Interstitial Lung Disease and Mediastinal Lymph Nodes: A Computed Tomography–based Biomarker beyond Nosological and Etiological Borders?

To the Editor:

We read with great interest the article by Adegunsoye and colleagues (1) recently published in the Journal. Using a rigorous multivalidated protocol, the authors demonstrate that mediastinal lymphadenopathy (MLA) is a strong predictor of clinical outcomes in interstitial lung disease (ILD), which is considered, in this article, to be a unique heterogeneous entity that includes idiopathic pulmonary fibrosis (IPF), interstitial pneumonia with autoimmune features, chronic hypersensitivity pneumonitis, connective tissue disease associated with ILD (CTD-ILD), and unclassifiable ILD. The strong prognostic value of MLA for survival in ILD could have important implications for patient stratification in the future. Nonetheless, considering ILD to be a unique entity may become partly irrelevant for the interpretation of results on plasmatic biomarkers. For example, based on their results and those of ongoing trials in IPF, the authors suggest that IL-6 might be protective in fibrotic ILD (1). This statement might be tempered, especially when considering CTD-ILD, as IL-6 may constitute a therapeutic target in scleroderma-associated ILD, with a recent clinical trial of tocilizumab reporting promising results regarding pulmonary involvement (2). From a pathogenetic and nosological viewpoint, separating each ILD subgroup may therefore remain relevant.

Beyond prognostic and therapeutic considerations, Adegunsoye and colleagues’ results may have far-reaching heuristic consequences, and raise the issue of the precise etiology and pathogenesis of MLA in ILD. In their work, obvious causes of MLA were carefully ruled out, as sarcoidosis, drug toxicity–related ILD, and cancers were excluded. Nonetheless, although age and sex were included in the multivariable Cox regression model (Table 2 in Reference 1), the possible role of chronic heart failure as a concurrent etiology of MLA (3), as well as a cause of all-cause hospitalization and/or respiratory hospitalization and/or death, cannot be completely excluded. This hypothesis is supported by the significant difference (P = 0.028) in the prevalence of coronary heart disease between patients with and without MLA (Table 1 in Reference 1). This is particularly true when considering the association of MLA with greater aorta and pulmonary artery diameters, male sex, older age, and tobacco use. Although we do not assume that heart failure alone may explain the strong prognostic value of MLA in ILD, exploring the association of MLA with cardiac biomarkers such as N-terminal pro–B-type natriuretic peptide levels (3) and their respective prognostic values may help to clarify this issue.

From an etiological viewpoint, this specific focus on MLA may bring back into light neglected causes of ILD with MLA, such as dust exposures. No mention is made of pneumoconiosis in Adegunsoye and colleagues’s work. The higher prevalence of MLA in men (Table 1 in Reference 1), in addition to the well-known association between occupational dust exposures and male sex, also highlights this issue. Recent studies have pointed out that the prevalence of crystalline silica exposure in CTD-ILD may be underevaluated (4). There is growing interest in the involvement of environmental airborne contaminants in ILDs of unknown etiology, such as IPF (5), as well as in CTD-ILD (4) and other fibrotic ILDs such as pulmonary alveolar proteinosis with fibrotic features (6). Beyond size, location, and number, obtaining a thorough description of MLA, with specific attention paid to density and calcifications, may offer new insights into the complex relationship between exposure to airborne contaminants and ILD. Histological examinations of MLA in ILD may also help to clarify the immune processes at stake. As was recently suggested with regard to pulmonary alveolar proteinosis of autoimmune origin, dysimmune is not synonymous with idiopathic (6). Therefore, further studies are needed to better elucidate the specific etiologies of MLA in ILD of unknown origin. In the end, this could help to refine the current nosological classification of these diseases and possibly improve the search for a proper cause, leading to efficient preventive measures.