Persistent fibroblast-related tissue activity in long COVID after moderate-to-severe acute COVID-19 assessed by [⁶⁸Ga]Ga-FAPI PET/CT.

PURPOSE: Long COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC), is characterized by persistent symptoms. Fibroblast activation protein (FAP), expressed on activated fibroblasts during tissue remodeling, can be visualized with [⁶⁸Ga]Ga-FAPI PET/CT. This study investigated lung and muscle fibroblastic activity in patients with post-acute sequelae of COVID-19 (PASC) following moderate-to-severe COVID-19 pneumonia more than two years after the acute infection, using [⁶⁸Ga]Ga-FAPI PET/CT. METHODS: In this pilot prospective observational study, we enrolled patients with PASC following severe acute COVID-19 requiring high-flow nasal cannula or mechanical ventilation and age- and sex-matched controls without pulmonary pathology between September 2023 and February 2024. PASC patients underwent high-resolution CT (HRCT), pulmonary function tests (PFTs), and [⁶⁸Ga]Ga-FAPI PET/CT. SUVmax and SUVmean were measured for each lung lobe. HRCT abnormalities were scored using a semi-quantitative scale (0-20) and categorized as ground-glass opacities, reticulations, parenchymal bands, traction bronchiectasis, or subpleural cysts. These findings were statistically compared and correlated with PET parameters, PFTs, and clinical symptoms. In addition, [⁶⁸Ga]Ga-FAPI uptake in the paravertebral muscles was assessed at the level of the L3 vertebra. RESULTS: Twenty patients with PASC and 10 control subjects were included (median ages: 64 and 58.5 years, respectively). The mean interval between hospitalization for acute COVID-19 and study imaging was 25 ± 4.5 months. PASC patients exhibited significantly increased [⁶⁸Ga]Ga-FAPI uptake in the lungs compared with controls. Lung [⁶⁸Ga]Ga-FAPI uptake was markedly increased in patients with traction bronchiectasis. No correlations were observed between lung [⁶⁸Ga]Ga-FAPI SUVmax and PFTs or symptom burden. However, lung [⁶⁸Ga]Ga-FAPI SUVmean demonstrated moderate inverse correlation with DLCO (r = -0.455, p = 0.044). In addition, [⁶⁸Ga]Ga-FAPI SUVmax in muscle was significantly higher in PASC patients than in controls, with particularly elevated uptake observed in patients with a history of mechanical ventilation. CONCLUSIONS: [⁶⁸Ga]Ga-FAPI PET/CT demonstrated increased lung tracer uptake in patients with PASC more than two years after moderate to severe COVID-19, supporting persistent fibroblast-related tissue activity. Limited associations between lung SUVmean and DLCO suggest a potential link between tracer uptake and functional impairment. Increased muscle [⁶⁸Ga]Ga-FAPI uptake was also observed as an exploratory finding requiring further functional and histopathological validation.