Increased Lung Immune Metabolic Activity in COVID-19 Survivors

Abstract

Purpose: We quantified lung glycolytic metabolic activity, clinical symptoms and inflammation, coagulation, and endothelial activation biomarkers in 2019 coronavirus disease (COVID-19) pneumonia survivors.

Methods: Adults previously hospitalized with moderate to severe COVID-19 pneumonia were prospectively included. Subjects filled out a questionnaire on clinical consequences, underwent chest CT and 18 F-FDG PET/CT, and provided blood samples on the same day. Forty-five volunteers served as control subjects. Analysis of CT images and quantitative voxel-based analysis of PET/CT images were performed for both groups. 18 F-FDG uptake in the whole-lung volume and in high- and low-attenuation areas was calculated and normalized to liver values. Quantification of plasma markers of inflammation (interleukin 6), d -dimer, and endothelial cell activation (angiopoietins 1 and 2, vascular cell adhesion molecule 1, and intercellular adhesion molecule 1) was also performed.

Results: We enrolled 53 COVID-19 survivors (62.3% were male; median age, 50 years). All survivors reported at least 1 persistent symptom, and 41.5% reported more than 6 symptoms. The mean lung density was greater in survivors than in control subjects, and more metabolic activity was observed in normal and dense lung areas, even months after symptom onset. Plasma proinflammatory, coagulation, and endothelial activation biomarker concentrations were also significantly higher in survivors.

Conclusion: We observed more metabolic activity in areas of high and normal lung attenuation several months after moderate to severe COVID-19 pneumonia. In addition, plasma markers of thromboinflammation and endothelial activation persisted. These findings may have implications for our understanding of the in vivo pathogenesis and long-lasting effects of COVID-19 pneumonia.

FIGURE 1

Patient inclusion flowchart.

FIGURE 2

Chest CT images of a patient with COVID-19 pneumonia (acute-phase) and follow-up CT and chest-dedicated ¹⁸F-FDG PET/CT images of the same patient. Acute-phase CT images (A and B) show bilateral peripheral GGOs and linear opacities. Those obtained 70 days after symptom onset (C and D) depict partial absorption of the opacifications. ¹⁸F-FDG PET/CT images (E–H) show greater uptake in the lung periphery, overlapping the mild areas of GGOs.

FIGURE 3

Liver-corrected mean SUV from the whole lung, areas <−700 HU, and areas >−700 HU. Columns are median; error bars are first and third quartiles, and circles are individual data. Metabolic activity was higher in survivors than in control subjects in the whole-lung parenchyma and normal- and high-attenuation areas.

FIGURE 4

Persistence of elevated biomarkers of endothelial cell activation, coagulation, and inflammation. Plasmatic concentrations of endothelial cell activation markers, Ang-1 (A) and Ang-2 (B), VCAM-1 (C) and human ICAM-1 (D), coagulation activation marker d-dimer (E), and the proinflammatory cytokine IL-6 (F), are shown. Median and IQR are represented.