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Background: Chronic obstructive pulmonary disease (COPD) is common around the world and carries a high morbidity and mortality. Symptom- and risk-oriented drug treatment is recommended, both in Germany and in other countries. It is not yet known to what extent the treatment that is actually delivered in Germany corresponds to the current recommendations in the guidelines. Methods: As recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) in 2017, 2281 patients of the national COPD cohort COSYCONET (COPD and Systemic Consequences--Comorbidities Network) were classified into Gold classes A--D on the basis of disease-specific manifestations and the frequency of exacerbations. Moreover, the regular use of medications was documented and categorized according to active substance groups. For all groups, the documented treatment that was actually given was compared to the recommended treatment. Results: 67.6% of the patients received a combination of a long-acting anticholinergic drug (LAMA) and a long-acting beta-mimetic drug (LABA), while 65.8% received inhaled corticosteroids (ICS), 11.7% theophylline, and 12.6% oral corticosteroids (OCS). Despite recommendations to the contrary, 66% of the patients in Groups A and B (low exacerbation rates) were treated with ICS; some of these patients carried an additional diagnosis of bronchial asthma. There was evidence of undertreatment mainly in groups C and D (high exacerbation rate), because many of the patients in these groups were not treated with LAMA or LAMA/LABA as recommended. Conclusion: The observed deviations from the recommended treatment, some of which were substantial, might lead to suboptimal treatment outcomes as well as to avoidable side effects of medication. [ABSTRACT FROM AUTHOR]

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Background: E-cigarettes are coming into wider use. They are advertised as an aid to smoking cessation, but there is concern that they may also serve as a gateway drug for cigarette smoking. Methods: The authors systematically searched the PubMed database for relevant publications on the mechanism of action of e-cigarettes, the nature of their emissions, their assessment by potential users, their efficacy in smoking cessation, and their potential for addiction. Results: There have been many reports of epidemiologically uninformative case series in which smokers were helped to stop smoking by the use of e- cigarettes. Only two controlled trials have shown that e-cigarettes have approximately the same effect as nicotine substitution therapy when used as an aid to smoking cessation. The effect is nearly independent of nicotine content. E-cigarettes are also consumed, to a small extent, by nonsmokers. As far as can be estimated toxicologically at present, the danger to active and passive smokers of e-cigarettes is presumably orders of magnitude less than that of tobacco smokers, although the variable composition of the fluids used in e-cigarettes introduces a degree of uncertainty. Conclusion: Preclinical and initial clinical data, including some data from randomized controlled trials, indicate that e-cigarettes may be useful as an aid to smoking cessation or as a means of lowering risk in high-risk groups. In contrast to the demonstrated efficacy of multimodal smoking-cessation programs with pharmacological and psychotherapeutic support, the efficacy of e-cigarettes in smoking cessation has not yet been satisfactorily shown. Valid and informative clinical trials are urgently needed. These should also be designed to determine what predisposition(s), if any, might make the use of e-cigarettes more or less successful than that of other aids to smoking cessation. Moreover, e-cigarettes might be a gateway drug for cigarette smoking; thus, no clear recommendation about their use can be made at present. [ABSTRACT FROM AUTHOR]

Objectives: To compare the prognostic value of FENO with bronchoprovocation testing when the clinical course within the first year after assessment was taken into account; to compare the prognostic values with respect to eosinophilic versus non-eosinophilic inflammatory pattern. Methods: Cross-sectional diagnostic study with a delayed-type reference standard in 393 patients attending a private practice of pneumologists with complaints suspicious of obstructive airway disease. Index test: FENO measurement. Reference standard: ratio FEV1/VC or airway resistance assessed by body plethysmography, with additional bronchoprovocation or bronchodilator testing, as well as spontaneous sputum (smear slides). This was combined with a follow-up evaluation by a structured interview after 12 months. Results: 302 (76.8%) patients were reached for follow-up. Regarding asthma diagnosis, the area under the curve (AUC) for FENO was 0.603 (95%CI 0.528-0.677) for the whole group. With eosinophilic asthma as target, AUC increased (0.819 (95%CI 0.703-0.934)) and exceeded that of bronchoprovocation (0.711 (95%CI 0.584-0.874)). FENO showed no diagnostic value in noneosinophilic asthma. In patients reporting wheezing and allergic rhinitis at the initial assessment, its positive predictive value was 90.9% (95%CI 62.3%-98.4) at a cut - off of 45 ppb, and 100% (95%CI 56.6-100%) at 81 ppb. Conclusions: FENO bears limited information when measured non-specifically in primary care, but is useful for diagnosing eosinophilic asthma. If sputum is not available, information on wheezing and rhinitis can narrow down the range of patients in whom FENO is informative. Moreover, the evaluation of the clinical value of FENO benefits from taking into account follow-up data to confirm the diagnosis. [ABSTRACT FROM AUTHOR]

Background: Pulmonary hypertension (PH) is considered a clinically important feature of Obesity-Hypoventilation Syndrome (OHS). We aimed to determine prevalence, characteristics and severity of PH including associations with clinical outcomes after established non-invasive positive pressure ventilation (NPPV). Methods: In a prospective cross-sectional study, clinically stable OHS-patients (NPPV duration 3 months) were consecutively assessed using echocardiography, serum markers and right-heart catheterization (RHC). NPPV use was quantified via ventilator counters. Blood gases, lung function, Epworth-Sleepiness Scale (ESS), sleep-quality, WHO-functional class (WHO-FC), 6-min walk distance, and health-related quality of life (HRQL) via Severe Respiratory Insufficiency (SRI) questionnaire were assessed. Results: Of 177 patients considered, 64 fulfilled inclusion criteria. Among these, 21 patients (10 female/11 male; BMI 45 [40; 53] kg/m², PaCO2 39.6 [37.8; 45.5] mmHg (median [quartiles])) gave consent for RHC. Four patients (19%) had normal mean pulmonary artery pressure (mPAP < 20 mmHg), 8 (38.1%) mPAP 20 -24 mmHg and 9 (42.9%) manifest PH(mPAP ≥ 25 mmHg), 3 of them with combined pre- and/or postcapillary PH. mPAP was negatively correlated to NPPV use, vital capacity and lung diffusing capacity (p < 0.01 each), and positively to BMI (p < 0.05). NPPV use and vital capacity independently predicted mPAP. In patients with PH, ESS, WHO-FC, and some SRI-items were worse (p < 0.05 each) compared to patients without PH. Multivariate analyses revealed mPAP as the only independent predictor of the SRI-physical functioning domain. Conclusions: Mild to moderate PH is frequent in patients with OHS despite NPPV, mPAP being inversely related to NPPV adherence. PH is associated with impairments in daytime-sleepiness, WHO-FC, HRQL and physical functioning. [ABSTRACT FROM AUTHOR]

BACKGROUND: In patients with COPD, chronic anemia is known as an unfavorable prognostic factor. Whether the association between hemoglobin (Hb) levels and long-term survival is restricted to anemia or extends to higher Hb levels has not yet been systematically assessed. METHODS: We determined Hb levels in 309 subjects with COPD and chronic respiratory failure prior to initiation of noninvasive ventilation, accounting for confounders that might affect Hb. Subjects were categorized as anemic (Hb < 12 g/dL in females, Hb < 13 g/dL in males), polycythemic (Hb ≥ 15 g/dL in females, Hb ≥ 17 g/dL in males), or normocythemic. In addition, percentiles of Hb values were analyzed with regard to mortality from any cause. RESULTS: Two-hundred seven subjects (67.0%) showed normal Hb levels, 46 (14.9%) had anemia, and 56 (18.1%) had polycythemia. Polycythemic subjects showed a higher survival rate than anemic (P. = 01) and normocythemic subjects (P = .043). In a univariate Cox hazards model, Hb was associated with long-term survival (hazard ratio 0.855; 95% CI 0.783- 0.934, P < .001). The 58th percentiles of Hb (14.3 g/dL in females, 15.1 g/dL in males) yielded the highest discriminative value for predicting survival (hazard ratio 0.463, 95% CI 0.324-0.660, P < .001). In the multivariate analysis this cutoff was an independent predictor for survival (hazard ratio 0.627, 95% CI 0.414-0.949, P = .03), in addition to age and body mass index. CONCLUSIONS: In subjects with COPD and chronic respiratory failure undergoing treatment with noninvasive ventilation and LTOT, high Hb levels are associated with better long-term survival. The optimal cutoff level for prediction was above the established threshold defining anemia. Thus, predicting survival only on the basis of anemia does not fully utilize the prognostic potential of Hb values in COPD. [ABSTRACT FROM AUTHOR]

Objectives: To determine the diagnostic accuracy of fractional exhaled nitric oxide (FENO) measurement in pneumologists routine diagnostic work-up; and to determine the impact of the inflammatory pattern on diagnostic accuracy. Methods: Prospective diagnostic study in 393 patients attending a private practice of pneumologists with complaints suspicious of obstructive airway disease (OAD). Index test was FENO measurement. Reference standard was the Tiffeneau ratio (FEV1/VC) or airway resistance as assessed by whole body plethysmography, with additional bronchoprovocation or bronchodilator testing. Morning sputum was analysed with smear slides which were prepared and stained by Giemsa. Results: 154 patients were diagnosed as having asthma (145 diagnoses based on bronchial provocation, 9 based on bronchodilator results), 5 had COPD. For the whole group, asthma could be ruled in at FENO > 71 ppb (PPV 80%; 95% CI 63-90%) and ruled out at FENO ≤ 9 ppb (NPV 82%; 95% CI 67-91%) (area under the curve (AUC) = 0.656; 95% CI 0.600-0.712; p < 0.001). 128 patients delivered sputum. FENO was 44.3 ppb (sd 48.9) in patients with predominant eosinophilic inflammation, 18.5 ppb with neutrophilic inflammation, and 23.1 ppb in others (p = 0.003). Diagnostic accuracy of FENO increased when patients with neutrophilic inflammation were omitted from analysis (AUC = 0.745; 95% CI 0.651-0.838; p < 0.001). Then asthma could be ruled in at FENO > 31 ppb (PPV 82%; 95% CI 63-92%) and ruled out at FENO ≤ 12 ppb (NPV 81%; 95% CI 62-91%). Conclusions: FENO measurement can be useful as an additional diagnostic tool in pneumologists' practice. The diagnostic value of FENO could be improved when infammatory patterns are taken into account. [ABSTRACT FROM AUTHOR]

Abstract: Physical Activity (PA) plays an important role in the health and quality of life of cystic fibrosis (CF) patients, but little is known about their PA in daily living. With the use of accelerometers it is now possible to monitor activity profiles in detail. The goals of this study are to assess feasibility and acceptance of a longer-term use of accelerometers in daily living in CF patients, study the possibility of detecting changes in PA in relation to the patients’ clinical state and compare the findings between a CF and an age-matched healthy control group. We asked 15 CF patients to wear two accelerometers for 21 days and fill in a diary. Ten of them (age 21 to 40, mean 29.5 years) participated and delivered data that could be evaluated. We also recruited 10 age-matched control subjects. Data was processed for calculating usage time and features extracted to construct models of activity. The younger patients, particularly females, were concerned with fashion and style and considered wearing the sensors a challenge. Overall, the compliance of patients with CF seemed to be lower than reported for elder subjects in the literature. Time-series analysis of the data indicated characteristic patterns of PA over time, provided that data pre-processing and noise-filtering had been optimized. Further studies have to assess whether the continuous recording of PA yields additional clinical information in CF and in particular, whether it is possible to detect or even predict exacerbations in patients with CF or other diseases. [Copyright &y& Elsevier]

Summary: Aim: While it is known that severe COPD has substantial economic consequences, evidence on resource use and costs in mild disease is scarce. The objective of this study was to investigate excess costs of early stages of COPD. Methods: Using data from two population-based studies in Southern Germany, current GOLD criteria were applied to pre-bronchodilator spirometry for COPD diagnosis and staging in 2255 participants aged 41 to 89. Utilization of physician visits, hospital stays and medication was compared between participants with COPD stage I, stage II+ (II or higher) and controls. Costs per year were calculated by applying national unit costs. In controlling for confounders, two-part generalized regression analyses were used to account for the skewed distribution of costs and the high proportion of subjects without costs. Results: Utilization in all categories was significantly higher in COPD patients than in controls. After adjusting for confounders, these differences remained present in physician visits and medication, but not in hospital days. Adjusted annual costs did not differ between stage I (€ 1830) and controls (€ 1822), but increased by about 54% to € 2812 in stage II+. Conclusion: The finding that utilization and costs are considerably higher in moderate but not in mild COPD highlights the economic importance of prevention and of interventions aiming at early diagnosis and delayed disease progression. [ABSTRACT FROM AUTHOR]

Summary: 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, 514.33pg/mL, [SD 279.41 ]) compared with healthy controls (mean, 251.32pg/mL, [SD 44.71]) and stable COPD patients (mean, 242.01pg/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. [Copyright &y& Elsevier]

Summary: Background: The evaluation of exhaled breath profiles by electronic nose (eNose) is considered as a promising non-invasive diagnostic tool, and the discrimination of breathprints between patients with COPD and asthma has been reported. The aim of this study was to assess, whether exhaled breath profile analysis can detect the inflammatory airway response induced by ozone inhalation. Methods: In a randomized double-blind, cross-over study 14 healthy ozone-responsive subjects were exposed to 250ppb ozone and filtered room air for 3h with intermittent exercise. Blood biomarkers, exhaled NO, exhaled CO, and breathprints (Cyranose 320®) were assessed prior and at 3 time points up to 24h post exposure. Induced sputum was collected at baseline and 3h post exposure. Multivariate analysis of eNose data was performed using transformed and normalized datasets. Results: Significantly increased numbers of sputum and blood neutrophils were observed after ozone, whereas the eNose signals showed no differences between exposures and no correlation with neutrophilic airway inflammation. However, independent of ozone exposure, sensor data correlated with serum SP-D levels and to a smaller extent with blood neutrophil numbers. Conclusions: Exhaled breath profiles as measured by the Cyranose 320® did not reflect airway responses to ozone. This suggests that exhaled volatiles did not change with ozone challenges or that the changes were below the detection limits. Conversely, the correlation of eNose signals with blood neutrophils and serum SP-D, i.e. markers of systemic inflammation and lung permeability, suggested that the Cyranose 320® can detect volatile organic compounds of systemic origin. [Copyright &y& Elsevier]

Summary: The aim of the current study was to determine the impact and interaction of important influencing factors on the fraction of exhaled nitric oxide (FeNO). FeNO was measured in a population-based sample of 1250 middle-aged subjects from the KORA F4 cohort (Augsburg, Germany). Analysis of covariance models was performed including the factors age, height, FVC, FEV1, sex, current smoking status, recent respiratory tract infection, and respiratory allergy. Geometric mean (SD as factor; 95% confidence interval as factor) FeNO was 13.9 (1.9; 1.033) ppb. FeNO significantly depended on age, height, smoking, infection and allergy. Smoking reduced FeNO by 21%, while infection and allergy led to increases by 9 and 11%, respectively. Increases in age by 10 years and in height by 10 cm were associated with increases of FeNO by 15 and 10%, respectively. Non-smokers demonstrated independent multiplicative superposition of factors affecting FeNO while the effect of allergy was virtually eliminated in smokers without infection. We conclude that in middle-aged non-smokers the effects of infection, age and height can be easily taken into account and do not significantly disturb the effect of respiratory tract allergies on FeNO. In current smokers, however, effects were heterogeneous and information on smoking intensity seems to be useful for better adjustment. [ABSTRACT FROM AUTHOR]

Summary: Forced inspiratory measures have been described to reflect the reduction in dyspnoea upon bronchodilation in severe COPD. Based on this we evaluated the applicability and usefulness of a portable device for the assessment of forced inspiration. In 37 patients with COPD (GOLD II/II/IV n = 16/15/6, mean ± SD FEV1 46.2 ± 15.4%pred) lung function was recorded prior to inhalation of 24 μg formoterol and 30 min later. Assessments comprised spirometry including forced inspiration, body plethysmography, maximum inspiratory flow (InCheck, Clement Clarke), and changes in dyspnoea via visual analogue scale (VAS). The sequence was repeated on a second day to assess reproducibility. Bronchodilation by formoterol was detectable in all functional indices (p < 0.05 each) except total lung capacity. FEV1 improved by (mean ± SD) 11.1 ± 10.3%, forced inspiratory volume in 1s (FIV1) by 11.6 ± 13.5%, inspiratory peak flow (PIF) by 10.7 ± 16.2%, and inspiratory flow determined by the InCheck device (IF-IC) by 11.9 ± 14.4%. Remarkably, the changes of IF-IC (p < 0.001) but not those of other measures except FIV1 (p < 0.05) were related to those of dyspnoea. Effects on IF-IC showed reproducibility comparable to that of other indices. The results suggest that a simple, portable device for recording forced inspiration could be useful in monitoring COPD, as a functional correlate of acute changes in dyspnoea. (ClinicalTrial.gov number NCT00561886). [ABSTRACT FROM AUTHOR]

Summary: Background: Pulmonary sarcoidosis shows a remarkable heterogeneity of phenotypes ranging from bihilar lymphadenopathy to progressive fibrosis. Individual disease assessment is demanding and requires sensible, practical measures. We tested whether gas exchange measurements during exercise reflects disease activity and clinical course in sarcoidosis. Methods: In 149 patients with proven pulmonary sarcoidosis the alveolar-arterial oxygen pressure gradient (P(A-a)O2) during exercise was assessed and compared with chest X-ray typing, pulmonary function, single breath-diffusing capacity for carbon monoxide (DLCO), serological markers, cell composition of bronchoalveolar lavage fluid (BALF) and clinical course. Patients were categorized according to thresholds of P(A-a)O2 during exercise. Measurements and Main Results: Chest X-ray typing, pulmonary function, DLCO and the need for immunosuppressive treatment differed between the disease categories based on P(A-a)O2 during exercise (p < 0.0001 each). Patients with an impairment of gas exchange during exercise also showed elevated levels of neopterin (p = 0.002) and higher percentages of neutrophils (p = 0.013) and eosinophils (p < 0.0001) in BALF. Multivariate regression analysis showed that forced vital capacity (FVC) (p = 0.009) and P(A-a)O2 during exercise (p < 0.0001) were independently associated with a prolonged need for immunosuppressive treatment (>1 year), but not DLCO. About 50% (n = 75) of the study population showed a normal spirometry. Even in this subgroup 23% had an impaired gas exchange during exercise, which correlated with chest X-ray types (p < 0.0001) and the need for immunosuppressive treatment (p < 0.005). Conclusions: Impaired gas exchange during exercise reflects disease activity and its extent and is associated with a prolonged need for immunosuppressive treatment during follow-up in patients with pulmonary sarcoidosis. [Copyright &y& Elsevier]

Summary: Background & aims: In patients with chronic respiratory diseases body mass index (BMI) is a predictor of long-term survival, whereas the prognostic value of body composition, especially fat-free mass index (FFMI), is unknown. Methods: In a prospectively collected cohort of 131 patients (50 females, 81 males; 71% chronic obstructive pulmonary disease, 29% severe restrictive disorders) undergoing home mechanical ventilation (HMV) due to chronic hypercapnic respiratory failure (CHRF), the prognostic value of nutritional composition assessed by bioelectrical impedance analysis was evaluated during a 4-year follow-up and compared to that of BMI, anthropometrics, and functional parameters. Results: After follow-up, 53 patients (40.5%) had died. Regarding all-cause mortality cumulative survival percentages after 1, 2 and 3 years were 89.3, 76.3 and 67.9%, respectively. In univariate analyses, FFMI, BMI, sex, age, leukocyte number, FEV1 and 6-min walking distance were associated with survival (p <0.05). Multivariate analyses using the most significant percentiles identified by univariate analysis revealed FFMI (25th percentile; hazard ratio 0.338 [95% confidence interval: 0.189–0.605]), sex, leukocyte number (50th percentile) and FEV1 (50th percentile) as independent predictors of mortality. Conclusions: In patients with CHRF and HMV, body composition in terms of FFMI was an independent predictor of long-term survival. FFMI was superior to BMI and seems informative in the multidimensional assessment of these patients. [Copyright &y& Elsevier]

Summary: Methacholine testing is an important diagnostic tool for asthma. Newly available dosimeter and software technology allows for simplification of the test. This study aimed to evaluate a single-concentration dosimeter protocol for methacholine testing by comparison with a multi-concentration dosimeter protocol similar to that recommended by the American Thoracic Society (ATS) (standard protocol). Fifty young subjects with high pretest probability for bronchial hyperresponsiveness underwent two challenges in randomized order within one week. The novel protocol used a Medic-Aid Sidestream nebulizer and a fixed methacholine concentration of 16mg/mL. Number and duration of nebulizations were matched to the last four doses of the standard protocol, and results were expressed cumulatively. The rank correlation between log slopes (n =50) was 0.86; that between log provocative doses (n =18), which differed at low values, was 0.58. When requiring a 20% fall in FEV1 at any methacholine dose, 18 subjects were hyperresponsive and 28 normoresponsive in both tests (46/50 concordant). One subject was positive only with the standard, and 3 only with the novel protocol (Cohen''s kappa 83%). The novel protocol for methacholine testing yielded qualitative results similar to those of the ATS multi-concentration protocol, although there were quantitative differences at low doses. However, its design and handling may offer advantages for clinical practice. [Copyright &y& Elsevier]

Summary: Classically, the development of emphysema in chronic obstructive pulmonary disease is believed to involve inflammation induced by cigarette smoke and leukocyte activation, including oxidant-antioxidant and protease-antiprotease imbalances. While there is substantial evidence for this, additional aspects have been suggested by a number of clinical and experimental observations. Smokers exhibit signs of premature aging, particularly obvious in the skin. The link between aging and chronic disease is well-known, e.g., for the brain and musculoskeletal or cardiovascular system, as well as the clinical link between malnutrition and emphysema, and the experimental link to caloric restriction. Interestingly, this intervention also increases lifespan, in parallel with alterations in metabolism, oxidant burden and endocrine signaling. Of special interest is the observation that, even in the absence of an inflammatory environment, lung fibroblasts from patients with emphysema show persistent alterations, possibly based on epigenetic mechanisms. The importance of these mechanisms for cellular reprogramming and response patterns, individual risk profile and therapeutic options is becoming increasingly recognized. The same applies to cellular senescence. Recent findings from patients and experimental models open novel views into the arena of gene-environment interactions, including the role of systemic alterations, cellular stress, telomeres, CDK inhibitors such as p16, p21, pRb, PI3K, mTOR, FOXO transcription factors, histone modifications, and sirtuins. This article aims to outline this emerging picture and to stimulate the identification of challenging questions. Such insights also bear implications for the long-term course of the disease in relation to existing or future therapies and the exploration of potential lung regeneration. [Copyright &y& Elsevier]

Summary: Measurement of exhaled nitric oxide is widely used in respiratory research and clinical practice, especially in patients with asthma. However, interpretation is often difficult, due to common interfering factors, and little is known about interactions between factors. We assessed the influences and interactions of factors such as smoking, respiratory tract infections and respiratory allergy concerning exhaled nitric oxide values, with the aim to derive a scheme for adjustment. We studied 897 subjects (514 females, 383 males; mean age±standard deviation 34.5±13.0 years) with and without respiratory allergy (allergic rhinitis and/or asthma), smoking and respiratory tract infection. Logarithmic nitric oxide levels were described by an additive model comprising respiratory allergy, smoking, respiratory tract infection, gender and height (p⩽0.001 each), without significant interaction terms. Geometric mean was 17.5ppb in a healthy female non smoker of height 170cm, whereby respiratory allergy corresponded to a change by factor 1.50, smoking 0.63, infection 1.24, male gender 1.17, and each 10cm increase (decrease) in height to 1.11 (0.90). Factors were virtually identical when excluding asthma and using the category allergic rhinitis instead of respiratory allergy (n=863). Within each category formed by combinations of these different predictors, the range of residual variation was approximately constant. We conclude that the factors influencing exhaled nitric oxide, which we analyzed, act independently of each other. Thus, circumstances such as smoking and respiratory tract infection do not appear to affect the usefulness of exhaled nitric oxide, provided that appropriate factors for adjustment are applied. [Copyright &y& Elsevier]

Summary: Background: Patients with severe COPD suffer from impairments of exercise capacity which affects daily activity. Conversely, activity might exert effects on the functional state. We studied whether a short-term intervention by regular phone calls caused an increase in activity at home and whether this resulted in a gain in exercise capacity. Methods: Over a 2-week period (P1) normal daily activity was assessed in 21 patients with stable severe COPD (GOLD III/IV). After this, the individual setting was explored in a short home visit. The subsequent 2-week period (P2) involved phone calls every other day to raise home-based activity (target: 3×15min daily at 75% of maximum dyspnea). During the study, patients wore an actograph plus pedometer and kept a diary. Before P1 and after P2, 6-min walking distance (6MWD), lung function, the Borg score and quality of life (SF-36, SGRQ) were determined. Results: Compared to P1, actograph counts (p<0.05) were higher in P2. There was also an increase in 6MWD (p<0.05) and quality of life scores (SF-36, p<0.05) between initial and final visit, whereby improvements in 6MWD correlated with changes in activity (p<0.01). Conversely, four patients who experienced an exacerbation in P2 showed no increase in activity or 6MWD. Conclusions: In patients with stable severe COPD, it was possible to increase activity by regular phone calls without performing previous rehabilitation. Increased activity resulted in increased exercise capacity and quality of life within 2 weeks, underlining the effectiveness of continued motivational support in patients with severe COPD. [Copyright &y& Elsevier]

Summary: Background: Mouth occlusion pressure measurement is widely used for assessment of respiratory muscle function, particularly in patients with respiratory failure. However, its predictive value for long-term survival remains largely unexplored. Methods: In 464 patients with chronic hypercapnic respiratory failure (CHRF) due to various underlying disorders and receiving non-invasive ventilation (NIV), maximal inspiratory mouth pressure (PImax), mouth occlusion pressure at 100ms during quiet breathing (P 0.1) and the ratio P 0.1/PImax were assessed prior to and after treatment including NIV. Baseline data and changes at follow-up were used to evaluate their predictive value for long-term survival. Results: Overall, median (quartiles) P 0.1 was 177.0 (109.2;287.0) %pred, PImax 35.0 (24.0;47.0) %pred, and P 0.1/PImax 564.0 (275.7;1082.3) %pred. In multivariate analyses, P 0.1 was related to airflow obstruction, lung hyperinflation, haemoglobin (Hb) and leukocytes, and PImax to airflow obstruction and hyperinflation (p<0.05 each). All-cause mortality during follow-up (median 31.6 months) was 31.5%. Survival was associated with age, body-mass index (BMI), lung function, leukocytes, Hb, PImax, P 0.1 and P 0.1/PImax (p<0.01 each, univariate). Among these multivariate Cox regression identified age, BMI, FEV1, leukocytes and P 0.1/PImax as independent predictors (p<0.05 each). Furthermore, the decrease of P 0.1/PImax at follow-up was associated with improved survival in patients with high baseline P 0.1/PImax (>50th or 75th percentile; p<0.05). Conclusions: In patients with CHRF and current NIV therapy, P 0.1/PImax was an independent predictor of long-term survival, in addition to previously established risk factors. Moreover, a decrease in P 0.1/PImax after treatment including NIV was associated with an improved survival in patients with high baseline P 0.1/PImax values. [Copyright &y& Elsevier]

Summary: Background: Natriuretic peptides are considered as reliable indicators of left-heart failure (HF) and are useful for differential diagnosis of dyspnoea. Aim: We evaluated the clinical significance of N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with chronic hypercapnic respiratory failure (CHRF). Methods: In 60 patients with CHRF, plasma concentrations of NT-proBNP were assessed at baseline and after treatment including non-invasive ventilation (NIV). The relationship of NT-proBNP to disease severity and its predictive value for survival were evaluated up to 4 years. Results: NT-proBNP levels were markedly elevated in patients with CHRF (n=60; geometric mean (SD) 546.4 (4.9)pg/mL; p<0.001) compared to healthy controls (n=182; 49.0 (2.2)pg/mL). After excluding patients with concomitant HF or renal impairment, levels were still increased (n=43; 393.2 (3.8)pg/mL; p<0.001). According to multivariate regression, hypoxia and exacerbation independently determined NT-proBNP levels (p<0.05 each). After initiation of NIV, blood gases and lung function improved and NT-proBNP decreased (−31.3 (0.3)%; p<0.001). During 22.5 (2.2) months follow-up, NT-proBNP was not significantly associated with survival in the total population, however, the subgroup of patients with levels >722pg/mL (67th percentile) and no adherence to NIV displayed poor prognosis (hazard ratio=0.21; 95%-CI=0.022–0.580; p=0.0091). Conclusions: NT-proBNP was highly elevated in patients with CHRF and correlated with the degree of respiratory impairment and exacerbation. Correspondingly, treatment including NIV led to reduction of NT-proBNP. These data indicate a potential role of NT-proBNP in assessing disease severity, treatment efficacy and prognosis in CHRF. [Copyright &y& Elsevier]

Abstract: Budweiser S, Moertl M, Jörres RA, Windisch W, Heinemann F, Pfeifer M. Respiratory muscle training in restrictive thoracic disease: a randomized controlled trial. Objective: To investigate the effects of respiratory muscle training (RMT) in patients with restrictive thoracic disorders and intermittent noninvasive positive-pressure ventilation (NPPV). Design: Prospective randomized controlled trial. Setting: Home-based RMT, with assessment in a primary care pulmonary center. Participants: Thirty patients with restrictive thoracic disorders; 28 patients completed the trial. Intervention: Three months of RMT by isocapnic hyperpnea or sham training. Main Outcome Measures: Respiratory muscle strength and endurance, lung function, exercise performance, and health-related quality of life (HRQOL). Results: After RMT, maximal inspiratory mouth pressure was increased (27.6%±36.5%, P=.013). In patients who could perform cycle ergometer testing (n=17), peak oxygen consumption (2.24±3.39mL·kg−1·min−1 vs −1.71±2.54mL·kg−1·min−1, P=.014) and maximal work rate (9.4±14.8W vs −5.1±10.8W, P=.043) increased relative to a control group. Similar differences occurred regarding changes of HRQOL (physical performance, 3.3±11.4 score vs −6.6±9.0 score; P=.012) and time of ventilator use (−0.6±1.2h/d vs 0.4±0.5h/d, P=.010). Lung volumes, 12-second maximum voluntary ventilation, 6-minute walking distance, and blood gases were unchanged. Conclusions: In patients with restrictive thoracic disorders and NPPV, RMT improved inspiratory muscle strength. Exercise performance and HRQOL were improved when the 2 groups were compared. RMT was practicable and safe despite severe respiratory impairment. Further evaluation, including different training intensities and modalities, seems warranted. [Copyright &y& Elsevier]

Summary: Hypertonic saline aerosol can elicit airway obstruction in patients with moderate or severe COPD. In the present study we assessed whether cetirizine dihydrochloride is capable of modulating this response. After a screening visit, 20 patients with COPD (mean FEV1 49% pred) were treated with cetirizine 10mg daily or placebo over 1 week in a randomized, double-blind, cross-over fashion and measurements performed at the end of treatment periods. At each visit, patients were challenged by 3% saline aerosol (screening: 0.9%) over 5min after prior inhalation of salbutamol, and 45min later sputum was obtained after inhalation of 0.9% saline. Lung function was quantified in terms of forced expiratory (FEV1) and inspiratory (FIV1) volumes. Spirometric values did not differ between visits and salbutamol-induced bronchodilation was not altered by cetirizine. Compared to baseline or post-salbutamol values, the saline-induced fall in FEV1 was smallest at screening (), without a significant difference between treatments. Regarding FIV1, however, the percent fall from baseline was higher after placebo (; ) compared to screening (0.4%) or cetirizine (−4.3%). Sputum composition showed no significant differences except for a tendency towards reduced concentrations of α 2-macroglobulin after cetirizine compared to placebo (). The present data indicate some, though small, effects of the H1 receptor antagonist cetirizine on hypertonic saline-induced airway obstruction in patients with moderate-to-severe COPD. In view of the mechanisms involved, it is an open question whether stronger effects can be elicited with higher doses and whether such effects would translate into clinical benefits, e.g. during exacerbations. [Copyright &y& Elsevier]

Summary: The 6-min walking (6MWD) and 6-min treadmill distance (6MTD) are often used as measures of exercise performance in patients with COPD. The aim of our study was to assess their relationship to daily activity in the course of an exercise training program. Eighty-eight patients with stable COPD (71m/17f; mean±sd age, 60±8year; FEV1, 43±14% pred) were recruited, 66 of whom performed a hospital-based 10-day walking training, whereas 22 were treated as control. On day 16MTD, and on days 8 and 10, 6MTD and 6MWD were determined. In addition, patients used an accelerometer (TriTrac-R3D®) to record 24h-activity, whereby training sessions were excluded. In both groups there was a linear relationship ( and ) between 6MTD and 24h-activity, the slope of which was 2.5-fold greater in the training group (). Similar relationships emerged for 6MWD. There was no association between baseline 6MTD, FEV1 or BMI and any of the other measures. These data suggest that daily activity did not markedly vary with exercise capacity under baseline conditions. Participation in a training program increased activity significantly stronger than predicted from the gain in exercise capacity. This underlines the importance of non-physiological, patient-centered factors associated with training in COPD. [Copyright &y& Elsevier]

While exposure to ambient particulate matter (PM) and nitrogen dioxide (NO 2) is thought to be associated with diseases via inflammatory response, the association between exposure to ozone, an oxidative pollutant, and inflammation has been less investigated. We analyzed associations between short-term exposure to ozone and three inflammatory biomarkers among children and adolescents. These cross-sectional analyses were based on two follow-ups of the GINIplus and LISA German birth cohorts. We included 1330 10-year-old and 1591 15-year-old participants. Fractional exhaled nitric oxide (FeNO) and high-sensitivity C-reactive protein (hs-CRP) were available for both age groups while interleukin (IL)-6 was measured at 10 years only. Maximum 8-h averages of ozone and daily average concentrations of NO 2 and PM with an aerodynamic diameter <10 μm (PM 10) were adopted from two background monitoring stations 0 (same day), 1, 2, 3, 5, 7, 10 and 14 days prior to the FeNO measurement or blood sampling. To assess associations, we utilized linear regression models for FeNO, and logistic regressions for IL-6 and hs-CRP, adjusting for potential covariates and co-pollutants NO 2 and PM 10. We found that short-term ozone exposure was robustly associated with higher FeNO in adolescents at age 15, but not at age 10. No consistent associations were observed between ozone and IL-6 in children aged 10 years. The relationship between hs-CRP levels and ozone was J-shaped. Relatively low ozone concentrations (e.g., <120 μg/m³) were associated with reduced hs-CRP levels, while high concentrations (e.g., ≥120 μg/m³) tended to be associated with elevated levels for both 10- and 15-year-old participants. Our study demonstrates significant associations between short-term ozone exposure and FeNO at 15 years of age and a J-shaped relationship between ozone and hs-CRP. The finding indicates that high ozone exposure may favor inflammatory responses in adolescents, especially regarding airway inflammation. Image 1 • Ozone exposure was associated with FeNO in adolescents aged 15 years, not 10 years. • Ozone exposure was not associated with IL-6 in children aged 10 years. • Ozone exposure and hs-CRP possibly had a J-shaped exposure-response relationship. Exposure to higher levels of ambient ozone in adolescents was associated linearly with higher FeNO, and J-shaped with hs-CRP, but not with IL-6. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "E-Cigarettes?Prevention, Pulmonary Health, and Addiction, by Dennis Nowak in a 2014 issue along with the author's response to the same.