Reply to: Lung pathophysiology in patients with long COVID-19: one size definitely does not fit all

To the Editor:

We were very pleased that our recent paper on long COVID [1] was found worthy to be accompanied by an editorial. We fully agree with Radovanovic and D’Angelo [2] that, as for most medical conditions, one size does not fit all, but we think some of the issues they raised to our study deserve further clarification.

First, we did not consider our results suggestive of reduced operational volumes to be the major determinant of dyspnoea in long COVID patients, because this would have required lung volumes and rebreathing lung diffusing capacities for nitric oxide (D_LNO) and carbon monoxide (D_LCO) being measured during exercise. Rather, our interpretation was that loss of alveolar volume (V_A), using combined single-breath (4–6 s breath-hold time) D_LNO–D_LCO, was not the main reason for the reductions in D_LNO and D_LCO, though we made no causal inference with dyspnoea. Radovanovic and D’Angelo [2] suggest uneven peripheral ventilation as the main putative mechanism underlying the decrement of V_A. However, V_A/total lung capacity ratio was close to unity (∼0.996) in our subjects, which makes poor mixing of the tracer gas unlikely.

Second, Radovanovic and D’Angelo [2] also question our interpretation of post-exercise recruitment of pulmonary capillary blood volume (V_C) because we did not measure D_LCO at different fractions of inspired oxygen. However, we used the simultaneous D_LNO–D_LCO technique, which has been proposed as an alternative to solve the Roughton–Forster equation without the need of measurements of CO uptake at different alveolar oxygen tensions [3], which would have been unfeasible over a short time after exercise. Although values of alveolar membrane diffusive conductance and V_C could have been derived from our D_LNO–D_LCO measurements (table 1), we decided not to present them because their validity has been an object of debate due to the critical dependence on the assumed values for the rate of haemoglobin uptake, as for the Roughton–Forster method, and NO/CO diffusivity ratio [4].