Bita Hajian

Functional respiratory imaging to assess the interaction between systemic roflumilast and inhaled ICS/LABA/LAMA

Background Patients with COPD show a significant reduction of the lobar hyperinflation at the functional residual capacity level in the patients who improved >120 mL in forced expiratory volume in 1 second (FEV1) after 6 months of treatment with roflumilast in addition to inhaled corticosteroids (ICSs)/long-acting beta-2 agonists (LABAs)/long-acting muscarinic antagonists (LAMAs). Methods Functional respiratory imaging was used to quantify lobar hyperinflation, blood vessel density, ventilation, aerosol deposition, and bronchodilation. To investigate the exact mode of action of roflumilast, correlations between lobar and global measures have been tested using a mixed-model approach with nested random factors and Pearson correlation, respectively. Results The reduction in lobar hyperinflation appears to be associated with a larger blood vessel density in the respective lobes (t=−2.154, P=0.040); lobes with a higher percentage of blood vessels reduce more in hyperinflation in the responder group. Subsequently, it can be observed that lobes that reduce in hyperinflation after treatment are better ventilated (t=−5.368, P<0.001). Functional respiratory imaging (FRI)-based aerosol deposition showed that enhanced ventilation leads to more peripheral particle deposition of ICS/LABA/LAMA in the better-ventilated areas (t=2.407, P=0.024). Finally, the study showed that areas receiving more particles have increased FRI-based bronchodilation (t=2.564, P=0.017), leading to an increase in FEV1 (R=0.348, P=0.029). Conclusion The study demonstrated that orally administered roflumilast supports the reduction of regional hyperinflation in areas previously undertreated by inhalation medication. The local reduction in hyperinflation induces a redistribution of ventilation and aerosol deposition, leading to enhanced efficacy of the concomitant ICS/LABA/LAMA therapy. FRI appears to be a sensitive tool to describe the mode of action of novel compounds in chronic obstructive pulmonary disease. Future studies need to confirm the enhanced sensitivity and the potential of FRI parameters to act as surrogates for clinically relevant, but more difficult to measure, end points such as exacerbations.

Assessment of lung deposition and analysis of the effect of fluticasone/salmeterol hydrofluoroalkane (HFA) pressurized metered dose inhaler (pMDI) in stable persistent asthma patients using functional respiratory imaging

ABSTRACT Background: Unambiguously for inhaled products, PK measures are best suited for ensuring that the total systemic exposure is equivalent for two products but cannot provide regional information about lung deposition and structural changes. Functional respiratory imaging (FRI) has been demonstrated to be sensitive for distinguishing small but imperative differences related to a single treatment. Methods: In this study FRI is used in 16 asthmatic patients to assess equivalence in regional deposition for two products (fluticasone/salmeterol, test and reference) by directly measuring regional functional and structural changes within the lungs following its administration. Results: No differences were observed between the lung deposition patterns and the effects on lung structure and function of two products, having the same formulation and manufactured by different organizations using FRI. Conclusions: Results using FRI complement PK assessments. The added value of this approach to the conventional clinical methods could be significant.

Functional respiratory imaging (FRI) for optimizing therapy development and patient care

Abstract Functional imaging techniques offer the possibility of improved visualization of anatomical structures such as; airways, lobe volumes and blood vessels. Computer-based flow simulations with a three-dimensional element add functionality to the images. By providing valuable detailed information about airway geometry, internal airflow distribution and inhalation profile, functional respiratory imaging can be of use routinely in the clinic. Three dimensional visualization allows for highly detailed follow-up in terms of disease progression or in assessing effects of interventions. Here, we explore the usefulness of functional respiratory imaging in different respiratory diseases. In patients with asthma and COPD, functional respiratory imaging has been used for phenotyping these patients, to predict the responder and non-responder phenotype and to evaluate different innovative therapeutic interventions.

Pathophysiological mechanism of long-term noninvasive ventilation in stable hypercapnic patients with COPD using functional respiratory imaging

Introduction Patients with severe COPD often develop chronic hypercapnic respiratory failure. Their prognosis worsens and they are more likely to develop exacerbations. This has major influence on the health-related quality of life. Currently, there is no information about the success of long-term noninvasive ventilation (NIV) among patients who receive NIV in acute settings. Also, little is known about the pathophysiological mechanism of NIV. Methods Ten Global Initiative for Obstructive Lung Disease stage III and IV COPD patients with respiratory failure who were hospitalized following acute exacerbation were treated with NIV using a Synchrony BiPAP device for 6 months. Arterial blood gases and lung function parameters were measured. Low-dose computed tomography of the thorax was performed and used for segmentation. Further analyses provided lobe volume, airway volume, and airway resistance, giving an overall functional description of the separate airways and lobes. Ventilation perfusion (VQ) was calculated. Patient-reported outcomes were evaluated. Results PaCO2 significantly improved from 50.03 mmHg at baseline to 44.75 mmHg after 1 month and 43.37 mmHg after 6 months (P=0.006). Subjects showed improvement in the 6-minute walk tests (6MWTs) by an average of 51 m (from 332 m at baseline to 359 m at 1 month and 383 m at 6 months). Patients demonstrated improvement in self-reported anxiety (P=0.018). The improvement in image-based VQ was positively associated with the 6MWT and the anxiety domain of the Severe Respiratory Insufficiency Questionnaire. Conclusion Though previous studies of long-term NIV have shown conflicting results, this study demonstrates that patients can benefit from long-term NIV treatment, resulting in improved VQ, gas exchange, and exercise tolerance.

Pulmonary vascular effects of pulsed inhaled nitric oxide in COPD patients with pulmonary hypertension

Introduction Severe chronic obstructive pulmonary disease (COPD) is often associated with secondary pulmonary hypertension (PH), which worsens prognosis. PH can be lowered by oxygen, but also by inhaled nitric oxide (NO), which has the potential to improve the health status of these patients. NO is an important mediator in vascular reactions in the pulmonary circulation. Oral compounds can act through NO-mediated pathways, but delivering pulsed inhaled NO (iNO) directly to the airways and pulmonary vasculature could equally benefit patients. Therefore, a proof-of-concept study was performed to quantify pulmonary blood vessel caliber changes after iNO administration using computed tomography (CT)-based functional respiratory imaging (FRI). Methods Six patients with secondary PH due to COPD received “pulsed” iNO in combination with oxygen for 20 minutes via a nasal cannula. Patients underwent a high-resolution CT scan with contrast before and after iNO. Using FRI, changes in volumes of blood vessels and associated lobes were quantified. Oxygen saturation and blood pressure were monitored and patients were asked about their subjective feelings. Results Pulmonary blood vessel volume increased by 7.06%±5.37% after iNO. A strong correlation (Ω20=0.32, P=0.002) was obtained between ventilation and observed vasodilation, suggesting that using the pulsed system, iNO is directed toward the ventilated zones, which consequently experience more vasodilation. Patients did not develop oxygen desaturation, remained normotensive, and perceived an improvement in their dyspnea sensation. Conclusion Inhalation of pulsed NO with oxygen causes vasodilation in the pulmonary circulation of COPD patients, mainly in the well-ventilated areas. A high degree of heterogeneity was found in the level of vasodilation. Patients tend to feel better after the treatment. Chronic use trials are warranted.

Efficacy of inhaled medications in asthma and COPD related to disease severity

ABSTRACT Introduction: The administration of medication by inhalation has become the most important route in treating airway diseases. The efficacy of this route depends on several factors like correct inhalation techniques, compliance and the size of the particles. The flow properties and internal flow distribution contribute to the deposition pattern. Areas covered: What has been less well studied is the effect of the internal flow distribution. We know from recent studies that using systemic anti-inflammatory compounds that open up the distal airways redistributes flow internally and enhances the deposition of inhaled particles to the active site of bronchoconstriction or airway inflammation. We discuss this in more detail in this paper, and also make reference to the use of functional respiratory imaging (FRI) that allows for the description of this flow pattern starting from chest CT followed by post processing with segmentation software and the application of fluid dynamics. Expert opinion: The method that was previously validated does show the importance of redistribution of flow in the final clinical results that could be obtained with inhaled medication, especially in more severe obstructive airway diseases. Based on these insights and novel diagnostic tools, patients in end stage respiratory failure would benefit from a personalized approach with inhaled medication.

Changes in ventilation–perfusion during and after an COPD exacerbation: an assessment using fluid dynamic modeling

Introduction Severe exacerbations associated with chronic obstructive pulmonary disease (COPD) that require hospitalization significantly contribute to morbidity and mortality. Definitions for exacerbations are very broad, and it is unclear whether there is one predominant underlying mechanism that leads to them. Functional respiratory imaging (FRI) with modeling provides detailed information about airway resistance, hyperinflation, and ventilation–perfusion (V/Q) mismatch during and following an acute exacerbation. Materials and methods Forty-two patients with COPD participating in a multicenter study were assessed by FRI, pulmonary function tests, and self-reported outcome measures during an acute exacerbation and following resolution. Arterial blood gasses and lung function parameters were measured. Results A significant correlation was found between alveolar–arterial gradient and image-based V/Q (iV/Q), suggesting that iV/Q represents V/Q mismatch during an exacerbation (p<0.05). Conclusion Recovery of an exacerbation is due to decreased (mainly distal) airway resistance (p<0.05). Improvement in patient-reported outcomes were also associated with decreased distal airway resistance (p<0.05), but not with forced expiratory volume. FRI is, therefore, a sensitive tool to describe changes in airway caliber, ventilation, and perfusion during and after exacerbation. On the basis of the fact that FRI increased distal airway resistance seems to be the main cause of an exacerbation, therapy should mainly focus on decreasing it during and after the acute event.

A randomized study using functional respiratory imaging to characterize bronchodilator effects of glycopyrrolate/formoterol fumarate delivered by a metered dose inhaler using co-suspension delivery technology in patients with COPD

Background Functional respiratory imaging (FRI) uses high-resolution computed tomography (HRCT) scans to assess changes in airway volume and resistance. Patients and methods In this randomized, double-blind, 2-week, crossover, Phase IIIB study, patients with moderate-to-severe COPD received twice-daily glycopyrrolate/formoterol fumarate delivered by a metered dose inhaler (GFF MDI, 18/9.6 μg) and placebo MDI, formulated using innovative co-suspension delivery technology. Co-primary endpoints included the following: specific image-based airway volume (siVaw) and specific image-based airway resistance (siRaw) at Day 15, measured using FRI. Secondary and other endpoints included the following: change from baseline in post-dose forced expiratory volume in 1 second (FEV1) and inspiratory capacity (IC; spirometry) and ratio to baseline in post-dose functional residual capacity (FRC) and residual volume (RV; body plethysmography). Results Twenty patients (46–78 years of age) were randomized and treated; of whom 19 completed the study. GFF MDI treatment increased siVaw by 75% and reduced siRaw by 71% vs placebo MDI (both P<0.0001). Image-based airway volume (iVaw) and image-based airway resistance (iRaw), without adjusting for lobe volume, demonstrated corresponding findings to the co-primary endpoint, as lobe volumes did not change with either treatment. Approximately 48% of the delivered dose of glycopyrronium and formoterol fumarate was estimated to be deposited in the lungs. Compared with placebo, GFF MDI treatment improved post-dose FEV1 and IC (443 mL and 454 mL, respectively; both P<0.001) and reduced FRC and RV (13% and 22%, respectively; both P<0.0001). There were no significant safety findings. Conclusion GFF MDI demonstrated significant, clinically meaningful benefits on FRI-based airway volume and resistance in patients with moderate-to-severe COPD. Benefits were associated with improvements in FEV1, IC, and hyperinflation. Clinical trial registration ClinicalTrials.gov: NCT02643082.

Functional respiratory imaging: heterogeneity of acute exacerbations of COPD

Background Exacerbations of COPD are a major burden to patients, and yet little is understood about heterogeneity. It contributes to the current persistent one-size-fits-all treatment. To replace this treatment by more personalized, precision medicine, new insights are required. We assessed the heterogeneity of exacerbations by functional respiratory imaging (FRI) in 3-dimensional models of airways and lungs. Methods The trial was designed as a multicenter trial of patients with an acute exacerbation of COPD who were assessed by FRI, pulmonary function tests, and patient-reported outcomes, both in the acute stage and during resolution. Results Forty seven patients were assessed. FRI analyses showed significant improvements in hyperinflation (a decrease in total volume at functional residual capacity of −0.25±0.61 L, p≤0.01), airway volume at total lung capacity (+1.70±4.65 L, p=0.02), and airway resistance. As expected, these improvements correlated partially with changes in the quality of life and in conventional lung function test parameters. Patients with the same changes in pulmonary function differ in regional disease activity measured by FRI. Conclusion FRI is a useful tool to get a better insight into exacerbations of COPD, and significant improvements in its indices can be demonstrated from the acute phase to resolution even in relatively small groups. It clearly visualizes the marked variability within and between individuals in ventilation and resistance during exacerbations and is a tool for the assessment of the heterogeneity of COPD exacerbations.