The long term effects of COVID-19 on Pulmonary diffusing capacity for nitric oxide (DLNO) and carbon monoxide (DLCO)

Hypothesis: This study hypothesized that combining lung diffusing capacities for nitric oxide (DLNO) and carbon monoxide (DLCO) enhances detection of COVID-19-related lung pathologies over using DLCO alone, or spirometry, total lung capacity (TLC), or single measures. A combined DLNO+DLCO z-score was expected to better classify post-COVID lung function abnormalities, capturing a broader spectrum of pulmonary impairment.

Data Overview: The filtered pooled dataset (Covid19_Controls_Filtered.sav) includes 572 COVID-19 survivors & 72 controls (644 total) who completed all pulmonary function tests (PFTs) across five countries: Italy, France, Spain, Denmark, and Australia. About 98% of data from these centers is published in 6 peer-reviewed journals & 2 conference abstracts. Controls and COVID-19 cases were tested with the same equipment and protocols. The full PFT battery included DLNO and DLCO (median breath-hold 5.6 s), spirometry, and TLC, with z-scores from reference equations. COVID-19 survivors were tested 32–575 days post-infection (median 130 days). Missing TLC data was imputed. Mixed model binary logistic regression was used with “Study Site” as a random intercept, COVID-19 (1) vs. control (0) as the dependent variable, and z-scores for spirometry, TLC, and diffusion capacity as independent variables. Matthews correlation coefficient (MCC) assessed model classification using a threshold that maximized Youden's J.

Notable Findings: Among 572 post-COVID subjects aged 20–90 (median 60), 61 (11%) had confirmed restriction (TLC < LLN, z-score < -1.645). Additionally, 53% showed some type of impairment (obstruction, restriction, mixed disorder, or DLNO/DLCO < LLN). Of 18 models evaluated, the one with the lowest Bayesian Information Criterion (BIC) was a combined DLNO+DLCO z-score model (DLNO and DLCO z-scores summed), showing superior COVID-19 detection. Four of the top five models were combined DLNO+DLCO or DLNO-only, while one was DLCO-only. MCC values showed all top five models were either combined or DLNO-only, with MCCs around 0.48. Dyspnea severity also correlated with combined, DLNO-only, and DLCO-only z-scores (p < 0.001).

Data Interpretation and Implications: This study highlights that DLNO, when combined with DLCO, provides insights into COVID-19-altered lung diffusion, especially across the alveolar-capillary membrane. Combined z-scores improve post-COVID abnormality classification, supporting targeted follow-up for symptomatic survivors. Wider adoption of this approach would require regulatory approval and standardization. The combined technique shows promise in detecting subclinical COVID-19-related lung impairments, enhancing sensitivity in long-term monitoring.