Magnetic Resonance Imaging of Lung Perfusion.

"Lung perfusion" in the context of imaging conventionally refers to the delivery of blood to the pulmonary capillary bed through the pulmonary arteries originating from the right ventricle required for oxygenation. The most important physiological mechanism in the context of imaging is the so-called hypoxic pulmonary vasoconstriction (HPV, also known as "Euler-Liljestrand-Reflex"), which couples lung perfusion to lung ventilation. In obstructive airway diseases such as asthma, chronic-obstructive pulmonary disease (COPD), cystic fibrosis (CF), and asthma, HPV downregulates pulmonary perfusion in order to redistribute blood flow to functional lung areas in order to conserve optimal oxygenation. Imaging of lung perfusion can be seen as a reflection of lung ventilation in obstructive airway diseases. Other conditions that primarily affect lung perfusion are pulmonary vascular diseases, pulmonary hypertension, or (chronic) pulmonary embolism, which also lead to inhomogeneity in pulmonary capillary blood distribution. Several magnetic resonance imaging (MRI) techniques either dependent on exogenous contrast materials, exploiting periodical lung signal variations with cardiac action, or relying on intrinsic lung voxel attributes have been demonstrated to visualize lung perfusion. Additional post-processing may add temporal information and provide quantitative information related to blood flow. The most widely used and robust technique, dynamic-contrast enhanced MRI, is available in clinical routine assessment of COPD, CF, and pulmonary vascular disease. Non-contrast techniques are important research tools currently requiring clinical validation and cross-correlation in the absence of a viable standard of reference. First data on many of these techniques in the context of observational studies assessing therapy effects have just become available. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 5.

GOLD stage-specific phenotyping of emphysema and airway disease using quantitative computed tomography.

Background: In chronic obstructive pulmonary disease (COPD) abnormal lung function is related to emphysema and airway obstruction, but their relative contribution in each GOLD-stage is not fully understood. In this study, we used quantitative computed tomography (QCT) parameters for phenotyping of emphysema and airway abnormalities, and to investigate the relative contribution of QCT emphysema and airway parameters to airflow limitation specifically in each GOLD stage. Methods: Non-contrast computed tomography (CT) of 492 patients with COPD former GOLD 0 COPD and COPD stages GOLD 1-4 were evaluated using fully automated software for quantitative CT. Total lung volume (TLV), emphysema index (EI), mean lung density (MLD), and airway wall thickness (WT), total diameter (TD), lumen area (LA), and wall percentage (WP) were calculated for the entire lung, as well as for all lung lobes separately. Results from the 3rd-8th airway generation were aggregated (WT3-8, TD3-8, LA3-8, WP3-8). All subjects underwent whole-body plethysmography (FEV1%pred, VC, RV, TLC). Results: EI was higher with increasing GOLD stages with 1.0 ± 1.8% in GOLD 0, 4.5 ± 9.9% in GOLD 1, 19.4 ± 15.8% in GOLD 2, 32.7 ± 13.4% in GOLD 3 and 41.4 ± 10.0% in GOLD 4 subjects (p < 0.001). WP3-8 showed no essential differences between GOLD 0 and GOLD 1, tended to be higher in GOLD 2 with 52.4 ± 7.2%, and was lower in GOLD 4 with 50.6 ± 5.9% (p = 0.010 - p = 0.960). In the upper lobes WP3-8 showed no significant differences between the GOLD stages (p = 0.824), while in the lower lobes the lowest WP3-8 was found in GOLD 0/1 with 49.9 ± 6.5%, while higher values were detected in GOLD 2 with 51.9 ± 6.4% and in GOLD 3/4 with 51.0 ± 6.0% (p < 0.05). In a multilinear regression analysis, the dependent variable FEV1%pred can be predicted by a combination of both the independent variables EI (p < 0.001) and WP3-8 (p < 0.001). Conclusion: QCT parameters showed a significant increase of emphysema from GOLD 0-4 COPD. Airway changes showed a different spatial pattern with higher values of relative wall thickness in the lower lobes until GOLD 2 and subsequent lower values in GOLD3/4, whereas there were no significant differences in the upper lobes. Both, EI and WP5-8 are independently correlated with lung function decline.

The effect of bradykinin 1 receptor antagonist BI 1026706 on pulmonary inflammation after segmental lipopolysaccharide challenge in healthy smokers.

BACKGROUND: Bradykinin 1 receptor (B1R) signalling pathways may be involved in the inflammatory pathophysiology of chronic obstructive pulmonary disease (COPD). B1R signalling is induced by inflammatory stimuli or tissue injury and leads to activation and increased migration of pro-inflammatory cells. Lipopolysaccharide (LPS) lung challenge in man is an experimental method of exploring inflammation in the lung whereby interference in these pathways can help to assess pharmacologic interventions in COPD. BI 1026706, a potent B1R antagonist, was hypothesized to reduce the inflammatory activity after segmental lipopolysaccharide (LPS) challenge in humans due to decreased pulmonary cell influx. METHODS: In a monocentric, randomized, double-blind, placebo-controlled, parallel-group, phase I trial, 57 healthy, smoking subjects were treated for 28 days with either oral BI 1026706 100 mg bid or placebo. At day 21, turbo-inversion recovery magnitude magnetic resonance imaging (TIRM MRI) was performed. On the last day of treatment, pre-challenge bronchoalveolar lavage fluid (BAL) and biopsies were sampled, followed by segmental LPS challenge (40 endotoxin units/kg body weight) and saline control instillation in different lung lobes. Twenty-four hours later, TIRM MRI was performed, then BAL and biopsies were collected from the challenged segments. In BAL samples, cells were differentiated for neutrophil numbers as the primary endpoint. Other endpoints included assessment of safety, biomarkers in BAL (e.g. interleukin-8 [IL-8], albumin and total protein), B1R expression in lung biopsies and TIRM score by MRI as a measure for the extent of pulmonary oedema. RESULTS: After LPS, but not after saline, high numbers of inflammatory cells, predominantly neutrophils were observed in the airways. IL-8, albumin and total protein were also increased in BAL samples after LPS challenge as compared with saline control. There were no significant differences in cells or other biomarkers from BAL in volunteers treated with BI 1026706 compared with those treated with placebo. Unexpectedly, neutrophil numbers in BAL were 30% higher and MRI-derived extent of oedema was significantly higher with BI 1026706 treatment compared with placebo, 24 h after LPS challenge. Adverse events were mainly mild to moderate and not different between treatment groups. CONCLUSIONS: Treatment with BI 1026706 for four weeks was safe and well-tolerated in healthy smoking subjects. BI 1026706 100 mg bid did not provide evidence for anti-inflammatory effects in the human bronchial LPS challenge model. TRIAL REGISTRATION: The study was registered on January 14, 2016 at ClinicalTrials.gov (NCT02657408).

Echo time-dependent observed T1 and quantitative perfusion in chronic obstructive pulmonary disease using magnetic resonance imaging.

Introduction: Due to hypoxic vasoconstriction, perfusion is interesting in the lungs. Magnetic Resonance Imaging (MRI) perfusion imaging based on Dynamic Contrast Enhancement (DCE) has been demonstrated in patients with Chronic Obstructive Pulmonary Diseases (COPD) using visual scores, and quantification methods were recently developed further. Inter-patient correlations of echo time-dependent observed T1 [T1(TE)] have been shown with perfusion scores, pulmonary function testing, and quantitative computed tomography. Here, we examined T1(TE) quantification and quantitative perfusion MRI together and investigated both inter-patient and local correlations between T1(TE) and quantitative perfusion. Methods: 22 patients (age 68.0 ± 6.2) with COPD were examined using morphological MRI, inversion recovery multi-echo 2D ultra-short TE (UTE) in 1-2 slices for T1(TE) mapping, and 4D Time-resolved angiography With Stochastic Trajectories (TWIST) for DCE. T1(TE) maps were calculated from 2D UTE at five TEs from 70 to 2,300 µs. Pulmonary Blood Flow (PBF) and perfusion defect (QDP) maps were produced from DCE measurements. Lungs were automatically segmented on UTE images and morphological MRI and these segmentations registered to DCE images. DCE images were separately registered to UTE in corresponding slices and divided into corresponding subdivisions. Spearman's correlation coefficients were calculated for inter-patient correlations using the entire segmented slices and for local correlations separately using registered images and subdivisions for each TE. Median T1(TE) in normal and defect areas according to QDP maps were compared. Results: Inter-patient correlations were strongest on average at TE2 = 500 µs, reaching up to |ρ| = 0.64 for T1 with PBF and |ρ| = 0.76 with QDP. Generally, local correlations of T1 with PBF were weaker at TE2 than at TE1 or TE3 and with maximum values of |ρ| = 0.66 (from registration) and |ρ| = 0.69 (from subdivision). In 18 patients, T1 was shorter in defect areas than in normal areas, with the relative difference smallest at TE2. Discussion: The inter-patient correlations of T1 with PBF and QDP found show similar strength and TE-dependence as those previously reported for visual perfusion scores and quantitative computed tomography. The local correlations and median T1 suggest that not only base T1 but also the TE-dependence of observed T1 in normal areas is closer to that found previously in healthy volunteers than in defect areas.

Unsupervised clustering algorithms improve the reproducibility of dynamic contrast-enhanced magnetic resonance imaging pulmonary perfusion quantification in muco-obstructive lung diseases.

Background: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) allows the assessment of pulmonary perfusion, which may play a key role in the development of muco-obstructive lung disease. One problem with quantifying pulmonary perfusion is the high variability of metrics. Quantifying the extent of abnormalities using unsupervised clustering algorithms in residue function maps leads to intrinsic normalization and could reduce variability. Purpose: We investigated the reproducibility of perfusion defects in percent (QDP) in clinically stable patients with cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Methods: 15 CF (29.3 ± 9.3y, FEV1%predicted = 66.6 ± 15.8%) and 20 COPD (66.5 ± 8.9y, FEV1%predicted = 42.0 ± 13.3%) patients underwent DCE-MRI twice 1 month apart. QDP, pulmonary blood flow (PBF), and pulmonary blood volume (PBV) were computed from residue function maps using an in-house quantification pipeline. A previously validated MRI perfusion score was visually assessed by an expert reader. Results: Overall, mean QDP, PBF, and PBV did not change within 1 month, except for QDP in COPD (p < 0.05). We observed smaller limits of agreement (± 1.96 SD) related to the median for QDP (CF: ± 38%, COPD: ± 37%) compared to PBF (CF: ± 89%, COPD: ± 55%) and PBV (CF: ± 55%, COPD: ± 51%). QDP correlated moderately with the MRI perfusion score in CF (r = 0.46, p < 0.05) and COPD (r = 0.66, p < 0.001). PBF and PBV correlated poorly with the MRI perfusion score in CF (r =-0.29, p = 0.132 and r =-0.35, p = 0.067, respectively) and moderately in COPD (r =-0.57 and r =-0.57, p < 0.001, respectively). Conclusion: In patients with muco-obstructive lung diseases, QDP was more robust and showed a higher correlation with the MRI perfusion score compared to the traditionally used perfusion metrics PBF and PBV.