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Background: The Phase III slope from a single breath nitrogen washout test provides information about ventilation heterogeneity (VH) in the lungs., Purpose: To determine if the Phase III slope from the exhaled tracer gas concentration during a standard, single breath D L CO test using rapid gas analysis provides similar information about VH., Basic Procedures: Retrospective analysis of clinical pulmonary function laboratory data including spirometry, lung volumes, and D L CO. The normalized Phase III slope from the exhaled CH 4 concentration (SnCH 4 ) was compared among different patterns of physiologic abnormality and with VA/TLC as an indicator of VH., Main Findings: SnCH 4 was the steepest in the group with "Obstruction and Low D L CO", with significant differences between this group and the "Normal", "Obstruction with Normal D L CO", "Mixed Obstruction and Restriction" and "Isolated Low D L CO" groups. SnCH 4 was steeper in current and former smokers compared to non-smokers. Among the entire study sample, SnCH 4 correlated with VA/TLC (Spearman rho = -0.56, p < 0.01) and remained a significant determinant of VA/TLC by regression modeling., Principal Conclusions: The SnCH 4 derived from a standard, single breath D L CO test using rapid gas analysis varied among distinct patterns of physiologic abnormalities and was associated with VA/TLC as a measure of VH., Competing Interests: Declaration of competing interest DAK: speaker for MGC Diagnostics, Inc. and Vitalograph, Inc.; royalties from UptoDate, Inc.; writing fees from Elsevier, Inc. VTA: None. SV: None. BLG: speaker fees: Lung Saskatchewan, MGC Diagnostics, Vyaire Medical, Lung Nova Scotia and PEI; consulting fees: Chiesi Faraceutici, AstraZeneca Global, Merz Pharmaceuricals, ArtiuQ, UCLA; conference travel: Novus Medical Inc; patent agreement: Hans Rudolph Inc., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Endurance exercise at altitude can increase cardiac output and pulmonary vascular pressure to levels that may exceed the stress tolerability of the alveolar-capillary unit. This study examined the effect of ultramarathon trail racing at different altitudes (ranging from <1000 m to between 1500 and 2700 m) on alveolar-capillary recruitment and lung diffusion., Methods: Cardiac and lung function were examined before and after an ultramarathon in 67 runners (age: 41 ± 9 yr, body mass index: 23 ± 2 kg·m -2 , 10 females), and following 12-24 h of recovery in a subset ( n = 27). Cardiac biomarkers (cTnI and BNP) were assessed from whole blood, whereas lung fluid accumulation (comet tails), stroke volume (SV), and cardiac output ( Q ) were quantified via echocardiography. Lung diffusing capacity for carbon monoxide (DLco) and its components, alveolar membrane conductance (Dm) and capillary blood volume (Vc), were determined via a single-breath method at rest and during three stages of submaximal semirecumbent cycling (20, 30, and 40 W)., Results: Average race time was 25 ± 12 h. From pre- to post-race, there was an increase in cardiac biomarkers (cTnI: 0.04 ± 0.02 vs 0.13 ± 0.03 ng·mL -1 , BNP: 20 ± 2 vs 112 ± 21 pg·mL -1 ; P < 0.01) and lung comet tails (2 ± 1 vs 7 ± 6, P < 0.01), a decrease in resting and exercise SV (76 ± 2 vs 69 ± 2 mL, 40 W: 93 ± 2 vs 88 ± 2 mL; P < 0.01), and an elevation in Q at rest (4.1 ± 0.1 vs 4.6 ± 0.2 L·min -1 , P < 0.01; 40 W: 7.3 ± 0.2 vs 7.4 ± 0.3 L·min -1 , P = 0.899). Resting DLco and Vc decreased after the race ( P < 0.01), whereas Dm was unchanged ( P = 0.465); however, during the three stages of exercise, DLco, Vc, and Dm were all reduced from pre- to post-race (40 W: 36.3 ± 0.9 vs 33.0 ± 0.8 mL·min -1 ·mm Hg -1 , 83 ± 3 vs 73 ± 2 mL, 186 ± 6 vs 170 ± 7 mL·min -1 ·mm Hg -1 , respectively; P < 0.01). When corrected for alveolar volume and Q , DLco decreased from pre- to post-race ( P < 0.01), and changes in DLco were similar for all ultramarathon events ( P > 0.05)., Conclusions: Competing in an ultramarathon leads to a transient increase in cardiac injury biomarkers, mild lung-fluid accumulation, and impairments in lung diffusion. Reductions in DLco are predominantly caused by a reduced Vc and possible pulmonary capillary de-recruitment at rest. However, impairments in alveolar-capillary recruitment and Dm both contribute to a fall in exertional DLco following an ultramarathon. Perturbations in lung diffusion were evident across a range of event distances and varying environmental exposures., (Copyright © 2024 by the American College of Sports Medicine.)

Background: Diffusing capacity (DLCO) measurements are affected by hemoglobin. Two adjustment equations are used: Cotes (recommended by ATS/ERS) and Dinakara (used in the hematopoietic stem cell transplantation comorbidity index [HCT-CI]). It is unknown how these methods compare, and which is better from a prognostication standpoint., Study Design: This is a retrospective cohort of 1273 adult patients who underwent allogeneic HCT, completed a pre-transplant DLCO and had a concurrent hemoglobin measurement. Non-relapse mortality was measured using competing risk analysis., Results: Patients had normal spirometry (FEV 1 99.7% [IQR: 89.4-109.8%; FVC 100.1% [IQR: 91.0-109.6%] predicted), left ventricular ejection fraction (57.2[6.7]%) and right ventricular systolic pressure (30.1[7.0] mmHg). Cotes-DLCO was 85.6% (IQR: 76.5-95.7%) and Dinakara-DLCO was 103.6% (IQR: 90.7-117.2%) predicted. For anemic patients (Hb<10g/dL), Cotes-DLCO was 84.2% (IQR: 73.9-94.1%) while Dinakara-DLCO 111.0% (97.3-124.7%) predicted. Cotes-DLCO increased HCT-CI score for 323 (25.4%) and decreased for 4 (0.3%) patients. Cotes-DLCO was superior for predicting non-relapse mortality: for both mild (66-80% predicted, HR 1.55 [95%CI: 1.26-1.92, p < 0.001]) and moderate (<65% predicted, HR 2.11 [95%CI: 1.55-2.87, p<0.001]) impairment. In contrast, for Dinakara-DLCO, only mild impairment (HR 1.69 [95%CI 1.26-2.27, p < 0.001]) was associated with lower survival while moderate impairment was not (HR 1.44 [95%CI: 0.64-3.21, p = 0.4]). In multivariable analyses, after adjusting for demographics, hematologic variables, cardiac function and FEV 1 , Cotes-DLCO was predictive of overall survival at 1-year (OR 0.98 [95%CI: 0.97-1.00], p = 0.01), but Dinakara-DLCO was not (OR 1.00 [95%CI: 0.98-1.00], p = 0.20)., Conclusion: The ERS/ATS recommended Cotes method likely underestimates DLCO in patients with anemia, whereas the Dinakara (used in the HCT-CI score) overestimates DLCO. The Cotes method is superior to the Dinakara method score in predicting overall survival and relapse-free survival in patients undergoing allogeneic HCT., Competing Interests: Conflicts of interest None., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background: Fighter aircraft pilots are regularly exposed to physiological challenges from high acceleration (G z ) forces, as well as increased breathing pressure and oxygen supply in the support systems. We studied whether effects on the lung and systemic oxidative stress were detectable after real training flights comprising of a wide variety of exposure conditions, and their combinations., Methods: Thirty-five pilots of the German Air Force performed 145 flights with the Eurofighter Typhoon. Prior to and after flight lung diffusing capacity for carbon monoxide (DL CO ) and nitric oxide (DL NO ), alveolar volume (V A ), and diffusing capacities per volume (K CO , K NO ) were assessed. In addition, the fractional concentration of exhaled nitric oxide (FeNO) was determined, and urine samples for the analysis of molecular species related to 8-hydroxy-2'-deoxyguanosine (8-OHdG) were taken. For statistical analysis, mixed ANOVA models were used., Results: DL NO , DL CO , K NO , K CO and V A were reduced (p < 0.001) after flights, mean ± SD changes being 2.9 ± 5.0, 3.2 ± 5.2, 1.5 ± 3.7, 1.9 ± 3.7 and 1.4 ± 3.1%, respectively, while FeNO decreased by 11.1% and the ratio of 8-OHdG to creatinine increased by 15.7 ± 37.8%. The reductions of DL NO (DL CO ) were smaller (p < 0.001) than those of K NO (K CO ). In repeated flights on different days, baseline values were restored. Amongst various flight parameters comprising G z -forces and/or being indicative of positive pressure breathing and oxygenation support, the combination of long flight duration and high altitude appeared to be linked to greater changes in DL NO and DL CO ., Conclusions: The pattern of reductions in diffusing capacities suggests effects arising from atelectasis and increased diffusion barrier, without changes in capillary blood volume. The decrease in exhaled endogenous NO suggests bronchial mucosal irritation and/or local oxidative stress, and the increase in urinary oxidized guanosine species suggests systemic oxidative stress. Although changes were small and not clinically relevant, their presence demonstrated physiological effects of real training flights in a modern 4th generation fighter jet., (© 2024. The Author(s).)

Purpose: This study aimed to quantify the combined effects of heat exposure and exercise of increasing intensity on pulmonary blood flow using lung diffusing capacity for carbon monoxide (DLCO) as an indirect measure. We hypothesized that, during exercise in the heat, the well-documented increase in skin blood flow for thermoregulation would lead to alterations in pulmonary blood flow and a subsequent fall in DLCO versus a thermoneutral condition., Methods: Nine healthy subjects (4 F/5 M, 20-45 years, VO 2 max 46.7 ± 5.8 mL/kg/min) completed three 15-min stages including rest and during cycling at 20 and 40% of maximum workload (W max ) in either thermoneutral (TN; 22.2 ± 0.6 °C) or heat (HT; 39.4 ± 0.4 °C) conditions. DLCO, minute ventilation (V E ), oxygen consumption ([Formula: see text]), heart rate (HR), and core (T C ) and skin temperature (T sk ) were measured., Results: DLCO showed a significant interaction between exercise intensity and heat (P = 0.019); post hoc testing revealed that DLCO was higher at 40% of W max in HT vs. TN (53.2 ± 10.6 vs 50.0 ± 10.3 mL/min/mmHg, P = 0.003) only. V E and [Formula: see text] showed no difference in HT vs. TN. HR was higher in HT vs. TN (P < 0.001). T C and T sk showed a significant interaction between temperature and intensity (P < 0.05)., Conclusion: The unexpected increase in DLCO during exercise in HT vs. TN conditions suggests a larger lung surface area for gas exchange, perhaps due to increased pulmonary capillary recruitment and/or distension secondary to a higher cardiac output (Q) in the heat. This study furthers our understanding of how heat exposure might impact pulmonary blood flow, specifically as assessed via DLCO., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

There is limited knowledge of pulmonary physiology and pulmonary function after continuous flow-left ventricular assist device (CF-LVAD) implantation. Therefore, this study investigated whether CF-LVAD influenced pulmonary circulation by assessing pulmonary capillary blood volume and alveolar-capillary conductance in addition to pulmonary function in patients with heart failure. Seventeen patients with severe heart failure who were scheduled for CF-LVAD implantation (HeartMate II, III, Abbott, Abbott Park, IL or Heart Ware, Medtronic, Minneapolis, MN) participated in the study. They underwent pulmonary function testing (measures of lung volumes and flow rates) and unique measures of pulmonary physiology using a rebreathe technique that quantified the diffusing capacity of the lungs for carbon monoxide (DLCO) and diffusing capacity of the lungs for nitric oxide before and 3 months after CF-LVAD implantation. After CF-LVAD, pulmonary function was not significantly changed (p >0.05). For lung diffusing capacity, alveolar volume (VA) was not changed (p = 0.47), but DLCO was significantly reduced (p = 0.04). After correcting for VA, DLCO/VA showed a trend toward reduction (p = 0.08). For the alveolar-capillary component, capillary blood volume (Vc) was significantly reduced (p = 0.04), and alveolar-capillary membrane conductance trended toward a reduction (p = 0.06). However, alveolar-capillary membrane conductance/Vc was not altered (p = 0.92). In conclusion, soon after CF-LVAD implantation, Vc is reduced likely because of pulmonary capillary derecruitment, which contributes to the decrease in lung diffusing capacity., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The carbon monoxide diffusion capacity test (DLCO) is a clinically useful, routine, non-invasive lung function assessment to determine the status of lung function in patients with chronic disorders such as interstitial lung disease (ILD)., Aim: To describe the sociodemographic and clinical profile of users of the DLCO test in Valdivia, Chile., Materials and Methods: Observational, retrospective, documentary-based study. From the records of 490 patients who underwent the DLCO test between 2017 and 2019, sociodemographic and clinical characteristics and reports of cigarette consumption are described, such as cigarettes/d and pack-year index (PYI), comparing by sex., Results: The highest proportion of those evaluated were women (61%), with a median age of 65 years, higher in women (66 vs. 64 years; p = 0.0361). The majority consulted for ILD (54.5%). According to nutritional status, 38% presented pre-obesity and 24.7% obesity I (24.7%), highlighting that 40.5% of women and 33% of men were in some category of obesity. Among those who reported information on cigarette consumption (n = 346, 70.6%), 14.7% (n = 51) were current consumers, with a median consumption of 10 cigarettes/d, without differences by sex. Among exsmokers (n = 144; 50% men/women) there was significantly less daily (5 vs 15; p = 0.0300) and IPA (7 vs 18; p = 0.0083) consumption in women., Conclusions: In DLCO users, the main consultation diagnosis was ILD. High frequency of obesity and smoking stood out, with no difference in consumption by sex in current smokers, but yes in ex-smokers.

Aims: Type 1 diabetes is associated with a substantially increased risk of impaired lung function, which may impair aerobic fitness. We therefore aimed to examine the ventilatory response during maximal exercise and the pulmonary diffusion capacity function at rest in individuals with uncomplicated type 1 diabetes., Methods: In all, 17 adults with type 1 diabetes free from micro-macrovascular complications (glycated haemoglobin: 8.0 ± 1.3%), and 17 non-diabetic adults, carefully matched to the type 1 diabetes group according to gender, age, level of physical activity and body composition, participated in our study. Lung function was assessed by spirometry and measurements of the combined diffusing capacity for nitric oxide (DLNO) and carbon monoxide (DLCO) at rest. Subjects performed a maximal exercise test during which the respiratory parameters were measured., Results: At rest, DLCO (30.4 ± 6.1 ml min -1  mmHg -1 vs. 31.4 ± 5.7 ml min -1 mmHg -1 , respectively, p = 0.2), its determinants Dm (membrane diffusion capacity) and Vc (pulmonary capillary volume) were comparable among type 1 diabetes and control groups, respectively. Nevertheless, spirometry parameters (forced vital capacity = 4.9 ± 1.0 L vs. 5.5 ± 1.0 L, p < 0.05; forced expiratory volume 1 = 4.0 ± 0.7 L vs. 4.3 ± 0.7 L, p < 0.05) were lower in individuals with type 1 diabetes, although in the predicted normal range. During exercise, ventilatory response to exercise was different between the two groups: tidal volume was lower in type 1 diabetes vs. individuals without diabetes (p < 0.05). Type 1 diabetes showed a reduced VO 2max (34.7 ± 6.8 vs. 37.9 ± 6.3, respectively, p = 0.04) in comparison to healthy subjects., Conclusions: Individuals with uncomplicated type 1 diabetes display normal alveolar-capillary diffusion capacity and at rest, while their forced vital capacity, tidal volumes and VO 2 are reduced during maximal exercise., (© 2022 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

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) from upright rest to exercise. The D LCO/NO technique provides reliable indices of alveolar-capillary reserve, both during exercise and in the supine position., (© 2022 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Background: The medium- and long-term effects of COVID-19 infection on pulmonary function are still unknown. The present study aimed to investigate the pulmonary functions in healthcare professionals who had persistent complaints after contracting COVID-19 and returning to work., Methods: The study included COVID-19-infected healthcare professionals from the Düzce University Medical Faculty Hospital who volunteered to participate. Medical histories, medical records, pulmonary function tests, the diffusing capacity of the lungs for carbon monoxide (DLCO) test, and the 6-minute walk test (6MWT) were used to collect data from all participants., Results: The study included 53 healthcare professionals, with an average age of 38 ± 10 years (min: 24 years and max: 71 years), including 29 female (54.7%) and 24 male (45.3%) participants. Of the participants, 22.6% were smokers, 35.8% (19 individuals) had comorbidities, and 17% (9 individuals) were hospitalized. The mean length of stay was 9 ± 4 days (mean ± standard deviation). The most prevalent symptoms were weakness (88.7%), muscle aches (67.9%), inability to smell/taste (60.4%), headache (54.7%), fever (45.3%), cough (41.5%), and shortness of breath (37.7%). The mean time to return to work after a positive polymerase chain reaction (PCR) test for COVID-19 was 18 ± 13 days. The average time among post-disease pulmonary function, 6MW, and DLCO tests was 89 ± 36 days (min: 15 and max: 205). The DLCO level decreased in 39.6% (21) of the participants. Female participants had a significantly higher rate of decreased DLCO levels than male participants (25% vs. 55.2%, P = .026). DLCO levels were significantly higher in participants with long-term persistent complaints (P = .043). The later the time to return to work, the lower the DLCO value (r = -0.290 and P = .035). The 6MWT distance was positively correlated with hemoglobin and lymphocyte levels at the time of the disease onset and negatively correlated with D-dimer levels. The most prevalent symptoms during the control visits were shortness of breath/effort dyspnea (24.6%), weakness (9.5%), and muscle aches (7.6%)., Conclusion: Significant persistent complaints (47.2%) and low DLCO levels (39.6%) were observed in healthcare professionals during control visits at a mean time of 3 months after the COVID-19 infection. Symptoms and spirometry measurements, including DLCO, may be helpful in the follow-up of healthcare professionals who contracted COVID-19. Further comprehensive studies with long-term follow-up periods are required., (Copyright © 2022 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: Prospective and longitudinal data on pulmonary injury over one year after acute coronavirus disease 2019 (COVID-19) are sparse. We aim to determine reductions in pulmonary function and respiratory related quality of life up to 12 months after acute COVID-19., Methods: Patients with acute COVID-19 were enrolled into an ongoing single-centre, prospective observational study and prospectively examined 6 weeks, 3, 6 and 12 months after onset of COVID-19 symptoms. Chest CT-scans, pulmonary function and symptoms assessed by St. Georges Respiratory Questionnaire were used to evaluate respiratory limitations. Patients were stratified according to severity of acute COVID-19., Results: Median age of all patients was 57 years, 37.8% were female. Higher age, male sex and higher BMI were associated with acute-COVID-19 severity (p < 0.0001, 0.001 and 0.004 respectively). Also, pulmonary restriction and reduced carbon monoxide diffusion capacity was associated with disease severity. In patients with restriction and impaired diffusion capacity, FVC improved over 12 months from 61.32 to 71.82, TLC from 68.92 to 76.95, D LCO from 60.18 to 68.98 and K CO from 81.28 to 87.80 (percent predicted values; p = 0.002, 0.045, 0.0002 and 0.0005). The CT-score of lung involvement in the acute phase was associated with restriction and reduction in diffusion capacity in follow-up. Respiratory symptoms improved for patients in higher severity groups during follow-up, but not for patients with initially mild disease., Conclusion: Severity of respiratory failure during COVID-19 correlates with the degree of pulmonary function impairment and respiratory quality of life in the year after acute infection., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Alveolar-capillary membrane diffusing capacity for carbon monoxide (DMCO) and pulmonary capillary volume (Vcap) can be estimated by the multi-step Roughton and Foster (RF, original method from 1957) or the single-step NO-CO double diffusion technique (developed in the 1980s). The latter method implies inherent assumptions. We sought to determine which combination of the alveolar membrane diffusing capacity for nitric oxide (DMNO) to DMCO ratio, an specific conductance of the blood for NO (θ NO ) and CO (θ CO ) gave the lowest week-to-week variability in patients with heart failure., Methods: 44 heart failure patients underwent DMCO and Vcap measurements on three occasions over a ten-week period using both RF and double dilution NO-CO techniques., Results: When using the double diffusing method and applying θ NO = infinity, the smallest week-to-week coefficient of variation for DMCO was 10 %. Conversely, the RF method derived DMCO had a much greater week-to-week variability (2x higher coefficient of variation) than the DMCO derived via the NO-CO double dilution technique. The DMCO derived from the double diffusion technique most closely matched the DMCO from the RF method when θ NO = infinity and DMCO = DLNO/2.42. The Vcap measured week-to-week was unreliable regardless of the method or constants used., Conclusions: In heart failure patients, the week-to-week DMCO variability was lowest when using the single-step NO-CO technique. DMCO obtained from double diffusion most closely matched the RF DMCO when DMCO/2.42 and θ NO = infinity. Vcap estimation was unreliable with either method., (Copyright © 2021. Published by Elsevier B.V.)

Background: Treatment for interstitial lung disease (ILD) patients with acute respiratory failure (ARF) is challenging, and literature to guide such treatment is scarce. The reported in-hospital mortality rates of ILD patients with ARF are high (62-66%). Cyclophosphamide is considered a second-line treatment in steroid-refractory ILD-associated ARF. The first aim of this study was to evaluate the in-hospital mortality in patients with ILD-associated ARF treated with cyclophosphamide. The second aim was to compare computed tomographic (CT) patterns and physiological and ventilator parameters between survivors and non-survivors., Methods: Retrospective analysis of patients with ILD-associated ARF treated with cyclophosphamide between February 2016 and October 2017. Patients were categorized into three subgroups: connective tissue disease (CTD)-associated ILD, other ILD or vasculitis. In-hospital mortality was evaluated in the whole cohort and in these subgroups. Clinical response was determined using physiological and ventilator parameters: Sequential Organ Failure Assessment Score (SOFA), PaO2/FiO2 (P/F) ratio and dynamic compliance (Cdyn) before and after cyclophosphamide treatment. The following CT features were quantified: ground-glass opacification (GGO) proportion, reticulation proportion, overall extent of parenchymal disease and fibrosis coarseness score., Results: Fifteen patients were included. The overall in-hospital mortality rate was 40%. In-hospital mortality rates for CTD-associated ILD, other ILD and vasculitis were 20, 57, and 33%, respectively. The GGO proportion (71% vs 45%) was higher in non-survivors. There were no significant differences in the SOFA score, P/F ratio or Cdyn between survivors and non-survivors. However, in survivors the P/F ratio increased from 129 to 220 mmHg and Cdyn from 75 to 92 mL/cmH2O 3 days after cyclophosphamide treatment. In non-survivors the P/F ratio hardly changed (113-114 mmHg) and Cdyn even decreased (27-20 mL/cmH2O)., Conclusion: In this study, we found a mortality rate of 40% in patients treated with cyclophosphamide for ILD-associated ARF. Connective tissue disease-associated ILD and vasculitis were associated with a lower risk of death. In non-survivors, the CT GGO proportion was significantly higher. The P/F ratio and Cdyn in survivors increased after 3 days of cyclophosphamide treatment., (© 2021. The Author(s).)

Background: Evidence suggests lungs as the organ most affected by coronavirus disease 2019 (COVID-19). The literature on previous coronavirus infections reports that patients may experience persistent impairment in respiratory function after being discharged. Our objective was to determine the prevalence of restrictive pattern, obstructive pattern and altered diffusion in patients post-COVID-19 infection and to describe the different evaluations of respiratory function used with these patients., Methods: A systematic review was conducted in five databases. Studies that used lung function testing to assess post-infection COVID-19 patients were included for review. Two independent reviewers analysed the studies, extracted the data and assessed the quality of evidence., Results: Of the 1973 reports returned by the initial search, seven articles reporting on 380 patients were included in the data synthesis. In the sensitivity analysis, we found a prevalence of 0.39 (CI 0.24-0.56, p < 0.01, I 2  = 86%), 0.15 (CI 0.09-0.22, p = 0.03, I 2  = 59%), and 0.07 (CI 0.04-0.11, p = 0.31, I 2  = 16%) for altered diffusion capacity of the lungs for carbon monoxide (DL CO ), restrictive pattern and obstructive pattern, respectively., Conclusion: Post-infection COVID-19 patients showed impaired lung function; the most important of the pulmonary function tests affected was the diffusion capacity., (Copyright © 2020 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

There is limited knowledge about the long-term effects on pulmonary function of COVID-19 in patients that required intensive care treatment. Spirometry and diffusing capacity for carbon monoxide (DLCO) were measured in 60 subjects at 3-6 months post discharge. Impaired lung function was found in 52% of the subjects, with reduced DLCO as the main finding. The risk increased with age above 60 years, need for mechanical ventilation and longer ICU stay as well as lower levels of C-reactive protein at admission. This suggests the need of follow-up with pulmonary function testing in intensive-care treated patients., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A decreased lung diffusing capacity for carbon monoxide (DL CO ) 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 (DL NO ) 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 DL NO and DL CO 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. DL NO was abnormal in 57% of subjects, independent of time of lung function testing and severity of COVID-19, whereas standard DL CO was reduced in only 20% and mostly within the first 3 months. These differences were not associated with changes of simultaneous DL NO /DL CO ratio, while DL CO /V A and DL NO /V A were within normal range or slightly decreased. DL CO but not DL NO positively correlated with recovery time and DL CO was within the normal range in about 90% of cases after 3 months, while DL NO was reduced in more than half of subjects. Both DL NO and DL CO inversely correlated with persisting CT ground glass opacities and mean lung attenuation, but these were more frequently associated with DL NO than DL CO decrease. These data show that an impairment of DL NO exceeding standard DL CO 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&#95;DLNO 2020., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background: Chest physiotherapy plays a crucial role in managing cystic fibrosis, especially during pulmonary exacerbations. This study evaluated the effects of adding a new airway clearance device to chest physiotherapy in subjects with cystic fibrosis hospitalised due to pulmonary exacerbations., Methods: This prospective open-label study was carried out at the Pediatric Cystic Fibrosis Centre in Poland between October 2017 and August 2018. Cystic fibrosis patients aged 10 to 18 years who were admitted to the hospital and required intravenous antibiotic therapy due to pulmonary exacerbations were consecutively allocated (1:1) to either chest physiotherapy alone or chest physiotherapy with a new airway clearance device (Simeox; PhysioAssist). Patients performed spirometry and multiple-breath nitrogen washout for lung clearance index assessment upon admission and prior to discharge., Results: Forty-eight cystic fibrosis patients were included (24 in each group). Spirometry parameters in both groups improved significantly after intravenous antibiotic therapy. A significant improvement in the maximum expiratory flow at 25% of forced vital capacity was observed only in the group with a new airway clearance device (p < 0.01 vs. baseline). Trends towards a lower lung clearance index ratio were similar in both groups. No adverse events were observed in either group., Conclusions: Spirometry parameters increased significantly in cystic fibrosis patients treated for pulmonary exacerbations with intravenous antibiotic therapy and intensive chest physiotherapy. The new airway clearance device was safe and well tolerated when added to chest physiotherapy and may be another option for the treatment of pulmonary exacerbation in cystic fibrosis., (© 2020 Katarzyna Walicka-Serzysko et al., published by Sciendo.)

Expression of β2-microglobulin (β2M) is involved in fibrosis progression in kidney, liver, and heart. In this case-controlled retrospective study, we investigated the role of β2M in the development of pulmonary fibrosis in patients with chronic obstructive pulmonary disease (COPD). Analysis of 450 COPD patients revealed that patients with decreased pulmonary diffusing capacity (DLCO) had increased β2M serum levels. Compared to patients with lower β2M serum levels, patients with increased β2M levels exhibited increased alveolar wall/septal thickening and lung tissue β2M expression. In addition, patients with increased β2M levels had increased lung expression of TGF-β1, Smad4, and a-SMA. Animal experiments showed that increased β2M expression resulted in epithelial-mesenchymal transition (EMT), alveolar wall/septal thickening, and pulmonary fibrosis in a rat COPD model. Together, these results indicate that β2M serum levels may serve as a new indicator for assessment of pulmonary diffusion function and pulmonary fibrosis severity in clinical practice and may provide a potential target for treatment of pulmonary fibrosis in the future.

Forced expiratory volume in 1 s (FEV 1 ) is a standard physiological index of chronic obstructive pulmonary disease (COPD), but reflects emphysema and vascular abnormalities less sensitively than diffusion capacity for carbon monoxide (D LCO ). This study tested whether a disproportionally impaired D LCO relative to FEV 1 (FEV 1 z -score>-3 and D LCO z -score≤-3) is a common functional COPD phenotype associated with distinct clinical and structural features and the prognosis of two cohorts. The cross-sectional analyses of the Korea COPD Subgroup Study (KOCOSS) cohort (multicenter study in Korea) included 743 males with COPD whose D LCO was available. The cross-sectional and longitudinal analyses of the Kyoto University Cohort (single-center study in Japan) included 195 males with COPD who were prospectively followed for 10 years. A disproportionally impaired D LCO relative to FEV 1 was observed in 29% and 31% of patients in the KOCOSS and Kyoto University cohorts, respectively. In the multivariable analysis, the disproportionally impaired D LCO was associated with worse symptoms, shorter 6-minute walking distance, paraseptal and centrilobular emphysema on computed tomography, and reduced arterial oxygen and carbon dioxide pressures compared to the reference (FEV 1 z -score>-3 and D LCO z -score>-3). In the multivariable Cox proportional hazard model, a higher long-term mortality was observed in the disproportionally impaired D LCO group than in the reference group (hazard ratio [95% confidence interval] = 3.09 [1.52-6.29]) and similar to the D LCO z -score≤-3 and FEV 1 z -score≤-3 group. The disproportionally impaired D LCO relative to FEV 1 is common and associated with increased symptoms, emphysema, arterial blood gas abnormalities, and increased long-term mortality in patients with COPD.

Patients with heart failure with preserved ejection fraction (HFpEF) experience symptoms of exertional dyspnea that may be related to lung fluid accumulation during exercise. A computed tomography (CT)-based method was used to measure exercise-induced changes in extravascular lung fluid content and thoracic blood volumes and to determine the effect of lung fluid on lung diffusing capacity for carbon monoxide (DL CO ) in stable subjects with HFpEF and healthy controls. Nine subjects with HFpEF (age = 68 ± 8 yr; body mass index = 32.1 ± 2.6 kg/m 2 ) and eight healthy controls (62 ± 9 yr, 23.8 ± 2.4 kg/m 2 ) performed triplicate rebreathe DL CO /DL NO (lung diffusing capacity for nitric oxide) tests in a supine position at rest and duplicate measurements during two 5-min submaximal exercise stages (15W and 35W) and recovery. Subjects subsequently performed a 5-min exercise bout (35W) inside a CT scanner, and extravascular lung fluid content and thoracic blood volumes were quantified at rest and immediately following exercise from thoracic and contrast perfusion scans, respectively. Subjects with HFpEF had a higher lung fluid content at rest compared with controls (means ± SD, HFpEF: 14.4 ± 1.7%, control: 12.8 ± 1.7%, P = 0.043) and a higher lung fluid content following exercise (15.2 ± 2.0% vs. 12.6 ± 1.5%, P = 0.009). Higher lung fluid content was associated with a lower DL CO and alveolar-capillary membrane conductance (D m ) in subjects with HFpEF (DL CO : R  = -0.57, P = 0.022, D m : R  = -0.61, P = 0.012) but not in controls. Pulmonary blood volume was not altered by exercise and was similar between groups. Submaximal exercise elicited a greater accumulation of lung fluid in subjects with HFpEF compared with in controls, and lung fluid content was negatively correlated with lung diffusing capacity and alveolar-capillary membrane conductance in subjects with HFpEF.

Background: In cohort studies of pulmonary sarcoidosis, abnormal ventilatory patterns have generally been subdivided into restrictive and obstructive defects. Mixed ventilatory defects have largely been overlooked in pulmonary sarcoidosis, as total lung capacity has seldom been taken into account in historical series., Research Question: This study evaluated the prevalence of mixed disease in pulmonary sarcoidosis and its clinical associations., Study Design and Methods: In patients with pulmonary sarcoidosis (N = 1,110), mixed defects were defined according to American Thoracic Society/European Respiratory Society criteria. Clinical data, pulmonary function variables, and vital status were abstracted from clinical records. Chest radiographs were evaluated independently by two experienced radiologists., Results: The prevalence of a mixed ventilatory defect was 10.4% in the whole cohort, rising to 25.9% in patients with airflow obstruction. Compared with isolated airflow obstruction, mixed defects were associated with lower diffusing lung capacity for carbon monoxide levels (50.7 ± 16.3 vs 70.8 ± 18.1; P < .0001), a higher prevalence of chest radiographic stage IV disease (63.5% vs 38.3%; P < .0001), and higher mortality (hazard ratio, 2.36; 95% CI, 1.34-4.15; P = .003). These findings were reproduced in all patient subgroup analyses, including patients with a histologic diagnosis, a clinical diagnosis, incident disease, and prevalent disease., Interpretation: Mixed disease is present in approximately 25% of patients with pulmonary sarcoidosis and airflow obstruction and is associated with lower diffusing lung capacity for carbon monoxide levels, a higher prevalence of stage IV disease, and higher mortality than seen in a pure obstructive defect. These observations identify a distinct phenotype associated with a mixed ventilatory defect, justifying future studies of its clinical and pathogenetic significance., (Copyright © 2020. Published by Elsevier Inc.)

Background: As pulmonary diffusing capacity is related to mortality risk and prognosis in patients with heart failure (HF), it is measured frequently. As such, it would be essential to know the week-to-week variability (reproducibility) of pulmonary diffusing capacity for carbon monoxide (DLCO) and nitric oxide (DLNO). This variability would let clinicians understand what a clinically measurable change in DLCO and DLNO would be in these patients., Methods: On three different days spanning over ten weeks, 40 H F patients underwent testing for DLCO and DLNO. DLCO was determined after a 4 s and 10 s breath-hold maneuver, while DLNO was determined after a 4 s breath-hold maneuver., Results: Forty heart failure patients (66 ± 10 years; BMI = 28.4 ± 4.6 kg∙m -2 ; 28 males), that were referred to our clinic were able to complete the protocol. DLCO (4 s breath-hold) and DLNO (4 s breath-hold) were 79 ± 19 % and 59 ± 14 % predicted, respectively. Fifty percent of patients (n = 20) were below the lower limit of normal (LLN, below the 5th percentile) for predicted DLCO (4 s), while 78 % of patients (n = 31) were below the LLN for predicted DLNO. All 16 patients that were below the LLN for DLCO were also below the LLN for DLNO. Over a ten week period, the reproducibility of DLNO (4 s) DLCO (4 s) and DLCO (10 s) was 18.9, 8.2, and 5.9 mL min mmHg -1 , respectively., Conclusions: The week-to-week fluctuation in DLNO (4 s), as a percentage, is less than DLCO (4 s) in patients with HF. The reproducibility of DLNO in patients with HF is like that of healthy subjects., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The ratio of the diffusing capacity of the lung for carbon monoxide (DLCO) and for nitric oxide (DLNO) measured simultaneously is modified in patients with precapillary pulmonary hypertension (PH). The potential impact of targeted therapy on the DLCO/DLNO ratio is unknown. Simultaneous measurements of DLNO and DLCO were performed at baseline, 3-4 month follow-up (first evaluation) and 12-month follow-up (second evaluation) after initiation of targeted PH therapies in incident cases of precapillary PH. The main outcome was the change in DLNO/DLCO ratio under treatment between baseline and the first evaluation. Twenty-nine patients were included (mean age: 66.8 years, 62.1% female). No significant change in the DLNO/DLCO ratio was found between baseline and the first evaluation. Similarly, no significant differences were noted with regard to changes in Dm or Vc, the DLNO/DLCO ratio in different patient subgroups, or in the 20 patients evaluated at the second follow-up. Within the limitations of this study, the DLNO/DLCO ratio is not useful in monitoring the response to treatment in PH., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A 31-year non-smoker man, working in plastic making industry for 12 years presented with cough and streaking hemoptysis for 2 days. Computed tomography (CT) of chest showed patchy ground glass opacities with interlobular septal thickening in bilateral lung parenchyma. Fiber optic bronchoscopy (FOB) was done. Sequential lavage was taken which showed progressively increasing hemorrhagic fluid. His diffusion capacity for carbon monoxide (DLCO) was 38.08 mL/mmHg/Mi (126%) predicted on day 2 of admission, 32.36 ml/mmHg/Mi (106%) predicted on discharge and 39.63 mL/mmHg/Mi (130%) predicted on going back to work. He was diagnosed with plastic fume exposure related pulmonary alveolar hemorrhage.

Diffuse alveolar hemorrhage is a severe respiratory complication of systemic lupus erythematosus. The illness develops over hours to a few days and is the systemic lupus erythematosus-associated syndrome with highest mortality. Although no specific symptoms have been identified, a number of features are associated with diffuse alveolar hemorrhage, with a drop in blood hemoglobin the most prominent. Dyspnea, blood-stained sputum, diffuse infiltrates identified by chest imaging, elevated single breath-diffusing capacity for monoxide, thrombocytopenia and C3 hypocomplementemia are other commonly reported signs of diffuse alveolar hemorrhage. The etiology is not completely understood but many patients develop diffuse alveolar hemorrhage concomitant with lupus nephritis, suggesting immune complex-driven pathology. Biopsy studies have identified both cases with capillaritis and a bland non-inflammatory phenotype. An animal model of diffuse alveolar hemorrhage has indicated requirement of B lymphocytes and complement receptor-mediated apoptotic body phagocytosis by monocytes as part of the pathogenesis. This review will discuss considerations when diagnosing the condition and available therapies. Infections and other causes of hemorrhage have to be excluded as these require different treatment strategies. Methylprednisolone and cyclophosphamide remain the most commonly used therapies. Plasmapheresis and rituximab are other beneficial treatment options. A few studies have also considered intrapulmonary Factor VII therapy, extracorporeal membrane oxygenation and mesenchymal stem cell therapy. There is an unmet need of better definition of diffuse alveolar hemorrhages etiology and pathology for development of improved treatment strategies.

Background: Much remains unknown about the consequences of very low birth weight (VLBW) and bronchopulmonary dysplasia (BPD) on adult lungs. We hypothesized that VLBW adults would have impaired lung function compared with controls, and those with a history of BPD would have worse lung function than those without., Methods: At age 26 to 30 years, 226 VLBW survivors of the New Zealand VLBW cohort and 100 term controls born in 1986 underwent lung function tests including spirometry, plethysmographic lung volumes, diffusing capacity of the lung for carbon monoxide, and single-breath nitrogen washout (SBN 2 )., Results: An obstructive spirometry pattern was identified in 35% VLBW subjects versus 14% controls, with the majority showing mild obstruction. Compared with controls, VLBW survivors demonstrated significantly lower forced expiratory volume in 1 second (FEV 1 ), FEV 1 /forced vital capacity (FVC) ratio (FEV 1 /FVC), forced expiratory flow at 25% to 75% of FVC and higher residual volume (RV), RV/total lung capacity (TLC) ratio (RV/TLC), decreased diffusing capacity of the lung for carbon monoxide, and increased phase III slope for SBN 2 . The differences persisted after adjustment for sex and smoking status. Within the VLBW group, subjects with BPD showed significant reduction in FEV 1 , FEV 1 /FVC, and forced expiratory flow at 25% to 75% of FVC, and increase in RV, RV/TLC, and phase III slope for SBN 2 , versus subjects without. The differences remained after adjustment for confounders., Conclusions: Adult VLBW survivors showed a higher incidence of airflow obstruction, gas trapping, reduced gas exchange, and increased ventilatory inhomogeneity versus controls. The findings suggest pulmonary effects due to VLBW persist into adulthood, and BPD is a further insult on small airway function., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

CALIPER is a computer-based quantitative algorithm to accurately characterize and quantify pulmonary fibrosis, and a revised version of composite physiologic index (CPI) has been developed against this new algorithm. The prognostic capabilities of the original and CALIPER-revised versions of CPI were compared in a cohort of 185 patients with IPF prospectively followed in 2 centers. CALIPER-revised CPI was a significant risk factor towards lung transplant (LTx)-free survival, with enhanced hazard ratio (5.68) compared to the original CPI (5.36). Accuracy of LTx-free survival was substantially improved with CALIPER-revised CPI (area under the curve [AUC] 0.75 vs. 0.66), with much better specificity (83% vs. 55%). Six-month changes of CALIPER-revised CPI predicted survival significantly (AUC 0.65). CALIPER-revised CPI is a better predictor of LTx-free survival in patients with IPF. Since CALIPER technology is not available to all centers, this simple and easy to obtain tool may be used to guide management decisions in IPF.

Background and Objective: This study aims to evaluate the impact of diffusing capacity of the lung for carbon monoxide (DLco) before and after neoadjuvant concurrent chemoradiotherapy (CCRT) on postoperative pulmonary complication (PPC) among stage IIIA/N2 non-small-cell lung cancer (NSCLC) patients., Methods: We retrospectively studied 324 patients with stage IIIA/N2 NSCLC between 2009 and 2016. Patients were classified into 4 groups according to DLco before and after neoadjuvant CCRT; normal-to-normal (NN), normal-to-low (NL), low-to-low (LL), and low-to-very low (LVL). Low DLco and very low DLco were defined as DLco < 80% predicted and DLco < 60% predicted, respectively., Results: On average, DLco was decreased by 12.3% (±10.5) after CCRT. In multivariable-adjusted analyses, the incidence rate ratio (IRR) for any PPC comparing patients with low DLco to those with normal DLco before CCRT was 2.14 (95% confidence interval (CI) = 1.36-3.36). Moreover, the IRR for any PPC was 3.78 (95% CI = 1.68-8.49) in LVL group compared to NN group. The significant change of DLco after neoadjuvant CCRT had an additional impact on PPC, particularly after bilobectomy or pneumonectomy with low baseline DLco., Conclusions: The DLco before CCRT was significantly associated with risk of PPC, and repeated test of DLco after CCRT would be helpful for risk assessment, particularly in patients with low DLco before neoadjuvant CCRT.

Background: Diving challenges the respiratory system because of the pressure changes, breathing gases, and cardiovascular effects. We aimed to analyse the long term effect of occupational diving on pulmonary functions in terms of diving experience (year), smoking history, and occupational groups (commercial divers and SCUBA instructors)., Materials and Methods: We retrospectively analysed respiratory system examination results of the experienced occupational divers who were admitted to the Undersea and Hyperbaric Medicine Department for periodic medical examination between January 1, 2013 and February 28, 2019., Results: Sixty-four divers applied to our department. Candidate divers were not included in our study. The mean diving experience (year) was 13.6 ± 7.3. None of the divers complained of pulmonary symptoms. Pulmonary auscultation and chest radiography were normal in all cases. In divers with 20 years or more experience, the FEV1/FVC ratio and FEF25-75(%) was significantly lower (p < 0.001, p < 0.05, respectively). In addition, there was a statistically significant negative correlation between FEV1/FVC ratio and FEF25-75(%) and diving experience (year) (p < 0.05, r = -0.444, p < 0.05, r = -0.300, respectively). As the diving experience increase per 1 year, the FEF25-75(%) value decreases by 1.04% according to linear regression analyses. However, smoking and occupational groups did not show any significant influence on pulmonary function test parameters., Conclusions: Occupational diving seems to create clinically asymptomatic pulmonary function test changes related to small airway obstruction after long years of exposure.

Background: The interstitial lung disease-gender-age-physiology (ILD-GAP) index and staging system have been reported as a clinical prognostic factor for ILD, including all ILD subtypes., Objectives: The purpose of this study was to clarify the association of various prognostic indices, including the ILD-GAP index, with the prognosis, the incidence of acute exacerbations of ILD (ILD-AE), and the use of long-term oxygen therapy (LTOT) after surgery in surgically resected patients with ILD and concomitant lung cancer, to provide additional information when considering whether it is safe to perform surgery., Methods: The medical records of patients with ILD and concomitant lung cancer who had undergone surgery at Shinshu University Hospital between August 2001 and September 2016 were retrospectively analyzed., Results: There were significant differences in survival between the ILD-GAP index: 0-1 and ≥4 groups (p = 0.0001) and between the ILD-GAP index: 2-3 and ≥4 groups (p = 0.0236). A higher ILD-GAP index was independently associated with the risk of death (hazard ratio [HR] 1.32030; p = 0.0059). A higher body mass index (BMI) and a higher serum C-reactive protein (CRP) level were independently associated with the incidence of ILD-AE (HR 1.28336; p = 0.0206 and HR 26.3943; p = 0.0165, respectively). A higher severity of ILD on chest high-resolution computed tomography (HRCT) was independently associated with the use of LTOT (HR 2.78670; p = 0.0313)., Conclusions: The ILD-GAP index can predict the prognosis in surgically resected patients with ILD and concomitant lung cancer. The BMI and serum CRP levels were independent determinants that predicted the incidence of ILD-AE. The severity of ILD on chest HRCT was an independent determinant that predicted the use of LTOT., (© 2019 S. Karger AG, Basel.)

Background: For selected patients with severe emphysema, bronchoscopic lung volume reduction with endobronchial valves (EBV) is recognized as an additional treatment option. In most trials investigating EBV treatment, patients with a very low diffusing capacity (DLCO) were excluded from participation., Objectives: Our goal was to investigate whether EBV treatment in patients with emphysema with a very low DLCO is safe and effective., Methods: This was a single-center retrospective analysis including patients with emphysema and a DLCO ≤20%pred who underwent EBV treatment. Follow-up was performed 6 months post-treatment. Outcome parameters were compared to a historical matched control group (DLCO >20%pred, matched for sex, age, forced expiratory volume in 1 s [FEV1], and residual volume [RV])., Results: Twenty patients (80% female, 64 ± 6 years, FEV1 26 ± 6%pred, RV 233 ± 45%pred, DLCO 18 ± 1.6%pred) underwent EBV treatment. At 6 months follow-up, we found a statistically significant improvement in FEV1 (0.08 ± 0.12 L), RV (-0.45 ± 0.95 L), 6-min walking distance (38 ± 65 m), and St. George's Respiratory Questionnaire (-12 ± 13 points). With the exception of FEV1, all exceeded the minimal clinically important difference. The most common serious adverse event was a pneumothorax requiring intervention (15%). There were no significant differences in outcome compared to the DLCO >20%pred control group., Conclusions: In this single-center retrospective analysis, we showed statistically significant and clinically relevant improvements in lung function, exercise capacity, and quality of life up to 6 months after EBV treatment in emphysema patients with a DLCO ≤20% (14-20%) of predicted with no increased risk of serious adverse events., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Objective: To describe the phenotypic characteristics and natural history of patients with autoimmune forms of interstitial lung disease (ILD)., Methods: Retrospective, descriptive, single-center study of patients with autoimmune forms of ILD evaluated between February 2008 and August 2014. All data were extracted from the electronic medical record. Longitudinal changes in forced vital capacity (FVC%) and diffusion capacity for carbon monoxide (DLco%) in percent predicted were analyzed and time-to-event analyses for death were performed using Cox regression., Results: Of the entire cohort (n = 243), systemic sclerosis (SSc)-associated ILD (n = 88, 36%), interstitial pneumonia with autoimmune features (IPAF, n = 56, 23%), rheumatoid arthritis (RA)-associated ILD (n = 42, 17%), and idiopathic inflammatory myopathy (IIM)-associated ILD (n = 26, 11%) were the most common phenotypes. The SSc-ILD, IIM-ILD, and IPAF groups had similar features: average age in the mid-50s, strongly female predominant and more likely to have nonspecific interstitial pneumonia (NSIP). In contrast, RA-ILD patients were older, gender balanced, more likely to be past smokers and were UIP predominant. Adjusted longitudinal lung function was stable during a median follow-up period of nearly 4 years and the independent predictors for death were older age (p = 0.003), male sex (p = 0.019), and lower FVC (p =  < 0.001)., Conclusions: The predominant phenotypes of autoimmune ILD were SSc-ILD, IPAF, RA-ILD, and IIM-ILD. In contrast to the other subsets, those with RA-ILD may be older, gender balanced, with more smoking history, and higher proportion of UIP. Longitudinal lung function was stable among the groups and younger age, female gender, and better lung function were associated with improved survival.

New Findings: What is the Central question? Does dopamine, a pulmonary vascular vasodilator, contribute to the regulation of pulmonary diffusing capacity and capillary blood volume responses to exercise and exercise tolerance? What are the main findings and their importance? Dopamine appears not to be important for regulating pulmonary diffusing capacity or pulmonary capillary blood volume during exercise in healthy participants. Dopamine blockade trials demonstrated that endogenous dopamine is important for maintaining exercise tolerance; however, exogenous dopamine does not improve exercise tolerance., Abstract: Pulmonary capillary blood volume (V c ) and diffusing membrane capacity (D m ) expansion are important contributors to the increased pulmonary diffusing capacity (DL CO ) observed during upright exercise. Dopamine is a pulmonary vascular vasodilator, and recent studies suggest that it may play a role in V c regulation through changes in pulmonary vascular tone. The purpose of this study was to examine the effect of exogenous dopamine and dopamine receptor-2 (D 2 -receptor) blockade on DL CO , V c and D m at baseline and during cycle exercise, as well as time-to-exhaustion at 85% of V ̇ O 2 peak . We hypothesized that dopamine would increase DL CO , V c , D m and time-to-exhaustion, while D 2 -receptor blockade would have the opposite effect. We recruited 14 young, healthy, recreationally active subjects ( V ̇ O 2 peak 45.8 ± 6.6 ml kg -1  min -1 ). DL CO , V c and D m were determined at baseline and during exercise at 60% and 85% of V ̇ O 2 peak under the following randomly assigned and double blinded conditions: (1) intravenous saline and placebo pill, (2) intravenous dopamine (2 µg kg -1  min -1 ) and placebo pill, and (3) intravenous saline and D 2 -receptor antagonist (20 mg oral metoclopramide). Exogenous dopamine and dopamine blockade had no effect on DL CO , V c and D m responses at baseline or during exercise. Dopamine blockade reduced time-to-exhaustion by 47% (P = 0.04), but intravenous dopamine did not improve time-to-exhaustion. While dopamine modulation did not affect DL CO , V c or D m , the reduction in time-to-exhaustion with D 2 -receptor blockade suggests that endogenous dopamine is important for exercise tolerance., (© 2019 The Authors. Experimental Physiology © 2019 The Physiological Society.)

Objective: To derive reference values from white race adults, for DCO in a sample from different sites in Brazil, through the same equipment model (Sensormedics), and compare the results with the derivatives from Crapo, Miller, Neder equations and from the Global Lung Initiative (GLI) proposal., Methods: The tests were performed according to the norms suggested by ATS/ERS in 2005 in six Brazilian cities, with 120 adult volunteers of each gender, non-smokers, without referred anemia and without lung or cardio diseases. The expected values were derived from linear regressions and the differences between the values forecasted by some authors and the ones observed in the current study were calculated., Results: Among men, the age varied between 25 and 88 years old, and the height varied between 140 and 176 cm. DCO was correlated significantly and positively with the height and negatively with the age. The values forecasted by Crapo, Neder, and Miller equations were higher in comparison with the ones obtained by the current study (p<0.01) in both genders. Among men, the values did not differ when compared to the ones calculated by GLI (p=0.29); among women, the values derived by GLI were slightly higher: 0.99 ml/min/mmHg (p<0.01)., Conclusion: new values forecasted for DCO were derived in a sample of white adults in Brazil. The forecasted values are similar to the ones complied by GLI equations and differ from the previously proposed equations.

Objective: Lysyl oxidase (LOX) is an extracellular enzyme that cross-links collagen fibrils. LOX was found to be increased in serum of SSc patients and was suggested to be related to skin fibrosis, yet a vascular source of LOX has been demonstrated in idiopathic pulmonary arterial hypertension (iPAH). We aimed to validate elevated LOX serum levels in SSc and to study its correlation with clinical characteristics and investigate its main source at the tissue level., Methods: A total of 86 established SSc patients were compared with 86 patients with very early diagnosis of systemic sclerosis (VEDOSS), 110 patients with primary RP (PRP) and 80 healthy controls. LOX serum levels were determined by ELISA. Five lung and 12 skin biopsies from SSc patients were stained for LOX and compared with controls., Results: Serum levels of LOX in SSc were significantly higher than in VEDOSS, PRP and healthy controls (P < 0.001). LOX inversely correlated with the diffusing capacity of the lung for carbon monoxide diffusing capacity (DLCO) in diffuse SSc (r = -0.376, P = 0.02). Patients with moderate to severe estimated systolic PAH had higher LOX levels (P < 0.01). Lung biopsies demonstrated intense LOX staining in SSc patients with PAH that was predominantly located in the endothelium of the remodelled pulmonary vessels., Conclusion: Serum LOX levels are increased in established SSc and inversely correlate with the DLCO. LOX is elevated in patients with moderate to severe PAH and is located in the proliferating endothelium in lung arterioles, suggesting a possible role for LOX in SSc-associated PAH., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Rationale: The concept of interstitial pneumonia with autoimmune features (IPAF) was recently proposed by the American Thoracic Society. However, the clinical significance of the serologic domain of IPAF has not yet been established in idiopathic pulmonary fibrosis (IPF)., Objectives: We aimed to investigate the clinical significance of autoantibody positivity in IPF., Methods: We retrospectively reviewed the records of 512 patients diagnosed as IPF from January 2007 through March 2014. The patients were divided into two subgroups: (i) an autoantibody-positive IPF subgroup (n = 138), consisting of patients with anti-neutrophil cytoplasmic antibody (ANCA) or autoantibodies that met the criteria for the IPAF serologic domain; (ii) a lone IPF subgroup (n = 374), consisting of the rest of the IPF patients., Measurements and Main Results: Autoantibody-positivity (HR 0.736, p = 0.043) was an independent risk factors for 5-year mortality on multivariable analysis in the overall IPF patients. In the autoantibody-positive IPF patients, use of glucocorticoid (not for management of acute exacerbation, HR 2.121, p = 0.019), use of immunomodulators (HR 0.310, p = 0.002), malignancy (HR 3.359, p = 0.002), baseline forced vital capacity (HR 0.974, p = 0.017), baseline diffusing capacity of the lung for carbon monoxide (HR 0.981, p = 0.041), and baseline 6-min walk test distance (HR 0.996, p = 0.002) were independent risk factors for 5-year mortality., Conclusions: Presence of ANCA or autoantibodies of the IPAF serologic domain in IPF patients is associated with better survival outcomes, and the use of immunomodulators is associated with superior survival outcomes., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objectives: In healthy individuals, increasing pulmonary blood flow during exercise also increases the % of the diffusing capacity of the lungs for carbon monoxide (DLCO%), but its evolution after lung resection is unknown. In this study, our goal was to measure changes in exercise DLCO% during the first 3 days after anatomical lung resection., Methods: We performed a prospective observational study on consecutive patients with non-small-cell lung cancer scheduled for anatomical resection, except pneumonectomy, during a 6-month period. Patients underwent measurement of the DLCO% by a single-breath technique adjusted by the concentration of haemoglobin-before and after standardized exercise the day before and 3 consecutive days after surgery. The delta (Δ) variation (basal versus exercise) was calculated. The number of functioning resected segments was calculated by bronchoscopy. Postoperative pain and pleural air leak were estimated using a visual analogue scale and graduated conventional pleural drainage systems, respectively, and their influence on ΔDLCO each postoperative day was evaluated by linear regression analysis., Results: Fifty-seven patients were included. The visual analogue scale of pain and pleural air leaks were not correlated to Δ values (model R2: 0.0048). The evolution of Δ values during 3 postoperative days showed a progressive recovery of values, but on the third day, DLCO% capacity during exercise was still impaired (P < 0.01), especially in patients who underwent a resection of more than 3 functioning segments., Conclusions: Physiological increase in DLCO% during exercise is still impaired on the third postoperative day in patients undergoing resection of more than 3 functioning pulmonary segments. This fact should be considered before discharging those patients after anatomical lung resection., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Rationale: Alterations of acid-base metabolism are an important outcome predictor in acute exacerbations of COPD, whereas sufficient metabolic compensation and adequate renal function are associated with decreased mortality. In stable COPD there is, however, only limited information on the combined role of acid-base balance, blood gases, renal and respiratory function on exacerbation risk grading., Methods: We used baseline data of the COPD cohort COSYCONET, applying linear and logistic regression analyses, the results of which were implemented into a comprehensive structural equation model. As most informative parameters it comprised the estimated glomerular filtration rate (eGFR), lung function defined via forced expiratory volume in 1 s (FEV 1 ), intrathoracic gas volume (ITGV) and (diffusing capacity for carbon monoxide (DLCO), moreover arterial oxygen content (CaO 2 ), partial pressure of oxygen (PaCO 2 ), base exess (BE) and exacerbation risk according to GOLD criteria. All measures were adjusted for age, gender, body-mass index, the current smoking status and pack years., Results: 1506 patients with stable COPD (GOLD grade 1-4; mean age 64.5 ± 8.1 y; mean FEV 1 54 ± 18 %predicted, mean eGFR 82.3 ± 16.9 mL/min/1.73 m 2 ) were included. BE was linked to eGFR, lung function and PaCO 2 and played a role as indirect predictor of exacerbation risk via these measures; moreover, eGFR was directly linked to exacerbation risk. These associations remained significant after taking into account medication (diuretics, oral and inhaled corticosteroids), whereby corticosteroids had effects on exacerbation risk and lung function, diuretics on eGFR, BE and lung function., Conclusion: Even in stable COPD acid-base metabolism plays a key integrative role in COPD risk assessment despite rather small deviations from normality. It partially mediates the effects of impairments in kidney function, which are also directly linked to exacerbation risk., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Patients with pulmonary hypertension (PH) due to chronic lung disease (Group 3 PH) have poor long-term outcomes. However, predictors of survival in Group 3 PH are not well described., Methods: We performed a cohort study of Group 3 PH patients (n = 143; mean age 65 ± 12 years, 52% female) evaluated at the University of Minnesota. The Kaplan-Meier method and Cox regression analysis were used to assess survival and predictors of mortality, respectively. The clinical characteristics and survival were compared in patients categorized by PH severity based on the World Health Organization (WHO) classification and lung disease etiology., Results: After a median follow-up of 1.4 years, there were 69 (48%) deaths. The 1-, 3-, and 5-year survival rates were 79%, 48%, and 31%. Age, coronary artery disease, atrial fibrillation, Charlson comorbidity index, serum N-terminal pro‒brain natriuretic peptide (NT-proBNP), creatinine, diffusion capacity of carbon monoxide (DLCO), total lung capacity, left ventricular ejection fraction, right atrial and right ventricular enlargement on echocardiography, cardiac index, and pulmonary vascular resistance (PVR) were univariate predictors of survival. On multivariable analysis, DLCO was the only predictor of mortality (adjusted hazard ratio [HR] for every 10% decrease in predicted value: 1.31 [95% confidence interval 1.12 to 1.47]; p = 0.003). The 1-/5-year survival by tertiles of DLCO was 84%/56%, 82%/44%, and 63%/14% (p = 0.01), respectively. On receiver-operating characteristic curve analysis, DLCO <32% of predicted had the highest sensitivity and specificity for predicting survival. The 1- and 5-year survival in patients with a DLCO ≥32% predicted was 84% and 60% vs 68% and 13% in patients with a DLCO <32% predicted (adjusted HR: 2.5 [95% confidence interval 1.3 to 5.0]; p = 0.007). Lung volumes and DLCO were not related, but higher PVR was strongly associated with reduced DLCO. There was increased mortality in interstitial lung disease‒PH as compared with chronic obstructive pulmonary disease‒PH, but PH severity based on the WHO classification did not alter survival., Conclusions: Low DLCO is a predictor of mortality and should be used to risk-stratify Group 3 PH patients., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Phenotyping of chronic obstructive pulmonary disease (COPD) with computed tomography (CT) is used to distinguish between emphysema- and airway-dominated type. The phenotype is reflected in correlations with lung function measures. Among these, the relative value of body plethysmography has not been quantified. We addressed this question using CT scans retrospectively collected from clinical routine in a large COPD cohort. Three hundred and thirty five patients with baseline data of the German COPD cohort COPD and Systemic Consequences-Comorbidities Network were included. CT scans were primarily evaluated using a qualitative binary emphysema score. The binary score was positive for emphysema in 52.5% of patients, and there were significant differences between the positive/negative groups regarding forced expiratory volume in 1 second (FEV 1 ), FEV 1 /forced vital capacity (FVC), intrathoracic gas volume (ITGV), residual volume (RV), specific airway resistance (sRaw), transfer coefficient (KCO), transfer factor for carbon monoxide (TLCO), age, pack-years, and body mass index (BMI). Stepwise discriminant analyses revealed the combination of FEV 1 /FVC, RV, sRaw, and KCO to be significantly related to the binary emphysema score. The additional positive predictive value of body plethysmography, however, was only slightly higher than that of the conventional combination of spirometry and diffusing capacity, which if taken alone also achieved high predictive values, in contrast to body plethysmography. The additional information on the presence of CT-diagnosed emphysema as conferred by body plethysmography appeared to be minor compared to the well-known combination of spirometry and CO diffusing capacity.

Objectives: To investigate whether morphometric complexity in the lung can predict survival and act as a new prognostic marker in patients with chronic obstructive pulmonary disease (COPD)., Methods: COPD (n = 302) patients were retrospectively reviewed. All patients underwent volumetric computed tomography and pulmonary function tests at enrollment (2005-2015). For complexity analysis, we applied power law exponent of the emphysema size distribution (D size ) as well as box-counting fractal dimension (D box3D ) analysis. Patients' survival at February 2017 was ascertained. Univariate and multivariate Cox proportional hazards analyses were performed, and prediction performances of various combinatorial models were compared., Results: Patients were 66 ± 6 years old, had 41 ± 28 pack-years' smoking history and variable GOLD stages (n = 20, 153, 108 and 21 in stages I-IV). The median follow-up time was 6.1 years (range: 0.2-11.6 years). Sixty-three patients (20.9%) died, of whom 35 died of lung-related causes. In univariate Cox analysis, lower D size and D box3D were significantly associated with both all-cause and lung-related mortality (both p < 0.001). In multivariate analysis, the backward elimination method demonstrated that D box3D , along with age and the BODE index, was an independent predictor of survival (p = 0.014; HR, 2.08; 95% CI, 1.16-3.71). The contributions of D size and D box3D to the combinatorial survival model were comparable with those of the emphysema index and lung-diffusing capacity., Conclusions: Low morphometric complexity in the lung is a predictor of survival in patients with COPD., Key Points: • A newly suggested method for quantifying lung morphometric complexity is feasible. • Morphometric complexity measured on chest CT images predicts COPD patients' survival. • Complexity, diffusing capacity and emphysema index contribute similarly to the survival model.

Chronic obstructive pulmonary disease (COPD) is a progressive and disabling disease that has been associated with aging. Several factors may potentially impair performance during exercise in elderly patients with COPD. This study was conducted to evaluate what characteristics related to lung function, peripheral muscle strength and endurance can predict the performance of elderly patients with COPD during cardiopulmonary exercise testing (CPET). Forty elderly patients with COPD underwent resting lung function tests, knee isokinetic dynamometry, and CPET. Three models were developed to explain the variability in peak oxygen uptake (VO(2) peak) after controlling for age as an independent confounder. The pulmonary function model showed the highest explained variance (65.6 %); in this model, ventilation distribution (p<0.001) and pulmonary diffusion (0.013) were found to be independent predictors. Finally, the models that included the muscle strength and endurance variables presented explained variances of 51 % and 57.4 %, respectively. In these models that involved muscular dysfunction, however, only the endurance variables were found to be independent predictors (p<0.05). In conclusion, ventilation distribution and pulmonary diffusion, but not the degree of airway obstruction, independently predict CPET performance in elderly patients with COPD. In addition, peripheral muscle endurance, but not strength, also predicts CPET performance in these subjects.

The single breath hold maneuver for measuring lung diffusing capacity for carbon monoxide (DLCO) and nitric oxide (DLNO) incorporates multiple sources of variability. This study examined how changes in intrathoracic pressure, inhalation time, and breath hold time affect DLCO, DLNO, alveolar-capillary membrane conductance (DmCO) and pulmonary capillary blood volume (Vc) at rest and during submaximal exercise. Thirteen healthy subjects (mean ± SD; age = 26 ± 3y) performed duplicate tests at rest and during submaximal exercise. DLCO and Vc were lower with a positive versus negative intrathoracic pressure during the breath hold at rest (DLCO: 22.2 ± 5.5 vs. 22.7 ± 5.5 ml/min/mmHg, p = 0.028; Vc: 46.5 ± 11.6 vs. 48.2 ± 11.7 ml, p = 0.018). However, during exercise, DLCO and Vc were higher with positive versus negative pressure (DLCO: 26.7 ± 5.5 vs. 25.7 ± 5.7 ml/min/mmHg, p = 0.014; Vc: 56.2 ± 12.6 vs. 53.9 ± 13.1 ml, p = 0.039). The inhalation time did not significantly affect DLCO, DLNO, DmCO or Vc. Short breath hold times (<4s) may yield high DLNO/DLCO ratios and non-physiologic DmCO values. The single breath hold maneuver is useful for evaluating gas transfer at rest and during exercise, however intrathoracic pressure, inhalation time, and breath hold time should be kept consistent between repeated tests., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Respiratory muscle weakness and its relation to other impairments in children with cerebral palsy (CP) have been shown in the latest studies. The effects of inspiratory muscle training (IMT) in this population have not been comprehensively investigated so far., Objectives: To investigate the effects of IMT on trunk control, pulmonary functions, respiratory muscle strength, daily living activities, exercise capacity and quality of life in children with CP., Methods: This was a prospective-randomized controlled trial. Twenty-five children with CP were randomly assigned to the treatment (n=13) or the control group (n=12). The treatment group received IMT at 30% of maximal inspiratory pressure (MIP) and the control group received sham therapy (5% of MIP) for 6 weeks. Also, both groups received routine conventional physical therapy (stretching, strengthening, and functional exercises, etc.) for 6 weeks. The primary outcome measure was trunk control. Secondary outcome measures were pulmonary function, respiratory muscle strength, daily living activities, functional exercise capacity and quality of life., Results: The treatment group had better outcome for trunk control (3.87, 95% CI 3.72-4.02). Also, respiratory muscle strength, daily living activities, functional exercise capacity and quality of life were significantly improved in the treatment group compared with controls. No improvements were observed in the pulmonary function test scores between the groups., Conclusion: Inspiratory muscle training improves trunk control, respiratory muscle strength, daily living activities, functional exercise capacity and quality of life in children with CP and it can be included in the physiotherapy and rehabilitation programs., (Copyright © 2018 Associação Brasileira de Pesquisa e Pós-Graduação em Fisioterapia. Publicado por Elsevier Editora Ltda. All rights reserved.)