Christoph Nell

Detection of obstructive sleep apnoea by an electronic nose

Diagnosis of obstructive sleep apnoea syndrome (OSAS) is technically demanding, cost-intensive and time-consuming. The measurement of volatile organic compounds by an electronic nose is an innovative method that determines distinct molecular patterns of exhaled breath in different patient groups. We addressed the following questions: What is the diagnostic accuracy of an electronic nose in the detection of OSAS and the ability to detect effects of standard therapy in patients with OSAS? Are these results related to changes in distinct markers of airway inflammation and extracellular remodelling? We included 40 OSAS patients and 20 healthy controls. Exhaled breath of all participants was analysed using the Cyranose 320 electronic nose. Pharyngeal washings were performed to sample the upper airway compartment. For statistical analysis linear discriminant analysis was employed. We identified a linear discriminant function separating OSAS from control (p<0.0001). The corresponding area under the receiver-operating curve was 0.85 (95% CI 0.75–0.96; sensitivity 0.93 and specificity 0.7). In pharyngeal washing fluids of OSAS patients, we observed higher levels of &agr;1-antitrypsin and markers of extracellular remodelling compared to controls. The electronic nose can distinguish between OSAS patients and controls with high accuracy.

Benefits of whole body vibration training in patients hospitalised for COPD exacerbations - a randomized clinical trial

BackgroundPatients with stable COPD show improvements in exercise capacity and muscular function after the application of whole body vibration. We aimed to evaluate whether this modality added to conventional physiotherapy in exacerbated hospitalised COPD patients would be safe and would improve exercise capacity and quality of life.Methods49 hospitalised exacerbated COPD patients were randomized (1:1) to undergo physiotherapy alone or physiotherapy with the addition of whole body vibration. The primary endpoint was the between-group difference of the 6-minute walking test (day of discharge – day of admission). Secondary assessments included chair rising test, quality of life, and serum marker analysis.ResultsWhole body vibration did not cause procedure-related adverse events. Compared to physiotherapy alone, it led to significantly stronger improvements in 6-minute walking test (95.55 ± 76.29 m vs. 6.13 ± 81.65 m; p = 0.007) and St. Georges Respiratory Questionnaire (-6.43 ± 14.25 vs. 5.59 ± 19.15, p = 0.049). Whole body vibration increased the expression of the transcription factor peroxisome proliferator receptor gamma coactivator-1-α and serum levels of irisin, while it decreased serum interleukin-8.ConclusionWhole body vibration during hospitalised exacerbations did not cause procedure-related adverse events and induced clinically significant benefits regarding exercise capacity and health-related quality of life that were associated with increased serum levels of irisin, a marker of muscle activity.Trial registrationGerman Clinical Trials Register DRKS00005979. Registered 17 March 2014.

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. AATD patients have higher healthcare utilisation relative to non-AATD COPD, emphysema and asthma patients http://ow.ly/pHHh303m025

A dual center study to compare breath volatile organic compounds from smokers and non-smokers with and without COPD.

There is increasing evidence that breath volatile organic compounds (VOC) have the potential to support the diagnosis and management of inflammatory diseases such as COPD. In this study we used a novel breath sampling device to search for COPD related VOCs. We included a large number of healthy controls and patients with mild to moderate COPD, recruited subjects at two different sites and carefully controlled for smoking. 222 subjects were recruited in Hannover and Marburg, and inhaled cleaned room air before exhaling into a stainless steel reservoir under exhalation flow control. Breath samples (2.5 l) were continuously drawn onto two Tenax(®) TA adsorption tubes and analyzed in Hannover using thermal desorption-gas chromatography-mass spectrometry (TD-GC-MS). Data of 134 identified VOCs from 190 subjects (52 healthy non-smokers, 52 COPD ex-smokers, 49 healthy smokers, 37 smokers with COPD) were included into the analysis. Active smokers could be clearly discriminated by higher values for combustion products and smoking related VOCs correlated with exhaled carbon monoxide (CO), indicating the validity of our data. Subjects from the study sites could be discriminated even after exclusion of cleaning related VOCs. Linear discriminant analysis correctly classified 89.4% of COPD patients in the non/ex-smoking group (cross validation (CV): 85.6%), and 82.6% of COPD patients in the actively smoking group (CV: 77.9%). We extensively characterized 134 breath VOCs and provide evidence for 14 COPD related VOCs of which 10 have not been reported before. Our results show that, for the utilization of breath VOCs for diagnosis and disease management of COPD, not only the known effects of smoking but also site specific differences need to be considered. We detected novel COPD related breath VOCs that now need to be tested in longitudinal studies for reproducibility, response to treatment and changes in disease severity.

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.

Combined lung-sound and reflux-monitoring: a pilot study of a novel approach to detect nocturnal respiratory symptoms in gastro-oesophageal reflux disease.

Aliment Pharmacol Ther 2011; 33: 592–600

Effect of a Three-Week Inpatient Rehabilitation Program on 544 Consecutive Patients with Very Severe COPD: A Retrospective Analysis.

Background: Pulmonary rehabilitation improves exercise capacity, symptoms, and quality of life in chronic obstructive pulmonary disease (COPD) patients, and is therefore recommended in all stages of the disease. However, there are insufficient data on patients with very severe disease. Objective: To describe the effect of an in-house multidisciplinary pulmonary rehabilitation program on patients with very severe COPD. Methods: We performed a retrospective analysis of 544 consecutive patients with very severe COPD (FEV1 0.97 ± 0.26 l) that underwent an in-house pulmonary rehabilitation program (23.44 ± 4.97 days). The studied outcome parameters were the 6-min walk test (6-MWT), health-related quality of life as analyzed by the COPD Assessment Test (CAT) and a dyspnea score [modified Medical Research Council (mMRC) scale], and lung function [forced expiratory volume in 1 s (FEV1) and residual volume (RV)]. Results: We found significant improvements regarding 6-MWT scores (from 321.93 ± 115.67 to 365.82 ± 111.79 m; p < 0.001), CAT scores (from 23.21 ± 6.75 to 19.57 ± 7.35; p < 0.001), mMRC scale scores (from 3.17 ± 1.14 to 2.81 ± 1.22; p < 0.001), and FEV1 (from 0.97 ± 0.26 to 1.08 ± 0.33 l; p < 0.001). A number of baseline variables were significantly correlated with the improvements that occurred during the program (Δ): baseline 6-MWT with Δ6-MWT (r = -0.316; p < 0.001), baseline CAT with ΔCAT (r = -0.302; p < 0.001), baseline mMRC with ΔmMRC (r = -0.444; p < 0.001), and baseline RV with ΔRV (r = -0.284; p < 0.001), demonstrating that improvements were more pronounced in patients with worse baseline characteristics. Patients on long-term oxygen therapy (LTOT) exhibited significantly greater improvements regarding CAT than patients not on LTOT. Conclusion: Patients with very severe COPD exhibit clinically meaningful improvements when undergoing pulmonary rehabilitation.

Measuring Compounds in Exhaled Air to Detect Alzheimer's Disease and Parkinson's Disease.

Background Alzheimer’s disease (AD) is diagnosed based upon medical history, neuropsychiatric examination, cerebrospinal fluid analysis, extensive laboratory analyses and cerebral imaging. Diagnosis is time consuming and labour intensive. Parkinson’s disease (PD) is mainly diagnosed on clinical grounds. Objective The primary aim of this study was to differentiate patients suffering from AD, PD and healthy controls by investigating exhaled air with the electronic nose technique. After demonstrating a difference between the three groups the secondary aim was the identification of specific substances responsible for the difference(s) using ion mobility spectroscopy. Thirdly we analysed whether amyloid beta (Aβ) in exhaled breath was causative for the observed differences between patients suffering from AD and healthy controls. Methods We employed novel pulmonary diagnostic tools (electronic nose device/ion-mobility spectrometry) for the identification of patients with neurodegenerative diseases. Specifically, we analysed breath pattern differences in exhaled air of patients with AD, those with PD and healthy controls using the electronic nose device (eNose). Using ion mobility spectrometry (IMS), we identified the compounds responsible for the observed differences in breath patterns. We applied ELISA technique to measure Aβ in exhaled breath condensates. Results The eNose was able to differentiate between AD, PD and HC correctly. Using IMS, we identified markers that could be used to differentiate healthy controls from patients with AD and PD with an accuracy of 94%. In addition, patients suffering from PD were identified with sensitivity and specificity of 100%. Altogether, 3 AD patients out of 53 participants were misclassified. Although we found Aβ in exhaled breath condensate from both AD and healthy controls, no significant differences between groups were detected. Conclusion These data may open a new field in the diagnosis of neurodegenerative disease such as Alzheimer’s disease and Parkinson’s disease. Further research is required to evaluate the significance of these pulmonary findings with respect to the pathophysiology of neurodegenerative disorders.

Exercise training leads to physiological left ventricular hypertrophy in COPD

Patients with chronic obstructive pulmonary disease (COPD) are affected by dyspnoea, limited exercise capacity and reduced quality of life [1,2]. COPD is associated with increased pulmonary vascular resistance, which leads to increased load of the right heart and decreased filling pressure and stroke volume of the left ventricle (LV). Cardiac involvement is usually considered as occurrence of cor pulmonale. Dedicated changes of the LV are less known. Since pulmonary rehabilitation was shown to provide beneficial effects, current COPD guidelines recommend exercise training in patients ranging from mild to severe disease (www.goldcopd.org) [3,4]. It is expected that the rate of hospitalizations and the perceived intensity of breathlessness is reduced. Pulmonary rehabilitation was shown to improve peripheral metabolism and breathing pattern, e.g. by reduced hyperinflation and increased respiratorymuscle endurance. It should be taken into account, that typical symptoms primarily attributed to COPD can also result, at least in part, from concomitant heart failure. Since exercise training is known to improve symptomsof heart failure, it is hypothesized thatmoderate exercise training exhibits beneficial effects on LV morphology and function in COPD. A total of 10 patients with stable COPD (Table 1) in accordance to the GOLD criteria based on spirometry [1] were enrolled into this prospective study. Spirometry was performed in standardized manner including the forced expiratory volume in the first second (FEV1), vital capacity (VC), the Tiffeneau ratio and carbon monoxide diffusion capacity (DLCO). Capillary blood gas analysis was performed under resting conditions. Medical treatment consisted of inhalation therapy and oral medication of hypertension. An intensive physical exercise training was initiated and follow up examinations were performed after 6 months of continued training. Spirometry, echocardiographyand concentration of Btype natriuretic peptide (BNP) was assessed at time of enrolment and at follow up [5]. The study was approved by the local institutional ethics committee and written informed consent was obtained from all study participants. Echocardiography was used to measure LV enddiastolic and endsystolic cavity diameters, interventricular septum and posterior wall thickness. LV enddiastolic volume (LVEDV), endsystolic volume (LVESV), strokevolume (LVSV), ejection fraction (LVEF) and LVmasswas obtained based on the Penn-cube convention [6–8]. LV enddiastolic and endsystolic wall stress was calculated using a thick-walled spheremodel and the wall stress index as described [9]. Although we have previously shown that an echocardiography based approach overestimates LV mass and underestimates LVwall stress when comparedwith cardiacmagnetic resonance imaging [8], the present study is valid since similar methods were used at time of enrolment and follow up. An individualized structured training program includingwarming up, strength and endurance components twice a week was initiated and continued over 6 months. Within the first 3 months, training for the improvement of maximal strength and endurance was done. In the second half, it was aimed to maintain the achieved physical status. Strength training consisted of consecutive exercises of the upper and lower limbs (rowing, pulling down forces, rope pulling, knee bends). Subsequently, 12 min of cycle ergometer endurance training was performed. Every 3 weeks, the maximal individual force development was measured and exercise intensity was increased from 35% at the beginning up to 80% within the first 3 months. In parallel, endurance intensity was continuously increased from 60% to 125% of the maximal

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. Georges 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.