Prognosticating Outcomes in Interstitial Lung Disease by Mediastinal Lymph Node Assessment. An Observational Cohort Study with Independent Validation

Abstract

Rationale: Mediastinal lymph node (MLN) enlargement on chest computed tomography (CT) is prevalent in patients with interstitial lung disease (ILD) and may reflect immunologic activation and subsequent cytokine-mediated immune cell trafficking.

Objectives: We aimed to determine whether MLN enlargement on chest CT predicts clinical outcomes and circulating cytokine levels in ILD.

Methods: MLN measurements were obtained from chest CT scans of patients with ILD at baseline evaluation over a 10-year period. Patients with sarcoidosis and drug toxicity-related ILD were excluded. MLN diameter and location were assessed. Plasma cytokine levels were analyzed in a subset of patients. The primary outcome was transplant-free survival (TFS). Secondary outcomes included all-cause and respiratory hospitalizations, lung function, and plasma cytokine concentrations. Cox regression was used to assess mortality risk. Outcomes were assessed in three independent ILD cohorts.

Measurements and main results: Chest CT scans were assessed in 1,094 patients (mean age, 64 yr; 52% male). MLN enlargement (≥10 mm) was present in 66% (n = 726) and strongly predicted TFS (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.12-2.10; P = 0.008) and risk of all-cause and respiratory hospitalizations (internal rate of return [IRR], 1.52; 95% CI, 1.17-1.98; P = 0.002; and IRR, 1.71; 95% CI, 1.15-2.53; P = 0.008, respectively) when compared with subjects with MLN <10 mm. Patients with MLN enlargement had lower lung function and decreased plasma concentrations of soluble CD40L (376 pg/ml vs. 505 pg/ml, P = 0.001) compared with those without MLN enlargement. Plasma IL-10 concentration >45 pg/ml predicted mortality (HR, 4.21; 95% CI, 1.21-14.68; P = 0.024). Independent analysis of external datasets confirmed these findings.

Conclusions: MLN enlargement predicts TFS and hospitalization risk in ILD and is associated with decreased levels of a key circulating cytokine, soluble CD40L. Incorporating MLN and cytokine findings into current prediction models might improve ILD prognostication.

Keywords: interstitial lung disease; mediastinal lymph nodes; mortality; pulmonary fibrosis.

Figure 1.

Mediastinal lymph node (MLN) features in interstitial lung disease and distinctive survival patterns. (A–D) Survival pattern by MLN diameter in University of Chicago (UCHICAGO) cohort (A), nontertiary medical centers (NONTERT) (B), INSPIRE cohort (C), and University of California Davis (UCDAVIS) cohort (D). In the INSPIRE cohort, 228 patients had high-resolution computed tomography scans of acceptable quality for mediastinal evaluation. INSPIRE = Effect of Interferon Gamma-1b on Survival in Patients with Idiopathic Pulmonary Fibrosis Trial.

Figure 2.

Mediastinal lymph node (MLN) location predicts mortality risk. (A) Digital representation of enlarged mediastinal lymph nodes stations >10 mm. (B) Survival pattern by MLN station. LZ = lower zone (International Association for the Study of Lung Cancer Lymph node stations 8–9); PT = paratracheal (International Association for the Study of Lung Cancer lymph node stations 1–7).

Figure 3.

(A) Bar graph shows percentage change in plasma cytokine concentrations for mediastinal lymph nodes (MLNs) ≥10 mm within the University of Chicago (UCHICAGO) primary cohort (n = 116). The color of each bar represents the directionality of the change (red indicates positive change; green indicates negative change). (B) Soluble CD40 ligand (pg/ml) stratified by MLN diameter in patients with unclassifiable interstitial lung disease (ILD) or interstitial pneumonia with autoimmune features (IPAF) within the UCHICAGO primary cohort (n = 36) and the University of California Davis (UCDAVIS) replication cohort (n = 34). (C) Epidermal growth factor (pg/ml) stratified by MLN diameter in patients with unclassifiable ILD or IPAF within the UCHICAGO primary cohort (n = 36) and the UCDAVIS replication cohort (n = 34). (D) MIP3a (pg/ml) stratified by MLN diameter in patients with idiopathic pulmonary fibrosis, chronic hypersensitivity pneumonitis, or chronic hypersensitivity pneumonitis–ILD within the UCHICAGO primary cohort (n = 80) and the UCDAVIS replication cohort (n = 84). Group comparisons for patients with MLNs ≥10 mm (green or red) to patients with MLNs <10 mm (gray) were conducted using the Wilcoxon signed-rank test for matched nonparametric data. All comparisons of cytokine concentrations were conducted in 10,000 bootstrap replications to improve precision at the 95% confidence interval level. EGF = epidermal growth factor; sCD40L = soluble CD40 ligand.

Figure 4.

Correlation of top cytokines with clinically acquired biologic variables stratified by mediastinal lymph node (MLN) size. Left panel depicts correlation matrix for MLNs <10 mm, whereas right panel depicts correlation matrix for MLNs ≥10 mm. Cytokine correlation with clinical variable was determined by Pearson’s correlation algorithm and is displayed in the corresponding box (coefficient of r value on top and P value in parentheses). The color of each box represents the directionality of the correlation (red indicates positive correlation; green indicates negative correlation). The bar below scales the degree of correlation. Pearson’s correlation was used to determine the significance of correlation (P < 0.05) between the concentrations of individual cytokines with clinical variables as shown above. ANA = antinuclear antibody; BMI = body mass index; CRP = C-reactive protein; PA/A = pulmonary artery/aorta ratio; WBC = white blood cell.