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. After instillation (10h), functional imaging was performed to quantify and compare regional perfusion, ventilation, fractional gas content (Fgas), and glucose uptake rate (Ki) between the baseline, diluent and allergen lobes. BAL cell counts were also compared. Results: In ANA subjects, compared to the baseline and diluent lobes, perfusion and ventilation were significantly lower in the allergen lobe (median [inter-quartile range], baseline vs. diluent vs. allergen: Mean-normalized perfusion; 0.87 [0.85–0.97] vs. 0.90 [0.86–0.98] vs. 0.59 [0.55–0.67]; p<0.05. Mean-normalized ventilation 0.89 [0.88–0.98] vs. 0.95 [0.89–1.02] vs. 0.63 [0.52–0.67], p<0.05). In contrast, no significant differences were found in Fgas between baseline, diluent and allergen lobes or in Ki. Total cell counts, eosinophil and neutrophil cell counts (cells/ml BAL) were significantly greater in the allergen lobe compared to the baseline lobe (all P<0.05). Conclusions: Despite having no clinical symptoms of a lower airway allergic response (cough and wheeze) allergic non-asthmatic subjects have a pulmonary response to allergen exposure which manifests as reduced ventilation and perfusion

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. aerosol distribute at each bifurcation, in the fraction of aerosol escaping feeding airways, and in the fraction of aerosol reaching the periphery that is exhaled. These factors were quantified in 12 of the subjects using PET-CT measurements of relative specific deposition sD*, relative specific ventilation sV* (measured with dynamic PET or estimated as change in expansion between two static HRCTs), average lobar expansion FVOL, and breathing frequency measured during aerosol inhalation fN. RESULTS: The fraction of the variance of sD* explained by sV* (0.38), by bifurcation effects (0.38), and by differences in deposition along feeding airways (0.31) were similar in magnitude. We could not directly estimate the contribution of aerosol that was exhaled. Differences in expansion did not explain any fraction of the variability in sD* among lobes. The dependence of sD* on sV* was high in subjects breathing with low fN, but weakened among those breathing faster. Finally, sD*/sV* showed positive dependence on FVOL among low fN subjects, while the dependence was negative among high fN subjects. CONCLUSION: The theoretical framework allowed us to analyze experimentally measured aerosol deposition imaging data. When considering bronchoconstricted asthmatic subjects, a dynamic measurement of ventilation is required to evaluate its effect on aerosol transport. The mechanisms behind the identified effects of fN and FVOL on aerosol deposition need further study and may have important implications for aerosol therapy in subjects with heterogeneous ventilation. Keywords: aerosol deposition; asthma; bronchoconstriction; escape fractions; sedimentation; ventilationNational Institutes of Health (U.S.) (Award R01HL68011

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. The data are compared with those that we previously obtained from a similar group of subjects inhaling air. Methods: Subjects with mild-to-moderate asthma were bronchoconstricted with methacholine and imaged with PET-CT while inhaling aerosol carried with He-O₂. Mean-normalized-values of lobar specific ventilation sV∗ and deposition sD∗ were derived and the factors affecting the distribution of sD∗ were evaluated along with the effects of breathing frequency (f) and regional expansion (FVOL). Results: Lobar distributions of sD∗ and sV∗ with He-O₂ were not statistically different from those previously measured with air. However, with He-O₂ there was a larger number of lobes having sV∗ and sD∗ closer to unity and, in those subjects with uneven deposition distributions, the correlation of sD∗ with sV∗ was on average higher (p < 0.05) in He-O₂ (0.84 ± 0.8) compared with air (0.55 ± 0.28). In contrast with air, where the frequency of breathing during nebulization was associated with the degree of sD∗-sV∗ correlation, with He-O₂ there was no association. Also, the modulation of f on the correlation between FVOL and sD∗/sV∗ in air, was not observed in He-O₂. Conclusion: There were no differences in the inter-lobar heterogeneity of sD∗ or sV∗ in this group of mild asthmatic subjects breathing He-O₂ compared with patients previously breathing air. Future studies, using these personalized 3D data sets as input to CFD models, are needed to understand if, and for whom, breathing He-O₂ during aerosol inhalation may be beneficial.National Institutes of Health (U.S.) (Award R01HL68011

Subject demographics, lung function and allergen dosing.

<p>Subject demographics, lung function and allergen dosing.</p

Example images.

<p>Representative images of Fgas, Q, sV, and Ki in the diluent and allergen lobes from two subjects who had ground glass opacities present on inspection of HRCT (Subject 1 and 4) and a separate subject with no ground glass opacities (Subject 6). Ground glass opacities are seen as regions with increased red and black colors. In each image, the boundaries of the diluent and allergen lobes are outlined in blue. Note: Color scales differ between subjects. Q, sV and Ki are represented as relative values, relative to the mean of the imaged lung.</p

Perfusion relative to gravitational height.

<p>Mean normalized perfusion vs. lung height (from the most dorsal point of the lung) in the baseline (grey-open circles), diluent (grey-filled circles) and allergen lobes (black-filled circles) in all subjects (subjects identified by marker in top left of each panel). Each lobe is divided into 8 equal volume regions along the gravitational axis and the mean perfusion and lung height of each region plotted. The allergen lobe can be seen to have lower perfusion across several lung heights (grey highlighted sections), compared to the diluent and allergen. In the remaining 3 subjects the allergen lobe can be seen to deviate to the left of the perfusion height trend for at least one lung height (grey striped highlighted sections). In the most dependent and most non–dependent heights the allergen lobe appears to have no difference in perfusion compared to the baseline and diluent lobes at those equivalent lung heights.</p