Konstantinos Kostikas

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 10u2005years 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.

Systemic Biomarkers in Exacerbations of COPD: The Evolving Clinical Challenge

BACKGROUNDnExacerbations 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.nnnMETHODSnAn 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.nnnRESULTSnSeveral 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.nnnCONCLUSIONSnSo 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.

The role of macrophages in obstructive airways disease: Chronic obstructive pulmonary disease and asthma

Macrophages are a major cellular component of the innate immune system, and play an important role in the recognition of microbes, particulates, and immunogens and to the regulation of inflammatory responses. In the lung, macrophages react with soluble proteins that bind microbial products in order to remove pathogens and particles and to maintain the sterility of the airway tract. Chronic obstructive pulmonary disease and asthma are both obstructive airway diseases that involve chronic inflammation of the respiratory tract which contributes to disease progression. In the case of COPD, there is increasing evidence that lung macrophages orchestrate inflammation through the release of chemokines that attract neutrophils, monocytes and T cells and the release of several proteases. On the other hand, in asthma, it seems that alveolar macrophages are inappropriately activated and are implicated in the development and progression of the disease. In this review we summarize the current basic and clinical research studies which highlight the role of macrophages in asthma and COPD.

Increased levels of angiopoietins 1 and 2 in sputum supernatant in severe refractory asthma

Airway and vascular remodeling may play a prominent role in the clinical severity of severe refractory asthma (SRA). Angiopoietin‐1 (Ang‐1) is an essential mediator of angiogenesis by establishing vascular integrity, whereas angiopoietin‐2 (Ang‐2) acts as its natural inhibitor.

Serum uric acid as a predictor of mortality and future exacerbations of COPD

Serum uric acid is increased in respiratory disease, especially in the presence of hypoxia and systemic inflammation. We evaluated serum uric acid as a biomarker for prediction of mortality and future acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Serum uric acid was measured in 314 eligible consecutive patients on admission for AECOPD. Patients were evaluated monthly for 1 year. Uric acid levels were higher in patients with more severe airflow limitation and in those experiencing frequent exacerbations. High uric acid levels (≥6.9 mg·dL−1) were an independent predictor of 30-day mortality in multivariate Cox regression analysis (HR 1.317, 95% CI 1.011–1.736; p=0.044), but not of 1-year mortality. Patients with high serum uric acid required more prolonged hospitalisation, and more often needed noninvasive ventilation and admission to the intensive care unit within 30 days. In addition, high uric acid levels were associated with increased risk and hospitalisation for AECOPD in 1 year in multivariate Poisson regression analysis (incidence rate ratio 1.184 (95% CI 1.125–1.246) and 1.190 (95% CI 1.105–1.282), respectively; both p<0.001). Serum uric acid is associated with increased 30-day mortality and risk for AECOPD and hospitalisations in 1-year follow-up. This low-cost biomarker may be useful in the identification of high-risk chronic obstructive pulmonary disease patients that could benefit from intensive management. Serum uric acid was linked with airflow limitation in COPD and predicted mortality and future exacerbations http://ow.ly/qflaZ

Exhaled breath condensate pH as a biomarker of COPD severity in ex-smokers

Endogenous airway acidification, as assessed by exhaled breath condensate (EBC) pH, is present in patients with stable COPD. The aim of this study was to measure EBC pH levels in a large cohort of COPD patients and to evaluate associations with functional parameters according to their smoking status.EBC was collected from 161 patients with stable COPD and 112 controls (current and ex-smokers). EBC pH was measured after Argon deaeration and all subjects underwent pulmonary function testing.EBC pH was lower in COPD patients compared to controls [7.21 (7.02, 7.44) vs. 7.50 (7.40, 7.66); p < 0.001] and ex-smokers with COPD had lower EBC pH compared to current smokers [7.16 (6.89, 7.36) vs 7.24 (7.09, 7.54), p = 0.03]. In ex-smokers with COPD, EBC pH was lower in patients with GOLD stage III and IV compared to patients with stage I disease (p = 0.026 and 0.004 respectively). No differences were observed among current smokers with different disease severity. EBC pH levels in ex-smokers were associated with static hyperinflation (as expressed by IC/TLC ratio), air trapping (as expressed by RV/TLC ratio) and diffusing capacity for carbon monoxide, whereas no associations were observed in current smokers.Endogenous airway acidification is related to disease severity and to parameters expressing hyperinflation and air trapping in ex-smokers with COPD. The possible role of EBC pH in COPD needs to be further evaluated in longitudinal studies.

Overnight changes in the cerebral vascular response to isocapnic hypoxia and hypercapnia in healthy humans: Protection against stroke

Background and Purpose— The reduction in hypercapnic cerebral vascular reactivity that occurs in the morning after sleep is associated with an increased risk of cerebral ischemia and stroke. It is not known if the cerebral vascular response to hypoxia is similarly reduced in the morning, but such a reduction could be considered a further risk factor for cerebral vascular disease. Methods— To test if the cerebral vascular response to hypoxia is reduced in the morning, the overnight changes in the left middle cerebral artery velocity (MCAV) in response to isocapnic hypoxia (IH) and hypercapnia before and after a normal night sleep were determined in 18 individuals. Results— From evening to morning, hypercapnic cerebral vascular reactivity decreased significantly (evening 2.0±0.4, morning 1.3±0.2 cm/sec/mm Hg; P<0.05); in contrast, the increase in MCAV in response to IH (−10% SaO2) was unchanged (evening 9.0±1.4, morning 8.7±2.2%; P>0.05). Conclusions— Our findings indicate that substantial differences exist in the regulation of the cerebral circulation in response to hypoxia and hypercapnia on waking from sleep. An intact cerebral vascular response to IH, during this time period, could be interpreted as a protective mechanism against cerebral ischemia and stroke; this is of particular relevance to patients with obstructive sleep apnea who arouse from sleep during hypoxia.

Pulmonary biomarkers in COPD exacerbations: a systematic review

Exacerbations of COPD (ECOPD) represent a major burden for patients and health care systems. Innovative sampling techniques have led to the identification of several pulmonary biomarkers. Although some molecules are promising, their usefulness in clinical practice is not yet established. Medline and Highwire databases were used to identify studies evaluating pulmonary sampled biomarkers in ECOPD. We combined 3 terms for ECOPD, 3 for biomarkers and 6 for the sampling method. Seventy-nine studies were considered eligible for inclusion in the review and were analyzed further. Pulmonary biomarkers sampled with non-invasive, semi-invasive and invasive methods were evaluated for their potential to illustrate the disease’s clinical course, to correlate to clinical variables and to predict clinical outcomes, ECOPD etiology and response to treatment. According to published data several pulmonary biomarkers assessed in ECOPD have the potential to illustrate the natural history of disease through the modification of their levels. Among the clinically relevant molecules, those that have been studied the most and appear to be promising are spontaneous and induced sputum biomarkers for reflecting clinical severity and symptomatic recovery, as well as for directing towards an etiological diagnosis. Current evidence on the clinical usefulness of exhaled breath condensate and bronchoalveolar lavage biomarkers in ECOPD is limited. In conclusion, pulmonary biomarkers have the potential to provide information on the mechanisms underlying ECOPD, and several correlate with clinical variables and outcomes. However, on the basis of published evidence, no single molecule is adequately validated for wide clinical use. Clinical trials that incorporate biomarkers in decisional algorithms are required.

Increased levels of osteopontin in sputum supernatant of smoking asthmatics.

Smoking may modify the inflammatory pattern of the asthmatic airways. Osteopontin (OPN) has been associated with inflammation and fibrosis. In asthma, sputum levels of OPN are elevated and have been related to the underlying severity and to mediators expressing remodeling and inflammation. To evaluate the levels of OPN in sputum supernatants of asthmatic patients and to investigate the possible role of smoking as well as associations with mediators and cells involved in the inflammatory and remodeling process. We studied 103 asthma patients (49 smokers) and 40 healthy subjects (20 smokers) who underwent lung function tests, bronchial hyperresponsiveness to methacholine, and sputum induction for cell count identification and measurement of OPN, TGF-β1, IL-8, IL-13 and ECP in sputum supernatants. The concentrations of all mediators were measured using enzyme immunoassays. OPN levels (pg/ml) were significantly higher in smoking asthmatics compared to non-smoking asthmatics, and both non-smoking and smoking controls [median (interquartile ranges) 1120 (651,1817) vs. 197 (118,341) vs. 50 (42,70) vs. 102 (77,110) pg/ml, respectively; p<0.001]. Regression analysis provided significant associations between OPN and sputum neutrophils, IL-8 and TGF-β1, the most significant being the one with TGF-β1. These associations were present only in smoking asthmatics. Smoking habit significantly affects sputum OPN levels in asthma. The associations of OPN with sputum neutrophils, TGF-β1 and IL-8 in smoking asthmatics suggest a possible role for OPN in the neutrophilic inflammation and remodeling process in this phenotype of asthma.