Background: The mechanisms driving poor exercise tolerance in patients with fibrotic interstitial lung diseases (f-ILD) showing a severe impairment in single-breath lung diffusing capacity (DL_CO<40% predicted) are not fully understood. A severely impaired DL_CO may signal multiple deranged physiologic adjustments to exercise which jointly increase the burden of exertional symptoms in f-ILD.

Methods: 67 patients (24 showing DL_CO<40%) and 22 controls underwent pulmonary function tests and an incremental cardiopulmonary exercise test with serial measurements of operating lung volumes and 0-10 Borg dyspnea and leg discomfort scores.

Results: The DL_CO<40% group showed lower spirometric values, more severe restriction, and lower transfer coefficient (K_CO) compared to controls and patients with DL_CO?40% (p<0.05). Peak work rate was ~45% (vs. controls) and ~20% (vs. DL_CO?40%) lower in the former group, being associated with lower O₂ pulse, an earlier anaerobic threshold, heightened submaximal ventilation, and lower O₂ saturation. Moreover, critically high inspiratory constrains were reached at lower exercise intensities in the DL_CO<40% group and they reported the highest dyspnea and legs discomfort scores (p<0.05).

Conclusion: A DL_CO<40% in f-ILD signals multiple interconnected derangements (cardiovascular impairment, early anaerobic metabolism, excess ventilation, inspiratory constraints, and hypoxemia) which ultimately lead to exercise limiting dyspnea and leg discomfort. DL_CO<40%, therefore, might help in clinical decision making to indicate f-ILD patients who might derive particular benefit from interventions aimed at lessening these systemic abnormalities.