IPF is a relatively rapid-progressing lethal disease which is characterized by the abnormal accumulation of collagen in lung tissue, impairing its ability for repair and regeneration1. These changes in the extracellular matrix enhance the migration and activation of quiescent fibroblasts, which further accelerate the fibrosing process2. Thus, early detection and initiation of antifibrotic therapy as well as a reliable therapy-monitoring tool appear to be essential for therapy management. Based on this unmet clinical need, several research groups investigated the novel-tracer family, FAP ligands, in the assessment of fibrosing processes of the lung with highly interesting, promising results6,8,9.
In the light of encouraging results obtained with 68Ga-labelled FAPI and to overcome some drawbacks of 68Ga-labelling, we hypothesized that the quantification of lung fibrosis using fibrotic active volume in [18F]FAPI-74 might correlate with the clinical severity and thus could serve as a non-invasive evaluation method. To the best of our knowledge, this is the first study to investigate [18F]FAPI-74 in pulmonary fibrosis.
In the current study, we could demonstrate that patients with clinically impaired lung function showed higher fibrotic active volume with corresponding pulmonary area with positive FAPI uptake. Because FAP tracers are known to accumulate in the non-quiescent, activated fibroblasts, our results indicate that FAPI-PET/CT can quantify the ongoing tissue remodelling, which might predict disease progression. Bergmann et al. have previously shown in the prospective study in patients with interstitial lung disease (ILD) in systemic sclerosis, that 68Ga-FAPI-04 accumulation at baseline was associated with the risk for ILD progression in the follow-up period of 6–10 months8. The authors observed this disease progression independently of other known risk factors, such as the extent of involvement on HRCT at baseline and FVC at baseline. Considering this, our data as one-point-assessment might imply further prognostic relevant information, which should be verified in the long-term period.
We found the fibrotic active volume of the fibrotic lung significantly correlates with Hounsfield scale on CT. This result is in coincidence with the previous work of Röhrich et al., which demonstrated that the tracer uptake of 68Ga-FAPI correlates with radiographic parameters such as Fibrosis (FIB)- and Ground-glass opacity (GGO)-Index7. These findings further support the utility of FAPI-PET/CT in the clinical setting, as it contains the radiographic as well as the fibrotic information, which might allow insight into the current disease activity with possible prognostic implications. Regarding the general image quality, 18F-labeled compounds reveal higher spatial resolution allowing the detection of smaller lesions as compared to 68Ga-labeled compounds, combined with several other advantages including cost-effective production and centralized supply.
Further, we could demonstrate an investigator-independent, readily reproducible evaluation method using a dedicated software package (Hermes Hybrid Viewer, Affinity 1.1.4; Hermes Medical Solutions, Stockholm, Sweden) that provides a clear delineation of fibrotic or chronic inflammatory changes of lung parenchyma in terms of fibrotic active volume. Although fibrotic active volume, as already mentioned, displayed a statistically significant, negative correlation with forced vital capacity, the correlation with CO diffusing capacity could not reach statistical significance, most probably due to the small cohort size.
The main limitation of our study seems to be the small cohort size. Additionally, PET images were acquired without respiratory gating so that there might be some difference in tracer uptake between respiratory phases.