Initial results with [¹⁸F]FAPI-74 PET/CT in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial lung disease of unknown cause with a very poor prognosis that is characterized by abnormal collagen accumulation in the lung parenchyma, leading to progressive impairment of regeneration and repair [1, 2]. Various genetic and environmental factors have been considered to trigger the cascade of inflammatory events, leading to permanent loss of normal lung tissue [3]. High-resolution computed tomography (HRCT) and pulmonary function tests represent currently the mainstay of diagnosis, of which HRCT is considered a gold standard due to the reported positive predictive value of 90% [4, 5]. However, since these examinations reveal fibrotic changes rather late during the course of the disease, lung areas with minor fibrotic changes in the short term during therapy might be difficult to detect—thus impairing the clinical decision-making process with optimal dynamic disease management.

The introduction of fibroblast activation protein (FAP) ligands as fibrosis monitoring agents offers great potential in order to fulfill this unmet clinical need. Several studies investigating the efficacy of ⁶⁸Ga-labelled FAP ligands provide highly promising insights into the mechanism and clinical course of fibrosis in lung parenchyma [6‐10]. However, due to the well-known drawbacks of ⁶⁸Ga-labelling such as high radiation burden with suboptimal imaging quality and poor cost-effectiveness, ¹⁸F-labelled FAP ligands draw great attention in routine clinical care [11, 12]. To the best of our knowledge, this is the first study, analyzing the efficacy of [¹⁸F]FAPI-74-PET/CT prospectively in a small patient cohort.

IPF is a relatively rapid-progressing lethal disease that is characterized by the abnormal accumulation of collagen in lung tissue, impairing its ability for repair and regeneration [1]. These changes in the extracellular matrix enhance the migration and activation of quiescent fibroblasts, which further accelerate the fibrosing process [2]. 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 results [6‐9].

In the light of encouraging results obtained with ⁶⁸Ga-labeled FAPI [13‐15] and to overcome some drawbacks of ⁶⁸ Ga-labeling, 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 ongoing tissue remodeling, which might predict disease progression. [¹⁸F]-FAPI uptake (median SUV_mean) in our study was 1.40 (1.10–1.90) in IPF vs. 0.90 (0.60–1.40) in the control group, similar to the results of Bergmann et al. [7] using [⁶⁸Ga]-FAPI-04 with median SUV_mean 0.80 (0.60–2.10) in ILD vs. 0.50 (0.40–0.50) in controls. A slightly higher tracer uptake observed in our study might result from the longer half-life of ¹⁸F remaining in the region of interest at the time point of the PET scan. Interestingly, Bergmann et al. [7] have previously shown in the mentioned 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 months. The authors observed this disease progression independently of other known risk factors, such as the extent of involvement in HRCT at baseline and FVC at baseline. Considering this, our data as a 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 the Hounsfield scale on CT. This result is consistent with the previous work of Röhrich et al. [8], which demonstrated that the tracer uptake of [⁶⁸Ga]-FAPI-46 correlates with radiographic parameters such as fibrosis (FIB)- and ground-glass opacity (GGO) index. Bergmann et al. [7] also reported on minor correlation of [⁶⁸Ga]-FAPI-04 with the extent of ground glass opacities. Because radiographic signs like ground-glass opacity can be easily affected by morphological changes of other causes (e.g., alveolitis or edema of infectious backgrounds) and might be rather unspecific, 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. Whereas ¹⁸F-labeled compounds allow larger batch production in facilities equipped with cyclotrons at lower cost and can be delivered to remote centers (satellite concepts), the typical batch size of a ⁶⁸Ge/Ga⁶⁸ generator allows the daily clinical performance of only a few patients per elution and requires an on-site and on-time synthesis of the radiotracer, also because of the shorter half-life (68 min).

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.

These encouraging results pave the way for further, multicentric, large-scale trials for the evaluation of fibrosing processes in lung parenchyma with [¹⁸F]FAPI-74.