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ObjectivesIdiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease. Chest high-resolution CT (HRCT) is instrumental in IPF management, and the Quantitative Lung Fibrosis (QLF) score is a computer-assisted metric for quantifying lung disease using HRCT. This study aimed to assess the change in QLF score associated with a minimum clinically important difference (MCID) of IPF symptoms and physiological lung function, and also determine the MCID of QLF change associated with all-cause mortality to serve as an imaging biomarker to confirm disease progression and response to therapy.Design and study settingWe conducted post hoc analyses of prospective data from two IPF phase II studies of pamrevlumab, a fully human monoclonal antibody that binds to and inhibits connective tissue growth factor activity.ParticipantsOverall, 152 patients with follow-up visits after week 24.MethodsWe used the anchor-based Jaeschke’s method to estimate the MCID of the QLF score that corresponded with the already established MCID of St. George’s Respiratory Questionnaire (SGRQ) and percent-predicted forced vital capacity (ppFVC). We also conducted a Cox regression analysis to establish a sensitive and robust MCID of the QLF score in predicting all-cause mortality.ResultsQLF changes of 4.4% and 3.6% corresponded to the established MCID of a 5-point increase in SGRQ and a 3.4% reduction in ppFVC, respectively. QLF changes of 1% (HR=4.98, p=0.05), 2% (HR=4.04, p=0.041), 20 mL (HR=6.37, p=0.024) and 22 mL (HR=6.38, p=0.024) predicted mortality.ConclusionA conservative metric of 2% can be used as the MCID of QLF for predicting all-cause mortality. This may be considered in IPF trials in which the degree of structural fibrosis assessed via HRCT is an endpoint. The MCID of SGRQ and FVC corresponds with a greater amount of QLF and may reflect that a greater amount of change in fibrosis is required before there is functional change.Trial registration numberNCT01262001, NCT01890265.

Background Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with poor prognosis and a significant unmet medical need. This study evaluated the safety, pharmacokinetics (PK) and target engagement in the lungs, of GSK3008348, a novel inhaled alpha-v beta-6 (αvβ6) integrin inhibitor, in participants with IPF. Methods This was a phase 1b, randomised, double-blind (sponsor unblind) study, conducted in the UK (two clinical sites, one imaging unit) between June 2017 and July 2018 (NCT03069989). Participants with a definite or probable diagnosis of IPF received a single nebulised dose of 1000 mcg GSK3008348 or placebo (ratio 5:2) in two dosing periods. In period 1, safety and PK assessments were performed up to 24 h post-dose; in period 2, after a 7-day to 28-day washout, participants underwent a total of three positron emission tomography (PET) scans: baseline, Day 1 (~ 30 min post-dosing) and Day 2 (~ 24 h post-dosing), using a radiolabelled αvβ6-specific ligand, [ 18 F]FB-A20FMDV2. The primary endpoint was whole lung volume of distribution (V T ), not corrected for air volume, at ~ 30 min post-dose compared with pre-dose. The study success criterion, determined using Bayesian analysis, was a posterior probability (true % reduction in V T  > 0%) of ≥80%. Results Eight participants with IPF were enrolled and seven completed the study. Adjusted posterior median reduction in uncorrected V T at ~ 30 min after GSK3008348 inhalation was 20% (95% CrI: − 9 to 42%). The posterior probability that the true % reduction in V T  > 0% was 93%. GSK3008348 was well tolerated with no reports of serious adverse events or clinically significant abnormalities that were attributable to study treatment. PK was successfully characterised showing rapid absorption followed by a multiphasic elimination. Conclusions This study demonstrated engagement of the αvβ6 integrin target in the lung following nebulised dosing with GSK3008348 to participants with IPF. To the best of our knowledge this is the first time a target-specific PET radioligand has been used to assess target engagement in the lung, not least for an inhaled drug. Trial registration clinicaltrials.gov: NCT03069989 ; date of registration: 3 March 2017.

Background Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease associated with high morbidity and mortality despite specific anti-fibrotic therapies. Management of IPF is complex and relies on pulmonary function tests (PFT) to evaluate severity and monitor progression. CT provides non-invasive morphologic assessment and emerging software techniques enable quantitative analysis. Methods We included 319 individuals with IPF from the OSIC dataset. A cross-sectional analysis was made for all patients, with a longitudinal evaluation for 143 of them. We used LungQ software (Thirona, The Netherlands) to quantify lung and pulmonary vessel volumes, as well as the extent of interstitial lung disease and to assess correlation with PFT and mortality. Results Quantitative extent of fibrotic abnormalities was correlated with baseline FVC and DLCO (r -0.47, p  < 0.0001 and r -0.55, p  < 0.0001 respectively) and longitudinal modifications over time (r -0.48, p  < 0.0001 and r-0.43 p  < 0.0001, respectively). Median baseline extent of ILD, expressed as a percentage of lung volume, was 16.5% (10.8–25.5) and increased to 17.3% (11.6–29) on follow-up ( p  < 0.001). The median ILD progression was of 9.8% (-9.5-40.0). Vascular enlargement quantification as well as ILD quantification were predictive marker of death ( p  < 0.0001). However, vascular abnormalities’ independent predictive value could not be assessed in multivariate models due to multicollinearity with other variables. Conclusions LungQ allows to quantify interstitial and vascular lung features and their changes over time in a large cohort of patients with IPF. Imaging markers were negatively correlated with PFT at baseline and follow-ups were predictive of mortality confirming their potential as disease quantifiers. Further clinical validation is needed to specify the potential clinical use.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis with short lifespan following diagnosis as patients have limited effective treatment options. A fundamental limitation is a lack of knowledge of the underlying collagen alterations in the disease, as this could lead to better diagnostics, prognostics, and measures of treatment efficacy. While the fibroses is the primary presentation of the disease, the collagen architecture has not been well studied beyond standard histology. Here, we used several metrics based on second harmonic generation (SHG) microscopy and optical scattering measurements to characterize the subresolution collagen assembly in human IPF and normal lung tissues. Using SHG directional analysis, we found that while collagen synthesis is increased in IPF, the resulting average fibril architecture is more disordered than in normal tissue. Wavelength-dependent optical scattering measurements lead to the same conclusion, and both optical approaches are consistent with ultrastructural analysis. SHG circular dichroism revealed significant differences in the net chirality between the fibrotic and normal collagen, where the former has a more randomized helical structure. Collectively, the measurements reveal significant changes in the collagen macro/supramolecular structure in the abnormal fibrotic collagen, and we suggest these alterations can serve as biomarkers for IPF diagnosis and progression.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease characterized by worsening dyspnea and lung function and has a median survival of 2–3 years. Forced vital capacity (FVC) is the primary endpoint used most commonly in IPF clinical trials as it is the best surrogate for mortality. This study assessed quantitative scores from high-resolution computed tomography (HRCT) developed by machine learning as a secondary efficacy endpoint in a 26-week phase II study of BMS-986020 – an LPA1 receptor antagonist – in patients with IPF. Methods: HRCT scans from 96% (137/142) of randomized subjects were utilized. Quantitative lung fibrosis (QLF) scores were calculated from the HRCT images. QLF improvement was defined as ⩾2% reduction in QLF score from baseline to week 26. Results: In the placebo arm, 5% of patients demonstrated an improvement in QLF score at week 26 compared with 15% and 27% of patients in the BMS-986020 600 mg once daily (QD) and twice daily (BID) arms, respectively [versus placebo: p = 0.08 (600 mg QD); p = 0.0098 (600 mg BID)]. Significant correlations were found between changes in QLF and changes in percent predicted FVC, diffusing capacity for carbon monoxide (DLCO), and shortness of breath at week 26 (ρ = −0.41, ρ = −0.22, and ρ = 0.27, respectively; all p < 0.01). Conclusions: This study demonstrated the utility of quantitative HRCT as an efficacy endpoint for IPF in a double-blind, placebo-controlled clinical trial setting. The reviews of this paper are available via the supplemental material section.

This document provides clinical recommendations for the diagnosis of idiopathic pulmonary fibrosis (IPF). It represents a collaborative effort between the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society. The evidence syntheses were discussed and recommendations formulated by a multidisciplinary committee of IPF experts. The evidence was appraised and recommendations were formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation approach. The guideline panel updated the diagnostic criteria for IPF. Previously defined patterns of usual interstitial pneumonia (UIP) were refined to patterns of UIP, probable UIP, indeterminate, and alternate diagnosis. For patients with newly detected interstitial lung disease (ILD) who have a high-resolution computed tomography scan pattern of probable UIP, indeterminate, or an alternative diagnosis, conditional recommendations were made for performing BAL and surgical lung biopsy; because of lack of evidence, no recommendation was made for or against performing transbronchial lung biopsy or lung cryobiopsy. In contrast, for patients with newly detected ILD who have a high-resolution computed tomography scan pattern of UIP, strong recommendations were made against performing surgical lung biopsy, transbronchial lung biopsy, and lung cryobiopsy, and a conditional recommendation was made against performing BAL. Additional recommendations included a conditional recommendation for multidisciplinary discussion and a strong recommendation against measurement of serum biomarkers for the sole purpose of distinguishing IPF from other ILDs. The guideline panel provided recommendations related to the diagnosis of IPF.

Abstract Rationale Quantitative computed tomographic (CT) measures of baseline disease severity might identify patients with idiopathic pulmonary fibrosis (IPF) with an increased mortality risk. We evaluated whether quantitative CT variables could act as a cohort enrichment tool in future IPF drug trials. Objectives To determine whether computer-derived CT measures, specifically measures of pulmonary vessel–related structures (VRSs), can better predict functional decline and survival in IPF and reduce requisite sample sizes in drug trial populations. Methods Patients with IPF undergoing volumetric noncontrast CT imaging at the Royal Brompton Hospital, London, and St. Antonius Hospital, Utrecht, were examined to identify pulmonary function measures (including FVC) and visual and computer-derived (CALIPER [Computer-Aided Lung Informatics for Pathology Evaluation and Rating] software) CT features predictive of mortality and FVC decline. The discovery cohort comprised 247 consecutive patients, with validation of results conducted in a separate cohort of 284 patients, all fulfilling drug trial entry criteria. Measurements and Main Results In the discovery and validation cohorts, CALIPER-derived features, particularly VRS scores, were among the strongest predictors of survival and FVC decline. CALIPER results were accentuated in patients with less extensive disease, outperforming pulmonary function measures. When used as a cohort enrichment tool, a CALIPER VRS score greater than 4.4% of the lung was able to reduce the requisite sample size of an IPF drug trial by 26%. Conclusions Our study has validated a new quantitative CT measure in patients with IPF fulfilling drug trial entry criteria—the VRS score—that outperformed current gold standard measures of outcome. When used for cohort enrichment in an IPF drug trial setting, VRS threshold scores can reduce a required IPF drug trial population size by 25%, thereby limiting prohibitive trial costs. Importantly, VRS scores identify patients in whom antifibrotic medication prolongs life and reduces FVC decline.

Abstract Rationale Interstitial lung abnormalities (ILA) are radiologic abnormalities on chest computed tomography scans that have been associated with an early or mild form of pulmonary fibrosis. Although ILA have been associated with radiologic progression, it is not known if specific imaging patterns are associated with progression or risk of mortality. Objectives To determine the role of imaging patterns on the risk of death and ILA progression. Methods ILA (and imaging pattern) were assessed in 5,320 participants from the AGES-Reykjavik Study, and ILA progression was assessed in 3,167 participants. Multivariable logistic regression was used to assess factors associated with ILA progression, and Cox proportional hazards models were used to assess time to mortality. Measurements and Main Results Over 5 years, 327 (10%) had ILA on at least one computed tomography, and 1,435 (45%) did not have ILA on either computed tomography. Of those with ILA, 238 (73%) had imaging progression, whereas 89 (27%) had stable to improved imaging; increasing age and copies of MUC5B genotype were associated with imaging progression. The definite fibrosis pattern was associated with the highest risk of progression (odds ratio, 8.4; 95% confidence interval, 2.7–25; P = 0.0003). Specific imaging patterns were also associated with an increased risk of death. After adjustment, both a probable usual interstitial pneumonia and usual interstitial pneumonia pattern were associated with an increased risk of death when compared with those indeterminate for usual interstitial pneumonia (hazard ratio, 1.7; 95% confidence interval, 1.2–2.4; P = 0.001; hazard ratio, 3.9; 95% confidence interval, 2.3–6.8;P < 0.0001), respectively. Conclusions In those with ILA, imaging patterns can be used to help predict who is at the greatest risk of progression and early death.

BackgroundRelatives of patients with familial interstitial pneumonia (FIP) are at increased risk for pulmonary fibrosis. We assessed the prevalence and risk factors for preclinical pulmonary fibrosis (PrePF) in first-degree relatives of patients with FIP and determined the utility of deep learning in detecting PrePF on CT.MethodsFirst-degree relatives of patients with FIP over 40 years of age who believed themselves to be unaffected by pulmonary fibrosis underwent CT scans of the chest. Images were visually reviewed, and a deep learning algorithm was used to quantify lung fibrosis. Genotyping for common idiopathic pulmonary fibrosis risk variants in MUC5B and TERT was performed.FindingsIn 494 relatives of patients with FIP from 263 families of patients with FIP, the prevalence of PrePF on visual CT evaluation was 15.6% (95% CI 12.6 to 19.0). Compared with visual CT evaluation, deep learning quantitative CT analysis had 84% sensitivity (95% CI 0.72 to 0.89) and 86% sensitivity (95% CI 0.83 to 0.89) for discriminating subjects with visual PrePF diagnosis. Subjects with PrePF were older (65.9, SD 10.1 years) than subjects without fibrosis (55.8 SD 8.7 years), more likely to be male (49% vs 37%), more likely to have smoked (44% vs 27%) and more likely to have the MUC5B promoter variant rs35705950 (minor allele frequency 0.29 vs 0.21). MUC5B variant carriers had higher quantitative CT fibrosis scores (mean difference of 0.36%), a difference that remains significant when controlling for age and sex.InterpretationPrePF is common in relatives of patients with FIP. Its prevalence increases with age and the presence of a common MUC5B promoter variant. Quantitative CT analysis can detect these imaging abnormalities.

In the absence of a surgical lung biopsy, patients diagnosed with idiopathic pulmonary fibrosis (IPF) in clinical practice could participate in the INPULSIS trials of nintedanib if they had honeycombing and/or traction bronchiectasis plus reticulation, without atypical features of usual interstitial pneumonia (UIP), on high-resolution computed tomography (HRCT). Thus, the patients in these trials represented patients with definite UIP and a large subgroup of patients with possible UIP. To investigate the potential impact of diagnostic subgroups on the progression of IPF and the effect of nintedanib. We conducted a post hoc subgroup analysis of patients with honeycombing on HRCT and/or confirmation of UIP by biopsy versus patients without either, using pooled data from the INPULSIS trials. Seven hundred twenty-three (68.1%) patients had honeycombing and/or biopsy, and 338 (31.9%) patients had no honeycombing or biopsy. In these subgroups, respectively, the adjusted annual rate of decline in FVC in patients treated with placebo was -225.7 and -221.0 ml/yr, and the nintedanib versus placebo difference in the adjusted annual rate of decline in FVC was 117.0 ml/yr (95% confidence interval, 76.3-157.8) and 98.9 ml/yr (95% confidence interval, 36.4-161.5). There was no significant treatment-by-subgroup interaction (P = 0.8139). Adverse events were similar between the subgroups. Patients with IPF diagnosed in clinical practice who had possible UIP with traction bronchiectasis on HRCT and had not undergone surgical lung biopsy had disease that progressed in a similar way, and responded similarly to nintedanib, to that of patients with honeycombing on HRCT and/or confirmation of UIP by biopsy.