Investigating the role of platelets and platelet-derived transforming growth factor-ß in idiopathic pulmonary fibrosis.

Transforming growth factor-ß1 (TGFß1) is the key profibrotic cytokine in idiopathic pulmonary fibrosis (IPF), but the primary source of this cytokine in this disease is unknown. Platelets have abundant stores of TGFß1, although the role of these cells in IPF is ill-defined. In this study, we investigated whether platelets, and specifically platelet-derived TGFß1, mediate IPF disease progression. Patients with IPF and non-IPF patients were recruited to determine platelet reactivity, and separate cohorts of patients with IPF were followed for mortality. To study whether platelet-derived TGFß1 modulates pulmonary fibrosis (PF), mice with a targeted deletion of TGFß1 in megakaryocytes and platelets (TGFß1fl/fl.PF4-Cre) were used in the well-characterized bleomycin-induced pulmonary fibrosis (PF) animal model. In a discovery cohort, we found significantly higher mortality in patients with IPF who had elevated platelet counts within the normal range. However, our validation cohort did not confirm this observation, despite significantly increased platelets, neutrophils, active TGFß1, and CCL5, a chemokine produced by inflammatory cells, in the blood, lung, and bronchoalveolar lavage (BAL) of patients with IPF. In vivo, we showed that despite platelets being readily detected within the lungs of bleomycin-treated mice, neither the degree of pulmonary inflammation nor fibrosis was significantly different between TGFß1fl/fl.PF4-Cre and control mice. Our results demonstrate for the first time that platelet-derived TGFß1 does not significantly mediate inflammation or fibrosis in a PF animal model. Furthermore, our human studies revealed blood platelet counts do not consistently predict mortality in IPF but other platelet-derived mediators, such as C-C chemokine ligand 5 (CCL5), may promote neutrophil recruitment and human IPF.NEW & NOTEWORTHY Platelets are a rich source of profibrotic TGFß; however, the role of platelets in idiopathic pulmonary fibrosis (IPF) is unclear. We identified that patients with IPF have significantly more platelets, neutrophils, and active TGFß in their airways than control patients. Using an animal model of IPF, we demonstrated that platelet-derived TGFß does not significantly drive lung fibrosis or inflammation. Our findings offer a better understanding of platelets in both human and animal studies of IPF.

Data driven surrogate signal extraction for dynamic PET using selective PCA: time windows versus the combination of components.

Respiratory motion correction is beneficial in PET, as it can reduce artefacts caused by motion and improve quantitative accuracy. Methods of motion correction are commonly based on a respiratory trace obtained through an external device (like the Real Time Position Management System) or a data driven method, such as those based on dimensionality reduction techniques (for instance PCA). PCA itself being a linear transformation to the axis of greatest variation. Data driven methods have the advantage of being non-invasive, and can be performed post-acquisition. However, their main downside being that they are adversely affected by the tracer kinetics of the dynamic PET acquisition. Therefore, they are mostly limited to static PET acquisitions. This work seeks to extend on existing PCA-based data-driven motion correction methods, to allow for their applicability to dynamic PET imaging. The methods explored in this work include; a moving window approach (similar to the Kinetic Respiratory Gating method from Schleyer et al.), extrapolation of the principal component from later time points to earlier time points, and a method to score, select, and combine multiple respiratory components. The resulting respiratory traces were evaluated on 22 data sets from a dynamic 18FFDG study on patients with Idiopathic Pulmonary Fibrosis. This was achieved by calculating their correlation with a surrogate signal acquired using a Real Time Position Management System. The results indicate that all methods produce better surrogate signals than when applying conventional PCA to dynamic data (for instance, a higher correlation with a gold standard respiratory trace). Extrapolating a late time point principal component produced more promising results than using a moving window. Scoring, selecting, and combining components held benefits over all other methods. This work allows for the extraction of a surrogate signal from dynamic PET data earlier in the acquisition and with a greater accuracy than previous work. This potentially allows for numerous other methods (for instance, respiratory motion correction) to be applied to this data (when they otherwise could not be previously used).

Optimisation of the air fraction correction for lung PET/CT: addressing resolution mismatch.

BACKGROUND: Increased pulmonary [Formula: see text]F-FDG metabolism in patients with idiopathic pulmonary fibrosis, and other forms of diffuse parenchymal lung disease, can predict measurements of health and lung physiology. To improve PET quantification, voxel-wise air fractions (AF) determined from CT can be used to correct for variable air content in lung PET/CT. However, resolution mismatches between PET and CT can cause artefacts in the AF-corrected image. METHODS: Three methodologies for determining the optimal kernel to smooth the CT are compared with noiseless simulations and non-TOF MLEM reconstructions of a patient-realistic digital phantom: (i) the point source insertion-and-subtraction method, [Formula: see text]; (ii) AF-correcting with varyingly smoothed CT to achieve the lowest RMSE with respect to the ground truth (GT) AF-corrected volume of interest (VOI), [Formula: see text]; iii) smoothing the GT image to match the reconstruction within the VOI, [Formula: see text]. The methods were evaluated both using VOI-specific kernels, and a single global kernel optimised for the six VOIs combined. Furthermore, [Formula: see text] was implemented on thorax phantom data measured on two clinical PET/CT scanners with various reconstruction protocols. RESULTS: The simulations demonstrated that at [Formula: see text] iterations (200 i), the kernel width was dependent on iteration number and VOI position in the lung. The [Formula: see text] method estimated a lower, more uniform, kernel width in all parts of the lung investigated. However, all three methods resulted in approximately equivalent AF-corrected VOI RMSEs (<10%) at [Formula: see text]200i. The insensitivity of AF-corrected quantification to kernel width suggests that a single global kernel could be used. For all three methodologies, the computed global kernel resulted in an AF-corrected lung RMSE <10%  at [Formula: see text]200i, while larger lung RMSEs were observed for the VOI-specific kernels. The global kernel approach was then employed with the [Formula: see text] method on measured data. The optimally smoothed GT emission matched the reconstructed image well, both within the VOI and the lung background. VOI RMSE was <10%, pre-AFC, for all reconstructions investigated. CONCLUSIONS: Simulations for non-TOF PET indicated that around 200i were needed to approach image resolution stability in the lung. In addition, at this iteration number, a single global kernel, determined from several VOIs, for AFC, performed well over the whole lung. The [Formula: see text] method has the potential to be used to determine the kernel for AFC from scans of phantoms on clinical scanners.

Multi-center evaluation of baseline neutrophil-to-lymphocyte (NLR) ratio as an independent predictor of mortality and clinical risk stratifier in idiopathic pulmonary fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder with a variable disease trajectory. The aim of this study was to assess the potential of neutrophil-to-lymphocyte ratio (NLR) to predict outcomes in IPF. Methods: We adopted a two-stage discovery (n = 71) and validation (n = 134) design using patients from the UCL partners (UCLp) cohort. We then combined discovery and validation cohorts and included an additional 794 people with IPF, using real-life data from 5 other UK centers, to give a combined cohort of 999 patients. Data were collected from patients presenting over a 13-year period (2006-2019) with mean follow up of 3.7 years (censoring: 2018-2020). Findings: In the discovery analysis, we showed that high values of NLR (>/ = 2.9 vs < 2.9) were associated with increased risk of mortality in IPF (HR 2.04, 95% CI 1.09-3.81, n = 71, p = 0.025). This was confirmed in the validation (HR 1.91, 95% CI 1.15-3.18, n = 134, p = 0.0114) and combined cohorts (HR 1.65, n = 999, 95% CI 1.39-1.95; p < 0·0001). NLR correlated with GAP stage and GAP index (p < 0.0001). Stratifying patients by NLR category (low/high) showed significant differences in survival for GAP stage 2 (p < 0.0001), however not for GAP stage 1 or 3. In a multivariate analysis, a high NLR was an independent predictor of mortality/progression after adjustment for individual GAP components and steroid/anti-fibrotic use (p < 0·03). Furthermore, incorporation of baseline NLR in a modified GAP-stage/index, GAP-index/stage-plus, refined prognostic ability as measured by concordance (C)-index. Interpretation: We have identified NLR as a widely available test that significantly correlates with lung function, can predict outcomes in IPF and refines cohort staging with GAP. NLR may allow timely prioritisation of at-risk patients, even in the absence of lung function. Funding: Breathing Matters, GSK, CF Trust, BLF-Asthma, MRC, NIHR Alpha-1 Foundation.

Delineating associations of progressive pleuroparenchymal fibroelastosis in patients with pulmonary fibrosis.

Background: Computer quantification of baseline computed tomography (CT) radiological pleuroparenchymal fibroelastosis (PPFE) associates with mortality in idiopathic pulmonary fibrosis (IPF). We examined mortality associations of longitudinal change in computer-quantified PPFE-like lesions in IPF and fibrotic hypersensitivity pneumonitis (FHP). Methods: Two CT scans 6-36 months apart were retrospectively examined in one IPF (n=414) and one FHP population (n=98). Annualised change in computerised upper-zone pleural surface area comprising radiological PPFE-like lesions (Δ-PPFE) was calculated. Δ-PPFE >1.25% defined progressive PPFE above scan noise. Mixed-effects models evaluated Δ-PPFE against change in visual CT interstitial lung disease (ILD) extent and annualised forced vital capacity (FVC) decline. Multivariable models were adjusted for age, sex, smoking history, baseline emphysema presence, antifibrotic use and diffusion capacity of the lung for carbon monoxide. Mortality analyses further adjusted for baseline presence of clinically important PPFE-like lesions and ILD change. Results: Δ-PPFE associated weakly with ILD and FVC change. 22-26% of IPF and FHP cohorts demonstrated progressive PPFE-like lesions which independently associated with mortality in the IPF cohort (hazard ratio 1.25, 95% CI 1.16-1.34, p<0.0001) and the FHP cohort (hazard ratio 1.16, 95% CI 1.00-1.35, p=0.045). Interpretation: Progression of PPFE-like lesions independently associates with mortality in IPF and FHP but does not associate strongly with measures of fibrosis progression.

Evolution of 18F-FDG PET/CT Findings in Patients After COVID-19: An Initial Investigation.

The aim of this study was to assess the temporal evolution of pulmonary 18F-FDG uptake in patients with coronavirus disease 2019 (COVID-19) and post-COVID-19 lung disease (PCLD). Methods: Using our hospital's clinical electronic records, we retrospectively identified 23 acute COVID-19, 18 PCLD, and 9 completely recovered 18F-FDG PET/CT patients during the 2 peaks of the U.K. pandemic. Pulmonary 18F-FDG uptake was measured as a lung target-to-background ratio (TBRlung = SUVmax/SUVmin) and compared with temporal stage. Results: In acute COVID-19, less than 3 wk after infection, TBRlung was strongly correlated with time after infection (rs = 0.81, P < 0.001) and was significantly higher in the late stage than in the early stage (P = 0.001). In PCLD, TBRlung was lower in patients treated with high-dose steroids (P = 0.003) and in asymptomatic patients (P < 0.001). Conclusion: Pulmonary 18F-FDG uptake in COVID-19 increases with time after infection. In PCLD, pulmonary 18F-FDG uptake rises despite viral clearance, suggesting ongoing inflammation. There was lower pulmonary 18F-FDG uptake in PCLD patients treated with steroids.

Update in diagnosis and management of interstitial lung disease .

The field of interstitial lung disease (ILD) has undergone significant evolution in recent years, with an increasing incidence and more complex, ever expanding disease classification. In their most severe forms, these diseases lead to progressive loss of lung function, respiratory failure and eventually death. Despite notable advances, progress has been challenged by a poor understanding of pathological mechanisms and patient heterogeneity, including variable progression. The diagnostic pathway is thus being continually refined, with the introduction of tools such as transbronchial cryo lung biopsy and a move towards genetically aided, precision medicine. In this review, we focus on how to approach a patient with ILD and the diagnostic process.

Update in diagnosis and management of interstitial lung disease.

The field of interstitial lung disease (ILD) has undergone significant evolution in recent years, with an increasing incidence and more complex, ever expanding disease classification. In their most severe forms, these diseases lead to progressive loss of lung function, respiratory failure and eventually death. Despite notable advances, progress has been challenged by a poor understanding of pathological mechanisms and patient heterogeneity, including variable progression. The diagnostic pathway is thus being continually refined, with the introduction of tools such as transbronchial cryo lung biopsy and a move towards genetically aided, precision medicine. In this review, we focus on how to approach a patient with ILD and the diagnostic process.