A novel seven-gene risk profile in BALF to identify high-risk patients with idiopathic pulmonary fibrosis

BackgroundIdiopathic pulmonary fibrosis (IPF) is a fatal heterogeneous disease with a varied clinical course that is difficult to predict. Accurate predictive models are urgently needed to identify individuals with poor survival for the optimal timing of referral for transplantation and provide some clues for mechanistic research on disease progression.MethodsWe obtained the gene expression profiles of bronchoalveolar lavage fluid (BALF) from the Gene Expression Omnibus. Individuals from the {"type":"entrez-geo","attrs":{"text":"GPL14550","term_id":"14550"}}GPL14550 platform were assigned to the derivation cohort (n=112) and individuals from the {"type":"entrez-geo","attrs":{"text":"GPL17077","term_id":"17077"}}GPL17077 platform to the validation cohort (n=64). Univariate Cox and least absolute shrinkage and selection operator (LASSO) regression analyses were applied to select candidate genes for overall survival. A nomogram model was constructed based on Cox hazard regression analysis. The model was assessed by C-statistic, calibration curve, and decision curve analysis (DCA) and was externally validated.ResultsA nomogram model comprising seven genes was constructed. Excellent discrimination and calibration were observed in the derivation (C-index 0.815) and validation (C-index 0.812) cohorts. The AUCs for predicting 1-, 2- and 3-year survival were 0.857, 0.918, 0.930 in the derivation cohort and 0.850, 0.880, 0.925 in the validation cohort, respectively. DCA confirmed the clinical applicability of the model. A risk score based on the model was an independent prognostic predictor and could divide patients into high- and low-risk groups. The Kaplan-Meier analysis displayed that high-risk patients exhibited significantly poorer survival compared with low-risk patients. Gene Set Enrichment Analysis (GSEA) showed that high-risk patients were primarily enriched in inflammatory hallmarks, and single sample GSEA (ssGSEA) indicated that the high-risk group is closely correlated with the immune process. These lead to increased insight into mechanisms associated with IPF progression that inflammation mediated by immune response might be involved in the disease progression.ConclusionsThe novel BALF seven-gene model performed well in risk stratification and individualized survival prediction for patients with IPF, facilitating personalized management of IPF patients. It deepened the understanding of the role of inflammation in IPF progression, which needs to be further studied.     

Corticosteroids in idiopathic pulmonary fibrosis

Corticosteroids were the mainstay of therapy for idiopathic pulmonary fibrosis (IPF) for more than four decades, but their efficacy is unproven and toxicities are substantial. The course of IPF is characterized by progressive respiratory insufficiency, leading to death within 3 to 8 years from the onset of symptoms. Although a subset (10-20%) of patients survives more than 10 years, there is no evidence that any form of therapy alters the natural history of the disease. Nonetheless, given the poor prognosis, a trial of corticosteroids is often given. Because of the rarity of IPF, randomized, placebo-controlled therapeutic trials have not been done. Further, no studies have compared differing dosages or duration of corticosteroid in matched patients. Interpretation of therapy efficacy is obscured by several factors including heterogeneous patient populations, inclusion of patients with histologic entities other than usual interstitial pneumonia, lack of objective, validated endpoints, different criteria for "response." We review published data regarding corticosteroid therapy for IPF and present a rationale for stratifying therapy based on host, demographic, and clinical factors that influence prognosis as well as risk for corticosteroid complications.     

端粒与特发性肺纤维化

特发性肺纤维化（idiopathic pulmonary fibrosis,IPF）是特发性间质性肺炎（idiopathic interstitial pneumonia,IIPs）中最常见的类型,人群中患病率为13～20/10万,男性较女性多见,其流行病学与患病率随着年龄增长而增加[1]。在IPF患病群体中,2%～20%的患者有家族史,     

MicroRNA 与特发性肺纤维化

特发性肺纤维化(idiopathic pulmonary fibrosis,IPF)是一种不明原因引起的以肺间质纤维化和肺功能损害为特点的进行性发展的肺部疾病,目前的治疗效果十分有限,存活期大概为诊断后的2.5~3.5年。虽然国内外有关肺纤维化的研究在不断取得新的进展,但迄今为止,IPF 的发病机制仍不得而知。微小 RNA (microRNA,miRNA)是一类由17~24个核苷酸构成的功能性非编码小分子 RNA。近年来,miRNA 因其对诸多生命活动的重要调控作用而备受关注,已经有部分 miRNA被证明与肺纤维化的发病机制存在着密切的关系。本文将对 miRNA 与 IPF 的关系的研究进展作一综述。     

Comparison of BALF concentrations of ENA-78 and IP10 in patients with idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia

BACKGROUND: Epithelial neutrophil-activating peptide 78 (ENA-78) and interferon gamma-inducible protein 10 (IP10) belong to the CXC chemokine family and are considered to be important factors in idiopathic pulmonary fibrosis (IPF). Idiopathic nonspecific interstitial pneumonia (NSIP) and IPF are the two largest subsets of idiopathic interstitial pneumonias (IIP). In patients with NSIP, the prognosis is generally good compared with IPF. Therefore, the pathogenesis of NSIP seems to be different from that of IPF, but this remains unclear. The aim of the present study was to evaluate the contribution of ENA-78 and IP10 in the two diseases. METHODS: We measured the levels of ENA-78 and IP10 in serum and bronchoalveolar lavage fluid (BALF) of patients with IPF (n=17), idiopathic NSIP (n=10) and healthy subjects (n=12) by enzyme-linked immunosorbent assays. RESULTS: The level of ENA-78 in BALF was significantly higher in IPF patients than in NSIP patients and controls. Serum levels of ENA-78 and BALF levels of IP10 in NSIP patients were significantly higher than in patients with IPF and controls. In BALF of patients with NSIP, IP10 level significantly correlated with the absolute number of lymphocytes. In IPF patients, BALF IP10 levels also correlated with the proportion of lymphocytes in BALF. CONCLUSION: Our results show distinct profiles of CXC chemokines in IPF and NSIP, and suggest that these chemokines play an important role in inflammatory cell recruitment into the lung in patients with IIP.     

Prediction of pulmonary hypertension in idiopathic pulmonary fibrosis

BACKGROUND: Reliable, noninvasive approaches to the diagnosis of pulmonary hypertension in idiopathic pulmonary fibrosis are needed. We tested the hypothesis that the forced vital capacity to diffusing capacity ratio and room air resting pulse oximetry may be combined to predict mean pulmonary artery pressure (MPAP) in idiopathic pulmonary fibrosis. METHODS: Sixty-one idiopathic pulmonary fibrosis patients with available right-heart catheterization were studied. We regressed measured MPAP as a continuous variable on pulse oximetry (SpO(2)) and percent predicted forced vital capacity (FVC) to percent-predicted diffusing capacity ratio (% FVC/% DL(co)) in a multivariable linear regression model. RESULTS: Linear regression generated the following equation: MPAP=-11.9+0.272 x SpO(2)+0.0659 x (100-SpO(2))(2)+3.06 x (% FVC/% DL(co)); adjusted R(2)=0.55, p<0.0001. The sensitivity, specificity, positive predictive and negative predictive value of model-predicted pulmonary hypertension were 71% (95% confidence interval (CI): 50-89%), 81% (95% CI: 68-92%), 71% (95% CI: 51-87%) and 81% (95% CI: 68-94%). CONCLUSIONS: A pulmonary hypertension predictor based on room air resting pulse oximetry and FVC to diffusing capacity ratio has a relatively high negative predictive value. However, this model will require external validation before it can be used in clinical practice.     

Pulmonary hypertension in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is an untreatable diffuse parenchymal lung disease with a median survival of < 3 years. Pulmonary hypertension (PH) is frequently seen in patients with IPF and is commonly attributed to hypoxic vasoconstriction and capillary destruction. Pathology findings include endothelial proliferation and medial hypertrophy that exceed those expected in the setting of hypoxia. Noninvasive evaluation has limited sensitivity and specificity for the diagnosis of PH in IPF; therefore, right-heart catheterization remains the "gold standard" diagnostic test. PH in patients with IPF is associated with decreased exercise capacity and worse survival. Given the grave consequences of this condition, treatment of PH could improve functional outcomes and survival. However, possible treatments such as long-term supplemental oxygen and targeted vascular therapy are either unstudied or remain unproven.     

Serum biomarkers in idiopathic pulmonary fibrosis

Within the group of Idiopathic Interstitial Pneumonias (IIPs), above all Idiopathic Pulmonary Fibrosis (IPF) poses a considerable diagnostic and therapeutic problem. Although genetic profiling indicates that IPF, Non Specific Interstitial Pneumonia (NSIP), and chronic hypersensitivity pneumonitis (HP) are distinctly different diseases, in every day practice these diseases can be difficult to tell apart. Furthermore, treatment of these diseases is notoriously difficult. Serum biomarkers reflect our understanding of the underlying pathogenesis and potentially fulfill a role in establishing a diagnosis, prognosis and therapy. While no single biomarker is currently able to accurately predict the presence or absence of an IIP, a composite of several markers holds promise for the future. Several biomarkers, such as KL-6, surfactant proteins and circulating fibrocytes, appear to contribute to our insight into disease progression and prognosis. It is however uncertain whether these markers give us additional information to common diagnostic tests and their value has as yet to be validated for every day practice. Fortunately, the potential of biomarkers is increasingly recognized and biomarker data are prospectively gathered in current placebo-controlled therapeutic trials.