Longitudinal prediction of outcome in idiopathic pulmonary fibrosis using automated CT analysis

ABSTRACTAIMSTo evaluate computer-derived (CALIPER) CT variables against FVC change as potential drug trials endpoints in IPF.METHODS71 Royal Brompton Hospital (discovery cohort) and 23 Mayo Clinic Rochester and 24 St Antonius Hospital Nieuwegein IPF patients (validation cohort) were analysed. Patients had two CTs performed 5-30 months apart, concurrent FVC measurements and were not exposed to antifibrotics (to avoid confounding of mortality relationships from antifibrotic use). Cox regression analyses (adjusted for patient age and gender) evaluated outcome for annualized FVC and CALIPER vessel-related structures (VRS) change and examined the added prognostic value of thresholded VRS changes beyond standard FVC change thresholds.RESULTSChange in VRS was a stronger outcome predictor than FVC decline when examined as continuous variables, in discovery and validation cohorts. When FVC decline (≥10%) and VRS thresholds were examined together, the majority of VRS change thresholds independently predicted outcome, with no decrease in model fit. When analysed as co-endpoints, a VRS threshold of ≥0·40 identified 30% more patients reaching an endpoint than a ≥10% FVC decline threshold alone.CONCLUSIONSChange in VRS is a strong predictor of outcome in IPF and can increase power in future drug trials when used as a co-endpoint alongside FVC change.Ethics committee approvalApproval for this study of clinically indicated CT and pulmonary function data was obtained from Liverpool Research Ethics Committee (Reference: 14/NW/0028) and the Institutional Ethics Committee of the Royal Brompton Hospital, Mayo Clinic Rochester and St. Antonius Hospital, Nieuwegein. Informed patient consent was not required.Take home messageChange in the vessel-related structures, a computer-derived CT variable, is a strong predictor of outcome in idiopathic pulmonary fibrosis and can increase power in future drug trials when used as a co-endpoint alongside forced vital capacity change.

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Prognostic classification in acute exacerbation of idiopathic pulmonary fibrosis: a multicentre retrospective cohort study

Scientific Reports ◽

10.1038/s41598-021-88718-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Takahito Suzuki ◽

Hironao Hozumi ◽

Koichi Miyashita ◽

Masato Kono ◽

Yuzo Suzuki ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Acute Exacerbation ◽

Cox Regression ◽

Recursive Partitioning ◽

Survival Rates ◽

First Episode ◽

Characteristic Analysis ◽

Cox Regression Analysis ◽

Cumulative Survival

AbstractAcute exacerbation (AE) in idiopathic pulmonary fibrosis (IPF) is a major prognostic determinant. However, evidence for its prognostic strength is mainly based on the results of small cohort studies with statistical limitations. This retrospective study, which included 108 patients with a first episode of AE-IPF, aimed to identify prognostic factors and to develop prognostic classification models. Multivariate Cox regression analysis revealed that a lower percent-predicted forced vital capacity within 12 months before AE onset (baseline %FVC) and a lower PaO2/FiO2 ratio at AE onset were independent mortality predictors. If the value of each predictor was lower than the cutoff determined by receiver-operating characteristic analysis, 1 point was assigned. Classification of patients into mild, moderate, and severe groups based on total score showed post-AE 90-day cumulative survival rates of 83.3%, 66.2%, and 22.2%, respectively (model 1: C-index 0.702). Moreover, a decision tree-based model was created with the recursive partitioning method using baseline %FVC and PaO2/FiO2 ratio at AE onset from among multivariable; accordingly, patients were classified into 3 groups with post-AE 90-day cumulative survival rates of 84.1%, 64.3%, and 24.0%, respectively (model 2: C-index 0.735). These models can guide clinicians in determining therapeutic strategies and help design future studies on AE-IPF.

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Plasma Leptin Is Elevated in Acute Exacerbation of Idiopathic Pulmonary Fibrosis

Mediators of Inflammation ◽

10.1155/2016/6940480 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 14

Author(s):

Mengshu Cao ◽

Jeffery J. Swigris ◽

Xin Wang ◽

Min Cao ◽

Yuying Qiu ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Acute Exacerbation ◽

Proportional Hazards ◽

Cox Regression ◽

Plasma Concentrations ◽

Cox Proportional Hazards ◽

Healthy Controls ◽

Cox Regression Analysis ◽

Plasma Leptin

Background. The natural history of idiopathic pulmonary fibrosis (IPF) is very complex and unpredictable. Some patients will experience acute exacerbation (AE) and fatal outcomes.Methods. The study included 30 AE-IPF patients, 32 stable IPF (S-IPF) patients, and 12 healthy controls. We measured the plasma concentrations of leptin and KL-6. Simple correlation was used to assess associations between leptin and other variables. Plasma leptin levels were compared between AE-IPF and S-IPF subjects, decedents, and survivors. Kaplan-Meier curves were used to display survival and Cox proportional hazards regression was used to examine risk factors for survival.Results. In subjects with AE-IPF, plasma leptin was significantly greater than in subjects with S-IPF (p=0.0003) or healthy controls (p<0.0001). Plasma leptin was correlated with BMI, KL-6, LDH, CRP, and PaO2/FiO2(p=0.007;p=0.005;p=0.003;p=0.033;andp=0.032,resp.). Plasma leptin was significantly greater in 33 decedents than in the 23 survivors (p=0.007). Multivariate Cox regression analysis showed leptin (>13.79 ng/mL) was an independent predictor of survival (p=0.004).Conclusions. Leptin could be a promising plasma biomarker of AE-IPF occurrence and predictor of survival in IPF patients.

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Incidence and predictive factors of lung cancer in patients with idiopathic pulmonary fibrosis

ERJ Open Research ◽

10.1183/23120541.00111-2016 ◽

2018 ◽

Vol 4 (1) ◽

pp. 00111-2016 ◽

Cited By ~ 23

Author(s):

Eisuke Kato ◽

Noboru Takayanagi ◽

Yotaro Takaku ◽

Naho Kagiyama ◽

Tetsu Kanauchi ◽

...

Keyword(s):

Risk Factors ◽

Lung Cancer ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Interstitial Pneumonia ◽

Cox Regression ◽

Usual Interstitial Pneumonia ◽

Cancer Development ◽

Smoking History ◽

Incidence Density

The incidence and risk factors of lung cancer in patients with idiopathic pulmonary fibrosis (IPF) have been poorly investigated.We conducted a retrospective study of 632 patients with IPF to assess the incidence and risk factors of lung cancer development.Seventy patients developed lung cancer over a median follow-up period of 3.8 years. The incidence density of lung cancer development was 25.2 cases per 1000 person-years. The most frequent type was squamous cell carcinoma (30%), the majority developed lung cancer in the peripheral lung (82.9%) and adjacent to usual interstitial pneumonia (75.7%). In a multivariate Cox regression hazard model, pack-years of smoking ≥35 and coexisting emphysema were associated with lung cancer development. The 1-, 3- and 5-year all-cause mortality rates after lung cancer diagnosis were 53.5%, 78.6% and 92.9%, respectively.The incidence density of lung cancer is high in IPF patients and occurs more frequently in patients with smoking history of pack-years of smoking ≥35 and with coexisting emphysema. The majority of lung cancers develop adjacent to usual interstitial pneumonia. Knowledge of these factors may help direct efforts for early detection of lung cancer and disease management.

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Hospitalizations in patients with idiopathic pulmonary fibrosis

Respiratory Research ◽

10.1186/s12931-021-01851-4 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Hyun J. Kim ◽

Laurie D. Snyder ◽

Ayodeji Adegunsoye ◽

Megan L. Neely ◽

Shaun Bender ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Cox Regression ◽

Ventilatory Support ◽

Patient Characteristics ◽

Risk Of Mortality ◽

Point Increase ◽

Increased Risk ◽

The Impact

Abstract Background Hospitalizations are common among patients with idiopathic pulmonary fibrosis (IPF). We investigated the impact of hospitalizations on outcomes in patients with IPF. Methods The IPF-PRO Registry is an observational US registry that enrolled patients with IPF that was diagnosed or confirmed at the enrolling center in the previous 6 months. Associations between patient characteristics and hospitalization, and between hospitalization and mortality, were analyzed using Cox regression models. Results A total of 1002 patients with IPF were enrolled into the IPF-PRO Registry. Over a median follow-up time of 23.7 months (maximum: 67.0 months), 568 patients (56.7%) had at least one hospitalization. Of these patients, 319 (56.2%) had at least one respiratory-related hospitalization and 120 (21.1%) had at least one hospitalization with ventilatory support. Younger age (HR 0.68 [95% CI 0.55, 0.84] per 5-year increase for patients < 62 years), lower BMI (0.96 [0.93, 0.98] per 1-point increase), lower FVC % predicted (0.90 [0.83, 0.97] per 10% increase), oxygen use at rest (2.85 [2.18, 3.72]) and history of pulmonary hypertension (2.02 [1.37, 2.96]) at enrollment were associated with an increased risk of respiratory-related hospitalization during follow-up. In a multivariable model, there was an eightfold increase in the risk of mortality during hospitalization or within 90 days of discharge compared with outside of this period. The risk of mortality associated with a respiratory hospitalization or a hospitalization with ventilatory support was even greater. Conclusions Data from the IPF-PRO Registry demonstrate that hospitalizations are common among patients with IPF. The risk of mortality during hospitalization or within 90 days of discharge was high, particularly among patients who were hospitalized for a respiratory cause or received ventilatory support. Trial registration ClinicalTrials.gov, NCT01915511. Registered 5 August 2013, https://clinicaltrials.gov/ct2/show/NCT01915511

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Serial CT analysis in idiopathic pulmonary fibrosis: comparison of visual features that determine patient outcome

Thorax ◽

10.1136/thoraxjnl-2019-213865 ◽

2020 ◽

Vol 75 (8) ◽

pp. 648-654 ◽

Cited By ~ 2

Author(s):

Joseph Jacob ◽

Leon Aksman ◽

Nesrin Mogulkoc ◽

Alex J Procter ◽

Bahareh Gholipour ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Lung Disease ◽

Cox Regression ◽

Univariate Analysis ◽

Clinical Importance ◽

Ground Glass Opacity ◽

Mortality Prediction ◽

Ground Glass ◽

Traction Bronchiectasis

AimsPatients with idiopathic pulmonary fibrosis (IPF) receiving antifibrotic medication and patients with non-IPF fibrosing lung disease often demonstrate rates of annualised forced vital capacity (FVC) decline within the range of measurement variation (5.0%–9.9%). We examined whether change in visual CT variables could help confirm whether marginal FVC declines represented genuine clinical deterioration rather than measurement noise.MethodsIn two IPF cohorts (cohort 1: n=103, cohort 2: n=108), separate pairs of radiologists scored paired volumetric CTs (acquired between 6 and 24 months from baseline). Change in interstitial lung disease, honeycombing, reticulation, ground-glass opacity extents and traction bronchiectasis severity was evaluated using a 5-point scale, with mortality prediction analysed using univariable and multivariable Cox regression analyses. Both IPF populations were then combined to determine whether change in CT variables could predict mortality in patients with marginal FVC declines.ResultsOn univariate analysis, change in all CT variables except ground-glass opacity predicted mortality in both cohorts. On multivariate analysis adjusted for patient age, gender, antifibrotic use and baseline disease severity (diffusing capacity for carbon monoxide), change in traction bronchiectasis severity predicted mortality independent of FVC decline. Change in traction bronchiectasis severity demonstrated good interobserver agreement among both scorer pairs. Across all study patients with marginal FVC declines, change in traction bronchiectasis severity independently predicted mortality and identified more patients with deterioration than change in honeycombing extent.ConclusionsChange in traction bronchiectasis severity is a measure of disease progression that could be used to help resolve the clinical importance of marginal FVC declines.

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Prognostic Value of Serum Osteopontin in Acute Exacerbation of Idiopathic Pulmonary Fibrosis

BioMed Research International ◽

10.1155/2020/3424208 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Xianhua Gui ◽

Xiaohua Qiu ◽

Miaomiao Xie ◽

Yaqiong Tian ◽

Cao Min ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Acute Exacerbation ◽

Prognostic Value ◽

Proportional Hazards ◽

Cox Regression ◽

Cox Proportional Hazards ◽

Alveolar Epithelial Cells ◽

Healthy Controls ◽

Alveolar Epithelial

Background. Acute exacerbation (AE) is a common cause of rapid deterioration and high mortality in idiopathic pulmonary fibrosis (IPF) patients. Osteopontin (OPN) plays an important role in IPF, but the studies about serum OPN in AE-IPF are unclear. We aimed to investigate whether OPN had a potential prognostic value in acute exacerbation and mortality in IPF. Methods. Thirty-two patients with AE-IPF, 39 with S-IPF, and 20 healthy controls were included. Serum OPN and KL-6 levels were compared between AE-IPF and S-IPF. Logistic regression analysis was applied to identify the predicted value of OPN for AE. Kaplan–Meier curves were used to display survival, and Cox proportional hazards regression was used to identify risk for mortality. Results. In AE-IPF patients, serum OPN levels were significantly higher than in S-IPF subjects (p<0.001) or healthy controls (p<0.001). Immunohistochemical staining in lung transplant specimens of IPF showed strong expression of OPN in the alveolar epithelial cells lining honeycomb space and alveolar macrophages accumulating in interalveolar spaces adjacent to the fibrotic lesion. Serum OPN was correlated with higher C-reactive protein (CRP) and lactate dehydrogenase (LDH). Serum OPN, KL-6, CRP, LDH, percent forced vital capacity (FVC%), and percent diffusing capacity (DLCO%) in IPF were correlated with AE status, with respective odds ratios of 1.305 (p=0.004), 1.001 (p=0.010), 1.039 (p=0.002), 1.035 (p<0.001), 0.950 (p=0.024), and 0.929 (p=0.010). Serum OPN (above 3.24 ng/ml) was associated with an increasing risk of mortality (p=0.019). Multivariate Cox regression demonstrated an association of OPN levels with mortality risk (p=0.036). Conclusion. Elevated OPN could be a potential serum predictor for AE status and survival in IPF patients.

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Assessment of survival in patients with idiopathic pulmonary fibrosis using quantitative HRCT indexes

Multidisciplinary Respiratory Medicine ◽

10.4081/mrm.2018.206 ◽

2018 ◽

Vol 13 ◽

Cited By ~ 2

Author(s):

Sebastiano Emanuele Torrisi ◽

Stefano Palmucci ◽

Alessandro Stefano ◽

Giorgio Russo ◽

Alfredo Gaetano Torcitto ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Cox Regression ◽

Pulmonary Function Tests ◽

Information Criterion ◽

Accurate Estimation ◽

High Attenuation ◽

Kaplan Meier ◽

Prediction Of Mortality ◽

Significant Survival

Background: The assessment of Idiopathic Pulmonary Fibrosis (IPF) using HRCT requires great experience and is limited by a significant inter-observer variability, even between trained radiologists. The evaluation of HRCT through automated quantitative analysis may hopefully solve this problem. The accuracy of CT-histogram derived indexes in the assessment of survival in IPF patients has been poorly studied. Methods: Forty-two patients with a diagnosis of IPF and a follow up time of 3 years were retrospectively collected; HRCT and Pulmonary Function Tests (PFTs) performed at diagnosis time were analysed; the extent of fibrotic disease was quantified on HRCT using kurtosis, skewness, Mean Lung Density (MLD), High attenuation areas (HAA%) and Fibrotic Areas (FA%). Univariate Cox regression was performed to assess hazard ratios for the explored variables and a multivariate model considering skewness, FVC, DLCO and age was created to test their prognostic value in assessing survival. Through ROC analysis, threshold values demonstrating the best sensitivity and specificity in predicting mortality were identified. They were used as cut-off points to graph Kaplan-Meier curves specific for the CT-indexes. Results: Kurtosis, skewness, MLD, HAA% and FA% were good predictors of mortality (HR 0.44, 0.74, 1.01, 1.12, 1.06; p = 0.03, p = 0.01, p = 0.02, p = 0.02 and p = 0.017 respectively). Skewness demonstrated the lowest Akaike’s information criterion value (55.52), proving to be the best CT variable for prediction of mortality. Significant survival differences considering proposed cut-off points were also demonstrated according to kurtosis (p = 0. 02), skewness (p = 0.005), MLD (p = 0.003), HAA% (p = 0.009) and FA% (p = 0.02) – obtained from quantitative HRCT analysis at diagnosis time. Conclusions: CT-histogram derived indexes may provide an accurate estimation of survival in IPF.

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A Novel Established Pyroptosis-participant Genes Signature for Predicting the Prognosis of Idiopathic Pulmonary Fibrosis

10.21203/rs.3.rs-1129674/v1 ◽

2021 ◽

Author(s):

Qian He ◽

Yi Cao ◽

Yue Zhao ◽

Yi Shen ◽

Xiong Xu ◽

...

Keyword(s):

Overall Survival ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Cox Regression ◽

Prognostic Significance ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Clinical Prognosis ◽

Threat Score ◽

High Threat

Abstract Idiopathic pulmonary fibrosis (IPF), caused by a strange reason and characterized by a bad clinical prognosis, is an advanced, long-time, and irreversible interstitial lung disease (ILD). In recent years, it has been confirmed that a pyroptosis is a phlogistic form of programmed cellular demise. At the same time, the expression of the pyroptosis-participant gene (PPG) in IPF and their pertinence behind prognosis remains indistinct. In this research, we identified 17 pyroptosis regulators that were distinguishingly expressed entre IPF and controls. The ground on these distinguishingly expressed genes (DEGs), entire IPF conditions could be uncoupled into two subtypes. The prognostic significance of respective PPG for surviving was assessed to find a polygenes signature doing with a Gene Expression Omnibus (GEO) pack (GSE28042). Via putting into use the least absolute shrinkage and selection operator (LASSO) Cox regression approach, a 6-gene signature was structured and ranged entire IPF sicks in GSE28042 into a shallow-threat or high-threat group. IPF sicks in the shallow-threat group revealed meaningfully upper survival chances than those in the high-threat group (pvalue < 0.001). Exploiting the mid threat-score from GSE28042, IPF sicks from another GEO cohort(GSE70866-GPL17077) were separated into two threat subgroups, and the shallow-threat set had augmented overall survival (OS) time ( P = 0.0018). United the clinical characteristics, the threat-score was a sole element for forecasting the overall survival of IPF sicks. Function enrichment analyses bespoke that modification of morphology or physiology of other organisms, killing of cellular of other organisms, and disruption of cellular of other organisms biological processes were increased in the high-threat group. GSEA(Gene Set Enrichment Analysis) showed that cancer- and autoimmune disease-participant “KEGG” gene sets were highly enriched in the high−threat phenotype. In general, PPGs play a crucial role in IPF and can be done to forecast the prognosis of IPFs, and our consequences suggest that the high-threat group of IPF may be linked with the response of other organisms and autoimmunity as well.

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An 8-ferroptosis-related genes signature from Bronchoalveolar Lavage Fluid for prognosis in patients with idiopathic pulmonary fibrosis

BMC Pulmonary Medicine ◽

10.1186/s12890-021-01799-7 ◽

2022 ◽

Vol 22 (1) ◽

Author(s):

Yaowu He ◽

Yu Shang ◽

Yupeng Li ◽

Menghan Wang ◽

Dongping Yu ◽

...

Keyword(s):

Regression Analysis ◽

High Risk ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Risk Score ◽

Poor Prognosis ◽

Cox Regression ◽

Risk Group ◽

Curve Analysis ◽

Cox Regression Analysis

Abstract Background With the rapid advances of genetic and genomic technologies, the pathophysiological mechanisms of idiopathic pulmonary fibrosis (IPF) were gradually becoming clear, however, the prognosis of IPF was still poor. This study aimed to systematically explore the ferroptosis-related genes model associated with prognosis in IPF patients. Methods Datasets were collected from the Gene Expression Omnibus (GEO). The least absolute shrinkage and selection operator (LASSO) Cox regression analysis was applied to create a multi-gene predicted model from patients with IPF in the Freiburg cohort of the GSE70866 dataset. The Siena cohort and the Leuven cohort were used for validation. Results Nineteen differentially expressed genes (DEGs) between the patients with IPF and control were associated with poor prognosis based on the univariate Cox regression analysis (all P < 0.05). According to the median value of the risk score derived from an 8-ferroptosis-related genes signature, the three cohorts’ patients were stratified into two risk groups. Prognosis of high-risk group (high risk score) was significantly poorer compared with low-risk group in the three cohorts. According to multivariate Cox regression analyses, the risk score was an independently predictor for poor prognosis in the three cohorts. Receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA) confirmed the signature's predictive value in the three cohorts. According to functional analysis, inflammation- and immune-related pathways and biological process could participate in the progression of IPF. Conclusions These results imply that the 8-ferroptosis-related genes signature in the bronchoalveolar lavage samples might be an effective model to predict the poor prognosis of IPF.

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