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Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by progressive surfactant accumulation and hypoxemia caused by autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF), which alveolar macrophages require to clear surfactant. Molgramostim is a formulation of inhaled recombinant human GM-CSF, but its efficacy and safety in patients with aPAP have not been studied sufficiently. In this phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with aPAP to receive molgramostim at a dose of 300 μg or placebo once daily for 48 weeks. The primary end point was the change from baseline to week 24 in the diffusing capacity of the lungs for carbon monoxide (DLCO), which was adjusted for hemoglobin concentration and expressed as a percentage of the predicted value. Secondary end points adjusted for multiplicity were the change from baseline in DLCO at 48 weeks and the change from baseline in the St. George's Respiratory Questionnaire total (SGRQ-T) and activity (SGRQ-A) scores (scores range from 0 to 100, with lower scores indicating better quality of life) and in exercise capacity at 24 and 48 weeks. A total of 164 patients underwent randomization: 81 were assigned to receive molgramostim and 83 to receive placebo. The least-squares mean change in DLCO from baseline to week 24 was 9.8 percentage points (95% confidence interval [CI], 7.3 to 12.3) with molgramostim and 3.8 percentage points (95% CI, 1.4 to 6.3) with placebo (estimated treatment difference, 6.0 percentage points; 95% CI, 2.5 to 9.4; P<0.001). The least-squares mean change in DLCO from baseline to week 48 was 11.6 percentage points (95% CI, 8.7 to 14.5) with molgramostim and 4.7 percentage points (95% CI, 1.8 to 7.6) with placebo (P<0.001), and the least-squares mean change in the SGRQ-T score at week 24 was -11.5 points (95% CI, -15.0 to -8.0) and -4.9 points (95% CI, -8.3 to -1.5), respectively (P = 0.007). No significant between-group difference in the change in SGRQ-A score was observed at 24 weeks, so no statistical inference was drawn with respect to subsequent secondary end points. The percentage of patients with at least one adverse event and the percentage with at least one serious adverse event were similar in the two groups. Once-daily inhaled molgramostim led to a greater increase in pulmonary gas transfer than placebo in patients with aPAP. (Funded by Savara; IMPALA-2 ClinicalTrials.gov number, NCT04544293; European Union Clinical Trials Information System number, 2024-511052-41-00.).

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. 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.

Total haemoglobin mass can be easily measured by applying the optimised CO-rebreathing method (oCOR-method). Prerequisite for its accurate determination is a homogenous CO distribution in the blood and the exact knowledge of the CO volume circulating in the vascular space. The aim of the study was to evaluate the mixing time of CO in the blood after inhaling a CO-bolus and to quantify the CO volume leaving the vascular bed due to diffusion to myoglobin and due to exhalation during processing the oCOR-method. The oCOR-method was also compared to a former commonly used CO-rebreathing procedure. In ten subjects, the time course of carboxy-haemoglobin (HbCO) formation was analysed simultaneously in capillary and venous blood for a period of 15 min after inhaling a CO bolus. The volume of CO diffusing from haemoglobin to myoglobin was calculated via the decrease of HbCO. As part of this decrease is due to CO exhalation, this volume was quantified by collecting the exhaled air in a Douglas bag system. Equal HbCO values in capillary and venous blood were reached at min 6 indicating complete mixing of CO. The loss of CO out of the vascular bed due to exhalation and due to diffusion to myoglobin was 0.32 +/- 0.12% min(-1) (0.25 +/- 0.09 ml min(-1)) and 0.32 +/- 0.18% min(-1) (0.24 +/- 0.13 ml min(-1)) of the administered CO volume, respectively. The loss of CO due to exhalation and diffusion to myoglobin is of minor impact. It should, however, be considered by using correction factors to obtain high accuracy when determining total haemoglobin mass.

In patients with chronic obstructive pulmonary disease (COPD) who exhibit reduced alveolar–capillary reserve, the combined assessment of pulmonary diffusing capacity for carbon monoxide and nitric oxide (DL,CO,NO) during exercise may pose difficulties, and the transition from upright to supine posture may offer a useful alternative. A total of 50 participants (35 with COPD and 15 healthy controls) underwent measurements of DL,CO,NO in the upright and supine postures. A subset (COPD: n = 12, controls: n = 12) also completed a 12‐week supervised high‐intensity interval training (HIIT) intervention. The reported DL,CO,NO metrics were diffusing capacity for nitric oxide and carbon monoxide (DL,NO and DL,CO,5s, respectively), alveolar–capillary membrane diffusing capacity (DM,CO), pulmonary capillary blood volume (VC), and alveolar volume (VA). The upright‐to‐supine change in neither DL,NO (P = 0.271), nor DM,CO (P = 0.068) nor VA (P = 0.934) differed between groups. In contrast, the upright‐to‐supine change in DL,CO5s was reduced in moderate and severe COPD compared with controls (control vs. moderate: median [IQR] 0.6 [0.3, 0.9] mmol/min/kPa, P < 0.001; control vs. severe: 0.9, [0.2, 1.5] mmol/min/kPa, P = 0.006), whereas it did not differ between controls and mild COPD (0.3 [−0.1, 0.7] mmol/min/kPa, P = 0.13). Similarly, the upright‐to‐supine VC change was reduced in moderate and severe COPD compared with healthy controls (control vs. moderate: 8.3 [3.9, 12.8] mL, P < 0.001; control vs. severe: 10.7 [1.2, 20.2] mL, P = 0.021), but not in mild COPD (5.3 [−0.2, 10.8] mL, P = 0.063). The HIIT intervention had no effect on these metrics. The blunted VC response to an upright‐to‐supine postural change in moderate‐to‐severe COPD is consistent with reduced alveolar–capillary reserve and may be useful when measurements during exercise are not possible. What is the central question of this study? Is alveolar–capillary reserve reduced in chronic obstructive pulmonary disease (COPD) when assessed by an upright‐to‐supine postural change? What is the main finding and its importance? The posture‐induced increase in pulmonary capillary blood volume is specifically blunted in moderate‐to‐severe COPD, likely reflecting underlying disease‐specific pulmonary vascular alterations. Assessment of alveolar–capillary reserve through an upright‐to‐supine postural change may represent an attractive alternative to exercise‐based measurements in individuals with COPD.

BackgroundCurrent guidelines for the evaluation of chronic obstructive pulmonary disease (COPD) do not recommend screening for pulmonary hypertension (PH), despite the high prevalence and impact on outcomes. A simple screening tool to identify patients with an elevated pulmonary vascular resistance (PVR) is urgently needed, as they may benefit from PH-specific therapy and more urgent referral for lung transplantation.Research questionWe sought to examine whether a ratio of forced expiratory volume in 1 s (FEV1) to diffusing capacity (DLCO) predicts haemodynamic patterns in COPD.Study design and methodsIndividuals with COPD who underwent right heart catheterisation from two academic medical centres were included. Adjusted multinomial models tested associations between FEV1/DLCO and haemodynamic patterns. Receiver operating curves were generated to assess the discriminative performance of the FEV1/DLCO ratio in predicting PH with an elevated PVR.ResultsApproximately 40% of the 411 individuals included had PH with an elevated PVR. For every 0.1 increase in the FEV1/DLCO ratio, there was a 12–14% increased rate of PH with an elevated PVR compared with No PH. FEV1/DLCO ratio had moderate discriminative performance (C-statistic 0.68–0.72), which was strengthened when combined in a model with elevated tricuspid regurgitant jet velocity on echocardiography (C-statistic 0.78–0.82). Above a threshold of 1.4, FEV1/DLCO demonstrated good specificity (75%) in predicting PH with an elevated PVR.InterpretationThese findings suggest that disproportionate reductions in DLCO predict PH with an elevated PVR in a COPD population. The FEV1/DLCO ratio should be considered in the evaluation of PH in COPD.

To assess the effects of alpha-tocopherol and ascorbic acid on skin thickening and lung function in patients with early diffuse systemic sclerosis (SSc), thirteen patients with early diffuse SSc, with positive anti-topoisomerase-I antibody, high skin thickening progression rate (STPR ≥ 12/year) and decreased lung diffusing capacity (DLCO ≤ 75%) were included in this study. Patients were randomized into two subgroups: Subgroup A —six patients, treated with intravenous cyclophosphamide (CyP) (500 mg/m 2 of body surface monthly) and antioxidants (alpha-tocopherol 400 IU/day and ascorbic acid 1,000 mg/day), and Subgroup B —seven patients, who received CyP without antioxidants. In both subgroups, effects of treatment on skin thickening and lung function were evaluated by comparison of the modified Rodnan skin score (MRSS), STPR, forced vital capacity (FVC), transfer-factor (DLCO) and diffusing coefficient for carbon monoxide (DLCO/VA) at baseline and 1 month after the sixth pulse of CyP. The mean MRSS did not change from baseline to the end of the follow-up in subgroup A (15.7 vs. 16.4, P  = 0.50), but it increased significantly in subgroup B (17.9 vs. 23.6, P  = 0.03). Although the mean STPR decreased notably in both subgroups of patients (in subgroup A–from 18.9/year to 2.2/year, P  = 0.03, and in subgroup B–from 17.5/year to 8.6/year, P  = 0.03), the mean STPR at the end of the treatment period was significantly lower in subgroup A (2.2/year vs. 8.6/year, P  = 0.04). The mean value of FVC did not change either in subgroup A (91.0–87%, P  = 0.2) or in subgroup B (from 101.2 to 99.7%, P  = 0.7). Parameters of lung diffusing capacity improved somewhat in subgroup A (DLCO from 55.7 to 62.0% and DLCO/VA from 68.7 to 74.2%) and decreased in subgroup B (DLCO from 66.2 to 60.6% and DLCO/VA from 76.9 to 71.6%), but differences were not statistically significant. After 6 months of therapy, patients treated with CyP and antioxidants had a significantly lower STPR, compared to patients treated with CyP only. Lung function parameters remained stable in both subgroups. However, lung diffusing capacity improved slightly, without statistical significance, in patients treated with CyP and antioxidants, and it deteriorated in patients without antioxidants.

Static and dynamic hyperinflation is an important factor of exertional dyspnea in patients with severe COPD. This proof-of-concept intervention trial sought to study whether laughter can reduce hyperinflation through repetitive expiratory efforts in patients with severe COPD. For small groups of patients with severe COPD (n = 19) and healthy controls (n = 10) Pello the clown performed a humor intervention triggering regular laughter. Plethysmography was done before and up to 24 hours after intervention. Laughing and smiling were quantified with video-analysis. Real-time breathing pattern was assessed with the LifeShirt, and the psychological impact of the intervention was monitored with self-administered questionnaires. The intervention led to a reduction of TLC in COPD (p = 0.04), but not in controls (p = 0.9). TLC reduction was due to a decline of the residual volume. Four (22 [CI 95% 7 to 46] %) patients were > or = 10% responders. The frequency of smiling and TLC at baseline were independent predictors of TLC response. The humor intervention improved cheerfulness, but not seriousness nor bad mood. In conclusion, smiling induced by a humor intervention was able to reduce hyperinflation in patients with severe COPD. A smiling-derived breathing technique might complement pursed-lips breathing in patients with symptomatic obstruction.

Abstract The single-breath carbon monoxide diffusing capacity (DlCO) is the product of two measurements during breath holding at full inflation: (1) the rate constant for carbon monoxide uptake from alveolar gas (kco [minute−1]) and (2) the “accessible” alveolar volume (Va). kco expressed per mm Hg alveolar dry gas pressure (Pb*) as kco/Pb*, and then multiplied by Va, equals DlCO; thus, DlCO divided by Va (DlCO/Va, also called Kco) is only kco/Pb* in different units, remaining, essentially, a rate constant. The notion that DlCO/Va “corrects” DlCO for reduced Va is physiologically incorrect, because DlCO/Va is not constant as Va changes; thus, the term Kco reflects the physiology more appropriately. Crucially, the same DlCO may occur with various combinations of Kco and Va, each suggesting different pathologies. Decreased Kco occurs in alveolar–capillary damage, microvascular pathology, or anemia. Increased Kco occurs with (1) failure to expand normal lungs to predicted full inflation (extrapulmonary restriction); or (2) increased capillary volume and flow, either globally (left-to-right intracardiac shunting) or from flow and volume diversion from lost or damaged units to surviving normal units (e.g., pneumonectomy). Decreased Va occurs in (1) reduced alveolar expansion, (2) alveolar damage or loss, or (3) maldistribution of inspired gases with airflow obstruction. Kco will be greater than 120% predicted in case 1, 100–120% in case 2, and 40–120% in case 3, depending on pathology. Kco and Va values should be available to clinicians, as fundamental to understanding the clinical implications of DlCO. The diffusing capacity for nitric oxide (DlNO), and the DlNO/DlCO ratio, provide additional insights.

There is limited knowledge on diffusing capacity in scoliosis patients. It remains to be determined if impaired pulmonary diffusing capacity is mostly influenced by reduced alveolar–capillary membrane diffusing capacity (DM, CO), reduced pulmonary capillary blood volume (VC) or both. This study aims to report findings from dual test gas pulmonary diffusing capacity for carbon monoxide and nitric oxide (DL, CO, NO) with quantification of pulmonary diffusing capacity for carbon monoxide corrected for haemoglobin with a five s breath‐hold (DL, COc, 5s) and nitric oxide with a five s breath‐hold (DL, NO, 5s), DM, CO and VC. The study included 57 patients with idiopathic scoliosis seen at our department from 1972 to 1983, all of whom underwent radiological assessment and measurement of DL, CO, NO during examination 40 years after diagnosis. One‐way ANOVA was performed for between‐group differences and Pearson's correlation coefficient was used to assess correlations between DL, CO, NO metrics and Cobb angle. No significant between‐group differences based on disease severity were detected. Thirty‐nine percent of the patients were presented with either reduced DL, COc, 5s or reduced DL, NO, 5s represented as Z‐scores below −1.65. No significant correlations between Cobb angle and Z‐scores for DL, COc, 5s, DL, NO, 5s, DM, CO and VC according to height measurements were found. When using arm span instead, a weak negative correlation between DL, COc, 5s and Cobb angle (r = −0.29; P = 0.04) was detected. In conclusion, approximately 39% of patients with idiopathic scoliosis had either reduced DL, COc, 5s or reduced DL, NO, 5s 40 years after diagnosis with varying contributions from VC or DM, CO. What is the central question of this study? Is pulmonary diffusing capacity for carbon monoxide and nitric oxide affected in patients diagnosed with juvenile or adolescent idiopathic scoliosis 40 years after diagnosis? What is the main finding and its importance? In patients diagnosed with juvenile or adolescent idiopathic scoliosis, about 39% were found to have reduced pulmonary diffusing capacity. No consistent relationship between scoliosis severity and pulmonary diffusing capacity was found.

Breathing oxygen with a partial pressure of > 50 kPa can cause pulmonary oxygen toxicity (POT). Diffusing capacity for carbon monoxide (DL(CO)) is thought to be a more sensitive indicator of POT than vital capacity (VC). Because diffusing capacity can be measured more specifically using nitric oxide (DL(NO)), we hypothesized that DL(NO) is better able to monitor and exclude POT than DL(CO). To compare changes in lung function after oxygen and air dives which include measurement of DL(NO) and DL(CO). Eleven healthy male divers (mean age 27.5 +/- 3.1 years) made two immersed dives to 150 kPa for three hours on two separate days, during which they randomly breathed 100% oxygen or air. VC, DL(NO) and DL(CO) were measured six times during a 26-hour period on both days and on a third non-diving day. There were no significant changes in DL(CO), DL(NO) or other diffusing capacity or spirometric parameters after either type of dive. Lung function after a single three-hour oxygen dive at a pO2 of approximately 150 kPa is comparable to that after an air dive at the same depth and duration. This suggests that such an oxygen dive does not induce detectable signs of POT. Our hypothesis that DL(NO) is more sensitive than DL(CO) for detection of POT could not be tested because the oxygen exposure did not affect either parameter.