Measuring Anatomical Distributions of Ventilation and Aerosol Deposition with PET-CT.

In disease, lung function and structure are heterogeneous, and aerosol transport and local deposition vary significantly among parts of the lung. Understanding such heterogeneity is relevant to aerosol medicine and for quantifying mucociliary clearance from different parts of the lung. In this chapter, we describe positron emission tomography (PET) imaging methods to quantitatively assess the deposition of aerosol and ventilation distribution within the lung.

Perfusion imaging heterogeneity during NO inhalation distinguishes pulmonary arterial hypertension (PAH) from healthy subjects and has potential as an imaging biomarker.

Background: Without aggressive treatment, pulmonary arterial hypertension (PAH) has a 5-year mortality of approximately 40%. A patient's response to vasodilators at diagnosis impacts the therapeutic options and prognosis. We hypothesized that analyzing perfusion images acquired before and during vasodilation could identify characteristic differences between PAH and control subjects.

Food groups associated with immune-mediated inflammatory diseases: a Mendelian randomization and disease severity study.

Background/objectives: Immune-mediated inflammatory diseases (IMIDs) are prevalent diseases. There is, however, a lack of understanding of the link between diet and IMIDs, how much dietary patterns vary between them and if there are food groups associated with a worsening of the disease.

Subjects/methods: To answer these questions we analyzed a nation-wide cohort of n = 11,308 patients from six prevalent IMIDs and 2050 healthy controls.

Elevation in lung volume and preventing catastrophic airway closure in asthmatics during bronchoconstriction.

Background: Asthma exacerbations cause lung hyperinflation, elevation in load to inspiratory muscles, and decreased breathing capacity that, in severe cases, may lead to inspiratory muscle fatigue and respiratory failure. Hyperinflation has been attributed to a passive mechanical origin; a respiratory system time-constant too long for full exhalation. However, because the increase in volume is also concurrent with activation of inspiratory muscles during exhalation it is unclear whether hyperinflation in broncho-constriction is a passive phenomenon or is actively controlled to avoid airway closure.

Anatomically Based Analysis of Radioaerosol Distribution in Pulmonary Scintigraphy: A Feasibility Study in Asthmatics.

Introduction: Manual analysis of two-dimensional (2D) scintigraphy to evaluate aerosol deposition is usually subjective and has reduced sensitivity to quantify regional differences between central and distal airways.

Aims: (1) To present a method to analyze 2D scans based on three-dimensional (3D)-linked anatomically consistent regions of interest (ROIs); (2) to evaluate peripheral-to-central counts ratio (P/C) and penetration indices (PIs) for a set of 16 subjects with moderate-to-severe asthma; and (3) to compare the reproducibility of this method against one with manually traced ROIs.

Methods: Two-dimensional scans were analyzed using custom software that scaled onto 2D-projections' 3D anatomical features, obtained from population-averaged computed tomography (CT) chest scans.

The effect of disease and respiration on airway shape in patients with moderate persistent asthma.

Computational models of gas transport and aerosol deposition frequently utilize idealized models of bronchial tree structure, where airways are considered a network of bifurcating cylinders. However, changes in the shape of the lung during respiration affect the geometry of the airways, especially in disease conditions. In this study, the internal airway geometry was examined, concentrating on comparisons between mean lung volume (MLV) and total lung capacity (TLC).

Hypoxic Pulmonary Vasoconstriction Does Not Explain All Regional Perfusion Redistribution in Asthma.

Rationale: Regional hypoventilation in bronchoconstricted patients with asthma is spatially associated with reduced perfusion, which is proposed to result from hypoxic pulmonary vasoconstriction (HPV).

Objectives: To determine the role of HPV in the regional perfusion redistribution in bronchoconstricted patients with asthma.

Methods: Eight patients with asthma completed positron emission tomographic/computed tomographic lung imaging at baseline and after bronchoconstriction, breathing either room air or 80% oxygen (80% O) on separate days.

Genome-wide pathway analysis identifies VEGF pathway association with oral ulceration in systemic lupus erythematosus.

Background: Systemic lupus erythematosus (SLE) is a genetically complex rheumatic disease characterized by heterogeneous clinical manifestations of unknown etiology. Recent studies have suggested the existence of a genetic basis for SLE heterogeneity. The objective of the present study was to identify new genetic variation associated with the clinically relevant phenotypes in SLE.

Lung Metabolic Activation as an Early Biomarker of Acute Respiratory Distress Syndrome and Local Gene Expression Heterogeneity.

Background: Acute respiratory distress syndrome (ARDS) is an inflammatory condition comprising diffuse lung edema and alveolar damage. ARDS frequently results from regional injury mechanisms. However, it is unknown whether detectable inflammation precedes lung edema and opacification and whether topographically differential gene expression consistent with heterogeneous injury occurs in early ARDS.

Regional tidal lung strain in mechanically ventilated normal lungs.

Parenchymal strain is a key determinant of lung injury produced by mechanical ventilation. However, imaging estimates of volumetric tidal strain (ε = regional tidal volume/reference volume) present substantial conceptual differences in reference volume computation and consideration of tidally recruited lung. We compared current and new methods to estimate tidal volumetric strains with computed tomography, and quantified the effect of tidal volume (V) and positive end-expiratory pressure (PEEP) on strain estimates.

Lung Tissue Volume is Elevated in Obesity and Reduced by Bariatric Surgery.

Background: Bariatric surgery (BS) in severely obese subjects causes a significant reduction of body weight with lung function improvement. We have shown that abnormalities in pulmonary gas exchange in morbidly obese subjects are substantially improved with BS. These abnormalities were thought to be related to reduced lung volumes as well as to abnormal endothelial function induced by low-grade chronic inflammation linked to perivascular adipose tissue (PVAT).

Bridging the Gap Between Science and Clinical Efficacy: Physiology, Imaging, and Modeling of Aerosols in the Lung.

Development of a new drug for the treatment of lung disease is a complex and time consuming process involving numerous disciplines of basic and applied sciences. During the 2015 Congress of the International Society for Aerosols in Medicine, a group of experts including aerosol scientists, physiologists, modelers, imagers, and clinicians participated in a workshop aiming at bridging the gap between basic research and clinical efficacy of inhaled drugs. This publication summarizes the current consensus on the topic.

Regional Ventilation and Aerosol Deposition with Helium-Oxygen in Bronchoconstricted Asthmatic Lungs.

Background: Theoretical models suggest that He-O2 as carrier gas may lead to more homogeneous ventilation and aerosol deposition than air. However, these effects have not been clinically consistent and it is unclear why subjects may or may not respond to the therapy. Here we present 3D-imaging data of aerosol deposition and ventilation distributions from subjects with asthma inhaling He-O2 as carrier gas.

MATHEMATICAL MODELING OF VENTILATION DEFECTS IN ASTHMA.

Airway narrowing by smooth muscle constriction is a hallmark of asthma attacks that may cause severe difficulties of breathing. However, the causes of asthma and the underlying mechanisms are not fully understood. Bronchoconstriction within a bronchial tree involves complex interactions among the airways that lead to the emergence of regions of poor ventilation (ventilation defects, VDefs) in the lungs.

Allergic Non-Asthmatic Adults Have Regional Pulmonary Responses to Segmental Allergen Challenge.

Background: Allergic non-asthmatic (ANA) adults experience upper airway symptoms of allergic disease such as rhinorrhea, congestion and sneezing without symptoms of asthma. The aim of this study was to utilize PET-CT functional imaging to determine whether allergen challenge elicits a pulmonary response in ANA subjects or whether their allergic disease is truly isolated to the upper airways.

Methods: In 6 ANA subjects, bronchoalveolar lavages (BAL) were performed at baseline and 24h after instillation of an allergen and a diluent in separate lung lobes.

A method for mapping regional oxygen and CO2 transfer in the lung.

This paper presents a novel approach to visualizing regional lung function, through quantitative three-dimensional maps of O2 and CO2 transfer rates. These maps describe the contribution of anatomical regions to overall gas exchange and demonstrate how transfer rates of the two gas species' differ regionally. An algorithm for generating such maps is presented, and for illustration, regional gas transfer maps were generated using values of ventilation and perfusion imaged by PET/CT for a healthy subject and an asthmatic patient after bronchoprovocation.

What Causes Uneven Aerosol Deposition in the Bronchoconstricted Lung? A Quantitative Imaging Study.

Background: A previous PET-CT imaging study of 14 bronchoconstricted asthmatic subjects showed that peripheral aerosol deposition was highly variable among subjects and lobes. The aim of this work was to identify and quantify factors responsible for this variability.

Methods: A theoretical framework was formulated to integrate four factors affecting aerosol deposition: differences in ventilation, in how air vs.

Estimation of noise-free variance to measure heterogeneity.

Variance is a statistical parameter used to characterize heterogeneity or variability in data sets. However, measurements commonly include noise, as random errors superimposed to the actual value, which may substantially increase the variance compared to a noise-free data set. Our aim was to develop and validate a method to estimate noise-free spatial heterogeneity of pulmonary perfusion using dynamic positron emission tomography (PET) scans.

Novel outcome measures for clinical trials in cystic fibrosis.

Cystic fibrosis (CF) is a common inherited condition caused by mutations in the gene encoding the CF transmembrane regulator protein. With increased understanding of the molecular mechanisms underlying CF and the development of new therapies there comes the need to develop new outcome measures to assess the disease, its progression and response to treatment. As there are limitations to the current endpoints accepted for regulatory purposes, a workshop to discuss novel endpoints for clinical trials in CF was held in Anaheim, California in November 2011.

Deep inspiration and the emergence of ventilation defects during bronchoconstriction: a computational study.

Deep inspirations (DIs) have a dilatory effect on airway smooth muscle (ASM) that helps to prevent or reduce more severe bronchoconstriction in healthy individuals. However, this bronchodilation appears to fail in some asthmatic patients or under certain conditions, and the reason is unclear. Additionally, quantitative effects of the frequency and magnitude of DIs on bronchodilation are not well understood.

18F-FDG kinetics parameters depend on the mechanism of injury in early experimental acute respiratory distress syndrome.

Unlabelled: PET with (18)F-FDG allows for noninvasive assessment of regional lung metabolism reflective of neutrophilic inflammation. This study aimed at determining during early acute lung injury whether local (18)F-FDG phosphorylation rate and volume of distribution were sensitive to the initial regional inflammatory response and whether they depended on the mechanism of injury: endotoxemia and surfactant depletion.

Methods: Twelve sheep underwent homogeneous unilateral surfactant depletion (alveolar lavage) and were mechanically ventilated for 4 h (positive end-expiratory pressure, 10 cm H2O; plateau pressure, 30 cm H2O) while receiving intravenous endotoxin (lipopolysaccharide-positive [LPS+] group; n = 6) or not (lipopolysaccharide-negative group; n = 6).

Pendelluft in the bronchial tree.

Inhomogeneous inflation or deflation of the lungs can cause dynamic pressure differences between regions and lead to interregional airflows known as pendelluft. This work first uses analytical tools to clarify the theoretical limits of pendelluft at a single bifurcation. It then explores the global and regional pendelluft that may occur throughout the bronchial tree in a realistic example using an in silico model of bronchoconstriction.