Integrative multi-omics analysis reveals novel idiopathic pulmonary fibrosis endotypes associated with disease progression.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of extracellular matrix in the pulmonary interstitium and progressive functional decline. We hypothesized that integration of multi-omics data would identify clinically meaningful molecular endotypes of IPF. METHODS: The IPF-PRO Registry is a prospective registry of patients with IPF. Proteomic and transcriptomic (including total RNA [toRNA] and microRNA [miRNA]) analyses were performed using blood collected at enrollment. Molecular data were integrated using Similarity Network Fusion, followed by unsupervised spectral clustering to identify molecular subtypes. Cox proportional hazards models tested the relationship between these subtypes and progression-free and transplant-free survival. The molecular subtypes were compared to risk groups based on a previously described 52-gene (toRNA expression) signature. Biological characteristics of the molecular subtypes were evaluated via linear regression differential expression and canonical pathways (Ingenuity Pathway Analysis [IPA]) over-representation analyses. RESULTS: Among 232 subjects, two molecular subtypes were identified. Subtype 1 (n = 105, 45.3%) and Subtype 2 (n = 127, 54.7%) had similar distributions of age (70.1 +/- 8.1 vs. 69.3 +/- 7.6 years; p = 0.31) and sex (79.1% vs. 70.1% males, p = 0.16). Subtype 1 had more severe disease based on composite physiologic index (CPI) (55.8 vs. 51.2; p = 0.002). After adjusting for CPI and antifibrotic treatment at enrollment, subtype 1 experienced shorter progression-free survival (HR 1.79, 95% CI 1.28,2.56; p = 0.0008) and similar transplant-free survival (HR 1.30, 95% CI 0.87,1.96; p = 0.20) as subtype 2. There was little agreement in the distribution of subjects to the molecular subtypes and the risk groups based on 52-gene signature (kappa = 0.04, 95% CI= -0.08, 0.17), and the 52-gene signature risk groups were associated with differences in transplant-free but not progression-free survival. Based on heatmaps and differential expression analyses, proteins and miRNAs (but not toRNA) contributed to classification of subjects to the molecular subtypes. The IPA showed enrichment in pulmonary fibrosis-relevant pathways, including mTOR, VEGF, PDGF, and B-cell receptor signaling. CONCLUSIONS: Integration of transcriptomic and proteomic data from blood enabled identification of clinically meaningful molecular endotypes of IPF. If validated, these endotypes could facilitate identification of individuals likely to experience disease progression and enrichment of clinical trials. TRIAL REGISTRATION: NCT01915511.

Syndrome of Combined Pulmonary Fibrosis and Emphysema: An Official ATS/ERS/JRS/ALAT Research Statement.

Background: The presence of emphysema is relatively common in patients with fibrotic interstitial lung disease. This has been designated combined pulmonary fibrosis and emphysema (CPFE). The lack of consensus over definitions and diagnostic criteria has limited CPFE research. Goals: The objectives of this task force were to review the terminology, definition, characteristics, pathophysiology, and research priorities of CPFE and to explore whether CPFE is a syndrome. Methods: This research statement was developed by a committee including 19 pulmonologists, 5 radiologists, 3 pathologists, 2 methodologists, and 2 patient representatives. The final document was supported by a focused systematic review that identified and summarized all recent publications related to CPFE. Results: This task force identified that patients with CPFE are predominantly male, with a history of smoking, severe dyspnea, relatively preserved airflow rates and lung volumes on spirometry, severely impaired DlCO, exertional hypoxemia, frequent pulmonary hypertension, and a dismal prognosis. The committee proposes to identify CPFE as a syndrome, given the clustering of pulmonary fibrosis and emphysema, shared pathogenetic pathways, unique considerations related to disease progression, increased risk of complications (pulmonary hypertension, lung cancer, and/or mortality), and implications for clinical trial design. There are varying features of interstitial lung disease and emphysema in CPFE. The committee offers a research definition and classification criteria and proposes that studies on CPFE include a comprehensive description of radiologic and, when available, pathological patterns, including some recently described patterns such as smoking-related interstitial fibrosis. Conclusions: This statement delineates the syndrome of CPFE and highlights research priorities.

The Association between Exposures and Disease Characteristics in Familial Pulmonary Fibrosis.

Rationale: Heterogeneous characteristics are observed in familial pulmonary fibrosis (FPF), suggesting that nongenetic factors contribute to disease manifestations. Objectives: To determine the relationship between environmental exposures and disease characteristics of FPF, including the morphological characteristics on chest computed tomography (CT) scan, and timing of FPF symptom onset, lung transplantation, or death. Methods: Subjects with FPF with an exposure questionnaire and chest CT were selected from a prospective cohort at Vanderbilt. Disease characteristics were defined by lung parenchymal findings on chest CT associated with fibrotic hypersensitivity pneumonitis (fHP) or usual interstitial pneumonia (UIP) and by time from birth to symptom onset or a composite of lung transplantation or death. After assessing the potential for confounding by sex or smoking, adjusted logistic or Cox proportional hazards regression models identified exposures associated with fHP or UIP CT findings. Findings were validated in a cohort of patients with sporadic pulmonary fibrosis enrolled in the LTRC (Lung Tissue Research Consortium) study. Results: Among 159 subjects with FPF, 98 (61.6%) were males and 96 (60.4%) were ever-smokers. Males were less likely to have CT features of fHP, including mosaic attenuation (FPF: adjusted [for sex and smoking] odds ratio [aOR], 0.27; 95% confidence interval [CI], 0.09-0.76; P = 0.01; LTRC: aOR, 0.35; 95% CI, 0.21-0.61; P = 0.0002). Organic exposures, however, were not consistently associated with fHP features in either cohort. Smoking was a risk factor for honeycombing in both cohorts (FPF: aOR, 2.19; 95% CI, 1.12-4.28; P = 0.02; LTRC: aOR, 1.69; 95% CI, 1.22-2.33; P = 0.002). Rock dust exposure may also be associated with honeycombing, although the association was not statistically-significant when accounting for sex and smoking (FPF: aOR, 2.27; 95% CI, 0.997-5.15; P = 0.051; LTRC: aOR, 1.51; 95% CI, 0.97-2.33; P = 0.07). In the FPF cohort, ever-smokers experienced a shorter transplant-free survival (adjusted hazard ratio, 1.64; 95% CI, 1.07-2.52; P = 0.02), whereas sex was not associated with differential survival (male adjusted hazard ratio, 0.75; 95% CI, 0.50-1.14; P = 0.18). Conclusions: In FPF, smoking contributes to shortened transplant-free survival and development of honeycombing, a finding that is also likely applicable to sporadic pulmonary fibrosis. Females are more likely to manifest CT features of fHP (mosaic attenuation), a finding that was incompletely explained by sex differences in exposures. These findings may have implications for pulmonary fibrosis classification and management.

Multiplatform Single-Cell Analysis Identifies Immune Cell Types Enhanced in Pulmonary Fibrosis.

Immune cells have been implicated in idiopathic pulmonary fibrosis (IPF), but the phenotypes and effector mechanisms of these cells remain incompletely characterized. We performed mass cytometry to quantify immune cell subsets in lungs of 12 patients with IPF and 15 organ donors without chronic lung disease and used existing single-cell RNA-sequencing data to investigate transcriptional profiles of immune cells overrepresented in IPF. Among myeloid cells, we found increased numbers of alveolar macrophages (AMØs) and dendritic cells (DCs) in IPF, as well as a subset of monocyte-derived DCs. In contrast, monocyte-like cells and interstitial macrophages were reduced in IPF. Transcriptomic profiling identified an enrichment for IFN-γ response pathways in AMØs and DCs from IPF, as well as antigen processing in DCs and phagocytosis in AMØs. Among T cells, we identified three subsets of memory T cells that were increased in IPF, including CD4+ and CD8+ resident memory T cells (TRM) and CD8+ effector memory cells. The response to the IFN-γ pathway was enriched in CD4 TRM and CD8 TRM cells in IPF, together with T cell activation and immune response-regulating signaling pathways. Increased AMØs, DCs, and memory T cells were present in IPF lungs compared with control subjects. In IPF, these cells possess an activation profile indicating increased IFN-γ signaling and upregulation of adaptive immunity in the lungs. Together, these studies highlight critical features of the immunopathogenesis of IPF.

Management of Idiopathic Pulmonary Fibrosis.

Progress in the past 2 decades has led to widespread use of 2 medications to slow loss of lung function in patients with pulmonary fibrosis. Treatment of individual patients with currently available pharmacotherapies can be limited by side effects, and neither drug has a consistent effect on patient symptoms or function. Several promising new pharmacotherapies are under development. Comprehensive management of pulmonary fibrosis hinges on shared decision making. Patient and caregiver education, and early identification and management of symptoms and comorbidities, can help improve quality of life.

A Phase I Randomized, Controlled, Clinical Trial of Valganciclovir in Idiopathic Pulmonary Fibrosis.

Rationale: Human herpesviruses Epstein-Barr virus and cytomegalovirus are frequently detectable in the lungs of patients with idiopathic pulmonary fibrosis (IPF) and could contribute to disease pathogenesis. Objectives: With the goal of inhibiting herpesvirus replication, we tested the safety and tolerability of adding valganciclovir to standard IPF therapy (pirfenidone). Methods: We performed a single-center, Phase I, double-blind, randomized, placebo-controlled trial comparing valganciclovir 900 mg daily with placebo in patients with IPF with serologic evidence of prior Epstein-Barr virus and/or cytomegalovirus infection who were tolerating full-dose pirfenidone (2,403 mg/d). Subjects were randomized to valganciclovir or placebo 2:1 for 12 weeks of active treatment with off-treatment follow-up for up to 12 months. The primary safety endpoint was the number of subjects discontinuing the study drug before completing 12 weeks of treatment. Results: Thirty-one subjects with IPF were randomized to valganciclovir (n = 20) or placebo (n = 11). All subjects completed assigned therapy except one subject in the valganciclovir group, who discontinued the study drug after developing a rash. The total number of adverse events was similar between study groups. In a prespecified analysis of secondary physiologic endpoints, we observed a trend toward improved forced vital capacity from randomization to Week 12 in valganciclovir-treated subjects (-10 ml; interquartile range [IQR], -65 to 70 ml) versus placebo-treated subjects (40 ml; IQR, -130 to 60 ml), which persisted through 12 months of follow-up. Conclusions: Valganciclovir is safe and well tolerated as an add-on therapy to pirfenidone in patients with IPF. Clinical trial registered with ClinicalTrials.gov (NCT02871401).

Identification of a unique temporal signature in blood and BAL associated with IPF progression.

Idiopathic pulmonary fibrosis (IPF) is a progressive and heterogeneous interstitial lung disease of unknown origin with a low survival rate. There are few treatment options available due to the fact that mechanisms underlying disease progression are not well understood, likely because they arise from dysregulation of complex signaling networks spanning multiple tissue compartments. To better characterize these networks, we used systems-focused data-driven modeling approaches to identify cross-tissue compartment (blood and bronchoalveolar lavage) and temporal proteomic signatures that differentiated IPF progressors and non-progressors. Partial least squares discriminant analysis identified a signature of 54 baseline (week 0) blood and lung proteins that differentiated IPF progression status by the end of 80 weeks of follow-up with 100% cross-validation accuracy. Overall we observed heterogeneous protein expression patterns in progressors compared to more homogenous signatures in non-progressors, and found that non-progressors were enriched for proteomic processes involving regulation of the immune/defense response. We also identified a temporal signature of blood proteins that was significantly different at early and late progressor time points (p < 0.0001), but not present in non-progressors. Overall, this approach can be used to generate new hypothesis for mechanisms associated with IPF progression and could readily be translated to other complex and heterogeneous diseases.

Diagnosis of Hypersensitivity Pneumonitis in Adults. An Official ATS/JRS/ALAT Clinical Practice Guideline.

Background: This guideline addresses the diagnosis of hypersensitivity pneumonitis (HP). It represents a collaborative effort among the American Thoracic Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax.Methods: Systematic reviews were performed for six questions. The evidence was discussed, and then recommendations were formulated by a multidisciplinary committee of experts in the field of interstitial lung disease and HP using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach.Results: The guideline committee defined HP, and clinical, radiographic, and pathological features were described. HP was classified into nonfibrotic and fibrotic phenotypes. There was limited evidence that was directly applicable to all questions. The need for a thorough history and a validated questionnaire to identify potential exposures was agreed on. Serum IgG testing against potential antigens associated with HP was suggested to identify potential exposures. For patients with nonfibrotic HP, a recommendation was made in favor of obtaining bronchoalveolar lavage (BAL) fluid for lymphocyte cellular analysis, and suggestions for transbronchial lung biopsy and surgical lung biopsy were also made. For patients with fibrotic HP, suggestions were made in favor of obtaining BAL for lymphocyte cellular analysis, transbronchial lung cryobiopsy, and surgical lung biopsy. Diagnostic criteria were established, and a diagnostic algorithm was created by expert consensus. Knowledge gaps were identified as future research directions.Conclusions: The guideline committee developed a systematic approach to the diagnosis of HP. The approach should be reevaluated as new evidence accumulates.

Antifibrotic Drug Use in Patients with Idiopathic Pulmonary Fibrosis. Data from the IPF-PRO Registry.

Rationale: Two antifibrotic medications, nintedanib and pirfenidone, have been approved for the treatment of idiopathic pulmonary fibrosis (IPF) in the United States. Few data have been published on the use of these medications in clinical practice.Objectives: To investigate patterns of use of antifibrotic medications in the United States.Methods: The Idiopathic Pulmonary Fibrosis Prospective Outcomes (IPF-PRO) Registry, a multicenter U.S. registry, has enrolled patients with IPF that was diagnosed or confirmed at the enrolling center in the past 6 months. Data from patients enrolled from June 5, 2014, to March 4, 2018, were used to determine antifibrotic medication use ("treatment") in the enrollment window and in a follow-up window approximately 6 months later. Associations between patient characteristics and treatment status were tested using logistic regression.Results: Overall, 551 of 782 eligible patients (70.5%) were treated in the enrollment window. Younger age, lower forced vital capacity percentage predicted, oxygen use with activity, worse self-rated health (based on the Short Form 12 or St. George's Respiratory Questionnaire score), referral to the enrolling center by a pulmonologist, use of a lung biopsy in diagnosis, and carrying a diagnosis of IPF to the enrolling center were associated with being treated. Among 534 patients treated at enrollment who had follow-up data, 94.0% remained treated in follow-up. Better self-rated health (based on the Short Form 12 mental component score or EuroQoL score) and not using oxygen with activity at enrollment were associated with continuing treatment in follow-up. Among 172 patients who were untreated at enrollment and had follow-up data, 29.7% started treatment in follow-up. Lower diffusing capacity of the lung for carbon monoxide percentage predicted, a family history of interstitial lung disease, a history of sleep apnea, and a definite diagnosis of IPF at enrollment were associated with starting treatment in follow-up.Conclusions: The majority of patients in the IPF-PRO Registry were receiving an approved medication for IPF at enrollment. Treatment at enrollment was associated with greater disease severity, more compromised quality of life, and the use of oxygen with activity.Clinical trial registered with ClinicalTrials.gov (NCT01915511).

Development and Progression of Radiologic Abnormalities in Individuals at Risk for Familial Interstitial Lung Disease.

Rationale: The preclinical natural history of progressive lung fibrosis is poorly understood.Objectives: Our goals were to identify risk factors for interstitial lung abnormalities (ILA) on high-resolution computed tomography (HRCT) scans and to determine progression toward clinical interstitial lung disease (ILD) among subjects in a longitudinal cohort of self-reported unaffected first-degree relatives of patients with familial interstitial pneumonia.Methods: Enrollment evaluation included a health history and exposure questionnaire and HRCT scans, which were categorized by visual assessment as no ILA, early/mild ILA, or extensive ILA. The study endpoint was met when ILA were extensive or when ILD was diagnosed clinically. Among subjects with adequate study time to complete 5-year follow-up HRCT, the proportion with ILD events (endpoint met or radiographic ILA progression) was calculated.Measurements and Main Results: Among 336 subjects, the mean age was 53.1 (SD, 9.9) years. Those with ILA (early/mild [n = 74] or extensive [n = 3]) were older, were more likely to be ever smokers, had shorter peripheral blood mononuclear cell telomeres, and were more likely to carry the MUC5B risk allele. Self-reported occupational or environmental exposures, including aluminum smelting, lead, birds, and mold, were independently associated with ILA. Among 129 subjects with sufficient study time, 25 (19.4%) had an ILD event by 5 years after enrollment; of these, 12 met the study endpoint and another 13 had radiologic progression of ILA. ILD events were more common among those with early/mild ILA at enrollment (63.3% vs. 6.1%; P < 0.0001).Conclusions: Rare and common environmental exposures are independent risk factors for radiologic abnormalities. In 5 years, progression of ILA occurred in most individuals with early ILA detected at enrollment.

Frailty and geriatric conditions in older patients with idiopathic pulmonary fibrosis.

BACKGROUND: Functional status, an important predictor of health outcomes in older patients, has not been studied in an IPF population. This study aimed to determine the prevalence of frailty and geriatric conditions in older patients with IPF. METHODS: IPF patients age ≥65 years were identified prospectively at the University of Michigan. Frailty was assessed using the Fried frailty phenotype. Questionnaires addressing functional status, geriatric conditions and symptoms were administered. Quantitative measurement of pectoralis muscle area was performed. Patient variables were compared among different frailty groups. RESULTS: Of the 50 participants, 48% were found to be frail and 40% had ≥2 geriatric conditions. Frailty was associated with increased age, lower lung function, shorter 6-min walk distance, higher symptom scores and a greater number of comorbidities, geriatric conditions and functional limitations (p < 0.05). Pectoralis muscle area was nearly significant (p = 0.08). Self-reported fatigue score (odds ratio [OR] = 2.13, confidence interval [CI] 95% 1.23-3.70, p = 0.0068) and diffusion capacity (OR = 0.54 CI 95% 0.35-0.85, p = 0.0071) were independent predictors of frailty. CONCLUSIONS: Frailty and geriatric conditions are common in older patients with IPF. The presence of frailty was associated with objective (diffusion capacity) and subjective (self-reported fatigue score) data. Longitudinal evaluation is necessary to determine impact of frailty on disease-related outcomes in IPF.

Lung Microbiota Contribute to Pulmonary Inflammation and Disease Progression in Pulmonary Fibrosis.

Rationale: Idiopathic pulmonary fibrosis (IPF) causes considerable global morbidity and mortality, and its mechanisms of disease progression are poorly understood. Recent observational studies have reported associations between lung dysbiosis, mortality, and altered host defense gene expression, supporting a role for lung microbiota in IPF. However, the causal significance of altered lung microbiota in disease progression is undetermined. Objectives: To examine the effect of microbiota on local alveolar inflammation and disease progression using both animal models and human subjects with IPF. Methods: For human studies, we characterized lung microbiota in BAL fluid from 68 patients with IPF. For animal modeling, we used a murine model of pulmonary fibrosis in conventional and germ-free mice. Lung bacteria were characterized using 16S rRNA gene sequencing with novel techniques optimized for low-biomass sample load. Microbiota were correlated with alveolar inflammation, measures of pulmonary fibrosis, and disease progression. Measurements and Main Results: Disruption of the lung microbiome predicts disease progression, correlates with local host inflammation, and participates in disease progression. In patients with IPF, lung bacterial burden predicts fibrosis progression, and microbiota diversity and composition correlate with increased alveolar profibrotic cytokines. In murine models of fibrosis, lung dysbiosis precedes peak lung injury and is persistent. In germ-free animals, the absence of a microbiome protects against mortality. Conclusions: Our results demonstrate that lung microbiota contribute to the progression of IPF. We provide biological plausibility for the hypothesis that lung dysbiosis promotes alveolar inflammation and aberrant repair. Manipulation of lung microbiota may represent a novel target for the treatment of IPF.

Hypersensitivity Pneumonitis: Radiologic Phenotypes Are Associated With Distinct Survival Time and Pulmonary Function Trajectory.

BACKGROUND: Hypersensitivity pneumonitis (HP) is an interstitial lung disease with a better prognosis, on average, than idiopathic pulmonary fibrosis (IPF). We compare survival time and pulmonary function trajectory in patients with HP and IPF by radiologic phenotype. METHODS: HP (n = 117) was diagnosed if surgical/transbronchial lung biopsy, BAL, and exposure history results suggested this diagnosis. IPF (n = 152) was clinically and histopathologically diagnosed. All participants had a baseline high-resolution CT (HRCT) scan and FVC % predicted. Three thoracic radiologists documented radiologic features. Survival time is from HRCT scan to death or lung transplant. Cox proportional hazards models identify variables associated with survival time. Linear mixed models compare post-HRCT scan FVC % predicted trajectories. RESULTS: Subjects were grouped by clinical diagnosis and three mutually exclusive radiologic phenotypes: honeycomb present, non-honeycomb fibrosis (traction bronchiectasis and reticulation) present, and nonfibrotic. Nonfibrotic HP had the longest event-free median survival (> 14.73 years) and improving FVC % predicted (1.92%; 95% CI, 0.49-3.35; P = .009). HP with non-honeycomb fibrosis had longer survival than IPF (> 7.95 vs 5.20 years), and both groups experienced a significant decline in FVC % predicted. Subjects with HP and IPF with honeycombing had poor survival (2.76 and 2.81 years, respectively) and significant decline in FVC % predicted. CONCLUSIONS: Three prognostically distinct, radiologically defined phenotypes are identified among patients with HP. The importance of pursuing a specific diagnosis (eg, HP vs IPF) among patients with non-honeycomb fibrosis is highlighted. When radiologic honeycombing is present, invasive diagnostic testing directed at determining the diagnosis may be of limited value given a uniformly poor prognosis.

Development and validation of a radiological diagnosis model for hypersensitivity pneumonitis.

High-resolution computed tomography (HRCT) may be useful for diagnosing hypersensitivity pneumonitis. Here, we develop and validate a radiological diagnosis model and model-based points score.Patients with interstitial lung disease seen at the University of Michigan Health System (derivation cohort) or enrolling in the Lung Tissue Research Consortium (validation cohort) were included. A thin-section, inspiratory HRCT scan was required. Thoracic radiologists documented radiological features.The derivation cohort comprised 356 subjects (33.9% hypersensitivity pneumonitis) and the validation cohort comprised 424 subjects (15.5% hypersensitivity pneumonitis). An age-, sex- and smoking status-adjusted logistic regression model identified extent of mosaic attenuation or air trapping greater than that of reticulation ("MA-AT>Reticulation"; OR 6.20, 95% CI 3.53-10.90; p<0.0001) and diffuse axial disease distribution (OR 2.33, 95% CI 1.31-4.16; p=0.004) as hypersensitivity pneumonitis predictors (area under the receiver operating characteristic curve 0.814). A model-based score >2 (1 point for axial distribution, 2 points for "MA-AT>Reticulation") has specificity 90% and positive predictive value (PPV) 74% in the derivation cohort and specificity 96% and PPV 44% in the validation cohort. Similar model performance is seen with population restriction to those reporting no exposure (score >2: specificity 91%).When radiological mosaic attenuation or air trapping are more extensive than reticulation and disease has diffuse axial distribution, hypersensitivity pneumonitis specificity is high and false diagnosis risk low (<10%), but PPV is diminished in a low-prevalence setting.

Possible UIP pattern on high-resolution computed tomography is associated with better survival than definite UIP in IPF patients.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing lung disease of unknown etiology. Inter-society consensus guidelines on IPF diagnosis and management outline radiologic patterns including definite usual interstitial pneumonia (UIP), possible UIP, and inconsistent with UIP. We evaluate these diagnostic categories as prognostic markers among patients with IPF. METHODS: Included subjects had biopsy-proven UIP, a multidisciplinary team diagnosis of IPF, and a baseline high-resolution computed tomography (HRCT). Thoracic radiologists assigned the radiologic pattern and documented the presence and extent of specific radiologic findings. The outcome of interest was lung transplant-free survival. RESULTS: IPF patients with a possible UIP pattern on HRCT had significantly longer Kaplan-Meier event-free survival compared to those with definite UIP pattern (5.21 and 3.57 years, respectively, p = 0.002). In a multivariable Cox proportional hazards model adjusted for baseline age, gender, %-predicted FVC, and %-predicted DLCO via the GAP Stage, extent of fibrosis (via the traction bronchiectasis score) and ever-smoker status, possible UIP pattern on HRCT (versus definite UIP) was associated with reduced hazard of death or lung transplant (HR = 0.42, CI 95% 0.23-0.78, p = 0.006). CONCLUSIONS: Radiologic diagnosis categories outlined by inter-society consensus guidelines is a widely-reported and potentially useful prognostic marker in IPF patients, with possible UIP pattern on HRCT associated with a favorable prognosis compared to definite UIP pattern, after adjusting for relevant covariates.