Stelios Loukides

Increased levels of exhaled carbon monoxide in bronchiectasis: a new marker of oxidative stress

BACKGROUND Bronchiectasis is a chronic inflammatory lung disease associated with increased production of oxidants due mostly to neutrophilic inflammation. Induction of heme oxygenase (HO-1) by reactive oxygen species is a general cytoprotective mechanism against oxidative stress. HO-1 catabolises heme to bilirubin, free iron and carbon monoxide (CO). Exhaled CO measurements may therefore reflect an oxidative stress and be clinically useful in the detection and management of inflammatory lung disorders. METHODS The levels of exhaled CO of 42 non-smoking patients with bronchiectasis treated or not treated with inhaled corticosteroids were compared with CO levels in 37 normal non-smoking subjects. RESULTS Levels of exhaled CO were raised in patients with bronchiectasis, both those treated with inhaled corticosteroids (n = 27, median 5.5 ppm, 95% CI 5.16 to 7.76) and those not treated with inhaled corticosteroids (n = 15, median 6.0 ppm, 95% CI 4.74 to 11.8), compared with normal subjects (n = 37, median 3.0 ppm, 95% CI 2.79 to 3.81, p = 0.0024). There was no correlation between exhaled CO and HbCO levels (r = 0.42, p = 0.12) in normal subjects (n = 7), nor between the urine cotinine concentration and exhaled CO levels (r = 0.2, p = 0.12). CONCLUSIONS Increased levels of exhaled CO may reflect induction of HO-1 and oxidative stress in bronchiectasis. Measurement of exhaled CO may be useful in the management of bronchiectasis and possibly other chronic inflammatory lung disorders.

Exhaled markers of oxidative stress in idiopathic pulmonary fibrosis

Background  Expired breath condensate (EBC) has never been used to explore the level of oxidative stress in idiopathic pulmonary fibrosis (IPF). Therefore, the aim of this study was to measure the levels of H2O2 and 8‐isoprostane, as biomarkers of oxidative stress, in the EBC of patients with IPF.

Exhaled cysteinyl-leukotrienes and 8-isoprostane in patients with asthma and their relation to clinical severity.

BACKGROUND Collection of exhaled breath condensate (EBC) is a safe, non-invasive method to collect droplets of the airway surface liquid and measure mediators of airway inflammation and oxidative stress, such as cysteinyl-leukotrienes (cys-LTs) and 8-isoprostane. OBJECTIVE The aim of our study was to investigate baseline values of inflammatory lipid mediators in EBC and their relation to asthma severity. METHODS Nineteen healthy subjects, 16 mild, 12 moderate and 15 severe asthmatics were studied. All subjects attended a clinic visit for spirometry and EBC collection. The concentrations of exhaled cys-LTs and 8-isoprostane were measured by means of specific enzyme immunoassays. RESULTS 8-isoprostane levels were significantly increased in mild (49.1+/-5.2 pg/mL, p<0.001), moderate (49.7+/-5.2 pg/mL, p<0.001) and severe asthmatics (77.7+/-7.3 pg/mL, p<0.001), compared to healthy controls (16.4+/-1.6 pg/mL). Moreover, 8-isoprostane levels were significantly higher in severe compared to mild and moderate asthmatics (p<0.01). Cys-LT levels were significantly higher in moderate (34.6+/-4.4 pg/mL, p<0.05) and severe asthmatics (47.9+/-6.0 pg/mL, p<0.001), while no significant difference was found between healthy controls and mild asthmatics. 8-isoprostane levels in EBC of asthmatics strongly correlated with cys-LT levels (r=0.61, p<0.0001). CONCLUSIONS 8-isoprostane and cys-LT are detectable in EBC of healthy subjects and their levels progressively increase in asthmatic patients according to disease severity. The correlation found between these two lipid mediators indicating a link between oxidative stress and airway inflammation.

Plasma leptin and adiponectin in COPD exacerbations: Associations with inflammatory biomarkers

BACKGROUND Various systemic inflammatory markers have been evaluated for their value in acute exacerbations of chronic obstructive pulmonary disease (COPD). Leptin and adiponectin have been linked to acute exacerbations and stable COPD. OBJECTIVES To assess plasma leptin, adiponectin and their ratio in acute exacerbations of COPD and to study possible associations with inflammatory biomarkers. METHODS Plasma leptin, adiponectin and their ratio (L/A) and serum biomarkers of systemic inflammation C-reactive protein (CRP), Tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) were assessed at three time points (admission, resolution and stable phase - 8 weeks after resolution) in a selected cohort of 63 COPD patients hospitalized for acute exacerbations. Subjects with comorbidities related to adipose tissue hormones were meticulously excluded. MEASUREMENTS AND MAIN RESULTS All systemic inflammatory biomarkers, leptin and L/A ratio were elevated during admission compared to resolution and stable phase (mean L/A ratio 2.6 vs. 1.57 vs. 1.22, respectively; p<0.0001), whereas adiponectin was elevated at resolution compared to admission. Log leptin, adiponectin and L/A ratio were significantly associated with variables of systemic inflammation, after proper adjustments, both on admission and in stable condition. In stepwise multiple linear regression models, IL-6 and TNF-alpha present the most significant associations with leptin, adiponectin and their ratio. CONCLUSIONS Our data suggest that both leptin and adiponectin are associated with the systemic inflammatory process during exacerbations of COPD. The most significant associations seem to be those with IL-6 and TNF-alpha.

Exhaled Nitric Oxide and Exhaled Breath Condensate pH in Severe Refractory Asthma

BACKGROUND Distinct inflammatory cellular phenotypes of severe refractory asthma (SRA) have been reported. Fractional exhaled nitric oxide (FeNO) primarily is related to eosinophilic inflammation. Exhaled breath condensate (EBC) pH has been suggested as a noninvasive tool in the assessment of patients with asthma. We sought to determine whether FeNO and EBC pH could identify the presence and type of the underlying cellular inflammation in patients with SRA. METHODS Twenty-nine patients with SRA, 27 patients with moderate asthma, and 17 healthy subjects underwent FeNO measurement, EBC collection for pH measurement, and sputum induction for cell count identification. RESULTS FeNO was significantly higher and pH significantly lower in patients with SRA than in the other groups. In SRA, FeNO levels of > 19 parts per billion were associated with a sensitivity of 0.78 and a specificity of 0.73 for sputum eosinophilia, whereas FeNO levels of < 19 parts per billion were associated with a sensitivity of 0.63 and a specificity of 0.9 for sputum neutrophilia irrespective of the presence of eosinophils. The pH failed to predict the cellular profile in SRA, but a cutoff value of < 7.37 could predict sputum eosinophilia in moderate asthma. CONCLUSIONS In patients with SRA, different FeNO threshold values can identify those with predominant eosinophilia as well as those with neutrophilia. FeNO levels were reduced in patients with predominant neutrophilia regardless of the concomitant presence of eosinophilia. Although pH could not identify the cellular profile in SRA, it seemed to be a better index for predicting eosinophilia in moderate asthma.

A European Respiratory Society technical standard: exhaled biomarkers in lung disease

Breath tests cover the fraction of nitric oxide in expired gas (FENO), volatile organic compounds (VOCs), variables in exhaled breath condensate (EBC) and other measurements. For EBC and for FENO, official recommendations for standardised procedures are more than 10 years old and there is none for exhaled VOCs and particles. The aim of this document is to provide technical standards and recommendations for sample collection and analytic approaches and to highlight future research priorities in the field. For EBC and FENO, new developments and advances in technology have been evaluated in the current document. This report is not intended to provide clinical guidance on disease diagnosis and management. Clinicians and researchers with expertise in exhaled biomarkers were invited to participate. Published studies regarding methodology of breath tests were selected, discussed and evaluated in a consensus-based manner by the Task Force members. Recommendations for standardisation of sampling, analysing and reporting of data and suggestions for research to cover gaps in the evidence have been created and summarised. Application of breath biomarker measurement in a standardised manner will provide comparable results, thereby facilitating the potential use of these biomarkers in clinical practice. ERS technical standard: exhaled biomarkers in lung disease http://ow.ly/mAjr309DBOP

The impact of depressive symptoms on recovery and outcome of hospitalised COPD exacerbations.

The impact of depressive symptoms on outcomes of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) has not been thoroughly evaluated in prospective studies. We prospectively enrolled 230 consecutive patients hospitalised for AECOPD, without previous diagnosis of depression. Depressive symptoms were evaluated with Becks depression inventory. Pulmonary function tests, arterial blood gases, COPD assessment test (CAT) and Borg dyspnoea scale were recorded on admission and on days 3, 10 and 40. Patients were evaluated monthly for 1 year. Patients with depressive symptoms required longer hospitalisation (mean±sd 11.6±3.7 versus 5.6±4.1 days, p<0.001). Clinical variables improved during the course of AECOPD, but depressive symptoms on admission had a significant impact on dyspnoea (p<0.001) and CAT score (p=0.012) improvement. Patients with depressive symptoms presented more AECOPD (p<0.001) and more hospitalisations for AECOPD (p<0.001) in 1 year. In multivariate analysis, depressive symptoms were an independent predictor of mortality (hazard ratio 3.568, 95% CI 1.302–9.780) and risk for AECOPD (incidence rate ratio (IRR) 2.221, 95% CI 1.573–3.135) and AECOPD hospitalisations (IRR 3.589, 95% CI 2.319–5.556) in 1 year. The presence of depressive symptoms in patients admitted for AECOPD has a significant impact on recovery and is related to worse survival and increased risk for subsequent COPD exacerbations and hospitalisations in 1 year.

NEXThaler, an innovative dry powder inhaler delivering an extrafine fixed combination of beclometasone and formoterol to treat large and small airways in asthma.

Introduction: Airway inflammation and remodelling in asthma occur in the large airways and also in the small airways. The small airways are those < 2 mm in diameter and are significant sites of chronic asthmatic inflammation. It is important, therefore, to target the small as well as the large airways in any strategy for effective treatment of this disease. Areas covered: The present review deals with the recently developed fixed dose drug combination of beclometasone dipropionate/formoterol fumarate that emits extrafine particles when delivered from an innovative dry powder inhaler (DPI), NEXThaler®. The aim is to present the technical and clinical aspects of aerosolized drug delivery to the lungs. Expert opinion: The data show that the NEXThaler DPI is an efficient device for the management of persistent asthma. The evaluation of the inhalation profiles through the NEXThaler DPI demonstrates that device activation and consistent dose delivery occurs at patient achievable inhalation flow rates, and supports the broad utility of the NEXThaler DPI in patients with asthma. Overall, all the effectiveness, efficiency and satisfaction outcomes demonstrate the NEXThaler DPI is easy to use.

Body mass index is associated with leukotriene inflammation in asthmatics.

Eur J Clin Invest 2010; 41 (1): 30–38

Systemic Biomarkers in Exacerbations of COPD: The Evolving Clinical Challenge

BACKGROUND Exacerbations of COPD (ECOPD) remain a major cause of mortality and morbidity. Despite advances in the understanding of their pathophysiology, their assessment relies primarily on clinical presentation, which can be variable and difficult to predict. A large number of biomarkers already have been assessed in this context, and some appear to be promising. METHODS An online search for articles published until December 2010 was conducted using three terms for ECOPD, five terms for biomarkers, and five terms for the sampling method. Biomarkers were evaluated for their potential role in the establishment and confirmation of the diagnosis of ECOPD, the evaluation of etiology and severity, the prediction of prognosis, and the guidance of treatment decisions. RESULTS Several systemic biomarkers have been measured in the context of ECOPD, and most have been found to increase at ECOPD onset and to subside during the course of exacerbations. Correlations have been reported among these biomarkers, but direct associations with clinical variables have been more difficult to establish. Although there are several limitations yet to be addressed, some of the biomarkers, most notably C-reactive protein for the identification of an ECOPD and procalcitonin for antibiotic guidance, may provide clinically relevant information. CONCLUSIONS So far, no single biomarker has been able to gain wide acceptance, but some provide clinically useful information. The evaluation of such biomarkers in large decision-making studies is expected to become an area of intense investigation in the near future.