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Many patients exhibit persistently reduced pulmonary diffusing capacity after coronavirus disease 2019 (COVID-19). In this study, dual test gas diffusing capacity for carbon monoxide and nitric oxide (DL,CO,NO) metrics and their relationship to disease severity and physical performance were examined in patients who previously had COVID-19. An initial cohort of 148 patients diagnosed with COVID-19 of all severities between March 2020 and March 2021 had a DL,CO,NO measurement performed using the single-breath method at 5.7 months follow-up. All patients with at least one abnormal DL,CO,NO metric (n = 87) were revaluated at 12.5 months follow-up. The DL,CO,NO was used to provide the pulmonary diffusing capacity for nitric oxide (DL,NO), the pulmonary diffusing capacity for carbon monoxide (DL,CO,5s), the alveolar–capillary membrane diffusing capacity and the pulmonary capillary blood volume. At both 5.7 and 12.5 months, physical performance was assessed using a 30 s sit-to-stand test and the 6 min walk test. Approximately 60% of patients exhibited a severity-dependent decline in at least one DL,CO,NO metric at 5.7 months follow-up. At 12.5 months, both DL,NO and DL,CO,5s had returned towards normal but still remained abnormal in two-thirds of the patients. Concurrently, improvements in physical performance were observed, but with no apparent relationship to any DL,CO,NO metric. The severity-dependent decline in DL,NO and DL,CO observed at 5.7 months after COVID-19 appears to be reduced consistently at 12.5 months follow-up in the majority of patients, despite marked improvements in physical performance.

The combined single-breath measurement of the diffusing capacity of carbon monoxide (DL,CO) and nitric oxide (DL,NO) is a useful technique to measure pulmonary alveolar-capillary reserve in both healthy and patient populations. The measurement provides an estimate of the participant's ability to recruit and distend pulmonary capillaries. The method has recently been reported to exhibit a high test-retest reliability in healthy volunteers during exercise of light to moderate intensity. Of note, this technique permits up to 12 repeated maneuvers and only requires a single breath with a relatively short breath-hold time of 5 s. Representative data are provided showing the gradual changes in DL,NO and DL,CO from rest to exercise at increasing intensities of up to 60% of maximal workload. The measurement of diffusing capacity and evaluation of alveolar-capillary reserve is a useful tool to evaluate the lung's ability to respond to exercise both in the healthy population as well as in patient populations such as those with chronic lung disease.

NEW FINDINGS: What is the central question in this study? How reliable is the combined measurement of the pulmonary diffusing capacity to carbon monoxide and nitric oxide (D LCO/NO ) during exercise and in the resting supine position, respectively? What is the main finding and its importance? The D LCO/NO technique is reliable with a very low day-to-day variability both during exercise and in the resting supine position, and may thus provide a useful physiological outcome that reflects the alveolar-capillary reserve in humans. ABSTRACT: D LCO/NO , the combined single-breath measurement of the diffusing capacity to carbon monoxide (D LCO ) and nitric oxide (D LNO ) measured either during exercise or in the resting supine position may be a useful physiological measure of alveolar-capillary reserve. In the present study, we investigated the between-day test-retest reliability of D LCO/NO -based metrics. Twenty healthy volunteers (10 males, 10 females; mean age 25 (SD 2) years) were randomized to repeated D LCO/NO measurements during upright rest followed by either exercise (n = 11) or resting in the supine position (n = 9). The measurements were repeated within 7 days. The smallest real difference (SRD), defined as the 95% confidence limit of the standard error of measurement (SEM), the coefficient of variance (CV), and intraclass correlation coefficients were used to assess test-retest reliability. SRD for D LNO was higher during upright rest (5.4 (95% CI: 4.1, 7.5) mmol/(min kPa)) than during exercise (2.7 (95% CI: 2.0, 3.9) mmol/(min kPa)) and in the supine position (3.0 (95% CI: 2.1, 4.8) mmol/(min kPa)). SRD for D LCOc was similar between conditions. CV values for D LNO were slightly lower than for D LCOc both during exercise (1.5 (95% CI: 1.2, 1.7) vs. 3.8 (95% CI: 3.2, 4.3)%) and in the supine position (2.2 (95% CI: 1.8, 2.5) vs. 4.8 (95% CI: 3.8, 5.4)%). D LNO increased by 12.3 (95% CI: 11.1, 13.4) and D LCOc by 3.3 (95% CI: 2.9, 3.7) mmol/(min kPa) f

BACKGROUND: Patients with a functionally univentricular heart, palliated a.m. Fontan, consequently have non-pulsatile pulmonary blood flow and are known to have a reduced pulmonary diffusing capacity. However, the cause of this reduction remains unclear. We aimed to assess the possible determinants in the aetiology of a reduced diffusing capacity and also to assess whether it could be increased. Furthermore, we aimed to search for predictors of a reduced diffusing capacity.MATERIAL AND METHODS: A total of 87 Fontan patients (mean age 16.3 ± 7.6 years) performed advanced pulmonary function tests and maximal cycle ergometer tests. A total of 10 Fontan patients and nine matched controls performed a supine pulmonary function test after a supine rest.RESULTS: In the sitting pulmonary function test, the mean z-scores were: diffusing capacity, 2.38 ± 1.20; pulmonary capillary blood volume, 2.04 ± 0.80; and alveolar capillary membrane diffusing capacity, 0.14 ± 0.84. In the supine compared with the sitting pulmonary function test, the diffusing capacity increased by 51.7 ± 11.9% in the Fontan group and by 23.3 ± 17.7% in the control group (p < 0.001); moreover, the pulmonary capillary blood volume increased by 48.3 ± 17.4% in the Fontan group and by 20.2 ± 13.9% in the control group (p = 0.001). In a multiple linear regression analysis including the explanatory variables of surgical data and exercise data at rest and peak exercise, the resting cardiac index was an independent predictor of the diffusing capacity (regression coefficient: 0.18, p < 0.001).CONCLUSIONS: The pulmonary diffusing capacity was reduced in Fontan patients because of a reduced pulmonary capillary blood volume, whereas the alveolar capillary membrane diffusing capacity was preserved. The diffusing capacity was highly increasable in Fontan patients compared with controls, and the resting cardiac index was an independent predictor of the diffusing capacity.

RATIONALE: The diffusing capacity (DL) of the lung can be divided into two components: the diffusing capacity of the alveolar membrane (Dm) and the pulmonary capillary volume (Vc). DL is traditionally measured using a single-breath method, involving inhalation of carbon monoxide, and a breath hold of 8-10 seconds (DL,CO). This method does not easily allow calculation of Dm and Vc. An alternative single-breath method (DL,CO,NO), involving simultaneous inhalation of carbon monoxide and nitric oxide, and traditionally a shorter breath hold, allows calculation of Dm and Vc and the DL,NO/DL,CO ratio in a single respiratory maneuver. The clinical utility of Dm, Vc, and DL,NO/DL,CO in the pediatric age range is currently unknown but also restricted by lack of reference values.OBJECTIVES: The aim of this study was to establish reference ranges for the outcomes of DL,CO,NO with a 5 second breath hold, including the calculated outcomes Dm, Vc, and the DL,NO/DL,CO ratio, as well as to establish reference values for the outcomes of the traditional DL,CO method, with a 10 second breath hold in children.METHODS: DL,CO,NO and DL,CO were measured in healthy children, of European descent, aged 5-17 years using a Jaeger Masterscreen PFT. The data were analyzed using the Generalized Additive Models for Location Scale and Shape (GAMLSS) statistical method.MEASUREMENTS AND MAIN RESULTS: A total of 326 children were eligible for diffusing capacity measurements, resulting in 312 measurements of DL,CO,NO and 297 of DL,CO, respectively. Reference equations were established for the outcomes of DL,CO,NO and DL,CO, including the calculated values: Vc, Dm, and the DL,NO/DL,CO ratio.CONCLUSION: These reference values are based on the largest sample of children to date and may provide a basis for future studies of their clinical utility in differentiating between alterations in the pulmonary circulation and changes in the alveolar membrane in pediatric patients.