Physiological and Clinical Relevance of Impaired Lung Diffusing Capacity for Carbon Monoxide Across the Spectrum of Fibrosing Interstitial Lung Disease Severity: Implications for Exertional Dyspnea and Exercise Intolerance

Abstract

Rationale: Patients with fibrosing interstitial lung disease (f-ILD) have burdensome exertional dyspnea and exercise tolerance, which are associated with a low lung diffusion capacity for carbon monoxide (DLCO). The precise mechanisms driving “out-of-proportion” dyspnea and exercise intolerance in patients with f-ILD are poorly understood. Objectives: To investigate the contribution of a low DLCO to exertional dyspnea and poor exercise tolerance in f-ILD patients with 1) largely preserved resting spirometry and 2) a severely reduced (<40%predicted) DLCO. Methods: All studies included resting pulmonary function tests (PFT) with single-breath DLCO and cardiopulmonary exercise tests (CPET). During CPET, physiological parameters were collected and evaluated, including breathing pattern, operating lung volumes, ventilatory requirements, pulmonary gas exchange, and perceptual responses (Borg 0-10 dyspnea and leg discomfort scores). General Results: 1) Patients with f-ILD and largely preserved resting spirometry had elevated dyspnea and poorer exercise tolerance compared to healthy age- and sex-matched controls and was associated with reduced ventilatory efficiency (i.e., a high ventilation relative to carbon dioxide production, ↑ V̇E/V̇CO2). Dyspnea-work rate correlated negatively with DLCO and peak oxygen uptake and positively with V̇E/V̇CO2 nadir. 2) Patients with f-ILD and a severely impaired DLCO had elevated dyspnea and poorer exercise tolerance compared to patients with a mild-to-moderately impaired (≥40%predicted) DLCO and healthy controls. These findings were associated with a lower (and flatter) O2 pulse, an earlier lactate (“anaerobic”) threshold, heightened submaximal ventilation, lower O2 saturation, and early critically high inspiratory constraints in the severely impaired DLCO group. Conclusions: This thesis has enhanced our understanding of DLCO as a physiological biomarker of activity-related impairment across the spectrum of f-ILD disease severity. Our data strongly support DLCO as the key index of physiologic impairment from early to end-stage f-ILD. Both studies support the current construct that demand-capacity imbalance is paramount to the genesis of exertional dyspnea. Moreover, they also provide a holistic view of the interconnected systemic abnormalities associated with exercise intolerance in f-ILD.