COPD: Rethinking Patient Management - How to Approach a Challenging Patient Group Successfully.

In comparison to other chronically ill people, patients suffering from chronic obstructive pulmonary disease (COPD) have many additional difficulties to face and conquer. Due to the contribution of avoidable causes of their illness ("smokers' lung"), society holds people with COPD responsible for their disease, which in return often leads to stigmatization and social isolation. In addition, COPD patients commonly belong to a less privileged social class, own a low socioeconomic status, and lower education. Their physical symptoms are easily observable and - by employing moderate adherence - treatable. Nonetheless, the influence of COPD on a patient's psyche often plays an overly prominent role during therapy. "There is only half a patient laying on the examination table," a revelation that sums up the current state of COPD research and the result of the expert meeting "Luftschlösser" ("castles in the clouds"), which took place in spring 2018. Within the limits of the meeting, participants identified practically applicable approaches aiming to enhance the patient management of this challenging patient group. These considerations are supposed to support healthcare professionals in their daily work and aim to improve the therapy as well as the outcome for COPD patients.

Myocardial homing of mesenchymal stem cells following intrapericardial application and amplification by inflammation - an experimental pilot study.

Recent studies demonstrated potential effects of stem cells on cardiac function in heart failure. However, influences of the technique of application remained undetermined. In the present study, the pericardial sac was used as depot for fluorescent-labeled mesenchymal stem cells in rats. To evaluate influences of inflammation on cell homing, a sterile pericarditis was induced by talc. It is shown that intrapericardial stem cell application is sufficient to provide myocardial penetration. The extent of homing was amplified by inflammation in a talc-induced pericarditis.

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.

European pathways of care in Alpha-1 Antitrypsin deficiency.

BACKGROUND: Despite initiatives to improve awareness and treatment of alpha-1 antitrypsin deficiency (AATD), country-level processes for AATD management remain unclear. OBJECTIVES: We conducted a pan-European physician survey to clarify the pathways for AATD care. METHOD: Professionals involved in AATD diagnosis and/or management completed a web-based survey on the detection, evaluation, monitoring and treatment of AATD and the utilisation of European reference network centres for rare lung diseases (ERN-LUNG). RESULTS: Surveys were completed by 166 physicians from 18 European countries. Overall, 25 % of respondents were unaware of local specific AATD testing guidelines, and most (72 %) had referred <10 patients to a specialist. However, there was general agreement regarding reasons for referral and the types of patient referred. Approaches to AATD testing are heterogenous, with significant between-country differences in the sample testing and collection methods used. Alpha-1 antitrypsin therapy is most frequently monitored using spirometry (98 %), gas transfer (79 %) or symptoms (82 %). Overall, 28 % of respondents were unfamiliar with ERN-LUNG centres, with Portugal and Spain reporting the lowest familiarity, and use of these centres for patient evaluation varied widely. However, engagement with ERN-LUNG centres was widely agreed to be useful when it did occur (especially in Italy and Poland). Little cross-border use of ERN-LUNG centres for patient testing/evaluation was reported. CONCLUSIONS: European care pathways for AATD are largely uniform, but with notable heterogeneity in testing approaches and a need for education and standardisation. Familiarity with and use of ERN-LUNG AATD services is variable, and increased awareness of these services is warranted.

Detection of microorganisms in exhaled breath condensate during acute exacerbations of COPD.

BACKGROUND AND OBJECTIVE: One hallmark of COPD is colonization and infection of the lung. Acute exacerbations of COPD (AECOPD) are acute deteriorations of the chronic disease and are associated with a change of the pulmonary microbial balance. The collection of exhaled breath condensate (EBC) can be used to non-invasively determine markers of lung disease. The aim of the present study was to compare the results of assays based on the detection of microbial nucleic acids from EBC and from spontaneous sputum in patients with AECOPD. METHODS: EBC and sputa of 29 adults with AECOPD were obtained. Isolated DNA or RNA were used as starting material for the PCR assays to detect Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae, Chlamydia pneumoniae, influenza viruses (AH 1, AH 3) and respiratory syncytial virus. RESULTS: Bacterial or viral nucleic acids were identified in 14 EBC and 21 sputa from 29 patients. Results from EBC did not correlate well with those from sputum. Viral and S. pneumoniae nucleic acids were detected only in sputum, whereas L. pneumophila DNA was only found in EBC. In three EBC and 10 sputa nucleic acids of more than one microorganism was detected. CONCLUSIONS: Bacterial nucleic acids can be identified in EBC of COPD patients with exacerbations. The results obtained from EBC and sputum did not correlate well.

Acute and chronic effects of smoking on inflammation markers in exhaled breath condensate in current smokers.

BACKGROUND: Long-term cigarette smoking is associated with pulmonary inflammation, but the acute effects of smoking have been less well studied. Analysis of the exhaled breath condensate (EBC) can provide noninvasive markers that might be indicative of inflammation. OBJECTIVES: The aim of the study was to determine whether the pH , electrical conductivity and the levels of ammonium and interleukin 8 (IL-8) of EBC were altered in smokers and whether they changed after smoking a single cigarette. METHODS: We included 19 healthy nonsmokers (controls), 29 asymptomatic smokers, 10 patients with stable chronic obstructive pulmonary disease (COPD) [Global Initiative for Chronic Obstructive Lung Disease stages (GOLD) stages II-III], and 10 patients with exacerbated COPD. In 13 smokers, EBC was also analyzed before and after smoking. EBC was obtained during 10 min tidal breathing with a cooled RTube. pH was determined after deaeration with argon. RESULTS: Acute smoking did not alter the pH or ammonium and IL-8 levels, but raised conductivity. As in COPD patients, the pH was significantly decreased in chronic smokers with a history of at least 10 pack-years compared to controls. CONCLUSIONS: EBC can be used to detect the acute and chronic effects of smoking. The increased conductivity of EBC after smoking suggests acute inflammatory effects. The reduced pH in chronic smokers shows cigarette-induced inflammation.

Impact of a smartphone application (KAIA COPD app) in combination with Activity Monitoring as a maintenance prOgram following PUlmonary Rehabilitation in COPD: the protocol for the AMOPUR Study, an international, multicenter, parallel group, randomized, controlled study.

BACKGROUND: Increasing physical activity (PA) is considered to be an important factor for the efficient management of chronic obstructive pulmonary disease (COPD). Successful methods required to achieve improvements in PA following pulmonary rehabilitation (PR), however, are rarely reported. Therefore, we will conduct this trial to evaluate the effectiveness of using a COPD management program delivered to the patient via the KAIA COPD app, a mobile medical application, after the completion of PR. METHODS: This is the protocol for a randomized, controlled, open-label, multicentered trial that will be carried out at inpatient PR hospital centers in Germany and Switzerland. The interventions will involve the use of the KAIA COPD app program (Arm 1) or an active comparator, i.e., usual care (Arm 2). Patients completing an in-hospital PR program and consenting to participate in the study will be screened with the inclusion and exclusion criteria and enrolled in the study. After fulfilling the screening requirements, the patients will be randomized into one of the two arms with parallel group assignment in a 1:1 ratio. The training program will be delivered to the participants grouped in Arm 1 via the KAIA COPD app and to participants grouped in Arm 2 via the regular recommendations or standard of care by the PI. In total, 104 participants will be included in the trial. The treatment period will last for 24 weeks. Electronic versions of questionnaires will be used to collect patient-reported assessments remotely. The primary outcome measure is the change in physical activity of the intervention group in comparison to the control group, measured over 1 week as the mean steps per day with a Polar A 370 activity tracker, from baseline (end of PR) to the 6-month follow-up. The secondary outcome measures are functional exercise capacity, health status, sleep quality, exacerbation rate, and depression and anxiety symptoms assessed at several intervals. DISCUSSION: This study seeks to prove the effects of the KAIA COPD mobile application in COPD patients after PR. The app offers educational, exercise training plus activity monitoring and motivational programs that can be easily implemented in the patient's home setting, enabling patients to maintain the effects that are typically elicited in the short term after pulmonary rehabilitation for the long term. TRIAL REGISTRATION: German Clinical Trials Register ( DRKS00017275 ). Protocol version 2.0 dated 3 June 2019.

Alpha 1 antitrypsin to treat lung disease in alpha 1 antitrypsin deficiency: recent developments and clinical implications.

Alpha 1 antitrypsin deficiency is a hereditary condition characterized by low alpha 1 proteinase inhibitor (also known as alpha 1 antitrypsin [AAT]) serum levels. Reduced levels of AAT allow abnormal degradation of lung tissue, which may ultimately lead to the development of early-onset emphysema. Intravenous infusion of AAT is the only therapeutic option that can be used to maintain levels above the protective threshold. Based on its biochemical efficacy, AAT replacement therapy was approved by the US Food and Drug administration in 1987. However, there remained considerable interest in selecting appropriate outcome measures that could confirm clinical efficacy in a randomized controlled trial setting. Using computed tomography as the primary measure of decline in lung density, the capacity for intravenously administered AAT replacement therapy to slow and modify the course of disease progression was demonstrated for the first time in the Randomized, Placebo-controlled Trial of Augmentation Therapy in Alpha-1 Proteinase Inhibitor Deficiency (RAPID) trial. Following these results, an expert review forum was held at the European Respiratory Society to discuss the findings of the RAPID trial program and how they may change the landscape of alpha 1 antitrypsin emphysema treatment. This review summarizes the results of the RAPID program and the implications for clinical considerations with respect to diagnosis, treatment and management of emphysema due to alpha 1 antitrypsin deficiency.

Wall stress determines systolic and diastolic function--Characteristics of heart failure.

INTRODUCTION: Heart failure can be caused by systolic or diastolic dysfunction. Diagnosing diastolic dysfunction remains challenging, although several criteria have been identified. Ventricular wall stress is crucially involved. It is hypothesized whether increased end-diastolic and end-systolic ventricular wall stress as assessed by the wall stress index is associated with cardiac dysfunction and thus provide novel diagnostic criteria. METHODS: 1050 consecutive patients with suspected non-ischemic heart failure covering a broad spectrum from normal to severely impaired cardiac function were observed. Cardiac magnetic resonance imaging was performed to assess left ventricular (LV) volumes, myocardial mass, peak ejection (PER) and filling rate (PFR). RESULTS: A reduced PFR was found in 348 patients (33.1%), which resulted from 275 of 422 patients (65.2%) with reduced and from 73 of 628 patients (11.6%) with preserved LVEF (p<0.0001). Increased LV volume and mass was correlated with reduced PER and PFR (p<0.0001). Increased end-diastolic wall stress was the strongest predictor of a reduced PER (OR 4.5 [2.6 to 7.8], p<0.0001) and increased end-systolic wall stress predicted a reduced PFR (OR 1.2 [1.1 to 1.3], p<0.0001). Increased end-systolic wall stress was correlated with increased pulmonary pressure (p<0.0001). Normal end-systolic wall stress<18 kPa had a favorable predictive value for the absence of an impaired filling and increased pulmonary capillary pressure. CONCLUSION: Increased end-diastolic wall stress precedes a reduced ventricular ejection rate and increased end-systolic wall stress determines an impaired diastolic filling. It is thus suggested to add assessment of ventricular wall stress as diagnostic criterion of heart failure.

From Heart Failure to Highly Unsaturated Fatty Acid Deficiency and Vice Versa: Bidirectional Heart and Liver Interactions.

BACKGROUND: In several trials, beneficial prognostic effects of highly unsaturated fatty acids (HUFAs) in heart failure were shown. Because other studies showed no incremental benefit in nearly preserved cardiac function, the question arises, whether the degree of cardiac dysfunction is involved. It is hypothesized that increased left ventricular (LV) wall stress affects the endogenous hepatic HUFA metabolism, which in turn exhibits adverse cardiac consequences. METHODS: Cardiac magnetic resonance imaging was performed in 30 patients with suspected cardiomyopathy. The serum fatty acid profile was assessed using gas chromatography/mass spectrometry. RESULTS: Docosahexaenoic acid (DHA; P = 0.002) and eicosapentaenoic acid (EPA; by trend) levels were decreased in patients with reduced LV ejection fraction (≤ 50%) or LV dilatation (≥ 90 mL/m(2)). Decreased DHA (P = 0.003) and EPA (P = 0.022) levels were associated with a reduced LV ejection fraction. Decreased DHA level was correlated with increased end-diastolic (P = 0.047) and end-systolic LV wall stress (P = 0.001). Pseudocholinesterase activity was inversely correlated with end-diastolic (P = 0.020) and end-systolic LV wall stress (P = 0.025). CONCLUSIONS: DHA level was significantly reduced in heart failure. Similar, but less pronounced effects were found for EPA and arachidonic acid by trend. Increased LV wall stress was correlated with a reduced DHA level. Increased LV wall stress exhibits various adverse consequences (eg, increased oxygen consumption, favouring of arrhythmias, and an unfavourable remodelling). The increase of wall stress was paralleled by reduced HUFA level. Increased LV wall stress was correlated with reduced pseudocholinesterase, which is suggestive of hepatic congestion (ie, a cardiohepatic syndrome, involved in the altered fatty acid profile in heart failure) and has major consequences regarding the dose-efficacy of HUFA treatment.

Alpha-1 antitrypsin is elevated in exhaled breath condensate and serum in exacerbated COPD patients.

BACKGROUND: Exacerbations of chronic obstructive pulmonary disease (COPD) significantly contribute to COPD-related morbidity. Diagnosis of COPD exacerbations may be improved by analyzing biomarkers such as alpha-1 antitrypsin (AAT). AAT is an acute-phase protein and inhibitor of neutrophil elastase. Deficiency of AAT may result in early-onset respiratory symptoms. Measurement of exhaled breath condensate (EBC) is a noninvasive method to investigate biomarkers present in the epithelial lining fluid, such as AAT. OBJECTIVE: To investigate whether AAT can be detected and quantified in EBC and to compare AAT levels in the EBC of healthy controls, patients with COPD, and during exacerbations of COPD. METHODS: EBC from 10 healthy controls, 17 subjects with COPD, and 18 subjects with exacerbations of COPD was collected with the RTube™ device. AAT from EBC and serum were quantified by ELISA. RESULTS: AAT in EBC was detectable in every individual. Patients with exacerbations of COPD had significantly increased AAT values (mean, 514.33 pg/mL, [SD 279.41 ]) compared with healthy controls (mean, 251.32 pg/mL, [SD 44.71]) and stable COPD patients (mean, 242.01 pg/mL [SD 65.74]) (P=0.0003; P=0.00003). EBC AAT showed only a correlation trend with serum AAT (r=0.3, P=0.054). CONCLUSIONS: AAT in EBC was detectable and quantifiable. AAT measured in EBC was significantly increased during exacerbations of COPD and can potentially be used as a biomarker in exacerbations.

Krüppel-like zinc finger proteins in end-stage COPD lungs with and without severe alpha1-antitrypsin deficiency.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is influenced by environmental and genetic factors. An important fraction of COPD cases harbor a major genetic determinant, inherited ZZ (Glu342Lys) α1-antitrypsin deficiency (AATD). A study was undertaken to investigate gene expression patterns in end-stage COPD lungs from patients with and without AATD. METHODS: Explanted lungs of end-stage ZZ AATD-related (treated and non-treated with AAT augmentation therapy) and "normal" MM COPD, and liver biopsies from patients suffering from liver cirrhosis with and without ZZ AATD were used for gene expression analysis by Affymetrix microarrays or RT-PCR. RESULTS: A total of 162 genes were found to be differentially expressed (p-value ≤ 0.05 and |FC| ≥ 2) between MM and ZZ COPD patients. Of those, 134 gene sets were up-regulated and 28 were down-regulated in ZZ relative to MM lung tissue. A subgroup of genes, zinc finger protein 165, snail homolog 1 (Drosophila) (SNAI1), and Krüppel-like transcription factors (KLFs) 4 (gut), 9 and 10, perfectly segregated ZZ and MM COPD patients. The higher expression of KLF 9 and KLF10 has been verified in the replication cohort with AATD-related end-stage lung emphysema and liver cirrhosis. Furthermore, higher expression of KLF9, SNAI1 and DEFA1 was found in ZZ COPD lungs without augmentation therapy relative to MM COPD or ZZ COPD with augmentation therapy. CONCLUSIONS: These results reveal the involvement of transcriptional regulators of the zinc-finger family in COPD pathogenesis and provide deeper insight into the pathophysiological mechanisms of COPD with and without AATD.