Alpha-1-antitrypsin-deficiency is associated with lower cardiovascular risk: an approach based on federated learning.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an inflammatory multisystemic disease caused by environmental exposures and/or genetic factors. Inherited alpha-1-antitrypsin deficiency (AATD) is one of the best recognized genetic factors increasing the risk for an early onset COPD with emphysema. The aim of this study was to gain a better understanding of the associations between comorbidities and specific biomarkers in COPD patients with and without AATD to enable future investigations aimed, for example, at identifying risk factors or improving care. METHODS: We focused on cardiovascular comorbidities, blood high sensitivity troponin (hs-troponin) and lipid profiles in COPD patients with and without AATD. We used clinical data from six German University Medical Centres of the MIRACUM (Medical Informatics Initiative in Research and Medicine) consortium. The codes for the international classification of diseases (ICD) were used for COPD as a main diagnosis and for comorbidities and blood laboratory data were obtained. Data analyses were based on the DataSHIELD framework. RESULTS: Out of 112,852 visits complete information was available for 43,057 COPD patients. According to our findings, 746 patients with AATD (1.73%) showed significantly lower total blood cholesterol levels and less cardiovascular comorbidities than non-AATD COPD patients. Moreover, after adjusting for the confounder factors, such as age, gender, and nicotine abuse, we confirmed that hs-troponin is a suitable predictor of overall mortality in COPD patients. The comorbidities associated with AATD in the current study differ from other studies, which may reflect geographic and population-based differences as well as the heterogeneous characteristics of AATD. CONCLUSION: The concept of MIRACUM is suitable for the analysis of a large healthcare database. This study provided evidence that COPD patients with AATD have a lower cardiovascular risk and revealed that hs-troponin is a predictor for hospital mortality in individuals with COPD.

Identification of extracellular vesicle microRNA signatures specifically linked to inflammatory and metabolic mechanisms in obesity-associated low type-2 asthma.

RATIONALE AND OBJECTIVE: Plasma extracellular vesicles (EVs) represent a vital source of molecular information about health and disease states. Due to their heterogenous cellular sources, EVs and their cargo may predict specific pathomechanisms behind disease phenotypes. Here we aimed to utilize EV microRNA (miRNA) signatures to gain new insights into underlying molecular mechanisms of obesity-associated low type-2 asthma. METHODS: Obese low type-2 asthma (OA) and non-obese low type-2 asthma (NOA) patients were selected from an asthma cohort conjointly with healthy controls. Plasma EVs were isolated and characterised by nanoparticle tracking analysis. EV-associated small RNAs were extracted, sequenced and bioinformatically analysed. RESULTS: Based on EV miRNA expression profiles, a clear distinction between the three study groups could be established using a principal component analysis. Integrative pathway analysis of potential target genes of the differentially expressed miRNAs revealed inflammatory cytokines (e.g., interleukin-6, transforming growth factor-beta, interferons) and metabolic factors (e.g., insulin, leptin) signalling pathways to be specifically associated with OA. The miR-17-92 and miR-106a-363 clusters were significantly enriched only in OA. These miRNA clusters exhibited discrete bivariate correlations with several key laboratory (e.g., C-reactive protein) and lung function parameters. Plasma EV miRNA signatures mirrored blood-derived CD4+ T-cell transcriptome data, but achieved an even higher sensitivity in identifying specifically affected biological pathways. CONCLUSION: The identified plasma EV miRNA signatures and particularly the miR-17-92 and -106a-363 clusters were capable to disentangle specific mechanisms of the obesity-associated low type-2 asthma phenotype, which may serve as basis for stratified treatment development.

Surface proteome of plasma extracellular vesicles as mechanistic and clinical biomarkers for malaria.

PURPOSE: Malaria is a life-threatening mosquito-borne disease caused by Plasmodium parasites, mainly in tropical and subtropical countries. Plasmodium falciparum (P. falciparum) is the most prevalent cause on the African continent and responsible for most malaria-related deaths globally. Important medical needs are biomarkers for disease severity or disease outcome. A potential source of easily accessible biomarkers are blood-borne small extracellular vesicles (sEVs). METHODS: We performed an EV Array to find proteins on plasma sEVs that are differentially expressed in malaria patients. Plasma samples from 21 healthy subjects and 15 malaria patients were analyzed. The EV array contained 40 antibodies to capture sEVs, which were then visualized with a cocktail of biotin-conjugated CD9, CD63, and CD81 antibodies. RESULTS: We detected significant differences in the protein decoration of sEVs between healthy subjects and malaria patients. We found CD106 to be the best discrimination marker based on receiver operating characteristic (ROC) analysis with an area under the curve of > 0.974. Additional ensemble feature selection revealed CD106, Osteopontin, CD81, major histocompatibility complex class II DR (HLA-DR), and heparin binding EGF like growth factor (HBEGF) together with thrombocytes to be a feature panel for discrimination between healthy and malaria. TNF-R-II correlated with HLA-A/B/C as well as CD9 with CD81, whereas Osteopontin negatively correlated with CD81 and CD9. Pathway analysis linked the herein identified proteins to IFN-γ signaling. CONCLUSION: sEV-associated proteins can discriminate between healthy individuals and malaria patients and are candidates for future predictive biomarkers. TRIAL REGISTRATION: The trial was registered in the Deutsches Register Klinischer Studien (DRKS-ID: DRKS00012518).

Differential Regulation of Interferon Signaling Pathways in CD4+ T Cells of the Low Type-2 Obesity-Associated Asthma Phenotype.

In the era of personalized medicine, insights into the molecular mechanisms that differentially contribute to disease phenotypes, such as asthma phenotypes including obesity-associated asthma, are urgently needed. Peripheral blood was drawn from 10 obese, non-atopic asthmatic adults with a high body mass index (BMI; 36.67 ± 6.90); 10 non-obese, non-atopic asthmatic adults with normal BMI (23.88 ± 2.73); and 10 healthy controls with normal BMI (23.62 ± 3.74). All asthmatic patients were considered to represent a low type-2 asthma phenotype according to selective clinical parameters. RNA sequencing (RNA-Seq) was conducted on peripheral blood CD4+ T cells. Thousands of differentially expressed genes were identified in both asthma groups compared with heathy controls. The expression of interferon (IFN)-stimulated genes associated with IFN-related signaling pathways was specifically affected in obese asthmatics, while the gap junction and G protein-coupled receptor (GPCR) ligand binding pathways were enriched in both asthma groups. Furthermore, obesity gene markers were also upregulated in CD4+ T cells from obese asthmatics compared with the two other groups. Additionally, the enriched genes of the three abovementioned pathways showed a unique correlation pattern with various laboratory and clinical parameters. The specific activation of IFN-related signaling and viral infection pathways might provide a novel view of the molecular mechanisms associated with the development of the low type-2 obesity-associated asthma phenotype, which is a step ahead in the development of new stratified therapeutic approaches.

Surface Proteome of Plasma Extracellular Vesicles as Biomarkers for Pneumonia and Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

BACKGROUND: Community-acquired pneumonia (CAP) and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) represent a major burden of disease and death and their differential diagnosis is critical. A potential source of relevant accessible biomarkers are blood-borne small extracellular vesicles (sEVs). METHODS: We performed an extracellular vesicle array to find proteins on plasma sEVs that are differentially expressed and possibly allow the differential diagnosis between CAP and AECOPD. Plasma samples were analyzed from 21 healthy controls, 24 patients with CAP, and 10 with AECOPD . The array contained 40 antibodies to capture sEVs, which were then visualized with a cocktail of biotin-conjugated CD9, CD63, and CD81 antibodies. RESULTS: We detected significant differences in the protein decoration of sEVs between healthy controls and patients with CAP or AECOPD. We found CD45 and CD28 to be the best discrimination markers between CAP and AECOPD in receiver operating characteristic analyses, with an area under the curve >0.92. Additional ensemble feature selection revealed the possibility to distinguish between CAP and AECOPD even if the patient with CAP had COPD, with a panel of CD45, CD28, CTLA4 (cytotoxic T-lymphocyte-associated protein 4), tumor necrosis factor-R-II, and CD16. CONCLUSION: The discrimination of sEV-associated proteins is a minimally invasive method with potential to discriminate between CAP and AECOPD.

High eosinophil blood counts are associated with a shorter length of hospital stay in exacerbated COPD patients - a retrospective analysis.

BACKGROUND: In COPD, the course of the disease including morbidity and mortality is strongly associated with severe exacerbations. The current GOLD recommendations emphasize blood eosinophil counts as a marker for responsiveness to inhaled corticosteroids (ICS). Retrospective analyses from randomized clinical trials indicate a favorable response to systemic corticosteroids in exacerbated COPD patients with blood eosinophils > 2%, however data outside clinical trials are scarce. PATIENTS AND METHODS: We retrospectively evaluated data from 1007 cases of patients who were admitted to the University Medical Center Marburg between 01/2013 and 12/2018. All patients had been diagnosed with an acute exacerbation of COPD (ICD-10 J44.0/J44.1). Our analysis was based on a subgroup of 417 patients in whom a full blood cell count was obtained at the day of admission. Patients were predominantly male (63.3%), had a median age of 74 years (IQR 65 years - 83 years) and a median FEV1 of 1.03 l (42.6% predicted). We compared the hospital length of stay and other outcome parameters using established thresholds for the eosinophil blood cell count (100 and 300 eosinophils/µl and 2%). RESULTS: Patients with low eosinophils (< 2%, <100 cells/µl) had a longer median time in hospital (length of hospital stay - LOS) as compared to patients with high eosinophils (< 2%: 9.31 vs. ≥2%:7 days, and < 100/µl: 10 vs. 100-300/µl: 8 vs. > 300/µl: 7 days). The median CRP was higher in patients with low eosinophils as compared to the other groups (< 2%: 22.7 vs. ≥2%: 9 mg/dl and < 100: 25 vs. 100-300: 13.5 vs. > 300: 7.1 mg/dl). Time to re-hospitalization or time to death did not differ between strata of eosinophils. Sensitivity analysis in a subgroup of patients in which pneumonia was excluded by chest x-ray did not significantly alter the results. CONCLUSION: The results support the hypothesis that patients with severe COPD exacerbations and elevated blood eosinophil counts respond better to systemic corticosteroid treatment than patients with a non-eosinophilic exacerbation.

Blood eosinophil count and airway epithelial transcriptome relationships in COPD versus asthma.

BACKGROUND: Whether the clinical or pathophysiologic significance of the "treatable trait" high blood eosinophil count in COPD is the same as for asthma remains controversial. We sought to determine the relationship between the blood eosinophil count, clinical characteristics and gene expression from bronchial brushings in COPD and asthma. METHODS: Subjects were recruited into a COPD (emphysema versus airway disease [EvA]) or asthma cohort (Unbiased BIOmarkers in PREDiction of respiratory disease outcomes, U-BIOPRED). We determined gene expression using RNAseq in EvA (n = 283) and Affymetrix microarrays in U-BIOPRED (n = 85). We ran linear regression analysis of the bronchial brushings transcriptional signal versus blood eosinophil counts as well as differential expression using a blood eosinophil > 200 cells/µL as a cut-off. The false discovery rate was controlled at 1% (with continuous values) and 5% (with dichotomized values). RESULTS: There were no differences in age, gender, lung function, exercise capacity and quantitative computed tomography between eosinophilic versus noneosinophilic COPD cases. Total serum IgE was increased in eosinophilic asthma and COPD. In EvA, there were 12 genes with a statistically significant positive association with the linear blood eosinophil count, whereas in U-BIOPRED, 1197 genes showed significant associations (266 positive and 931 negative). The transcriptome showed little overlap between genes and pathways associated with blood eosinophil counts in asthma versus COPD. Only CST1 was common to eosinophilic asthma and COPD and was replicated in independent cohorts. CONCLUSION: Despite shared "treatable traits" between asthma and COPD, the molecular mechanisms underlying these clinical entities are predominately different.

Effects of Vibration Training in Interstitial Lung Diseases: A Randomized Controlled Trial.

BACKGROUND: Numerous studies have reported positive effects of exercise training in patients with interstitial lung disease (ILD) on physical capacity and quality of life. However, evidence is rare on the effects of specific forms of training and further pathophysiological mechanisms in these patients. OBJECTIVES: In this multicenter study we aimed to explore the clinical effects of whole-body vibration training (WBVT) in patients with ILD on various outcome measures, including proinflammatory cytokines and myostatin. METHODS: We randomly assigned 26 patients with different forms of multidisciplinary confirmed fibrotic ILDs either to the WBVT group (n = 11; 55% male, 61 ± 14 years old, forced vital capacity 83.2 ± 29.3% predicted, 6-min walking distance [6MWD] 478 ± 79 m) performing 3 months of a standardized training (3 times per week), or to a control training group (CTG, n = 15; 60% male, 63 ± 9 years old, FVC 74.6 ± 20.5% predicted, 6MWD 455 ± 85 m) performing sham WBV training. Training in the two groups was performed on a GalileoTM vibration plate (6-20 vs. 5 Hz). The functional assessments before and after the intervention period included pulmonary function, 6MWD test, chair rise test, ultrasonographic measurement of quadriceps muscle thickness (cross-sectional area), quality of life questionnaires, and serum samples. RESULTS: We observed a significant increase in 6MWD (∆Training = 30 m [12-67], p = 0.024) and a decrease of myostatin (∆Training = -465 pg/mL [-713 to -166], p = 0.008) in the WBVT group. In contrast, no significant differences were observed in the CTG. CONCLUSIONS: The present study demonstrates that WBVT is able to significantly increase 6MWD and decrease myostatin in patients with fibrotic ILDs. Therefore, WBVT seems to be a beneficial and feasible training modality in ILD patients. Clinical Trial Registry: German Clinical Trials Registry (DRKS00012930).

Proviral MicroRNAs Detected in Extracellular Vesicles From Bronchoalveolar Lavage Fluid of Patients With Influenza Virus-Induced Acute Respiratory Distress Syndrome.

Influenza A virus (IAV) causes severe respiratory infections and alveolar epithelial damage resulting in acute respiratory distress syndrome (ARDS). Extracellular vesicles (EVs) have been shown to mediate cellular crosstalk in inflammation by transfer of microRNAs (miRNAs). In this study, we found significant changes in the miRNA composition of EVs in the bronchoalveolar lavage fluid from patients with IAV-induced ARDS. Among the 9 significantly deregulated microRNAs, miR-17-5p was upregulated in patients' BALF and in EVs of IAV-infected lung epithelial cells (A549). In these cells, transfer of miR-17-5p strongly downregulated expression of the antiviral factor Mx1 and significantly enhanced IAV replication.

Real world evaluation of a novel lateral flow assay (AlphaKit® QuickScreen) for the detection of alpha-1-antitrypsin deficiency.

BACKGROUND: Alpha-1-Antitrypsin (AAT) deficiency (AATD) is a hereditary disorder that manifests primarily as pulmonary emphysema and liver cirrhosis. The clinically most relevant mutation causing AATD is a single nucleotide polymorphism Glu342Lys (Z-mutation). Despite the recommendation to test every COPD patient, the condition remains severely underdiagnosed with a delay of several years between first symptoms and diagnosis. The Grifols' AlphaKit® QuickScreen is a novel qualitative point-of-care (POC) in vitro screening test developed for the detection of the Z AAT protein in capillary whole blood. The objective of this prospective, international, multi-center, diagnostic, interventional real-world study was to assess the performance of this device for the detection of AATD in test-naïve COPD patients. METHODS: 1044 test-naïve COPD patients were recruited from 9 centers in Spain and 10 centers in Germany, ranging from primary to tertiary care. To evaluate the performance of the test, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated compared with the gold standard (genotyping). RESULTS: Genotyping and phenotyping of all 1019 evaluable samples revealed 4.12% of patients as carriers of at least one Z-allele, while 0.29% carried the homozygous genotype Pi*ZZ. The evaluation of the test's ability to detect the PiZ protein yielded the following results: specificity 97.8%, sensitivity 73.8%, negative predictive value 98.9%, and positive predictive value 58.5%. All false negatives (n = 11) were heterozygote Pi*MZ samples. CONCLUSIONS: The tested device can be used as an appropriate tool to exclude AATD in primary care and in the overall COPD population, except in patients with a high a-priori- probability of AATD.

A GATA3-specific DNAzyme attenuates sputum eosinophilia in eosinophilic COPD patients: a feasibility randomized clinical trial.

BACKGROUND: A subset of COPD-patients presents with eosinophilic airway inflammation. While treatment of asthmatic patients with the GATA3-specific DNAzyme SB010 attenuated sputum eosinophilia after allergen challenge, this specific treatment has not been evaluated in patients with COPD. Our objective was to evaluate the feasibility and safety of inhaled SB010 in COPD patients with sputum eosinophilia. METHODS: We conducted a randomized, double-blind, placebo-controlled, multicentre clinical trial in COPD-patients with sputum eosinophilia (≥2.5% non-squamous cells). Patients inhaled 10 mg SB010 bid or matching placebo via the controlled inhalation system AKITA2 APIXNEB for 28 days. Endpoints included the feasibility of the study (primary), patient's safety, sputum eosinophils, FENO, lung function, symptoms, and biomarkers. The study was registered in the German Clinical Trials Register: DRKS00006087. RESULTS: One hundred thirty patients were screened, 23 patients were randomized (FEV1 49.4 ± 11.5%; sputum eosinophils 8.0 ± 8.4%) and 19 patients completed the study (10 placebo, 9 SB010. After 28 days, SB010 decreased the relative sputum eosinophil count (p = 0.004) as compared to no changes in placebo-treated patients. FENO, lung function, and symptoms were not affected significantly. We found an increase in blood IFN-γ (p = 0.02) and a trend to lower IL-5 levels in patients treated with SB010. SB010 was safe and well tolerated. Thirty five AEs (22 SB010, 13 placebo including 1 SAE) were observed with 3 AEs in each group judged to be possibly treatment-related. CONCLUSION: In patients with eosinophilic COPD, sputum eosinophils could be reduced by inhalation of SB010. Long-term studies are needed to demonstrate clinical efficacy.

The prevalence of diagnosed α1-antitrypsin deficiency and its comorbidities: results from a large population-based database.

α1-Antitrypsin deficiency (AATD) is a genetically determined disorder that is associated with different clinical manifestations. We aimed to assess the prevalence of diagnosed AATD and its comorbidities using a large healthcare database.In this retrospective longitudinal observational study, we analysed data from 4 million insurants. Using International Classification of Diseases revision 10 (ICD-10) codes, we assessed the prevalence, comorbidities and healthcare utilisation of AATD patients (E88.0 repeatedly coded) relative to non-AATD patients with chronic obstructive pulmonary disease (COPD), emphysema or asthma.In our study population, we identified 673 AATD patients (590 aged ≥30 years), corresponding to a prevalence of 23.73 per 100 000 in all age groups and 29.36 per 100 000 in those ≥30 years. Based on the number of AATD cases detected in the sample size (673 out of 2 836 585), we extrapolated that there were 19 162 AATD cases in Germany during the years studied. AATD patients had a higher prevalence of arterial hypertension, chronic kidney disease and diabetes relative to non-AATD asthma or emphysema patients. When compared to non-AATD COPD patients, AATD patients had significantly more consultations and more frequent and longer hospitalisations.Our data strengthen the assumption that AATD is associated with a variety of other diseases. Healthcare utilisation appears to be higher among AATD patients as compared to patients with non-AATD-related obstructive lung diseases.

Efficacy and safety of direct switch to indacaterol/glycopyrronium in patients with moderate COPD: the CRYSTAL open-label randomised trial.

BACKGROUND: Dual bronchodilation combining a long-acting ß2-agonist (LABA) and a long-acting muscarinic antagonist (LAMA) is the preferred choice of treatment recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 guidelines for the management of patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). The once-daily (q.d.) fixed-dose combination (FDC) of LABA, indacaterol 110 µg and LAMA, glycopyrronium 50 µg (IND/GLY 110/50 µg q.d.) demonstrated superior improvements in lung function, dyspnoea and overall health status and better tolerability against LABA or LAMA monotherapies and combination of LABA and inhaled corticosteroid (ICS) in more than 11,000 patients with moderate-to-severe COPD in several randomised controlled clinical trials. METHODS: The CRYSTAL study was the first, 12-week, randomised, open-label trial that evaluated the efficacy and safety of a direct switch from previous treatments to IND/GLY 110/50 µg q.d. on lung function and dyspnoea in patients with moderate COPD and a history of up to one exacerbation in the previous year. Patients were divided into 2 groups according to their background therapy and symptom scores and were randomised (3:1) to IND/GLY or to continue with their previous treatments. RESULTS: The study included 4389 randomised patients, of whom 2160 were in groups switched to IND/GLY (intention-to-treat population). The effect of IND/GLY was superior to LABA + ICS on trough forced expiratory volume in 1 s (FEV1; treatment difference, Δ = +71 mL) and transition dyspnoea index (TDI; [Δ = 1.09 units]), and to LABA or LAMA on trough FEV1 (Δ = +101 mL) and a TDI (Δ = 1.26 units). Improvements in health status and lower rescue medication use were also observed with IND/GLY. The safety profile of the study medication was similar to that observed in previous studies. CONCLUSIONS: IND/GLY demonstrated superior improvements in lung function and dyspnoea after direct switch from previous treatments. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT01985334 .

Costs and health-related quality of life in Alpha-1-Antitrypsin Deficient COPD patients.

BACKGROUND: Alpha-1-Antitrypsin Deficiency (AATD) is an economically unexplored genetic disease. METHODS: Direct and indirect costs (based on self-reported information on healthcare utilization) and health-related quality of life (HRQL, as assessed by SGRQ, CAT, and EQ-5D-3 L) were compared between 131 AATD patients (106 with, 25 without augmentation therapy (AT)) and 2,049 COPD patients without AATD participating in the COSYCONET COPD cohort. The medication costs of AT were excluded from all analyses to reveal differences associated with morbidity profiles. The association of AATD (with/without AT) with costs or HRQL was examined using generalized linear regression modelling (GLM) adjusting for age, sex, GOLD grade, BMI, smoking status, education and comorbidities. RESULTS: Adjusted mean direct annual costs were €6,099 in AATD patients without AT, €7,117 in AATD patients with AT (excluding costs for AT), and €7,460 in COPD patients without AATD. AATD with AT was significantly associated with higher outpatient (+273%) but lower inpatient (-35%) and medication costs (-10%, disregarding AT) compared with COPD patients without AATD. There were no significant differences between groups regarding indirect costs and HRQL. CONCLUSION: Apart from AT costs, AATD patients tended to have lower, though not significant, overall costs and similar HRQL compared to COPD patients without AATD. AT was not associated with lower costs or higher HRQL. TRIAL REGISTRATION: NCT01245933.

Cardiovascular risk in patients with alpha-1-antitrypsin deficiency.

BACKGROUND: Alpha-1-antitrypsin deficiency (AATD) is a rare inherited condition caused by mutations of the SERPINA1 gene that is associated with the development of a COPD like lung disease. The comorbidities in patients with AATD-related lung diseases are not well defined. The aim of this study was to analyze the clinical phenotype of AATD patients within the German COPD cohort study COSYCONET ("COPD and SYstemic consequences-COmorbidities NETwork") cohort focusing on the distribution of comorbidities. METHOD AND RESULTS: The data from 2645 COSYCONET patients, including 139 AATD patients (110 with and 29 without augmentation therapy), were analyzed by descriptive statistics and regression analyses. We found significantly lower prevalence of cardiovascular comorbidities in AATD patients as compared to non-AATD COPD patients. After correction for age, pack years, body mass index, and sex, the differences were still significant for coronary artery disease (p = 0.002) and the prevalence of peripheral artery disease as determined by an ankle-brachial-index <= 0.9 (p = 0.035). Also the distribution of other comorbidities such as bronchiectasis differed between AATD and non-deficient COPD. CONCLUSION: AATD is associated with a lower prevalence of cardiovascular disease, the underlying mechanisms need further investigation.

Work of Breathing in Fixed and Pressure Relief Continuous Positive Airway Pressure (C-Flex™): A post hoc Analysis.

BACKGROUND: Expiratory pressure relief continuous positive airway pressure (pressure relief CPAP; C-Flex™) causes increases in inspiratory duty cycle and shortening of expiratory time. It has been suggested that these changes are caused by an increase in work of breathing. OBJECTIVES: We studied the effects of C-Flex on work of breathing and intrinsic positive end-expiratory pressure as compared to fixed CPAP. METHODS: Work of breathing was analyzed in 24 patients with obstructive sleep apnea during treatment with fixed CPAP and C-Flex with 3 different pressure relief settings in a randomized order during rapid-eye-movement (REM) and non-REM sleep. Work of breathing was assessed on a breath-by-breath basis using a piezoelectric esophageal pressure catheter and a pneumotachograph for measuring airflow. RESULTS: We found there was no increase in inspiratory work of breathing observed using C-Flex compared to fixed CPAP. Instead, we found a linear decrease in inspiratory work of breathing with increasing pressure relief, with a mean difference of 1.22 J/min between CPAP and maximum pressure release (C-Flex 3; 90% of the value with nasal CPAP); however, the decrease was not statistically significant. The decrease in inspiratory work of breathing associated with C-Flex has a significant inverse correlation with BMI. CONCLUSIONS: The C-Flex technology does not change work of breathing but shows a tendency towards a reduction of inspiratory work of breathing in patients with a lower BMI using higher C-Flex. The effect is probably caused by diminishing airway resistance generated by the positive end-expiratory pressure. Our findings may lead to additional fields of application of the C-Flex technology, such as chronic obstructive pulmonary disease or muscular dystrophy.

Benefits of High-Intensity Exercise Training to Patients with Chronic Obstructive Pulmonary Disease: A Controlled Study.

BACKGROUND: Various exercise training programs are used for patients with chronic obstructive pulmonary disease (COPD) of different severity. OBJECTIVES: To investigate the impact of individualized high-intensity training on exercise capacity with COPD. METHODS: A total of 49 patients agreed to participate. Of these, 31 were assigned to the training group and 18 served as controls. The training group exercised twice a week for 90 min with consecutively increasing loads. At the time of enrollment (T0), as well as after 3 (T1) and 6 (T2) months, a 6-min walk test (6-MWT) was performed and data on health-related quality of life, femoral muscle thickness, and various serum markers were obtained. RESULTS: The training group improved in their 6-MWT results (T0 = 407 ± 152 m vs. T1 = 459 ± 127 m, p = 0.002, vs. T2 = 483.2 ± 130.1 m, p = 0.004), in their cross-sectional area of the musculus rectus femoris (T0 = 6.2 ± 1.2 cm2 vs. T1 = 6.9 ± 1.2 cm2, p = 0.003, vs. 7.5 ± 1.6 cm2, p = 0.002), and in their St. George's Respiratory Questionnaire (SGRQ) score (T0 = 43.3 ± 18.0 vs. T1 = 36.0 ± 18.4, p = 0.001, vs. T2 = 34.7 ± 18. 0, p = 0.004). Serum levels of myostatin, irisin, resistin, and α-Klotho did not change significantly within the training period. Of note, the exercise group showed an inverse relationship between serum levels of resistin and those of α-Klotho after 6 months (r = -0.608, p = 0.021). CONCLUSIONS: COPD patients undergoing an individualized, structured, high-intensity training program improved their exercise capacity, gained muscle mass, and improved their quality of life.

Physician perspectives on the burden and management of asthma in six countries: The Global Asthma Physician Survey (GAPS).

BACKGROUND: Despite recognition of asthma as a growing global issue and development of global guidelines, asthma treatment practices vary between countries. Several studies have reported patients' perspectives on asthma control. This study presents physicians' perspectives and strategies for asthma management. METHODS: Physicians seeing ≥4 adult patients with asthma per month in Australia, Canada, China, France, Germany, and Japan were surveyed (N=1809; ≈300 per country). A standardised questionnaire was developed for this study and administered by telephone, online or face-to-face. Statistics were weighted to account for the sampling scheme. RESULTS: Physicians estimated that 71% of their adult patients received maintenance medication, with adherence monitored by 76-97% of physicians. Perceived major barriers to patient adherence included: patients taking treatment as needed; acceptance of symptoms; and patients not perceiving treatment benefits. Written action plans (37%) and technology (15%) were seldom employed by physicians to aid patients' asthma management. Physicians rarely (10%) used validated patient-reported questionnaires to monitor asthma control, instead monitoring selected symptoms, exacerbations, and/or lung function measurements. Awareness of single maintenance and reliever therapy (SMART/MART) varied among countries (56-100%); although most physicians (72%) had prescribed SMART/MART, the majority (91%) co-prescribed a short-acting bronchodilator at least some of the time. CONCLUSIONS: These results show that physicians generally do not employ standardised tools to monitor asthma control or to manage its treatment and that despite high awareness of SMART/MART, the strategy appears to be commonly misapplied. Better education for patients and physicians is required to improve asthma management and resulting patient outcomes.

Alpha-1-Antitrypsin Deficiency: Disease Management and Learning from Studies.

Alpha-1-antitrypsin deficiency (AATD) is one of the most frequent genetic causes of liver and lung diseases. Despite its known association with chronic obstructive pulmonary disease (COPD), AATD is largely unrecognised and underdiagnosed. Cases of AATD exist within every COPD or spirometry population but must be actively investigated. AATD is a laboratory diagnosis that must be confirmed by a blood test. A number of clinical 'clues' can raise suspicion of AATD, potentially facilitating earlier diagnosis and initiation of appropriate treatment. Alpha-1-antitrypsin augmentation therapy has a clear role in patients with severe AATD and a FEV1 ≤65% predicted. Emerging evidence suggests that attenuating the decline in lung density may prolong the time to respiratory failure.