Prospective observational study in patients with obstructive lung disease: NOVELTY design.

Asthma and chronic obstructive pulmonary disease (COPD) have overlapping clinical features and share pathobiological mechanisms but are often considered distinct disorders. Prospective, observational studies across asthma, COPD and asthma-COPD overlap are limited. NOVELTY is a global, prospective observational 3-year study enrolling ∼12 000 patients ≥12 years of age from primary and specialist clinical practices in 19 countries (ClinicalTrials.gov identifier: NCT02760329). NOVELTY's primary objectives are to describe patient characteristics, treatment patterns and disease burden over time, and to identify phenotypes and molecular endotypes associated with differential outcomes over time in patients with a diagnosis/suspected diagnosis of asthma and/or COPD. NOVELTY aims to recruit real-world patients, unlike clinical studies with restrictive inclusion/exclusion criteria. Data collected at yearly intervals include clinical assessments, spirometry, biospecimens, patient-reported outcomes (PROs) and healthcare utilisation (HCU). PROs and HCU will also be collected 3-monthly via internet/telephone. Data will be used to identify phenotypes and endotypes associated with different trajectories for symptom burden, clinical progression or remission and HCU. Results may allow patient classification across obstructive lung disease by clinical outcomes and biomarker profile, rather than by conventional diagnostic labels and severity categories. NOVELTY will provide a rich data source on obstructive lung disease, to help improve patient outcomes and aid novel drug development.

T1 Relaxation Time in Lungs of Asymptomatic Smokers.

PURPOSE: Interest in using T1 as a potential MRI biomarker of chronic obstructive pulmonary disease (COPD) has recently increased. Since tobacco smoking is the major risk factor for development of COPD, the aim for this study was to examine whether tobacco smoking, pack-years (PY), influenced T1 of the lung parenchyma in asymptomatic current smokers. MATERIALS AND METHODS: Lung T1 measurements from 35 subjects, 23 never smokers and 12 current smokers were retrospectively analyzed from an institutional review board approved study. All 35 subjects underwent pulmonary function test (PFT) measurements and lung T1, with similar T1 measurement protocols. A backward linear model of T1 as a function of FEV1, FVC, weight, height, age and PY was tested. RESULTS: A significant correlation between lung T1 and PY was found with a negative slope of -3.2 ms/year (95% confidence interval [CI] [-5.8, -0.6], p = 0.02), when adjusted for age and height. Lung T1 shortens with ageing among all subjects, -4.0 ms/year (95%CI [-6.3, -1.7], p = 0.001), and among the never smokers, -3.7 ms/year (95%CI [-6.0, -1.3], p = 0.003). CONCLUSIONS: A correlation between lung T1 and PY when adjusted for both age and height was found, and T1 of the lung shortens with ageing. Accordingly, PY and age can be significant confounding factors when T1 is used as a biomarker in lung MRI studies that must be taken into account to detect underlying patterns of disease.

COPD Patients Have Short Lung Magnetic Resonance T1 Relaxation Time.

Magnetic resonance imaging (MRI) may provide attractive biomarkers for assessment of pulmonary disease in clinical trials as it is free from ionizing radiation, minimally invasive and allows regional information. The aim of this study was to characterize lung MRI T1 relaxation time as a biomarker of chronic obstructive pulmonary disease (COPD); and specifically its relationship to smoking history, computed tomography (CT), and pulmonary function test (PFT) measurements in comparison to healthy age-matched controls. Lung T1 and inter-quartile range (IQR) of T1 maps from 24 COPD subjects and 12 healthy age-matched non-smokers were retrospectively analyzed from an institutional review board approved study. The subjects underwent PFTs and two separate MR imaging sessions at 1.5 tesla to test T1 repeatability. CT scans were performed on the COPD subjects. T1 repeatability (intraclass correlation coefficient) was 0.72 for repeated scans acquired on two visits. The lung T1 was significantly shorter (p < 0.0001) and T1 IQR was significantly larger (p = 0.0002) for the COPD subjects compared to healthy controls. Lung T1 significantly (p = 0.001) correlated with lung density assessed with CT. Strong significant correlations (p < 0.0001) between lung T1 and all PFT measurements were observed. Cigarette exposure did not correlate with lung T1 in COPD subjects. In conclusion, lung MRI T1 mapping shows potential as a repeatable, radiation free, non-invasive imaging technique in the evaluation of COPD.

T1-weighted Dynamic Contrast-enhanced MR Imaging of the Lung in Asthma: Semiquantitative Analysis for the Assessment of Contrast Agent Kinetic Characteristics.

PURPOSE: To evaluate the contrast agent kinetics of dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging in healthy lungs and asthmatic lungs by using non-model-based semiquantitative parameters and to explore the relationships with pulmonary function testing and eosinophil level. MATERIALS AND METHODS: The study was approved by the National Research Ethical Committee (reference no. 11/NW/0387), and written informed consent was obtained from all individuals. Ten healthy subjects and 30 patients with asthma underwent pulmonary function tests, blood and sputum eosinophil counts, and 1.5-T DCE MR imaging within 7 days. Semiquantitative parameters of contrast agent kinetics were calculated from the relative signal intensity-time course curves on a pixel-by-pixel basis and were summarized by using whole-lung median values. The distribution heterogeneity was assessed by using the regional coefficient of variation. DCE MR imaging readouts were compared between groups by using one-way analysis of variance, and the relationships with pulmonary function testing and eosinophil counts were assessed by using Pearson correlation analysis. RESULTS: Asthmatic patients showed significantly lower peak enhancement (P < .001) and initial areas under the relative signal intensity curve in the first 60 seconds (P = .002) and significantly reduced late-phase washout slope (P = .002) when compared with healthy control subjects. The distribution heterogeneity of bolus arrival time (P = .029), time to peak (P = .008), upslope of the first-pass peak (P = .011), and late-phase washout slope (P = .032), estimated by using the median coefficient of variation, were significantly higher in asthmatic patients than in healthy control subjects. These imaging readouts also showed significant linear correlations with measurements of pulmonary function testing but not with eosinophil level in patients with asthma. CONCLUSION: The contrast agent kinetic characteristics of T1-weighted DCE MR images of asthmatic lungs are different from those of healthy lungs and are related to measurements of pulmonary function testing but not to eosinophil level.

MR Quantitative Equilibrium Signal Mapping: A Reliable Alternative to CT in the Assessment of Emphysema in Patients with Chronic Obstructive Pulmonary Disease.

PURPOSE: To compare magnetic resonance (MR) quantitative equilibrium signal (qS0) mapping with quantitative computed tomography (CT) in the estimation of emphysema in patients with chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS: Written informed consent of the original study permitted future reanalysis of data. This study was a retrospective analysis of data from an institutional review board-approved study. Twenty-four patients with COPD and 12 healthy patients who did not smoke underwent spirometry and two separate 1.5-T MR imaging examinations. All patients with COPD underwent additional chest CT. Lung MR qS0 maps were generated from MR images obtained with multiple inversion times by fitting the inversion recovery signal equation. Mean, 15th percentile, and standard deviation of whole-lung qS0 and relative lung area with a qS0 value below 0.20 (RA0.20) were measured and compared between groups with an unpaired t test. Reproducibility between two examinations was tested with intraclass correlation coefficients (ICCs), and their associations with spirometry and CT measurements of 15th percentile attenuation (PA15) and relative lung area with attenuation below -950 HU (RA-950) were assessed with the Pearson correlation coefficient. RESULTS: Whole-lung mean qS0 and 15th percentile of qS0 were significantly lower, whereas RA0.20 and standard deviation of qS0 were significantly higher in patients with COPD than in healthy control subjects (P = .014, P = .002, P = .005, and P < .001, respectively). Whole-lung mean qS0, the 15th percentile of qS0, and RA0.20 strongly correlated with RA-950 (r = -0.78, r = -0.81, and r = 0.86, respectively; P < .001) and PA15 (r = 0.78, r = 0.79, and r = -0.71, respectively; P < .001) and moderately correlated with the ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (r = 0.63, r = 0.67, and r = -0.60, respectively; P < .001) and percentage predicted FEV1 (r = 0.54, r = 0.62, and r = -0.56, respectively; P ≤ .001). Good reproducibility of qS0 readouts was found in both groups (ICC range, 0.89-0.98). CONCLUSION: Lung MR qS0 mapping may be a reliable noncontrast nonradiation alternative to CT in the assessment of emphysema in patients with COPD.

Dynamic oxygen-enhanced magnetic resonance imaging of the lung in asthma -- initial experience.

OBJECTIVES: To prospectively estimate the feasibility and reproducibility of dynamic oxygen-enhanced magnetic resonance imaging (OE-MRI) in the assessment of regional oxygen delivery, uptake and washout in asthmatic lungs. MATERIALS AND METHODS: The study was approved by the National Research Ethics Committee and written informed consent was obtained. Dynamic OE-MRI was performed twice at one month apart on four mild asthmatic patients (23±5 years old, FEV1=96±3% of predicted value) and six severe asthmatic patients (41±12 years old, FEV1=60±14% of predicted value) on a 1.5T MR scanner using a two-dimensional T1-weighted inversion-recovery turbo spin echo sequence. The enhancing fraction (EF), the maximal change in the partial pressure of oxygen in lung tissue (ΔPO2max_l) and arterial blood of the aorta (ΔPO2max_a), and the oxygen wash-in (τup_l, τup_a) and wash-out (τdown_l, τdown_a) time constants were extracted and compared between groups using the independent-samples t-test (two-tailed). Correlations between imaging readouts and clinical measurements were assessed by Pearson's correlation analysis. Bland-Altman analysis was used to estimate the levels of agreement between the repeat scans and the intra-observer agreement in the MR imaging readouts. RESULTS: The severe asthmatic group had significantly smaller EF (70±16%) and median ΔPO2max_l (156±52mmHg) and significantly larger interquartile range of τup_l (0.84±0.26min) than the mild asthmatic group (95±3%, P=0.014; 281±40mmHg, P=0.004; 0.20±0.07min, P=0.001, respectively). EF, median ΔPO2max_l and τdown_l and the interquartile range of τup_l and τdown_l were significantly correlated with age and pulmonary function test parameters (r=-0.734 to -0.927, 0.676-0.905; P=0.001-0.045). Median ΔPO2max_l was significantly correlated with ΔPO2max_a (r=0.745, P=0.013). Imaging readouts showed good one-month reproducibility and good intra-observer agreement (mean bias between repeated scans and between two observations did not significantly deviate from zero). CONCLUSIONS: Dynamic OE-MRI is feasible in asthma and sensitive to the severity of disease. The technique provides indices related to regional oxygen delivery, uptake and washout that show good one month reproducibility and intra-observer agreement.

Feasibility assessment of using oxygen-enhanced magnetic resonance imaging for evaluating the effect of pharmacological treatment in COPD.

OBJECTIVES: Oxygen-enhanced MRI (OE-MRI) biomarkers have potential value in assessment of COPD, but need further evaluation before treatment-induced changes can be interpreted. The objective was to evaluate how OE-MRI parameters of regional ventilation and oxygen uptake respond to standard pharmacological interventions in COPD, and how the response compares to that of gold standard pulmonary function tests. MATERIALS AND METHODS: COPD patients (n=40), mean FEV1 58% predicted normal, received single-dose inhaled formoterol 9µg, or placebo, followed by 8 weeks treatment bid with a combination of budesonide and formoterol Turbuhaler(®) 320/9µg or formoterol Turbuhaler(®). OE-MRI biomarkers were obtained, as well as X-ray computed tomography (CT) biomarkers and pulmonary function tests, in a two-center study. An ANCOVA statistical model was used to assess effect size of intervention measurable in OE-MRI parameters of lung function. RESULTS: OE-MRI data were successfully acquired at both study sites. 8-week treatment with budesonide/formoterol significantly decreased lung wash-out time by 31% (p<0.01), decreased the change in lung oxygen level upon breathing pure oxygen by 13% (p<0.05) and increased oxygen extraction from the lung by 58% (p<0.01). Single-dose formoterol increased both lung wash-out time (+47%, p<0.05) and lung oxygenation time (+47%, p<0.05). FEV1 was improved by single-dose formoterol (+12%, p<0.001) and 8 weeks of budesonide/formoterol (+ 18%, p<0.001), consistent with published studies. CONCLUSIONS: In COPD, OE-MRI parameters showed response to both single-dose bronchodilatory effects of a ß2-agonist, formoterol, and 8-week treatment with an inhaled corticosteroid, budesonide, and the measurements are feasible in a small-scale multi-center trial setting.

Efficacious inhaled PDE4 inhibitors with low emetic potential and long duration of action for the treatment of COPD.

Oral phosphodiesterase 4 (PDE4) inhibitors, such as cilomilast and roflumilast, have been shown to be efficacious against chronic obstructive pulmonary disease (COPD). However, these drugs have been hampered by mechanism-related side effects such as nausea and emesis at high doses. Compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index required to overcome side effects. This paper describes systematic and rational lead optimization to deliver highly potent, long-acting, and efficacious preclinical inhaled PDE4 inhibitors with low emetic potential.

Improved quantitative dynamic regional oxygen-enhanced pulmonary imaging using image registration.

Oxygen-enhanced MR imaging has been demonstrated in a number of recent studies as a potential method to visualize regional ventilation in the lung. A quantitative pixel-by-pixel analysis is hampered by motion and volume change due to breathing. In this study, image registration via active shape modeling is shown to produce significant improvements in the regional analysis of both static and dynamic oxygen-enhanced pulmonary MRI for five normal volunteers. The method enables the calculation of regional change in relaxation rate between breathing air and 100% oxygen, which is proportional to the change in regional oxygen concentration, and regional oxygen wash-in and wash-out time constants. Registration-corrected mapping of these parameters is likely to provide improved information in the regional assessment of a range of lung diseases.

Cardiopulmonary effects of romifidine/ketamine or xylazine/ketamine when used for short duration anesthesia in the horse.

The cardiovascular changes associated with anesthesia induced and maintained with romifidine/ketamine versus xylazine/ ketamine were compared using 6 horses in a cross over design. Anesthesia was induced and maintained with romifidine (100 microg/kg, IV)/ketamine (2.0 mg/kg, IV) and ketamine (0.1 mg/kg/min, IV), respectively, in horses assigned to the romifidine/ ketamine group. Horses assigned to the xylazine/ketamine group had anesthesia induced and maintained with xylazine (1.0 mg/kg, IV)/ketamine (2.0 mg/kg, IV) and a combination of xylazine (0.05 mg/kg/min, IV) and ketamine (0.1 mg/kg/min, IV), respectively. Cardiopulmonary variables were measured at intervals up to 40 min after induction. All horses showed effective sedation following intravenous romifidine or xylazine and achieved recumbency after ketamine administration. There were no significant differences between groups in heart rate, arterial oxygen partial pressures, arterial carbon dioxide partial pressures, cardiac index, stroke index, oxygen delivery, oxygen utilization, systemic vascular resistance, left ventricular work, or any of the measured systemic arterial blood pressures. Cardiac index and left ventricular work fell significantly from baseline while systemic vascular resistance increased from baseline in both groups. The oxygen utilization ratio was higher in the xylazine group at 5 and 15 min after induction. In conclusion, the combination of romifidine/ketamine results in similar cardiopulmonary alterations as a xylazine/ketamine regime, and is a suitable alternative for clinical anesthesia of the horse from a cardiopulmonary viewpoint.

Agreement of SpO2, SaO2 and ScO2 in anesthetized cynomolgus monkeys (Macaca fascicularis).

OBJECTIVE: To assess the agreement between three measurements of arterial oxygen saturation (SpO2, SaO2 and ScO2) in anesthetized cynomolgus monkeys. STUDY DESIGN: Prospective study. ANIMALS: Eleven mature, male cynomolgus monkeys (Macaca fasicularis). METHODS: Monkeys were anesthetized with intramuscular ketamine followed by intravenous propofol. The trachea of each was intubated and the lungs ventilated. Arterial oxygen saturation was measured with a Nonin 8500 V pulse oximeter, using a lingual clip on the cheek. Arterial blood samples were taken from an indwelling catheter. Inspired oxygen concentration was varied from 12 to 20%, and 88 paired arterial blood samples and saturation measurements were taken. Arterial oxygen saturation in the blood samples was measured using a cooximeter. The saturation was also calculated from the arterial oxygen tension using the Adair equation. The results were compared using Bland and Altman's method. RESULTS: The pulse oximeter readings were 2.7% higher than that of the cooximeter, with a limit of agreement of -3.9 to 9.3%. The pulse oximeter readings were 1.8% higher than the calculated saturation, with a limit of agreement of -6.5% to 10.1%. The cooximeter readings were 0.9% lower than the calculated saturation, with a limit of agreement of -5.6% to 3.8%. CONCLUSIONS: The agreement between SpO2 and other measurements of arterial oxygen saturation in this study is typical for this technique. The bias and limits of agreement are consistent with reports in other species. CLINICAL RELEVANCE: The Nonin 8500 V is a useful pulse oximeter for clinical use in primates.

Characterization of nasal obstruction in the allergic guinea pig using the forced oscillation method.

INTRODUCTION: This is the first report to evaluate changes in nasal resistance in a preclinical animal model using the forced oscillation method. METHODS: The method involves characterizing pressure-flow relationships of the respiratory system due to external oscillatory forces. RESULTS: First, we evaluated changes in nasal resistance using an established small-animal rhinometric technique. In these studies, aerosolized ovalbumin (3%) administered to the nasal cavity of ovalbumin-sensitized guinea pigs increased nasal resistance at 30 min by 99 +/- 14%. The histamine H1 antagonists, chlorpheniramine (1 mg/kg i.v.) and pyrilamine (1 mg/kg i.v.), blocked the increase in nasal resistance due to ovalbumin provocation (50 +/- 17% and 39 +/- 11% over baseline, respectively). The alpha-adrenergic agonist phenylpropanolamine (3 mg/ kg i.v.) had no effect on the nasal actions of ovalbumin. In separate studies, nasal resistance was measured at 2 Hz by forced oscillation and ovalbumin (3%) increased nasal resistance by 91 +/- 14%. Chlorpheniramine (1 mg/kg i.v.) significantly attenuated the increase in nasal resistance due to ovalbumin. Finally, changes in nasal resistance for each treatment group were evaluated at frequencies of 1 - 18 Hz. Area under the curve analysis demonstrated that chlorpheniramine blocked the nasal obstructive effect of ovalbumin. In contrast, a pharmacologically active dose of phenylpropanolamine (3 mg/kg i.v.) did not produce decongestant activity. DISCUSSION: The current data are inconsistent with the well-established clinical efficacy of alpha-adrenergic agonists as nasal decongestants. Consequently, we suggest that allergic nasal obstruction in the guinea pig may not be the best preclinical approach to assess the nasal decongestant activity of vasoconstrictor alpha-adrenergic agonists. Additionally, our studies demonstrate the utility of the forced oscillation technique in assessing changes in nasal resistance in small laboratory animals.