68Ga-FAPI PET/CT to detect ongoing fibroblast activity in post-acute COVID-19 with respiratory impairment after hospital discharge: *The FAPI COVID-CLIMATE Study*

The ongoing pandemic caused by the novel coronavirus (SARS-COV-2), which causes
the disease known as COVID-19, is leading to another epidemic of post-acute
patients with persistent health impairments. The majority of COVID-19 patients
survive the infection and acute illness, however, the long-term health effects
are largely unknown. A substantial proportion of patients experience long-term
symptoms, ranging from pure respiratory symptoms to disabling fatigue and
mental issues, referred to as long COVID-19 or post-acute sequelae of COVID-19
(PASC). It has been shown that the majority of COVID-19 survivors have some
persistent interstitial lung abnormalities (ILA) on high resolution computed
tomography (HRCT), most extensive in post-intensive care unit patients and
patients with longer duration of hospitalization. However, both the evolution
of these ILA and their nature are unknown, since they can reflect ongoing
inflammation, residual areas of organizing pneumonia, or early fibrosis. This
may result in persistent pulmonary complaints, with or without an abnormal lung
function test, with up to 76% of the patients still having normal diffuse
capacity. Although chest computed tomography (CT) has been shown to be a useful
tool in identifying lung abnormalities in patients with PASC, it does not
provide information about the pathogenesis and possible targets for
intervention. Advanced molecular imaging to assess ongoing fibroblast activity
has the potential to provide a pathophysiological model and, possibly,
personalized targeted pharmacological interventions. The recently developed
68Ga-FAPI PET tracer has this potential.
Fibroblast activation protein alpha (FAP) is a type II transmembrane protease
with dipeptidyl peptidase and endopeptidase activity which is induced in
fibroblasts upon activation and is negligible or absent in resting fibroblasts
or other cell types. The recently developed radiolabeled quinoline-based
positron emission tomography (PET) tracers binding to FAP demonstrate tracer
uptake in various tumor entities as well as in pulmonary fibrotic diseases and
are a major advance for molecular imaging.
68Ga-FAPI PET can aid in the understanding of the pathophysiology of PASC with
persistent pulmonary complaints. With 68Ga-FAPI PET we aim to quantify the
fibroblastic activity in relation to the % involvement interstitial lung
abnormalities on HRCT, lung function/diffusing capacity of the lungs for carbon
monoxide (DLCO), fibrotic blood markers, 6-minute walking test (6-MWT) and
self-reported daily impairments of patients with PASC at 3-months baseline and
1 year after hospital discharge.

Primary objective:
To relate pulmonary fibroblast activity, measured by FAPI-PET/CT at least 3
months after hospital discharge, to interstitial lung abnormalities on HRCT at
the same time point in post-acute COVID-19 patients with respiratory
complaints.

Secondary objectives:
To relate pulmonary fibroblast activity, measured by FAPI-PET/CT, to specific
fibrosis and inflammatory blood markers, 6-MWT, lung function including DLCO
and VC, and self-reported daily impairments measured by the EQ-5D questionnaire
at the same time point and to HRCT findings, EQ-5D and 6-MWT in case of
persistent respiratory complaints 8-10 months after the first study visit.

This is a prospective observational cohort study.

Total radiation dose 5 mSv. Completion of a short questionnaire (EQ5D, 5
multiple choice questions) once or twice, a 6-minute walking test once or twice
and a single blood draw.
Possible hematoma formation as a result of insertion of the intravenous canula.