Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease with a poor prognosis and a median survival of 3.8 years from the time of diagnosis.1 Despite the recent introduction of antifibrotic agents (nintedanib and pirfenidone), that have slowed down the rate of lung function decline, lung transplantation (LT) is the unique therapeutic modality that has demonstrated to improve survival for IPF patients, decreasing the risk of death by 75%.2

According to the most recent report of the ISHLT Registry, post-transplant median survival for IPF patients is 5.2 years, which is significantly worse than other LT indications, with higher rates of 30-day mortality, primary graft dysfunction (PGD), and longer hospital stay.3 Given the heterogeneity of IPF and the difficult prediction of the course of the disease, a careful selection of recipients with an appropriate assessment of postoperative risks is imperative. This makes necessary the establishment of accurate prediction models.

Even though IPF only affects lung parenchyma, the presence of an increased amount of fat in the anterior mediastinum has been described as a common finding in this disease. This is supported by the idea that mediastinal fat adapts to changes in lung volumes, as it has been also described after lobectomies or lung irradiation.4

The role of fat tissue in the pathogenesis of other diseases is well documented. Pericardial fat has been associated with metabolic risk factors and the severity of coronary artery disease, through the release of pro-inflammatory mediators.5 In addition, it has been suggested that higher volumes of epicardial fat tissue are associated with the severity of sclerodermia, regardless of other risk factors of cardiovascular disease or pulmonary fibrosis, hypothesizing that the proximity of the mediastinal fat to the pulmonary artery may exert pro-inflammatory effects contributing to disease progression.6

Translating this into the patient with IPF, we hypothesized that anterior mediastinal fat (AMF) may have an influence in the prognosis of the disease, irrespective of the changes in the pulmonary parenchyma. We then sought to determine whether the amount of AMF in fibrotic patients, candidates for LT, could be used as a surrogate marker of severity of disease, and therefore predict poor outcomes after the transplant procedure.

In the present study, we were able to demonstrate that the AMF volume in IPF patients may play a role in predicting poor outcomes after LT. Patients with high AMF volumes presented more 30-day mortality and poorer survival than those with low AMF volumes, both in univariable and multivariable analyses.

To our knowledge, this is the first report aiming to analyze the volume of mediastinal fat tissue in fibrotic patients and its potential use as a surrogate marker of severity of disease, and therefore, as an individual risk factor in patients undergoing LT.

For the purposes of this study, we selected a homogeneous group of IPF patients undergoing single LT. Even though bilateral LT have demonstrated better survival than single LT in IPF,3 in our Centre, most of fibrotic patients underwent single procedures on the basis of optimizing the scarcity of donor resources.12

Parenchymal radiological findings of the chest CT scan play an essential role in the initial assessment and disease progression. On the other hand, some extraparenchymal radiological findings have been proposed as factors related to poor prognosis in IPF patients. Tanizawa et al.13 reported poor outcomes of LT in patients with pleuroparenchymal fibroelastosis. Others have suggested that an increased amount of AMF and lymph node enlargement are associated to IPF progression,14 but current clinical guidelines do not include them as diagnostic or prognosis factors. For this reason, we hypothesized that an increased amount of AMF could be a predicting factor of post-transplant outcomes in IPF patients, by making a simple measurement in the preoperative chest CT scan. The calculation of AMF volume was obtained by using the formula widely used and validated for calculation of volumetric values in other organs.10

Several factors, such as coronary artery disease, gastroesophageal reflux, telomerase disorder, and pulmonary hypertension have been associated with a poorer prognosis after LT in IPF patients.2,3,15 In addition, older recipients, low exercise capacity, poor functional parameters, and high oxygen needs are additional risk factors. To deal with an accurate method of patient severity of illness, we used the LAS score, calculated at the time of transplantation, to establish a composite value of severity of illness that includes, age, gender, anthropometric data, diabetes, ventilation needs, forced vital capacity, pulmonary artery pressures, PCO2 changes, 6-min walk distance and serum creatinine.16 In our Centre, LAS score is not used to establish a priority on waiting list for LT.

In our series, higher AMF volumes did not correlate with BMI values, steroid therapy or age, although there was a trend to higher AMF volumes in older recipients (Fig. 3). These findings might suggest that AMF changes in fibrotic patients are not influenced by these factors, although opposite findings have been reported regarding the development of AMF in patients receiving high doses of steroids.17 Regarding novel antifibrotic treatments of IPF, there is no evidence that nintedanib and pirfenidone could alter body fat distribution.1 In the present series, a few numbers of patients were given antifibrotics and thus, this parameter was not included in the analysis.

Although it has been suggested an association between AMF and IPF severity, by a negative correlation with FVC and DLCO,4 we did not observe such a relationship, possibly due to the subtle differences on AMF volumes and its small influence on lung volumes in the present series. Therefore, we could not demonstrate a fat substitution as a consequence of the lung loss of volume and elastic recoil in end-stage IPF patients.

Compared with other indications, IPF presents the worst early and long-term outcomes after LT.3 In the present series, patients dying within 30 days post-transplant were those in poor general condition, with low BMI, higher LAS, ventilated patients and need of ECLS (Table 3). These are well known risk factors that have been documented in the literature.3,19 To note that only 3 patients in the group of high AMF volume underwent CPB (6%), as opposed to 27 patients undergoing ECMO (94%) and none of CPB patients died within 30 days. Potential subtle biases by grouping these methods of ECLS might be minimized by the low number of patients under CPB. In the present series, we also observed that LT patients with higher AMF volumes presented more PGD episodes and higher rates of 30-day mortality, which suggest that AMF may be an additional risk factor of early pulmonary dysfunction and subsequent early mortality post-transplantation.

To sustain this observation, the adjusted risk model for 30-day mortality confirmed that AMF volume was independently associated to early mortality, in addition to other well-known risk factors such as BMI, need of ECLS or ischaemic times.3,18

IPF patients with high AMF volumes presented less survival than those with low AMF volumes. These differences might be influenced by other confounding factors such as higher LAS, PGD, longer ischaemic times or the need of ECLS.18 However, after the exclusion of those recipients dying within 30 days post-transplant, the differences remained significant. In addition, the AMF volume remained an independent predictor, as well as other risk factors such as the need of ECLS or longer ischaemic times. It is possible that patients with higher AMF volumes were those in poor general condition, requiring preoperative ventilation, intraoperative ECLS, with longer ischaemic times, and developing PGD more frequently post-transplantation.

The mechanisms involved in the possible deleterious effects of AMF on LT outcomes are unknown. It has been well documented that visceral abdominal and epicardial fat are related with the pathogenesis of cardiovascular and systemic adverse events through the release of pro-inflammatory mediators by different mechanisms.5,19 On one hand, abdominal mesenteric fat has a circulatory communication path to the liver via the portal circulation and it has been thus associated with hepatic production of inflammatory factors. On the other hand, intrathoracic and pericardial fat depots are substantially smaller than abdominal fat and are unlikely to release substances that could be detected systemically. Therefore, their role is more likely to be paracrine via their local effect on inflammation in the underlying tissue.19 Accordingly, it has been postulated that the close proximity of the epicardial fat tissue to the heart and vessels and the lack of a physical barrier between these structures allow for diffusion of pro-inflammatory cytokines that could play role in the development of cardiometabolic diseases.19

We hypothesize that the same local effects of epicardial fat tissue observed in patients with cardiac disease may be translated to the AMF for patients with IPF. The role of AMF as a potential local source of pro-inflammatory mediators that could play a role in the natural history of IPF remains to be investigated.

The present study has several limitations. First, the retrospective nature of this analysis. Second, the method used for the calculation of AMF volumes is imperfect. Obtaining radiological measures from a chest CT scan to calculate volumes is subject of observer variability. Despite the excellent inter-reader agreement between observers, some bias in determining the exact dimensions of AMF is expectable, and, possibly, other computed methods for assessing AMF values could have been desirable.20 In addition, the election of a cut-point of 20cm3 of AMF to distribute patients into low and high AMF was arbitrary, based on the median AMF values of the patient series. Third, there was a time-gap between the preoperative chest CT scan, from which AMF measurements were obtained, and the transplant procedure, from which the LAS was calculated, and it is possible that AMF volumes were underestimated in some severely ill IPF patients at the time of the LT. Fourth, we did not consider for the analysis some variables that could have had an impact on the results reported herein, such as preoperative use of antifibrotic agents, variations in the intraoperative anaesthetic management, duration of ECLS, the intraoperative use of blood products, etc. Finally, although we observed an association between AMF volumes and LT outcomes in fibrotic patients, we cannot demonstrate a cause-effect relationship. Furthermore, the possible mechanisms of this association remain unanswered.

In conclusion, we have observed that IPF patients with high volumes of AMF undergoing LT present poorer early and long-term outcomes than those with low volumes of AMF preoperatively. Although the pathogenesis of this association is unknown, we hypothesize that either a mediastinal fat substitution associated to the progressive lung volume reduction in IPF patients, a paracrine effect of AMF by releasing pro-inflammatory mediators in these patients, or both, may be potential mechanisms involved. Additional investigations are warranted to determine whether AMF has a role in predicting IPF progression and, subsequently, poor outcomes after LT.

The authors declare no conflict of interest.