Mechanisms and consequences of exertional dyspnoea in combined pulmonary fibrosis and emphysema (CPFE)

Background: Emphysema is a common and disabling co-morbidity of pulmonary fibrosis (PF). The prevailing view is that exertional dyspnoea can be largely explained by hypoxemia in these patients. There is little evidence, however, to support these assumptions. Methods: We contrasted the sensory and physiological responses to exercise in 42 patients with combined PF and emphysema (CPFE) and 16 with PF matched by the severity of exertional hypoxemia. Emphysema and fibrosis were visually quantified on computed tomography scans. Mechanical constraints were assessed in a constant work rate test: capillary (c) blood gases were obtained in a sub-set of CPFE patients (N= 18). Results: Dyspnoea was the limiting symptom in 24 CPFE patients: despite similar resting lung volumes and PaO2, these subjects presented with lower transfer factor, lower PaCO2 and excessive exertional ventilation (high ventilation (VE)/CO2 output (VCO2)) compared to those with less dyspnoea (p<0.05). High dead space/tidal volume ratio, low PcCO2, emphysema severity (including admixed emphysema) and traction bronchiectasis were related to a high V̇E/V̇CO2 in the former group. On a logistic regression analysis, V̇E/V̇CO2 (>50) and more extensive emphysema (>15%)– but not hypoxemia, lung fibrosis or mechanical abnormalities - predicted poor exercise tolerance due to limiting dyspnoea in CPFE (p<0.05). Conclusion: Contrary to current understanding, hypoxemia per se is not the main determinant of exertional dyspnea in CPFE: heightened chemostimulation due to increased wasted ventilation and a downward shift in the PaCO2 set point holds a key mechanistic role that deserves therapeutic attention.