Pulmonary diffusing capacity for carbon monoxide and nitric oxide after COVID-19: A prospective cohort study (the SECURe study).

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.

Dual Test Gas Pulmonary Diffusing Capacity Measurement During Exercise in Humans Using the Single-Breath Method.

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.

Pulmonary diffusing capacity to nitric oxide and carbon monoxide during exercise and in the supine position: a test-retest reliability study.

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 (DLCO/NO ) during exercise and in the resting supine position, respectively? What is the main finding and its importance? The DLCO/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: DLCO/NO , the combined single-breath measurement of the diffusing capacity to carbon monoxide (DLCO ) and nitric oxide (DLNO ) 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 DLCO/NO -based metrics. Twenty healthy volunteers (10 males, 10 females; mean age 25 (SD 2) years) were randomized to repeated DLCO/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 DLNO 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 DLCOc was similar between conditions. CV values for DLNO were slightly lower than for DLCOc 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)%). DLNO increased by 12.3 (95% CI: 11.1, 13.4) and DLCOc by 3.3 (95% CI: 2.9, 3.7) mmol/(min kPa) from upright rest to exercise. The DLCO/NO technique provides reliable indices of alveolar-capillary reserve, both during exercise and in the supine position.

Correction: The Single-Breath Diffusing Capacity of CO and NO in Healthy Children of European Descent.

[This corrects the article DOI: 10.1371/journal.pone.0113177.].

The single-breath diffusing capacity of CO and NO in healthy children of European descent.

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.

New insights into the aspects of pulmonary diffusing capacity in Fontan patients.

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.

Aerobic fitness in children and young adults with primary ciliary dyskinesia.

BACKGROUND: Although aerobic fitness is regarded as an overall prognostic measure of morbidity and mortality, its evaluation in the chronic progressive sinopulmonary disease primary ciliary dyskinesia (PCD) has been infrequently and inconsistently reported. Here we assessed peak oxygen uptake (VO2peak) in a large well-characterized cohort of PCD patients, and explored whether VO2peak was associated with parameters of pulmonary function, self-reported physical limitations, and physical activity level. METHODS: VO2peak, spirometry, diffusing capacity, whole-body plethysmography, and nitrogen multiple breath inert gas washout (N2 MBW) were assessed in a cross-sectional, single-occasion study of clinically stable children and young adults with PCD. We used a questionnaire including self-reported physical limitations in everyday life or in vigorous activities, and estimation of weekly hours of strenuous physical activity. VO2peak in PCD patients was compared with that in matched, healthy control subjects and a national reference. RESULTS: Forty-four PCD patients aged 6-29 years exhibited reduced VO2peak compared to healthy controls (P<0.001) and the national reference. VO2peak was abnormal (z-score <-1.96) in 34% of PCD patients. Spirometric values, RV/TLC, and indices of N2 MBW were significantly abnormal, but VO2peak only correlated with FEV1 and DLCO/VA. VO2peak correlated with complaints of moderate or significant limitations in vigorous activities (P = 0.0001), exhibited by 39% of PCD patients. CONCLUSION: One-third of PCD patients exhibited substantially lower aerobic fitness than healthy subjects. Aerobic fitness correlated with FEV1, DLCO/VA and self-reported complaints of limitations in vigorous physical activity. These findings are most likely explained by PCD pulmonary disease and its impact on pulmonary function and physical ability. Considering fitness as an important outcome and including regular strenuous physical activity in PCD treatment would probably altogether increase pulmonary clearance, lung function, aerobic fitness, and quality of life, and prevent lifestyle-related diseases.

Hypoxic challenge test applied to healthy children: influence of body positions and exertion on pulse oximetric saturation.

BACKGROUND: Commercial aircraft are pressurised to ~2438 m (8000 ft) above sea level that equates breathing 15% oxygen at sea level. A preflight hypoxic challenge test (HCT) is therefore recommended for children with cystic fibrosis or other chronic lung diseases and inflight oxygen is advised if pulse oximetric saturation (SpO2) decreases <90%. OBJECTIVE: Study responses to a modified HCT, encompassing various body positions and light physical activity, reflecting relevant activities of children during flight, with a view to challenge the evidence of the current cut-off. METHODS: Oxygenation, heart rate and ventilation were observed in 34 healthy schoolchildren (17 boys) undergoing a modified HCT, alternating between breathing room air and 15% oxygen in nitrogen while seated, supine, standing and walking at 3 km/h and 5 km/h. RESULTS: Nadir SpO2 <90%, median (range), occurred in 9 subjects sitting, 89% (78-89%); 6 supine, 88.5% (87-89%); 9 standing, 89% (85-89%); 23 walking 3 km/h, 87% (74-89%); and 21 walking 5 km/h, 86% (74-89%). Total time <90% for these subjects in seconds was 20 (10-80) sitting, 30 (10-190) supine, 50 (10-150) standing, 80 (10-260) walking 3 km/h and 125 (10-300) walking 5 km/h. Light exercise in general led to lower SpO2: 91% (77-96%), p<0.0001. CONCLUSIONS: A modified HCT led to moments of desaturation below 90% in various body positions at rest and during light physical activity in healthy schoolchildren. It is questionable whether the international recommended cut-off of 90% for children with chronic lung disease reflects clinical oxygen dependence during flights.

Ventilation inhomogeneity in children with primary ciliary dyskinesia.

BACKGROUND: The lung clearance index (LCI) derived from the multiple breath inert gas washout (MBW) test reflects global ventilation distribution inhomogeneity. It is more sensitive than forced expiratory volume in 1 s (FEV(1)) for detecting abnormal airway function and correlates closely with structural lung damage in children with cystic fibrosis, which shares features with primary ciliary dyskinesia (PCD). Normalised phase III slope indices S(cond) and S(acin) reflect function of the small conducting and acinar airways, respectively. The involvement of the peripheral airways assessed by MBW tests has not been previously described in PCD. METHODS: A cross-sectional MBW study was performed in 27 children and adolescents with verified PCD, all clinically stable and able to perform lung function tests. LCI, S(cond) (n=23) and S(acin) (n=23) were derived from MBW using a mass spectrometer and sulfur hexafluoride as inert marker gas. MBW indices were compared with present age, age at diagnosis and spirometry findings, and were related to published normative values. RESULTS: LCI, S(cond) and S(acin) were abnormal in 85%, 96% and 78% of patients with PCD and in 81%, 93% and 79%, respectively, of 13/27 subjects with normal FEV(1). LCI and S(acin) correlated significantly while S(cond) did not correlate with any other lung function parameters. None of the lung function measurements correlated with age or age at diagnosis. CONCLUSIONS: PCD is characterised by marked peripheral airway dysfunction. MBW seems promising in the early detection of lung damage, even in young patients with PCD. The relationship of MBW indices to the outcome of long-term disease and their role in the management of PCD need to be assessed.

Accuracy of whole-body plethysmography requires biological calibration.

BACKGROUND: Specific airway resistance (sRaw) measured by whole-body plethysmography in young children is increasingly used in research and clinical practice. The method is precise and feasible. However, there is no available method for calibration of the resistance measure, which raises concern of accuracy. Our aim was to determine the agreement of sRaw measurements in six centers and expand normative sRaw values for nonasthmatic children including these centers. METHOD: Identical hardware with different software versions was used at the six centers. Measurements followed a standard operating procedure: (1) seven healthy young children were brought to each of the six centers for sRaw measurements; and (2) 105 healthy preschool children (52 boys; mean age, 5.1 years; interquartile range, 4.3 to 6.0) were recruited locally for sRaw measurements. RESULTS: (1) The sRaw of the seven-children study group was significantly lower at two centers compared with the other four centers, and one center had significantly higher sRaw than all the other centers (p < 0.05). Error in the factory settings of the software was subsequently discovered in one of the deviating centers. (2) Normative data (105 preschool children) were generated and were without significant difference between centers and independent of height, weight, age, and gender. We subsequently pooled these normative data (105 children) with our previous data from 121 healthy young children (overall mean sRaw, 1.27; SD, 0.25). CONCLUSION: Control using biological standards revealed errors in the factory setting and highlights the need for developing methods for verification of resistance measures to assure accuracy. Normative data were subsequently generated. Importantly, other centers using such normative data should first consider proper calibration before applying reference values.

Maximal rowing has an acute effect on the blood-gas barrier in elite athletes.

The purpose of the study was to evaluate the effects of maximal exercise on the integrity of the alveolar epithelial membrane using the clearance rate of aerosolized 99mTc-labeled diethylenetriaminepentaacetic acid as an index for the permeability of the lung blood-gas barrier. Ten elite rowers (24.3 +/- 4.6 yr of age) completed two 20-min pulmonary clearance measurements immediately after and 2 h after 6 min of all-out rowing (initial and late, respectively). All subjects participated in resting control measurements on a separate day. For each 20-min measurement, lung clearance was calculated for 0-7 and 10-20 min. Furthermore, scintigrams were processed from the initial and late measurements of diethylenetriaminepentaacetic acid clearance. Compared with control levels, the pulmonary clearance measurement after rowing was increased from 1.2 +/- 0.5 to 2.4 +/- 1.0%/min (SD) at 0-7 min (P < 0.01) and from 0.8 +/- 0.3 to 1.5 +/- 0.4%/min at 10-20 min (P < 0.0005), returning to resting levels within 2 h. In 6 of 10 subjects, ventilation distribution on the lung scintigrams was inhomogeneous at the initial measurement. The study demonstrates an acute increased pulmonary clearance after maximal rowing. The ventilation defects identified on the lung scintigrams may represent transient interstitial edema secondary to increased blood-gas barrier permeability induced by mechanical stress.