3 (n = 18) with high honeycombing and emphysema scores predominantly consisted of male smokers. Kaplan-Meier analysis revealed that cluster 2 had the lowest survival rate, followed by cluster 3 and cluster 1. CONCLUSION: Automated quantitative CT analysis provides valuable information for predicting clinical outcomes, and clustering based on these parameters may help identify the high-risk group for management.

Upregulation of receptor tyrosine kinase-like orphan receptor 2 in idiopathic pulmonary fibrosis.

BACKGROUND/AIMS: Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a major regulator of Wnt signaling, which is involved in fibroblast dysfunction. Because its role has not been evaluated in idiopathic pulmonary fibrosis (IPF), we examined the clinical implications of ROR2 expression. METHODS: ROR2 mRNA expression was measured using reverse transcription polymerase chain reaction in lung tissue-derived fibroblasts from IPF patients (n = 14) and from controls (n = 10). ROR2 protein was measured using enzyme-linked immunosorbent assay in primary fibroblasts from IPF patients (n = 14) and controls (n = 10), and in bronchoalveolar lavage (BAL) fluids obtained from normal controls (NC; n = 30). IPF patients (n = 84), and other patients with interstitial lung diseases, including nonspecific interstitial pneumonia (NSIP; n = 10), hypersensitivity pneumonitis (HP; n = 10), and sarcoidosis (n = 10). RESULTS: ROR2 mRNA and protein levels were significantly higher in IPF fibroblasts than in controls (p = 0.003, p = 0.0017, respectively). ROR2 protein levels in BAL fluids from patients with IPF were significantly higher than in those from NC (p < 0.001), and from patients with NSIP (p = 0.006), HP (p = 0.004), or sarcoidosis (p = 0.004). Receiver operating characteristic curves showed a clear difference between IPF and NC in ROR2 protein level (area under the curve, 0.890; confidence interval, 0.829 to 0.950; p < 0.001). ROR2 protein levels were significantly higher in GAP stage III than in GAP stages I and II (p = 0.016). CONCLUSION: ROR2 may be related to the development of IPF, and its protein level may be a useful and severity-dependent candidate marker for IPF.

The S100 calcium-binding protein A4 level is elevated in the lungs of patients with idiopathic pulmonary fibrosis.

BACKGROUND: Fibroblast dysfunction is the main pathogenic mechanism of idiopathic pulmonary fibrosis (IPF). S100 calcium-binding protein A4 (S100A4) plays critical roles in the proliferation of fibroblasts and in the development of pulmonary, hepatic, and renal fibrosis. However, the clinical implications of S100A4 in IPF have not been evaluated. METHODS AND MATERIALS: The S100A4 mRNA and protein levels were measured by real-time PCR and immunoblotting in fibroblasts from IPF patients and controls. The S100A4 level was measured by enzyme-linked immunosorbent assay in bronchoalveolar lavage fluid (BALF) from the normal controls (NCs; n = 33) and from patients with IPF (n = 87), non-specific interstitial pneumonia (NSIP; n = 22), hypersensitivity pneumonitis (HP; n = 19), and sarcoidosis (n = 9). S100A4 localization was evaluated by immunofluorescence staining. RESULTS: The S100A4 mRNA and protein levels were significantly higher in fibroblasts from IPF patients (n = 14) than in those from controls (n = 10, p < 0.001). The S100A4 protein level in BALF was significantly higher in the IPF (89.25 [49.92-203.02 pg/mL]), NSIP (74.53 [41.88-131.45 pg/mL]), HP (222.36 [104.92-436.92 pg/mL]) and sarcoidosis (101.62 [59.36-300.62 pg/mL]) patients than in the NCs (7.57 [1.31-14.04 pg/mL], p < 0.01, respectively). Cutoff S100A4 levels of 18.85 and 28.88 pg/mL had 87.4% and 87.8% accuracy, respectively, for discriminating IPF and other lung diseases from NCs. CONCLUSIONS: S100A4 is expressed by α-SMA-positive cells in the interstitium of the IPF patients. S100A4 may participate in the development of IPF, and its protein level may be a candidate diagnostic and therapeutic marker for IPF.