COVID-19 can cause life-threatening lung-inflammation that is suggested to be mediated by neutrophils, whose effector mechanisms in COVID-19 is inexplicit. The aim of the present work is to evaluate a novel PET tracer for neutrophil elastase in COVID-19 patients and healthy controls.

METHODS: In this open-label, First-In-Man study, four patients with hypoxia due to COVID-19 and two healthy controls were investigated with positron emission tomography (PET) using the new selective and specific neutrophil elastase PET-tracer [¹¹C]GW457427 and [¹⁵O]water for the visualization and quantification of NE and perfusion in the lungs, respectively.

RESULTS: [¹¹C]GW457427 accumulated selectively in lung areas with ground-glass opacities on computed tomography characteristic of COVID-19 suggesting high levels on NE in these areas. In the same areas perfusion was severely reduced in comparison to healthy lung tissue as measured with [¹⁵O]water.

CONCLUSION: The data suggests that NE may be responsible for the severe lung inflammation in COVID-19 patients and that inhibition of NE could potentially reduce the acute inflammatory process and improve the condition.

Background

Alveolar macrophages activation to the pro-inflammatory phenotype M1 is pivotal in the pathophysiology of Ventilator-Induced Lung Injury (VILI). Increased lung strain is a known determinant of VILI, but a direct correspondence between regional lung strain and macrophagic activation remains unestablished. [⁶⁸Ga]Ga-DOTA-TATE is a Positron Emission Tomography (PET) radiopharmaceutical with a high affinity for somatostatin receptor subtype 2 (SSTR2), which is overexpressed by pro-inflammatory-activated macrophages. Aim of the study was to determine, in a porcine model of VILI, whether mechanical strain correlates topographically with distribution of activated macrophages detected by [⁶⁸Ga]Ga-DOTA-TATE uptake.

Methods

Seven anesthetized pigs underwent VILI, while three served as control. Lung CT scans were acquired at incremental tidal volumes, simultaneously recording lung mechanics. [⁶⁸Ga]Ga-DOTA-TATE was administered, followed by dynamic PET scans. Custom MatLab scripts generated voxel-by-voxel gas volume and strain maps from CT slices at para-diaphragmatic (Para-D) and mid-thoracic (Mid-T) levels. Analysis of regional Voxel-associated Normal Strain (VoStrain) and [⁶⁸Ga]Ga-DOTA-TATE uptake was performed and a measure of the statistical correlation between these two variables was quantified using the linear mutual information (LMI) method.

Results

Compared to controls, the VILI group exhibited statistically significant higher VoStrain and Standardized Uptake Value Ratios (SUVR) both at Para-D and Mid-T levels. Both VoStrain and SUVR increased along the gravitational axis with an increment described by statistically different regression lines between VILI and healthy controls and reaching the peak in the dependent regions of the lung (for strain in VILI vs. control was at Para-D: 760 ± 210 vs. 449 ± 106; at Mid-T level 497 ± 373 vs. 193 ± 160; for SUVR, in VILI vs. control was at Para-D: 2.2 ± 1.3 vs. 1.3 ± 0.1; at Mid-T level 1.3 ± 1.0 vs. 0.6 ± 0.03). LMI in both Para-D and Mid-T was statistically significantly higher in VILI than in controls.

Conclusions

In this porcine model of VILI, we found a topographical correlation between lung strain and [⁶⁸Ga]Ga-DOTA-TATE uptake at voxel level, suggesting that mechanical alteration and specific activation of inflammatory cells are strongly linked in VILI. This study represents the first voxel-by-voxel examination of this relationship in a multi-modal imaging analysis.

Today, there is a lack of clinically available imaging techniques to detect and quantify specific immune cell populations. Neutrophils are one of the first immune cells at the site of inflammation, and they secrete the serine protease neutrophil elastase (NE), which is crucial in the fight against pathogens. However, the prolonged lifespan of neutrophils increases the risk that patients will develop severe complications, such as acute respiratory distress syndrome (ARDS). Here, we evaluated the novel radiolabeled NE inhibitor 11C-GW457427 in a pig model of ARDS, for detection and quantification of neutrophil activity in the lungs. Methods: ARDS was induced by intravenous administration of oleic acid to 5 farm pigs, and 4 were considered healthy controls. The severity of ARDS was monitored by clinical parameters of lung function and plasma biomarkers. Each pig was studied with 11C-GW457427 and PET/CT, before and after pretreatment with the NE inhibitor GW311616 to determine in vivo binding specificity. PET image data were analyzed as SUVs and correlated with immunohistochemical staining for NE in biopsies. Results: The binding of 11C-GW457427 was increased in pig lungs with induced ARDS (median SUVmean, 1.91; interquartile range [IQR], 1.67-2.55) compared with healthy control pigs (P < 0.05 and P = 0.03, respectively; median SUVmean, 1.04; IQR, 0.66-1.47). The binding was especially strong in lung regions with high levels of NE and ongoing inflammation, as verified by immunohisto-chemistry. The binding was successfully blocked by pretreatment of an NE inhibitor drug, which demonstrated the in vivo specificity of 11C-GW457427 (P < 0.05 and P = 0.04, respectively; median SUVmean, 0.60; IQR, 0.58-0.77). The binding in neutrophil-rich tissues such as bone marrow (P < 0.05 and P = 0.04, respectively; baseline median SUVmean, 5.01; IQR, 4.48-5.49; block median SUVmean, 1.57; IQR, 0.95-1.85) and spleen (median SUVmean, 2.14; IQR, 1.19-2.36) was also high in all pigs. Conclusion: 11C-GW457427 binds to NE in a porcine model of oleic acid-induced lung inflammation in vivo, with a specific increase in regional lung, bone marrow, and spleen SUV. 11C-GW457427 is a promising tool for localizing, tracking, and quantifying neutrophil-facilitated inflammation in clinical diagnostics and drug development.

Purpose In the characterization of severe lung diseases, early detection of specific inflammatory cells could help to monitor patients' response to therapy and increase chances of survival. Macrophages contribute to regulating the resolution and termination of inflammation and have increasingly been of interest for targeted therapies. [Ga-68]Ga-DOTA-TATE is an established clinical radiopharmaceutical targeting somatostatin receptor subtype 2 (SSTR 2). Since activated macrophages (M1) overexpress SSTR 2, the aim of this study was to investigate the applicability of [Ga-68]Ga-DOTA-TATE for positron emission tomography (PET) imaging of M1 macrophages in pulmonary inflammation. Methods Inflammation in the pig lungs was induced by warm saline lavage followed by injurious ventilation in farm pigs (n = 7). Healthy pigs (n = 3) were used as control. A 60-min dynamic PET scan over the lungs was performed after [Ga-68]Ga-DOTA-TATE injection and [F-18]FDG scan was executed afterward for comparison. The uptake of both tracers was assessed as mean standardized uptake values (SUVmean) 30-60-min post-injection. The PET scans were followed by computed tomography (CT) scans, and the Hounsfield units (HU) were quantified of the coronal segments. Basal and apical segments of the lungs were harvested for histology staining. A rat lung inflammation model was also studied for tracer specificity using lipopolysaccharides (LPS) by oropharyngeal aspiration. Organ biodistribution, ex vivo autoradiography (ARG) and histology samples were conducted on LPS treated, octreotide induced blocking and control healthy rats. Results The accumulation of [Ga-68]Ga-DOTA-TATE on pig lavage model was prominent in the more severely injured dorsal segments of the lungs (SUVmean = 0.91 +/- 0.56), compared with control animals (SUVmean = 0.27 +/- 0.16, p < 0.05). The tracer uptake corresponded to the damaged areas assessed by CT and histology and were in line with HU quantification. The [Ga-68]Ga-DOTA-TATE uptake in LPS treated rat lungs could be blocked and was significantly higher compared with control group. Conclusion The feasibility of the noninvasive assessment of tissue macrophages using [Ga-68]Ga-DOTA-TATE/PET was demonstrated in both porcine and rat lung inflammation models. [Ga-68]Ga-DOTA-TATE has a great potential to be used to study the role and presence of macrophages in humans in fight against severe lung diseases.

Background: Cardiac positron emission tomography (PET) offers non-invasive assessment of perfusion and left ventricular (LV) function from a single dynamic scan. However, no prior assessment of mitral regurgitation severity by PET has been presented. Application of indicator dilution techniques and gated image analyses to PET data enables calculation of forward stroke volume and total LV stroke volume. We aimed to evaluate a combination of these methods for measurement of regurgitant volume (RegVol) and fraction (RegF) using dynamic 15O-water and 11C-acetate PET in comparison to cardiovascular magnetic resonance (CMR).

Results: Twenty-one patients with severe primary mitral valve regurgitation underwent same-day dynamic PET examinations (O-15-water and C-11-acetate) and CMR. PET data were reconstructed into dynamic series with short time frames during the first pass, gated O-15-water blood pool images, and gated C-11-acetate myocardial uptake images. PET-based RegVol and RegF correlated strongly with CMR (RegVol: O-15-water r = 0.94, C-11-acetate r = 0.91 and RegF: O-15-water r = 0.88, C-11-acetate r = 0.84, p < 0.001). A systematic underestimation (bias) was found for PET (RegVol: O-15-water - 11 +/- 13 mL, p = 0.002, C-11-acetate - 28 +/- 16 mL, p < 0.001 and RegF: O-15-water - 4 +/- 6%, p = 0.01, C-11-acetate - 10 +/- 7%, p < 0.001). PET measurements in patients were compared to healthy volunteers (n = 18). Mean RegVol and RegF was significantly lower in healthy volunteers compared to patients for both tracers. The accuracy of diagnosing moderately elevated regurgitant volume (> 30mL) was 95% for O-15-water and 92% for C-11-acetate.

Conclusions: LV regurgitation severity quantified using cardiac PET correlated with CMR and showed high accuracy for discriminating patients from healthy volunteers.

Objective

[¹¹C]metomidate PET/CT is used for adrenocortical cancer imaging and is currently evaluated as an adjunct to adrenal vein sampling (AVS) for lateralization of aldosterone-producing adenomas (APA) in patients with primary aldosteronism (PA). This study assessed the image quality of a block-sequential regularized expectation maximization (BSREM) reconstruction algorithm (Q.Clear, GE Healthcare, Milwaukee, USA), to determine the optimal penalization factor (expressed as beta values) for clinical [¹¹C]metomidate PET/CT. The time-of-flight coupled ordered subset expectation maximization (TOF OSEM) algorithm was used as the reference reconstruction.

Methods

Retrospectively, seven patients with primary aldosteronism were assessed, for whom raw data and TOF OSEM reconstructions of [¹¹C]metomidate PET were available. Raw data were reconstructed applying BSREM with β-values 70-800. Tumour SUV_max in the APAs was measured and image quality was assessed mainly in terms of signal-to-background ratio (SBR) and signal-to-noise ratio (SNR) in comparison with TOF OSEM, applying a two-tailed Wilcoxon matched-pairs signed rank test. In addition, we addressed the effect of BSREM on lateralization.

Results

With the BSREM algorithm, and as compared to TOF OSEM reconstruction, the average lesion SUV_max increased for β-values 70 and 130 (p=0.0156).

SBR increased for β-values 130 or higher (p=0.0156) and SNR increased only for β-value 130 (p=0.0156). By using an adenoma-to-normal-adrenal gland ratio of 1.25 as the cut-off, one additional patient was lateralized by [¹¹C]metomidate PET reconstructed with the BSREM (β 70 and 130, p=0.0156 and p=0.0312) as compared to TOF OSEM.

Conclusions

The BSREM reconstruction algorithm improves image quality, without compromising SUVmax quantification. In this study, a β-value between 70 and 130 was found optimal. BSREM may therefore improve lateralization by [¹¹C]metomidate PET/CT in primary aldosteronism, with the expectation of the greatest impact on small adenomas.