In this study we retrospectively evaluated the impact of mediastinal LNE on survival and disease behaviour in patients with IPF followed up at a tertiary ILD centre in Italy. The results from our cohort suggest that a diffuse involvement of mediastinal lymph nodes in IPF patients is an independent predictor of both mortality and functional deterioration in these patients.
Predicting the course of IPF represents a historical challenge for clinicians. Current risk prediction models, robustly developed using data from large randomized clinical trials, may not be suitable for individual prognostication in the real life heterogeneous IPF populations. Furthermore, no parameters have shown to be useful in predicting future trends of functional decline, the hallmark of progressive disease in IPF . Mediastinal lymph node enlargement on CT scan has been recently investigated as a prognostic biomarker in IPF and other fibrotic ILD, for reflecting pathobiological mechanisms of activated immune response that may be relevant to easily stratify patient with at risk of poorer outcome. Sin and collagues  demonstrated that mediastinal LNE was a strong, independent predictor of mortality in a retrospective cohort of 132 patients with IPF. Adegunsoye and colleagues  nicely reported the association of several features of mediastinal lymphadenopathies with disease severity and higher risk of mortality or hospitalization in patients with a variety of forms of ILD, including IPF, IPAF (interstitial pneumonia with autoimmune features), CTD-ILD (connective tissue disease-associated interstitial lung disease) and unclassifiable ILD, suggesting a role for mediastinal lymph node assessment in ILD prognostication beyond specific etiology.
In our cohort, a “diffuse” lymph node involvement - as defined by 3 or more enlarged mediastinal lymph nodes - was strongly associated with lower survival rates, in line with previous findings. Sin and coworkers  demonstrated the impact of mediastinal LNE on survival in an equally-sized IPF cohort with comparable size and similar proportion of patients showing lymph node enlargement on CT. Notably though, the large majority of patients in our study received antifibrotic treatment after diagnosis, suggesting that the presence of multiple mediastinal lymphadenopathies may predict poorer prognosis despite treatment.
Importantly, our study provided first evidence as to the relationships between mediastinal LNE and disease progression expressed by means of functional decline. The involvement of 3 or more lymph nodes involved was found to be associated with an increased risk of disease progression as defined by significant drop (≥ 10%) in percent predicted FVC, suggesting that diffuse mediastinal LNE represent a marker of more aggressive disease behaviour in these patients. Patients with higher number of lymph nodal stations involved also showed decreased annual trends of pulmonary function and gas diffusion capacity, although the slopes of change were not found significantly different as compared to patients with no or lesser lymph node involvement. Whilst our study was not powered to detect the impact of LNE on continuous change in pulmonary function parameters in a treated IPF population with reduced progression rates, these findings further support the hypothesis that major lymph node involvement predicts future functional deterioration.
The longitudinal evaluation of mediastinal LNE in a subpopulation with follow up imaging data showed that such finding is stable over time in most patients despite currently available antifibrotic treatment, which seems to preclude the role of LNE as a marker of response to treatment. Indeed, further studies are needed to clarify the pathobiological mechanisms at the basis of this prevalent finding in IPF patients. The study of histological features of LNE may help shed a light on the immune processes involved and whether a subset of patients exists where such pathways are paramount for driving disease progression.
The main limitations of our study are represented by its retrospective nature and the small size of our cohort. Nevertheless, the study was adequately powered based on previously reports of mortality hazard ratio for IPF patients with LNE , which increases the robustness of our results. Another theoretical limitation consists in the heterogeneity of CT reconstruction protocols and contrast medium administration, as the exams have been performed in different centres.
In conclusion, we demonstrated that the presence of diffuse mediastinal lymphadenopathy on CT scan is independently associated with higher risks of mortality and clinically significant disease progression in a cohort of IPF patients despite antifibrotic treatment. Altogether, our results support the utility of mediastinal LNE in the risk stratification of the heterogeneous IPF population. Ongoing trials and future research will eventually clarify the pathobiology of mediastinal lymphadenopathy in IPF and if such finding may be useful to identify patients responding to treatments targeting specific immune pathways.