In Vivo Visualization and Quantification of Neutrophil Elastase in Lungs of COVID-19 Patients: A First-in-Humans PET Study with ¹¹C-NES

Subjects

This study was approved by the Swedish Medical Products Agency (EudraCT 2020-003980-24) and the Swedish Ethical Review Authority (Diarienummer 2020-07017). The Helsinki Declaration and its subsequent revisions were observed. We recruited 4 symptomatic and hospitalized patients, at least one of either sex, who had polymerase chain reaction–verified COVID-19 and had been admitted to the hospital because of hypoxic respiratory failure and treated with supplemental oxygen at a non–intensive-care unit. We also recruited 2 healthy controls, in accordance with the approved procedure in the ethical permit. The characteristics of the patients and healthy controls are presented in Table 1 and Supplemental Table 1 (supplemental materials are available at http://jnm.snmjournals.org).

Verbal and written informed consent was obtained from the participants.

Tracer Production

¹¹C-NES was produced in accordance with good manufacturing practices, and its safety was investigated in a microdosing toxicology study (9).

Safety

¹¹C-NES was used for the first time in humans. Before and after PET, all subjects were examined for vital signs, phlebitis, and rash and underwent electrocardiography. No subject showed any adverse effects after being administrated approximately 5 MBq/kg of body weight, corresponding to a total ¹¹C-NES amount of about 5 μg.

PET Scanning

All subjects were scanned on a digital time-of-flight PET/CT system (Discovery MI-5; GE Healthcare) with a 25-cm axial field of view. The subjects were supine during the entire examination. After a low-dose CT scan for anatomic localization and attenuation correction, a 4-min dynamic PET scan was started simultaneously with administration of a controlled bolus injection of 400 MBq of ¹⁵O-water (5 mL at 1 mL/min followed by 35 mL of saline at 2 mL/min). At least 15 min later, a second dynamic PET scan was started simultaneously with administration of a 5 MBq/kg controlled bolus injection of ¹¹C-NES (range, 4.2–5.3 MBq/kg), with a duration of 15 min in healthy controls and 60 min in COVID-19 patients. List-mode data were rebinned into frames of increasing durations over the course of the scan (1 × 10, 8 × 5, 4 × 10, 2 × 15, 3 × 20, and 2 × 30 s for ¹⁵O-water and 1 × 10, 8 × 5, 4 × 10, 3 × 20, 2 × 30, and 5 × 60 s for ¹¹C-NES in all subjects, followed by 4 × 300 and 3 × 600 s in patients). Dynamic images were reconstructed using time-of-flight ordered-subset expectation maximization, including resolution recovery, with 3 iterations, 16 subsets, and a 5-mm gaussian postprocessing filter. All appropriate corrections for accurate quantification were applied. A whole-body low-dose CT and PET scan of ¹¹C-NES (3 min per bed position) was acquired at approximately 1 h after injection and reconstructed using block-sequential regularized expectation maximization (Q.Clear; GE Healthcare) with a regularization parameter of 500.

Pulmonary Perfusion

For calculation of lung perfusion based on the ¹⁵O-water PET data, systemic and pulmonary circulation blood time–activity curves were determined using automated cluster analysis in aQuant Research software (Medtrace Pharma A/S). Lung perfusion images were calculated by implementing a nonnegative least-squares basis function in a single-tissue-compartment model in which the pulmonary circulation blood curve was the input function, with fitted pulmonary and systemic blood volume parameters. Only voxels with density of less than 0.9 g/cm³, based on the low-dose CT images, were included in the calculations. Pulmonary perfusion was calculated as the influx rate of ¹⁵O-water. Volumes of interest were drawn on pulmonary perfusion images over representative parts of normal-appearing and GGO and consolidated lung tissue based on the CT images.

¹¹C-NES Data Analysis

Volumes of interest were drawn on summed ¹¹C-NES images as above and transferred to the dynamic PET images to obtain time–activity curves. ¹¹C-NES SUVs were calculated as radioactivity concentrations normalized to injected activity per kilogram of body weight.