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.

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.

Recent trials demonstrated that a single brief exposure to secondhand smoke (SHS) generates acute adverse health effects. We evaluated the acute (immediately after exposure) and short-term (0.5, 1, 2, 3 and 4 h after exposure) effects of SHS on cardiac autonomic control and myocardial integrity. Nineteen adult healthy never-smokers underwent a 1 h exposure to SHS at bar/restaurant levels and a 1 h control exposure. Heart rate variability (HRV), serum cotinine, and six cardiac protein markers were assessed before, during, and up to four hours following each exposure. SHS reduced the standard deviation of normal-to-normal intervals and increased cotinine levels, creatine kinase (CK)-MB, and myoglobin (p < 0.05). We conclude that acute exposure to SHS suppresses HRV and augments CK-MB and myoglobin. The SHS-induced elevations in CK-MB and myoglobin may reflect a generalized lytic state, especially of the cardiac muscle, which is apparent for at least 2 h following the SHS exposure.

The BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity) index is well-validated for mortality prediction in chronic obstructive pulmonary disease (COPD). Concentrations of plasma pro-adrenomedullin, a surrogate for mature adrenomedullin, independently predicted 2-year mortality among inpatients with COPD exacerbation. We compared accuracy of initial pro-adrenomedullin level, BODE and BODE components, alone or combined, in predicting 1-year or 2-year all-cause mortality in a multicentre, multinational observational cohort with stable, moderate to very severe COPD. Pro-adrenomedullin was significantly associated (p<0.001) with 1-year mortality (4.7%) and 2-year mortality (7.8%) and comparably predictive to BODE regarding both (C statistics 0.691 versus 0.745 and 0.635 versus 0.679, respectively). Relative to using BODE alone, adding pro-adrenomedullin significantly improved 1-year and 2-year mortality prognostication (C statistics 0.750 and 0.818, respectively; both p<0.001). Pro-adrenomedullin plus BOD was more predictive than the original BODE including 6-min walk distance. In multivariable analysis, pro-adrenomedullin (likelihood ratio Chi-squared 13.0, p<0.001), body mass index (8.5, p=0.004) and 6-min walk distance (7.5, p=0.006) independently foretold 2-year survival, but modified Medical Research Council dyspnoea score (2.2, p=0.14) and forced expiratory volume in 1 s % predicted (0.3, p=0.60) did not. Pro-adrenomedullin plus BODE better predicts mortality in COPD patients than does BODE alone; pro-adrenomedullin may substitute for 6-min walk distance in BODE when 6-min walk testing is unavailable.

In recent years special interest has been expressed for the contribution of small airways in the pathophysiology, clinical manifestations and treatment of asthma and COPD. Small airways contribute little to the total respiratory resistance so that extensive damage of small airways may occur before the appearance of any symptoms, and this is the reason why they are characterized as the "silent zone" of airways. Furthermore, the peripheral localization of the small airways and their small diameter constitutes difficult their direct assessment. Thus, they are usually studied indirectly, taking advantage of the effects of their obstruction, such as premature closure, air trapping, heterogeneity of ventilation, and lung volume dependence of airflow limitation. Today, several heterogeneous methods for the assessment of small airways are available. These can be either functional (spirometry, plethysmography, resistance measurements, nitrogen washout, alveolar nitric oxide, frequency dependence of compliance, flow-volume curves breathing mixture of helium-oxygen) or imaging (mainly through high resolution computed tomography). The above-mentioned methods are summarized in Table 1. However, no method is currently considered as the "gold standard" and it seems that combinations of tests are needed. Furthermore, it is not clear whether the small airways are affected in all patients with asthma or COPD and their clinical significance remains under investigation. Well-designed future studies with large numbers of patients are expected to reveal which of the methods for assessing the small airways is the most accurate, reliable and reproducible, for which patients, and which can be used for the evaluation of the effects of treatment.

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.

Fetuin-A is a liver protein that may serve as an inhibitor of systemic inflammation in humans. In the present study we assessed the levels of fetuin-A in COPD patients in stable condition and on exacerbation in an attempt to evaluate it as a clinically relevant biomarker that may serve as predictor of exacerbations of COPD (ECOPD). One hundred COPD outpatients (GOLD stage I to IV) were enrolled in a tertiary University hospital and were submitted to a detailed evaluation, including pulmonary function testing, exercise capacity, quality of life and evaluation of the presence of metabolic syndrome and serum CRP. All patients were followed-up for 1 year, and 36 were re-evaluated at the onset of an ECOPD. Forty otherwise healthy smokers served as controls. Serum fetuin-A levels were reproducible at baseline, 6 and 12 months. COPD patients presented lower levels of fetuin compared to controls [394.5 (321.8-419.6) vs. 487.3 (441.0-548.0) mg/L, p < 0.001]. COPD patients with GOLD stage IV had lower fetuin-A levels compared to stages I-II and III (p < 0.05). Fetuin-A was significantly reduced at the onset of an ECOPD compared to baseline (p < 0.001) and the time to the first ECOPD significantly different between patients with high and low levels of fetuin-A [HR 2.163 (95%CI 1.104-4.238), p = 0.024). The results of the present study suggest that fetuin-A is a reproducible and clinically relevant biomarker in patients with COPD that may be useful in the identification of exacerbation-prone patients.

Chronic obstructive pulmonary disease (COPD) is a complex, multicomponent disease at the clinical, cellular, and molecular levels. Over the past few years there has been a growing interest in the field of biomarkers in COPD and a large number of studies have evaluated potential candidate molecules in different patient settings. Data on systemic biomarkers from large cohorts, including the well-characterized population of the ECLIPSE study, are now available and provide exciting information on the association of biomarkers with clinically important outcomes, including exacerbations, hospitalizations and mortality. Moreover, recent research has provided proof for the existence of distinct "systemic inflammatory" phenotypes. This review summarizes the currently available evidence on systemic biomarkers in COPD, providing clinically relevant information on the possible role of systemic biomarkers in the evaluation of disease activity and severity, phenotypes, outcomes, COPD exacerbations and treatment response and guidance. Despite the fact that no single biomarker is currently ready to characterize sufficiently the status of COPD patients, guide treatment options, and predict future events, recent studies have rendered our current knowledge definitely more advanced than a few years ago and the possible use of biomarkers in the diagnosis and management of COPD patients looks even more promising.

Chronic obstructive pulmonary disease (COPD) has been recently characterized as a disease of accelerated lung aging. The prevalence of COPD is age-dependent suggesting an intimate relationship between the pathogenesis of COPD and aging. Lung function decline, the hallmark feature of COPD evolution, is more prominent with increasing age and this decline is greater in smoking individuals. One of the major goals of COPD pharmacotherapy is the development of drugs that would be able to result in a decrease of the decline in lung function over years. However, till nowadays smoking cessation is the only known intervention which is able to decelerate lung function decline. Several mechanisms of aging, including oxidative stress, inflammation and telomere shortening have been shown to be implicated in COPD. Furthermore, numerous anti-aging molecules, including sirtuins and Nrf-2 are reduced, and pathways such as mTOR and genes such as Klotho have also been shown to be abnormal in the lungs of COPD patients. The above mechanisms have been associated with the accelerated lung aging in COPD patients. Numerous therapeutic interventions have been studied in an attempt to reverse accelerated lung aging, and some of them have already been tested in clinical trials. The aim of the present review is to summarize the mechanisms associated with the accelerated lung aging in COPD and to provide information about the possible therapeutic implications targeting those mechanisms.