Ventilation Heterogeneity Is a Treatable Trait in Severe Asthma.

BACKGROUND: Ventilation heterogeneity (VH) is a feature of asthma and indicates small airway disease. Nuclear imaging methods assess VH, which can facilitate clinical diagnosis and further our understanding of disease aetiology. OBJECTIVE: We sought to assess VH in severe eosinophilic asthma (SEA) using ventilation/perfusion single-photon emission computed tomography (V/P SPECT), and to assess its use as an objective test of the effect of biologic treatment for ventilation defects in SEA. METHODS: Adults (≥18 y) with severe asthma were recruited to participate in a cross-sectional observational study. Participants underwent a clinical assessment and V/P SPECT CT using Technegas as the ventilation agent. Measures were repeated for a nested before-after treatment study in people with SEA commencing biologics. RESULTS: A total of 62 participants with severe asthma were recruited. From this, 38 participants with SEA were included in the before-after study. The VH was associated with clinical variables such as lung function impairment and significantly improved after monoclonal antibody treatment in the severe asthma group. The changes in VH correlated with change in post bronchodilator forced expiratory volume in 1 second (FEV1) %predicted (r = -0.503; P = .001) and post bronchodilator FEV1/FVC (forced vital capacity) (r = -0.415; P = .01). CONCLUSIONS: The VH is clinically significant, measurable, and treatable, which establishes VH as a treatable trait in severe asthma.

Comparison of ventilation defects quantified by Technegas SPECT and hyperpolarized 129Xe MRI.

Introduction: The ideal contrast agents for ventilation SPECT and MRI are Technegas and 129Xe gas, respectively. Despite increasing interest in the clinical utility of ventilation imaging, these modalities have not been directly compared. Therefore, our objective was to compare the ventilation defect percent (VDP) assessed by Technegas SPECT and hyperpolarized 129Xe MRI in patients scheduled to undergo lung cancer resection with and without pre-existing obstructive lung disease. Methods: Forty-one adults scheduled to undergo lung cancer resection performed same-day Technegas SPECT, hyperpolarized 129Xe MRI, spirometry, and diffusing capacity of the lung for carbon monoxide (DLCO). Ventilation abnormalities were quantified as the VDP using two different methods: adaptive thresholding (VDPT) and k-means clustering (VDPK). Correlation and agreement between VDP quantified by Technegas SPECT and 129Xe MRI were determined by Spearman correlation and Bland-Altman analysis, respectively. Results: VDP measured by Technegas SPECT and 129Xe MRI were correlated (VDPT: r = 0.48, p = 0.001; VDPK: r = 0.63, p < 0.0001). A 2.0% and 1.6% bias towards higher Technegas SPECT VDP was measured using the adaptive threshold method (VDPT: 23.0% ± 14.0% vs. 21.0% ± 5.2%, p = 0.81) and k-means method (VDPK: 9.4% ± 9.4% vs. 7.8% ± 10.0%, p = 0.02), respectively. For both modalities, higher VDP was correlated with lower FEV1/FVC (SPECT VDPT: r = -0.38, p = 0.01; MRI VDPK: r = -0.46, p = 0.002) and DLCO (SPECT VDPT: r = -0.61, p < 0.0001; MRI VDPK: r = -0.68, p < 0.0001). Subgroup analysis revealed that VDP measured by both modalities was significantly higher for participants with COPD (n = 13) than those with asthma (n = 6; SPECT VDPT: p = 0.007, MRI VDPK: p = 0.006) and those with no history of obstructive lung disease (n = 21; SPECT VDPT: p = 0.0003, MRI VDPK: p = 0.0003). Discussion: The burden of ventilation defects quantified by Technegas SPECT and 129Xe MRI VDP was correlated and greater in participants with COPD when compared to those without. Our observations indicate that, despite substantial differences between the imaging modalities, quantitative assessment of ventilation defects by Technegas SPECT and 129Xe MRI is comparable.

Technegas, A Universal Technique for Lung Imaging in Nuclear Medicine: Technology, Physicochemical Properties, and Clinical Applications.

Technegas was developed in Australia as an imaging radioaerosol in the late 1980s and is now commercialized by Cyclomedica, Pty Ltd. for diagnosing pulmonary embolism (PE). Technegas is produced by heating technetium-99m in a carbon crucible for a few seconds at high temperatures (2750 °C) to generate technetium-carbon nanoparticles with a gas-like behaviour. The submicron particulates formed allow easy diffusion to the lung periphery when inhaled. Technegas has been used for diagnosis in over 4.4 m patients across 60 countries and now offers exciting opportunities in areas outside of PE, including asthma and chronic obstructive pulmonary disease (COPD). The Technegas generation process and the physicochemical attributes of the aerosol have been studied over the past 30 years in parallel with the advancement in different analytical methodologies. Thus, it is now well established that the Technegas aerosol has a radioactivity aerodynamic diameter of <500 nm and is composed of agglomerated nanoparticles. With a plethora of literature studying different aspects of Technegas, this review focuses on a historical evaluation of the different methodologies' findings over the years that provides insight into a scientific consensus of this technology. Also, we briefly discuss recent clinical innovations using Technegas and a brief history of Technegas patents.

A Technical Overview of Technegas as a Lung Ventilation Agent.

Technegas is a carbon-based nanoparticle developed in Australia in 1984 and has been in widespread clinical use, including SPECT imaging, since 1986. Although 81mKr offers the ideal ventilation properties of a true gas, Technegas is considered preferred in more than 60 countries for ventilation imaging yet has limited adoption in the United States. In March 2020, a new U.S. Food and Drug Administration application was lodged for Technegas, and the impending approval warrants a detailed discussion of the technical aspects of the technology for those for whom it is new. Technegas is a simple yet versatile system for producing high-quality 99mTc-based ventilation studies. The design affords safety to patients and staff, including consideration of radiation and biologic risks. Technegas is the gold standard for the ventilation portion of SPECT-based ventilation-perfusion studies in pulmonary embolism and several respiratory pathologies. When approved by the U.S. Food and Drug Administration, Technegas will extend advantages to workflow, safety, and study quality for departments that adopt the technology.

Quantitative comparison between single-photon emission computed tomography and positron emission tomography imaging of lung ventilation with 99mTc-technegas and 68Ga-gallgas in patients with chronic obstructive pulmonary disease: A pilot study.

The aim of this study was quantitative comparison between 68Ga-Gallgas positron emission tomography (PET) and 99mTc-Technegas single photon emission computed tomography (SPECT) for lung ventilation function assessment in patients with moderate-to-severe obstructive pulmonary disease and to identify image-derived texture features correlating to the physiologic parameters. Five patients with moderate-to-severe chronic obstructive pulmonary disease with PET and SPECT lung ventilation scans were selected for this study. Threshold-based segmentations were used to compare ventilated regions between both imaging techniques. Histograms of both scans were compared to reveal main differences in distributions of radiotracers. Volumes of segmentation as well as 50 textural features measured in the pulmonary region were correlated to the forced expiratory volume in 1 s (FEV1) as the relevant physiological variable. A better peripheral distribution of the radiotracer was observed in PET scans for three out of five patients. A segmentation threshold of 27% and 31% for normalized scans, for PET and SPECT respectively, was found optimal for volume correlation with FEV1. A high correlation (Pearson correlation coefficient >0.9) was found between 16 texture features measured from SPECT and 7 features measured from PET and FEV1. Quantitative measurements revealed different tracer distribution in both techniques. These results suggest that tracer distribution patterns may depend on the cause of the pulmonary obstruction. We found several texture features measured from SPECT to correlate to FEV1.

Identifying the heterogeneity of COPD by V/P SPECT: a new tool for improving the diagnosis of parenchymal defects and grading the severity of small airways disease.

INTRODUCTION: Airway obstruction and possible concomitant pulmonary diseases in COPD cannot be identified conventionally with any single diagnostic tool. We aimed to diagnose and grade COPD severity and identify pulmonary comorbidities associated with COPD with ventilation/perfusion single-photon emission computed tomography (V/P SPECT) using Technegas as the functional ventilation imaging agent. METHODS: 94 COPD patients (aged 43-86 years, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages I-IV) were examined with V/P SPECT and spirometry. Ventilation and perfusion defects were analyzed blindly according to the European guidelines. Penetration grade of Technegas in V SPECT measured the degree of obstructive small airways disease. Total preserved lung function and penetration grade of Technegas in V SPECT were assessed by V/P SPECT and compared to GOLD stages and spirometry. RESULTS: Signs of small airway obstruction in the ventilation SPECT images were found in 92 patients. Emphysema was identified in 81 patients. Two patients had no signs of COPD, but both of them had a pulmonary embolism, and in one of them we also suspected a lung tumor. The penetration grade of Technegas in V SPECT and total preserved lung function correlated significantly to GOLD stages (r=0.63 and -0.60, respectively, P<0.0001). V/P SPECT identified pulmonary embolism in 30 patients (32%). A pattern typical for heart failure was present in 26 patients (28%). Parenchymal changes typical for pneumonia or lung tumor were present in several cases. CONCLUSION: V/P SPECT, using Technegas as the functional ventilation imaging agent, is a new tool to diagnose COPD and to grade its severity. Additionally, it revealed heterogeneity of COPD caused by pulmonary comorbidities. The characteristics of these comorbidities suggest their significant impact in clarifying symptoms, and also their influence on the prognosis.

Optimisation of quantitative lung SPECT applied to mild COPD: a software phantom simulation study.

BACKGROUND: The amount of inhomogeneities in a (99m)Tc Technegas single-photon emission computed tomography (SPECT) lung image, caused by reduced ventilation in lung regions affected by chronic obstructive pulmonary disease (COPD), is correlated to disease advancement. A quantitative analysis method, the CVT method, measuring these inhomogeneities was proposed in earlier work. To detect mild COPD, which is a difficult task, optimised parameter values are needed. METHODS: In this work, the CVT method was optimised with respect to the parameter values of acquisition, reconstruction and analysis. The ordered subset expectation maximisation (OSEM) algorithm was used for reconstructing the lung SPECT images. As a first step towards clinical application of the CVT method in detecting mild COPD, this study was based on simulated SPECT images of an advanced anthropomorphic lung software phantom including respiratory and cardiac motion, where the mild COPD lung had an overall ventilation reduction of 5%. RESULTS: The best separation between healthy and mild COPD lung images as determined using the CVT measure of ventilation inhomogeneity and 125 MBq (99m)Tc was obtained using a low-energy high-resolution collimator (LEHR) and a power 6 Butterworth post-filter with a cutoff frequency of 0.6 to 0.7 cm(-1). Sixty-four reconstruction updates and a small kernel size should be used when the whole lung is analysed, and for the reduced lung a greater number of updates and a larger kernel size are needed. CONCLUSIONS: A LEHR collimator and 125 (99m)Tc MBq together with an optimal combination of cutoff frequency, number of updates and kernel size, gave the best result. Suboptimal selections of either cutoff frequency, number of updates and kernel size will reduce the imaging system's ability to detect mild COPD in the lung phantom.

Contribution of V/Q SPECT to planar scintigraphy in the diagnosis of pulmonary embolism.

AIM: To evaluate the feasibility of V/Q SPECT and analyze its contribution to planar V/Q lung scintigraphy in the diagnosis of pulmonary embolism (PE). MATERIAL AND METHODS: A total of 109 patients with suspected PE showing Wells score>2 and elevated D-dimer were studied. The V/Q could not be completed in 7 patients, so they were excluded. Ventilation and perfusion scans were done using Technegas and (99m)Tc-MAA. Planar study included 8 projections on a 256×256 matrix and 128 projections on a 128×128 matrix were acquired for the SPECT study, applying an iterative method. Planar images were interpreted according to modified PIOPED criteria, and SPECT by the guidelines of the EANMMI. The results with both techniques were compared. RESULTS: V/Q planar scintigraphy and SPECT could be performed in 102 patients. V/Q planar scintigraphy was considered "diagnostic" in 39 of the 102 patients, and "non-diagnostic" in 63. Of the 39 "diagnostic" studies, 31 were reported as high probability of PE and 8 as normal. Of the 63 "non-diagnostic", 26 corresponded to intermediate, 29 to low, and 8 to very low probability. The SPECT study was "diagnostic" in 97 and indeterminate in only 5. All patients with a high probability planar scintigraphy had a positive SPECT. In the 8 patients with a normal planar scintigraphy SPECT was negative in 5 and positive in 3. In the 63 patients with a "non-diagnostic" planar scintigraphy SPECT was "diagnostic" in 58 of them, positive in 17 and negative in 41. CONCLUSION: V/Q SPECT is a feasible technique as it was performed in 102 of the 109 patients who were enrolled in the study (94%). The addition of V/Q SPECT to planar V/Q decreases the number of "non-diagnostic" reports from 62% in planar scintigraphy to 4.9% in SPECT. Therefore, V/Q SPECT should be included in the diagnosis approach of PE due to its high diagnostic yield.

Regional lung ventilation in humans during hypergravity studied with quantitative SPECT.

Recently we challenged the view that arterial desaturation during hypergravity is caused by redistribution of blood flow to dependent lung regions by demonstrating a paradoxical redistribution of blood flow towards non-dependent regions. We have now quantified regional ventilation in 10 healthy supine volunteers at normal and three times normal gravity (1G and 3G). Regional ventilation was measured with Technegas ((99m)Tc) and quantitative single photon emission computed tomography (SPECT). Hypergravity caused arterial desaturation, mean decrease 8%, p<0.05 vs. 1G. The ratio for mean ventilation per voxel for non-dependent and dependent lung regions was 0.81±0.12 during 1G and 1.63±0.35 during 3G (mean±SD), p<0.0001. Thus, regional ventilation was shifted from dependent to non-dependent regions. We suggest that arterial desaturation during hypergravity is caused by quantitatively different redistributions of blood flow and ventilation. To our knowledge, this is the first study presenting high-resolution measurements of regional ventilation in humans breathing normally during hypergravity.