Lung diffusing capacity for nitric oxide and carbon monoxide following mild-to-severe COVID-19

Abstract

A decreased lung diffusing capacity for carbon monoxide (DLCO ) has been reported in a variable proportion of subjects over the first 3 months of recovery from severe coronavirus disease 2019 (COVID-19). In this study, we investigated whether measurement of lung diffusing capacity for nitric oxide (DLNO ) offers additional insights on the presence and mechanisms of gas transport abnormalities. In 94 subjects, recovering from mild-to-severe COVID-19 pneumonia, we measured DLNO and DLCO between 10 and 266 days after each patient was tested negative for severe acute respiratory syndrome coronavirus 2. In 38 subjects, a chest computed tomography (CT) was available for semiquantitative analysis at six axial levels and automatic quantitative analysis of entire lungs. DLNO was abnormal in 57% of subjects, independent of time of lung function testing and severity of COVID-19, whereas standard DLCO was reduced in only 20% and mostly within the first 3 months. These differences were not associated with changes of simultaneous DLNO /DLCO ratio, while DLCO /VA and DLNO /VA were within normal range or slightly decreased. DLCO but not DLNO positively correlated with recovery time and DLCO was within the normal range in about 90% of cases after 3 months, while DLNO was reduced in more than half of subjects. Both DLNO and DLCO inversely correlated with persisting CT ground glass opacities and mean lung attenuation, but these were more frequently associated with DLNO than DLCO decrease. These data show that an impairment of DLNO exceeding standard DLCO may be present during the recovery from COVID-19, possibly due to loss of alveolar units with alveolar membrane damage, but relatively preserved capillary volume. Alterations of gas transport may be present even in subjects who had mild COVID-19 pneumonia and no or minimal persisting CT abnormalities. TRIAL REGISTRY: ClinicalTrials.gov PRS: No.: NCT04610554 Unique Protocol ID: SARS-CoV-2_DLNO 2020.

Keywords: COVID-19; alveolar membrane diffusive conductance; carbon monoxide; ground glass opacities; lung diffusing capacity; nitric oxide.

Conflict of interest statement

G.B. and V.B have no financial/nonfinancial interests to disclose.

© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.

Figures

FIGURE 1

Panel a: Relationship between z‐scores of standard lung diffusing capacity for carbon monoxide (DLCO) and lung diffusing capacity for nitric oxide (DLNO). Horizontal and vertical lines correspond to the 5th (dashed) and 2.5th (dotted) percentiles of reference values, that is, −1.645 and −1.96 z‐scores, respectively. The numbers within brackets indicate the subjects falling into each quadrant (Q1‐Q4) bounded within 5th or 2.5th percentiles. Symbols indicate subjects recovering from mild (white), moderate (gray), and severe (black) COVID‐19 pneumonia. Panel b: Correlation between simultaneous measures of DLNO and DLCO. Upper and lower oblique dashed lines indicate the 95% confidence interval for DLNO/DLCO ratio in healthy controls

FIGURE 2

Relationships between standard DLCO (panel a) or DLNO (panel b) and time elapsed from negative testing for SARS‐CoV‐2 to lung function studies. Symbols indicate subjects who recovered from mild (white), moderate (gray), and severe (black) COVID‐19 pneumonia. Horizontal lines correspond to the 5th (dashed) and 2.5th (dotted) percentiles of reference values, that is, −1.645 and −1.96 z‐scores, respectively. The shaded areas include the subjects with abnormal standard DLCO or DLNO values after the first 3 months of recovery

FIGURE 3

Correlations between standard DLCO (panels a, c, and e), or DLNO (panels b, d, and f) and ground glass opacities (GGO), as percentage of total CT volume, mean lung attenuation (MLA) in Hounsfield units (HU), and its coefficient of variation (MLA CV%). Symbols indicate subjects who recovered from mild (white), moderate (gray), and severe (black) COVID‐19 pneumonia. Horizontal lines correspond to the 5th (dashed) and 2.5th (dotted) percentiles of reference values, that is, −1.645 and −1.96 z‐scores, respectively

FIGURE 4

Axial CT scan acquired at the bifurcation of main bronchi (carina) in supine position in a representative subject who had severe COVID‐19 pneumonia treated by invasive mechanical ventilation. Note the discrepancy between DLNO and standard DLCO in the presence of moderate GGO extent. Abbreviations as in Table 1

FIGURE 5

Panel a: Correlation between absolute values of DLCO measured by standard method with breath‐hold time of 11 ± 0.4 s (DLCO,11±0.4 s) or by simultaneous DLNO‐DLCO method with breath‐hold time of 5 ± 0.3 s (DLCO,5±0.3 s). Asterisks (*) indicate healthy controls while circles indicate subjects who recovered from mild (white), moderate (gray), and severe (black) COVID‐19 pneumonia. Panel b: Bland‐Altman plot of difference vs. mean DLCO measured by the two methods. Shaded area is the standard deviation of differences, and horizontal dashed lines indicate the 95% confidence interval