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. METHODS: We studied 5 controls and 4 subjects with PAH using HRCT and 13NN PET imaging of pulmonary perfusion and ventilation. The total spatial heterogeneity of perfusion (CV2Qtotal) and its components in the vertical (CV2Qvgrad) and cranio-caudal (CV2Qzgrad) directions, and the residual heterogeneity (CV2Qr), were assessed at baseline and while breathing oxygen and nitric oxide (O2 + iNO). The length scale spectrum of CV2Qr was determined from 10 to 110 mm, and the response of regional perfusion to O2 + iNO was calculated as the mean of absolute differences. Vertical gradients in perfusion (Qvgrad) were derived from perfusion images, and ventilation-perfusion distributions from images of 13NN washout kinetics. RESULTS: O2 + iNO significantly enhanced perfusion distribution differences between PAH and controls, allowing differentiation of PAH subjects from controls. During O2 + iNO, CV2Qvgrad was significantly higher in controls than in PAH (0.08 (0.055-0.10) vs. 6.7 × 10-3 (2 × 10-4-0.02), p < 0.001) with a considerable gap between groups. Qvgrad and CV2Qtotal showed smaller differences: - 7.3 vs. - 2.5, p = 0.002, and 0.12 vs. 0.06, p = 0.01. CV2Qvgrad had the largest effect size among the primary parameters during O2 + iNO. CV2Qr, and its length scale spectrum were similar in PAH and controls. Ventilation-perfusion distributions showed a trend towards a difference between PAH and controls at baseline, but it was not statistically significant. CONCLUSIONS: Perfusion imaging during O2 + iNO showed a significant difference in the heterogeneity associated with the vertical gradient in perfusion, distinguishing in this small cohort study PAH subjects from controls.

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% O2) on separate days. Relative perfusion, specific ventilation (sV), and gas fraction (Fgas) in the 25% of the lung with the lowest specific ventilation (sVlow) and the remaining lung (sVhigh) were quantified and compared. MEASUREMENTS AND MAIN RESULTS: In the sVlow region, bronchoconstriction caused a significant decrease in sV under both room air and 80% O2 conditions (baseline vs. bronchoconstriction, mean ± SD, 1.02 ± 0.20 vs. 0.35 ± 0.19 and 1.03 ± 0.20 vs. 0.32 ± 0.16, respectively; P < 0.05). In the sVlow region, relative perfusion decreased after bronchoconstriction under room air conditions and also, to a lesser degree, under 80% O2 conditions (1.02 ± 0.19 vs. 0.72 ± 0.08 [P < 0.001] and 1.08 ± 0.19 vs. 0.91 ± 0.12 [P < 0.05], respectively). The Fgas increased after bronchoconstriction under room air conditions only (0.99 ± 0.04 vs. 1.00 ± 0.02; P < 0.05). The sVlow subregion analysis indicated that some of the reduction in relative perfusion after bronchoconstriction under 80% O2 conditions occurred as a result of the presence of regional hypoxia. However, relative perfusion was also significantly reduced in sVlow subregions that were hyperoxic under 80% O2 conditions. CONCLUSIONS: HPV is not the only mechanism that contributes to perfusion redistribution in bronchoconstricted patients with asthma, suggesting that another nonhypoxia mechanism also contributes. We propose that this nonhypoxia mechanism may be either direct mechanical interactions and/or unidentified intercellular signaling between constricted airways, the parenchyma, and the surrounding vasculature.

PET Imaging Reveals Early Pulmonary Perfusion Abnormalities in HIV Infection Similar to Smoking.

Chronic obstructive pulmonary disease (COPD) is the most common noninfectious pulmonary disease among people living with HIV, independent of smoking. However, the cause for this enhanced susceptibility remains unclear, and the effects of HIV on pulmonary perfusion and ventilation are unknown. Methods: We used PET/CT in 46 smokers and nonsmokers, 23 of whom had documented HIV infection. Emphysema was assessed by CT and perfusion by 13N (13NN) PET scans. After removal of image noise, vertical and axial gradients in perfusion were calculated. We tested for differences in the total spatial heterogeneity of perfusion (CV2Qtotal) and its components (CV2Qtotal = CV2Qvgrad [vertical gradient] + CV2Qzgrad [axial gradient] + CV2Qr [residual heterogeneity]) among groups. Results: There were no significant differences in demographic parameters among groups, and all subjects had minimal radiographic evidence of emphysema. Compared with controls, nonsmokers living with HIV had a significantly greater CV2Qr/CV2Qtotal (0.48 vs. 0.36, P = 0.05) and reduced CV2Qvgrad/CV2Qtotal (0.46 vs. 0.65, P = 0.038). Smokers also had a reduced CV2Qvgrad/CV2Qtotal, however, there was no significant difference in CV2Qvgrad/CV2Qtotal between smokers living with and without HIV (0.39 vs. 0.34, P = 0.58), despite a decreased vertical perfusion gradient (Qvgrad) in smokers living with HIV. Conclusion: In nonsmokers living with well-controlled HIV and minimal radiographic emphysema, HIV infection contributes to pulmonary perfusion abnormalities similar to smokers. These data indicate the onset of subclinical pulmonary perfusion abnormalities that could herald the development of significant lung disease in these susceptible individuals.

A phase I trial of low-dose inhaled carbon monoxide in sepsis-induced ARDS.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a prevalent disease with significant mortality for which no effective pharmacologic therapy exists. Low-dose inhaled carbon monoxide (iCO) confers cytoprotection in preclinical models of sepsis and ARDS. METHODS: We conducted a phase I dose escalation trial to assess feasibility and safety of low-dose iCO administration in patients with sepsis-induced ARDS. Twelve participants were randomized to iCO or placebo air 2:1 in two cohorts. Four subjects each were administered iCO (100 ppm in cohort 1 or 200 ppm in cohort 2) or placebo for 90 minutes for up to 5 consecutive days. Primary outcomes included the incidence of carboxyhemoglobin (COHb) level ≥10%, prespecified administration-associated adverse events (AEs), and severe adverse events (SAEs). Secondary endpoints included the accuracy of the Coburn-Forster-Kane (CFK) equation to predict COHb levels, biomarker levels, and clinical outcomes. RESULTS: No participants exceeded a COHb level of 10%, and there were no administration-associated AEs or study-related SAEs. CO-treated participants had a significant increase in COHb (3.48% ± 0.7% [cohort 1]; 4.9% ± 0.28% [cohort 2]) compared with placebo-treated subjects (1.97% ± 0.39%). The CFK equation was highly accurate at predicting COHb levels, particularly in cohort 2 (R2 = 0.9205; P < 0.0001). Circulating mitochondrial DNA levels were reduced in iCO-treated participants compared with placebo-treated subjects. CONCLUSION: Precise administration of low-dose iCO is feasible, well-tolerated, and appears to be safe in patients with sepsis-induced ARDS. Excellent agreement between predicted and observed COHb should ensure that COHb levels remain in the target range during future efficacy trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT02425579. FUNDING: NIH grants P01HL108801, KL2TR002385, K08HL130557, and K08GM102695.

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.

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.

Analysis of three-dimensional aerosol deposition in pharmacologically relevant terms: beyond black or white ROIs.

BACKGROUND: This article presents a novel methodological approach to evaluate images of aerosol deposition taken with PET-CT cameras. Traditionally, Black-or-White (BW) Regions of Interest (ROIs) are created to cover Anatomical Regions (ARs) segmented from the high-resolution CT. Such ROIs do not usually consider blurring effects due to limited spatial resolution or breathing motion, and do not consider uncertainty in the AR position within the PET image. The new methodology presented here (Grayscale) addresses these issues, allows estimates of aerosol deposition within ARs, and expresses the deposition in terms of Tissue Dosing (in the lung periphery) and Inner Surface Concentration (in the larger airways). METHODS: Imaging data included a PET deposition image acquired during breathing and two CT scans acquired during breath holds at different lung volumes. The lungs were segmented into anatomically consistent ARs to allow unbiased comparisons across subjects and across lobes. The Grayscale method involves defining Voxel Influence Matrices (VIMs) to consider how average activity within each AR influences the measured activity within each voxel. The BW and Grayscale methods were used to analyze aerosol deposition in 14 bronchoconstricted asthmatics. RESULTS: Grayscale resulted in a closer description of the PET image than BW (p<0.0001) and exposed a seven-fold underestimation in measures of specific deposition. The Average Tissue Dosing was 2.11×10(-6) Total Lung Dose/mg. The average Inner Surface Concentration was 45×10(-6) Total Lung Dose/mm(2), with the left lower lobe having a lower ISC than lobes of the right lung (p<0.05). There was a strong lobar heterogeneity in these measures (COV=0.3). CONCLUSION: The Grayscale approach is an improvement over the BW approach and provides a closer description of the PET image. It can be used to characterize heterogeneous concentrations throughout the lung and may be important in translational research and in the evaluation of aerosol delivery systems.

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.

The effect of omalizumab on ventilation and perfusion in adults with allergic asthma.

Omalizumab promotes clinical improvement in patients with allergic asthma, but its effect on pulmonary function is unclear. One possibility is that omalizumab improves asthma symptoms through effects on the regional distributions of ventilation, perfusion, and ventilation/perfusion matching, metrics which can be assessed with Nitrogen-13-saline Position Emission Tomography (PET). Four adults with moderate to severe uncontrolled allergic asthma underwent symptom assessment, spirometry and functional pulmonary imaging with Nitrogen-13-saline PET before and after 4-5 months of treatment with omalizumab. PET imaging was used to determine ventilation/perfusion ratios, the heterogeneity (coefficient of variation, COV) of ventilation and perfusion, and lung regions with ventilation defects. There were no significant changes in spirometry values after omalizumab treatment, but there was a trend towards an improvement in symptom scores. There was little change in the matching of ventilation and perfusion. The COV of perfusion was similar before and after omalizumab treatment. The COV of ventilation was also similar before (0.57 (0.28)) and after (0.66 (0.13)) treatment, and it was similar to previously published values for healthy subjects. There was a non-significant trend towards an increase in the extent of ventilation defects after omalizumab treatment, from 5 (15)% to 12.8 (14.7)%. Treatment of moderate to severe uncontrolled allergic asthma with omalizumab did not result in a significant improvement in ventilation and perfusion metrics assessed with functional PET imaging. The normal COV of ventilation which was unaffected by treatment supports the hypothesis that omalizumab exerts its clinical effect on lung function during allergen exposure rather than in between exacerbations.

18F-FDG uptake rate is a biomarker of eosinophilic inflammation and airway response in asthma.

UNLABELLED: In asthma, the relationship among airway inflammation, airway hyperresponsiveness, and lung function is poorly understood. Methods to noninvasively assess these relationships in human subjects are needed. We sought to determine whether (18)F-FDG uptake rate (K(i), min(-1)) could serve as a biomarker of eosinophilic inflammation and local lung function. METHODS: We used PET/CT to assess regional pulmonary perfusion (Q), specific ventilation per unit volume (sV(A)), fractional gas content (Fgas), airway wall thickness, and regional K(i) 10 h after segmental allergen challenge to the right middle lobe in 6 asthmatic subjects with demonstrated atopy. Q, sV(A), and Fgas in the allergen-challenged lobe were compared with the right upper lobe, where diluent was applied as a control. The airway wall thickness aspect ratio (ω) of the allergen-challenged airway was compared with those of similarly sized airways from unaffected areas of the lung. Differences in K(i) between allergen and diluent segments were compared with those in cell counts obtained 24 h after the allergen challenge by a bronchoalveolar lavage of the respective segments. RESULTS: We found systematic reductions in regional Q, sV(A), and Fgas and increased ω in all subjects. The ratio of eosinophil count (allergen to diluent) was linearly related (R(2) = 0.9917, P < 0.001) to the ratio of K(i). CONCLUSION: Regional K(i) measured with PET is a noninvasive and highly predictive biomarker of eosinophilic airway inflammation and its functional effects. This method may serve to help in the understanding of allergic inflammation and test the therapeutic effectiveness of novel drugs or treatments.