Elevated serum polyclonal immunoglobulin free light chains in patients with severe asthma.

Background: Inflammation plays a pivotal role in the pathophysiology of asthma. Free light chains (FLC) can cause inflammation by mast cell antigen-activation. Serum immunoglobulin (Ig) FLC κ, but not λ, were shown elevated in adult males with asthma. We sought to investigate if serum Ig FLC concentrations are affected by asthma severity and their relationships with inflammatory outcomes. Methods: By using immunoassays, we measured serum κ and λ Ig FLCs in 24 severe persistent asthma patients, 15 patients with moderate persistent asthma, 15 steroid-naïve mild persistent asthma patients and 20 healthy control subjects in a cross-sectional observational study. Total and specific serum IgE concentrations, fractional exhaled nitric oxide (FENO), lung function, peripheral blood eosinophils and neutrophils, and C reactive protein (CRP) were also measured. Results: Serum κ FLC concentrations were elevated in severe asthma patients compared mild asthma patients (p < 0.05) and healthy subjects (p < 0.05). Serum λ FLCs were higher in severe asthma patients than in healthy subjects (p < 0.05) and correlated with blood eosinophil counts (percentage, κ: r = 0.51, p = 2.9678-6; λ: r = 0.42, p = 1.7377-4; absolute values, κ: r = 0.45, p = 6.1284-5; λ: r = 0.38, p = 7.8261-4), but not with total or specific serum IgE. In severe asthma patients, serum Ig FLC correlated with serum CRP (κ: r = 0.33; p = 0.003; λ: r = 0.38, p = 8.8305-4) and blood neutrophil cell counts (percentage, κ: r = 0.31; p = 0.008; λ: r = 0.29, p = 0.01; absolute values, κ: r = 0.40; p = 3.9176-4; λ: r = 0.40, p = 4.5479-4), were elevated in subjects with blood eosinophilia (≥300 cells/µL) (n = 13) compared with non-eosinophilic subjects (n = 10) (κ: 19.2 ± 1.2 mg/L versus 12.1 ± 1.3 mg/L, p < 0.001; λ: 27.2 ± 2.6 mg/L versus 16.8 ± 2.5 mg/L, p < 0.01), but were similar in atopic (n = 15) versus nonatopic subjects (n = 9) (κ: p = 0.20; λ: p = 0.80). Serum FLC were negatively correlated with lung function tests, including forced expiratory volume in one second (FEV1) (κ: r = -0.33; p = 0.0034; λ: r = -0.33; p = 0.0035), and FEV1/forced vital capacity ratio (κ: r = -0.33; p = 0.0034; λ: r = -0.33; p = 0.0036). Conclusion: Serum Ig FLCs are elevated in severe asthma adults and might represent new surrogate markers of inflammation. The pathophysiological implications of these findings require further research. This study was approved by the ethics committee of the University Hospital Agostino Gemelli Foundation and Catholic University of the Sacred Heart (approval number P/1034/CE2012).

Effects of different steam injection conditions on cappuccino's nutritional profile.

The quality parameters of cappuccinos prepared with pasteurized milk or ultra-high-temperature milk steam-injected at different temperatures by a professional coffee machine have been assessed. In particular, the protein profile, the content of vitamins and lactose, the lipid peroxidation process, and the involvement of milk proteins in the foam formation were evaluated. The nutritional quality of milk seems not affected by the steam injection treatment carried out at a temperature of 60-65 °C, but at higher temperatures a decrement of lactoperoxidase, vitamin B6 and folic acid was observed. The milk used in cappuccino preparation is very important: pasteurized milk can form a more consistent and lasting foam with respect to ultra-high-temperature milk because of the presence of ß-lactoglobulin and lactoferrin, both playing an important role in the foam formation and stability. This work would provide additional information to the coffee industry for the preparation of high nutritional and organoleptic quality cappuccinos.

Effects of Ageing on Donkey Meat Chemical Composition, Fatty Acid Profile and Volatile Compounds.

Donkey meat samples obtained from muscle Longissimus Thoracis Lumborum (LTL) taken from 14 entire donkey males slaughtered at 20 months and aged for 1, 8 and 15 days were analysed with the aim of determining the chemical composition, physical attributes, fatty acid profile and volatile compounds. Ageing did not significantly affect the chemical composition and colour parameters, while cooking loss was significantly (p < 0.05) higher at 8 and 15 days of ageing. Thiobarbituric acid reactive substances (TBARS) content significantly (p < 0.01) increased during ageing, while shear force values significantly (p < 0.01) decreased. Ageing significantly (p < 0.05) increased polyunsaturated fatty acids (PUFAs) determined both at 8 and 15 days after slaughter. Volatile compounds were analysed using solid-phase microextraction (SPME) and gas chromatography−mass spectrometry (GC−MS). Among 109 volatile compounds determined in donkey meat, hydrocarbons were the most common molecules detected. Ageing affected 21 of the detected volatile compounds; both total aldehydes and total ketones contents were significantly (p < 0.05) higher 15 days after slaughter. Total furans and total alcohols were significantly (p < 0.01) higher 15 days after slaughter, as well. Significant modifications of donkey meat volatile compounds can be attributed to ageing periods longer than 7 days.

Effects of Donkeys Rearing System on Performance Indices, Carcass, and Meat Quality.

This study compared growth rates, carcass, and meat quality obtained from 24 male crossbred donkey foals reared for meat production under an intensive (I) or extensive (E) feeding system. Donkeys were slaughtered at 16 months of age; the average final body weight, hot and cold carcass weight, and hot and cold dressing percentage were significantly higher (p < 0.05) in the I group. Samples of Longissimus Thoracis et Lumborum (LTL) were taken from each foal for chemical and physical analysis. Group I showed significant (p < 0.05) higher intramuscular fat, while the E group showed significantly (p < 0.05) higher protein and unsaturated fatty acids (UFA) contents, including n-3 essential fatty acids. Saturated fatty acids (SFA) and glycogen were significantly higher (p < 0.05) in the intensive system, monounsaturated fatty acids (MUFA) were significantly higher in the extensive system. The ratio PUFA/SFA was significantly higher (p < 0.05) in group E. The Thrombogenic Index (TI) was significantly higher (p < 0.05) in the I group. Meat tenderness was significantly higher (p < 0.05) in group I. The feeding system had no effect on cholesterol content and meat color characteristics. Donkeys average daily gain, carcass weight, and some meat quality parameters were significantly affected by the rearing system.

Vitamins in Human and Donkey Milk: Functional and Nutritional Role.

BACKGROUND: Whole milk is a good source of all the nutrients, and it also contains a sufficient number of vitamins to permit regular the growth of the neonate. Dairy cow milk can create allergy in infants less than 12 months old because of the high caseins and ß-lactoglobulin content. In these circumstances, donkey milk can represent a good replacement for dairy cows' milk in children affected by Cow Milk Protein Allergy (CMPA) because of its close chemical composition with human milk, mainly due to its low protein and low mineral content. Milk vitamin content is highly variable among mammalian species and it is strictly correlated with the vitamin status and the diet administered to the mother. Fat-soluble vitamins content in donkey milk is, on average, lower compared to ruminants' milk, while vitamin C content determined in donkey milk is higher compared to dairy cows' milk, showing a great similarity with human milk. In donkey milk, the content of vitamins of the B-complex such as thiamine, riboflavin, niacin, pyridoxine, and folic acid is higher compared to human milk. The use of donkey milk as a new functional food must be further evaluated in interdisciplinary clinical trials in which pediatricians, dietitians, and food scientists must be involved to deepen the knowledge about the positive health impact of donkey milk in different sensitive people, especially children and the elderly.

Proteomic characterization of kefir milk by two-dimensional electrophoresis followed by mass spectrometry.

Kefir is a type of fermented milk obtained thanks to the introduction of "kefir grains" in mammalian milk. Kefir grains consist of lactic and acetic acid bacteria and yeasts in alternative proportions that are held together by a matrix of complex sugars known as "kefiran." Thanks to the fermentative process, the kefir milk is rich in nutraceutical substances such as amino acids, vitamins, and mineral salts. The most valuable compounds of kefir fermentation are mainly lactic acid, exopolysaccharides, and bioactive peptides, the resulting products of proteolytic release from milk proteins (caseins and whey proteins). Among the nutraceutical properties of kefir are antimicrobial and antitumor activity, immunomodulating effect, and cholesterol-lowering effect. Therefore, in light of these intriguing properties of kefir milk, in this work, a proteomic analysis, by two-dimensional electrophoresis followed by mass spectrometry, has been performed. As a result, milk-derived polypeptides were identified in commercial kefir milk from organic farming. In particular, polypeptides deriving from κ-, αs1 -, and αs2 -caseins that may have potentially beneficial effects on human health have been detected.

Development of a Sensing Array for Human Breath Analysis Based on SWCNT Layers Functionalized with Semiconductor Organic Molecules.

A sensor array based on heterojunctions between semiconducting organic layers and single walled carbon nanotube (SWCNT) films is produced to explore applications in breathomics, the molecular analysis of exhaled breath. The array is exposed to gas/volatiles relevant to specific diseases (ammonia, ethanol, acetone, 2-propanol, sodium hypochlorite, benzene, hydrogen sulfide, and nitrogen dioxide). Then, to evaluate its capability to operate with real relevant biological samples the array is exposed to human breath exhaled from healthy subjects. Finally, to provide a proof of concept of its diagnostic potential, the array is exposed to exhaled breath samples collected from subjects with chronic obstructive pulmonary disease (COPD), an airway chronic inflammatory disease not yet investigated with CNT-based sensor arrays, and breathprints are compared with those obtained from of healthy subjects. Principal component analysis shows that the sensor array is able to detect various target gas/volatiles with a clear fingerprint on a 2D subspace, is suitable for breath profiling in exhaled human breath, and is able to distinguish subjects with COPD from healthy subjects based on their breathprints. This classification ability is further improved by selecting the most responsive sensors to nitrogen dioxide, a potential biomarker of COPD.

NMR-Based Metabolomics for the Assessment of Inhaled Pharmacotherapy in Chronic Obstructive Pulmonary Disease Patients.

The aim of this proof-of-concept, pilot study was the evaluation of the effects of steroid administration and suspension of an inhaled corticosteroid (ICS)-long-acting ß2-agonist (LABA) extrafine fixed dose combination (FDC) on metabolomic fingerprints in subjects with chronic obstructive pulmonary disease (COPD). We hypothesized that a comprehensive metabolomics approach discriminates across inhaled pharmacotherapies and that their effects on metabolomic signatures depend on the biological fluids analyzed. We performed metabolomics via nuclear magnetic resonance (NMR) spectroscopy in exhaled breath condensate (EBC), sputum supernatants, serum, and urine. Fourteen patients suffering from COPD who were on regular inhaled fluticasone propionate/salmeterol therapy (visit 1) were consecutively treated with 2-week beclomethasone dipropionate/formoterol (visit 2), 4-week formoterol alone (visit 3), and 4-week beclomethasone/formoterol (visit 4). The comprehensive NMR-based metabolomics approach showed differences across all pharmacotherapies and that different biofluids provided orthogonal information. Serum formate was lower at visits 1 versus 3 (P = 0.03), EBC formate was higher at visit 1 versus 4 (P = 0.03), and urinary 1-methyl-nicotinamide was lower at 3 versus 4 visit (P = 0.002). NMR-based metabolomics of different biofluids distinguishes across inhaled pharmacotherapies, provides complementary information on the effects of an extrafine ICS/LABA FDC on metabolic fingerprints in COPD patients, and might be useful for elucidating the ICS mechanism of action.

Metabolomic Analysis by Nuclear Magnetic Resonance Spectroscopy as a New Approach to Understanding Inflammation and Monitoring of Pharmacological Therapy in Children and Young Adults With Cystic Fibrosis.

15-F2t-Isoprostane, a reliable biomarker of oxidative stress, has been found elevated in exhaled breath condensate (EBC), a non-invasive technique for sampling of airway secretions, in patients with cystic fibrosis (CF). Azithromycin has antioxidant properties in experimental models of CF, but its effects on oxidative stress in CF patients are largely unknown. Primary objective of this pilot, proof-of-concept, prospective, parallel group, pharmacological study, was investigating the potential antioxidant effects of azithromycin in CF patients as reflected by EBC 15-F2t-isoprostane. Secondary objectives included studying the effect of azithromycin on EBC and serum metabolic profiles, and on serum 15-F2t-isoprostane. In CF patients who were on maintenance treatment with oral vitamin E (200 UI once daily), treatment with oral azithromycin (250 or 500 mg depending on body weight) plus vitamin E (400 UI once daily) (group A) (n = 24) or oral vitamin E alone (400 UI once daily) (group B) (n = 21) was not associated with changes in EBC 15-F2t-isoprostane concentrations compared with baseline values after 8-weeks treatment or 2 weeks after treatment suspension. There was no between-group difference in post-treatment EBC 15-F2t-isoprostane. Likewise, no within- or between-group differences in serum 15-F2t-isoprostane concentrations were observed in either study group. NMR spectroscopy-based metabolomics of EBC shows that suspension of both azithromycin plus vitamin E and vitamin E alone has a striking effect on metabolic profiles in EBC. Between-group comparisons show that EBC metabolite distribution after treatment and 2 weeks after treatment suspension is different. Quantitative differences in ethanol, saturated fatty acids, acetate, acetoin/acetone, and methanol are responsible for these differences. Our study was unable to show antioxidant effect of azithromycin as add-on treatment with doubling the dose of oral vitamin E as reflected by 15-F2t-isoprostane concentrations in EBC. Add-on therapy with azithromycin itself does not induce EBC metabolite changes, but its suspension is associated with EBC metabolic profiles that are different from those observed after vitamin E suspension. The pathophysiological and therapeutic implications of these findings in patients with stable CF are unknown and require further research. Preliminary data suggest that EBC NMR-based metabolomics might be used for assessing the effects of pharmacological treatment suspension in stable CF patients.

Breathomics for Assessing the Effects of Treatment and Withdrawal With Inhaled Beclomethasone/Formoterol in Patients With COPD.

Background: Prospective pharmacological studies on breathomics profiles in COPD patients have not been previously reported. We assessed the effects of treatment and withdrawal of an extrafine inhaled corticosteroid (ICS)-long-acting ß2-agonist (LABA) fixed dose combination (FDC) using a multidimensional classification model including breathomics. Methods: A pilot, proof-of-concept, pharmacological study was undertaken in 14 COPD patients on maintenance treatment with inhaled fluticasone propionate/salmeterol (500/50 µg b.i.d.) for at least 8 weeks (visit 1). Patients received 2-week treatment with inhaled beclomethasone dipropionate/formoterol (100/6 µg b.i.d.) (visit 2), 4-week treatment with formoterol alone (6 µg b.i.d.) (visit 3), and 4-week treatment with beclomethasone/formoterol (100/6 µg b.i.d.) (visit 4). Exhaled breath analysis with two e-noses, based on different technologies, and exhaled breath condensate (EBC) NMR-based metabolomics were performed. Sputum cell counts, sputum supernatant and EBC prostaglandin E2 (PGE2) and 15-F2t-isoprostane, fraction of exhaled nitric oxide, and spirometry were measured. Results: Compared with formoterol alone, EBC acetate and sputum PGE2, reflecting airway inflammation, were reduced after 4-week beclomethasone/formoterol. Three independent breathomics techniques showed that extrafine beclomethasone/formoterol short-term treatment was associated with different breathprints compared with regular fluticasone propionate/salmeterol. Either ICS/LABA FDC vs. formoterol alone was associated with increased pre-bronchodilator FEF25-75% and FEV1/FVC (P = 0.008-0.029). The multidimensional model distinguished fluticasone propionate/salmeterol vs. beclomethasone/formoterol, fluticasone propionate/salmeterol vs. formoterol, and formoterol vs. beclomethasone/formoterol (accuracy > 70%, P < 0.01). Conclusions: Breathomics could be used for assessing ICS treatment and withdrawal in COPD patients. Large, controlled, prospective pharmacological trials are required to clarify the biological implications of breathomics changes. EUDRACT number: 2012-001749-42.

The discovery and development of aclidinium bromide for the treatment of chronic obstructive pulmonary disease.

INTRODUCTION: Bronchodilators, including long-acting muscarinic receptor antagonists (LAMAs), are a mainstay of the pharmacological treatment of chronic obstructive pulmonary disease (COPD). LAMAs act as bronchodilators principally by antagonizing airway smooth muscle cells M3 muscarinic receptors. Aclidinium bromide is a twice-daily LAMA which was developed to improve on the efficacy and/or safety of previous LAMAs. Area covered: Herein, the authors present the pharmacotherapeutic role of aclidinium in COPD and point out unmet need in this research area. The following aspects are covered: a) the discovery and medicinal chemistry of aclidinium bromide; b) an overview of the market; c) its mechanism of action; d) its pharmacokinetic/pharmacodynamic profile derived from pre-clinical studies; e) the clinical studies which led to its licensing; f) the evidence from meta-analyses; g) the aclidinium/formoterol fixed dose combination for COPD and h) priorities in this area of research. Expert opinion: Aclidinium bromide has the pharmacological properties, safety and efficacy profile and inhaler characteristics which makes it a valuable therapeutic option for pharmacological management of patients with COPD. Due to its rapid biotransformation into inactive metabolites, aclidinium is potentially one of the safest LAMAs. Further head-to-head randomized clinical trials are required to define efficacy and safety of aclidinium when compared to once-daily LAMAs. The clinical relevance of airway anti-remodeling effects of aclidinium has to be defined.

Comparison of two exhaled biomarkers in children with and without sleep disordered breathing.

OBJECTIVE: Airway oxidative stress and inflammation are likely to be involved in sleep disordered breathing (SDB) in children. We aimed to measure concentrations of 8-isoprostane (8-IsoP) in the exhaled breath condensate (EBC) and exhaled nitric oxide (FENO) in patients with SBD and healthy children, in order to assess the relationship between these two biomarkers, disease severity, and overnight changes. METHODS: Patients with SDB (n = 46) and healthy controls (n = 20) aged 4.5-15.1 years (M/F: 36/30) underwent exhaled measurements. Patients with SDB underwent standard polysomnography to define primary snoring (PS: AHI < 1) and obstructive sleep apnea (OSA). Upon awakening the following morning, FENO was measured and EBC was collected for the measurement of EBC 8-IsoP. RESULTS: OSA patients yielded higher awakening levels of 8-IsoP in EBC than PS patients and control subjects. The 8-IsoP levels, though not FENO, correlated with AHI (r = 0.40, p = 0.003) and SaO2 (r = -0.50, p = 0.001). Cut-off levels of 8-IsoP predicted OSA with a high AUC value (0.84, p = 0.000). Sensitivity and specificity for 8-IsoP levels above the percentile 50 (33.3 pg/mL) were 76.5% and 78.1%, respectively. 8-IsoP levels did not change from the evening to morning session, whereas morning FENO levels rose significantly only in patients with mild OSA (p = 0.03). CONCLUSION: Levels of 8-IsoP, though not FENO, distinguish children with OSA from those with PS or healthy, correlate with disease severity and closely predict OSA in the whole sample.

Single-inhaler triple therapy utilizing the once-daily combination of fluticasone furoate, umeclidinium and vilanterol in the management of COPD: the current evidence base and future prospects.

Maintenance pharmacological treatment for stable chronic obstructive pulmonary disease (COPD) is based on inhaled drugs, including long-acting muscarinic receptor antagonists (LAMA), long-acting ß2-adrenoceptor agonists (LABA) and inhaled corticosteroids (ICS). Inhaled pharmacological treatment can improve patients' daily symptoms and reduce decline of pulmonary function and acute exacerbation rate. Treatment with all three inhaled drug classes is reserved for selected, more severe, patients with COPD when symptoms are not sufficiently controlled by dual LABA/LAMA therapy and exacerbations are frequent. This review focuses on the role of single-inhaler triple therapy with once-daily fluticasone furoate/umeclidinium/vilanterol fixed-dose combination, which is in phase III clinical development for maintenance treatment of severe-to-very severe COPD. In this review, we summarize evidence providing the rationale for its use in COPD and discuss the gaps to be filled in this pharmacotherapeutic area.

Dupilumab for the treatment of asthma.

INTRODUCTION: Dupilumab (REGN668/SAR231893), produced by a collaboration between Regeneron and Sanofi, is a monoclonal antibody currently in phase III for moderate-to-severe asthma. Dupilumab is directed against the α-subunit of the interleukin (IL)-4 receptor and blocks the IL-4 and IL-13 signal transduction. Areas covered: Pathophysiological role of IL-4 and IL-13 in asthma; mechanism of action of dupilumab; pharmacology of IL-4 receptor; phase I and phase II studies with dupilumab; regulatory affairs. Expert opinion: Patients with severe asthma who are not sufficiently controlled with standard-of-care represent the target asthma population for dupilumab. If confirmed, efficacy of dupilumab in both eosinophilic and non-eosinophilic severe asthma phenotype might represent an advantage over approved biologics for asthma, including omalizumab, mepolizumab, and reslizumab. Head-to-head studies to compare dupilumab versus other biologics with different mechanism of action are required. Pediatric studies with dupilumab are currently lacking and should be undertaken to assess efficacy and safety of this drug in children with severe asthma. The lack of preclinical data and published results of the completed four phase I studies precludes a complete assessment of the pharmacological profile of dupilumab. Dupilumab seems to be generally well tolerated, but large studies are required to establish its long-term safety and tolerability.

Triple inhaled therapy for chronic obstructive pulmonary disease.

Combining individual drugs in a single inhaler is the most convenient way to deliver triple therapy. A long-acting muscarinic receptor antagonist (LAMA) added to an inhaled corticosteroid (ICS)/long-acting ß2-adrenoceptor agonist (LABA) fixed-dose combination (FDC) can improve efficacy of pharmacological treatment of patients with chronic obstructive pulmonary disease (COPD). New inhaled ICS/LABA/LAMA FDCs, including fluticasone furoate/vilanterol/umeclidinium, budesonide/formoterol/glycopyrronium and beclometasone/formoterol/glycopyrronium, are in Phase III of clinical development for COPD. Triple inhaled therapy might be particularly useful in patients with severe to very severe COPD, above all in those with peripheral blood or sputum eosinophilia, asthma-COPD overlap syndrome (ACOS) or frequent exacerbators. Future prospective studies should assess efficacy and safety of triple ICS/LABA/LAMA therapy in selected COPD phenotypes.

Investigational prostaglandin D2 receptor antagonists for airway inflammation.

INTRODUCTION: By activating DP1 and DP2 receptors on immune and non-immune cells, prostaglandin D2 (PGD2), a major metabolic product of cyclo-oxygenase pathway released after IgE-mediated mast cell activation, has pro-inflammatory effects, which are relevant to the pathophysiology of allergic airway disease. At least 15 selective, orally active, DP2 receptor antagonists and one DP1 receptor antagonist (asapiprant) are under development for asthma and/or allergic rhinitis. AREAS COVERED: In this review, the authors cover the pharmacology of PGD2 and PGD2 receptor antagonists and look at the preclinical, phase I and phase II studies with selective DP1 and DP2 receptor antagonists. EXPERT OPINION: Future research should aim to develop once daily compounds and increase the drug clinical potency which, apart from OC000459 and ADC-3680, seems to be relatively low. Further research and development of DP2 receptor antagonists is warranted, particularly in patients with severe uncontrolled asthma, whose management is a top priority. Pediatric studies, which are not available, are required for assessing the efficacy and safety of this novel drug class in children with asthma and allergic rhinitis. Studies on the efficacy of DP2 receptor antagonists in various asthma phenotypes including: smokers, obese subjects, early vs late asthma onset, fixed vs reversible airflow limitation, are required for establishing their pharmacotherapeutic role.

Exhaled and non-exhaled non-invasive markers for assessment of respiratory inflammation in patients with stable COPD and healthy smokers.

We aimed at comparing exhaled and non-exhaled non-invasive markers of respiratory inflammation in patients with chronic obstructive pulmonary disease (COPD) and healthy subjects and define their relationships with smoking habit. Forty-eight patients with stable COPD who were ex-smokers, 17 patients with stable COPD who were current smokers, 12 healthy current smokers and 12 healthy ex-smokers were included in a cross-sectional, observational study. Inflammatory outcomes, including prostaglandin (PG) E2 and 15-F2t-isoprostane (15-F2t-IsoP) concentrations in exhaled breath condensate (EBC) and sputum supernatants, fraction of exhaled nitric oxide (FENO) and sputum cell counts, and functional (spirometry) outcomes were measured. Sputum PGE2 was elevated in both groups of smokers compared with ex-smoker counterpart (COPD: P < 0.02; healthy subjects: P < 0.03), whereas EBC PGE2 was elevated in current (P = 0.0065) and ex-smokers with COPD (P = 0.0029) versus healthy ex-smokers. EBC 15-F2t-IsoP, a marker of oxidative stress, was increased in current and ex-smokers with COPD (P < 0.0001 for both) compared with healthy ex-smokers, whereas urinary 15-F2t-IsoP was elevated in both smoker groups (COPD: P < 0.01; healthy subjects: P < 0.02) versus healthy ex-smokers. FENO was elevated in ex-smokers with COPD versus smoker groups (P = 0.0001 for both). These data suggest that the biological meaning of these inflammatory markers depends on type of marker and biological matrix in which is measured. An approach combining different types of outcomes can be used for assessing respiratory inflammation in patients with COPD. Large studies are required to establish the clinical utility of this strategy.

Electronic Nose and Exhaled Breath NMR-based Metabolomics Applications in Airways Disease.

Breathomics, the multidimensional molecular analysis of exhaled breath, includes analysis of exhaled breath with gas-chromatography/mass spectrometry (GC/MS) and electronic noses (e-noses), and metabolomics of exhaled breath condensate (EBC), a non-invasive technique which provides information on the composition of airway lining fluid, generally by high-resolution nuclear magnetic resonance (NMR) spectroscopy or MS methods. Metabolomics is the identification and quantification of small molecular weight metabolites in a biofluid. Specific profiles of volatile compounds in exhaled breath and metabolites in EBC (breathprints) are potentially useful surrogate markers of inflammatory respiratory diseases. Electronic noses (e-noses) are artificial sensor systems, usually consisting of chemical cross-reactive sensor arrays for characterization of patterns of breath volatile compounds, and algorithms for breathprints classification. E-noses are handheld, portable, and provide real-time data. E-nose breathprints can reflect respiratory inflammation. E-noses and NMR-based metabolomics of EBC can distinguish patients with respiratory diseases such as asthma, COPD, and lung cancer, or diseases with a clinically relevant respiratory component including cystic fibrosis and primary ciliary dyskinesia, and healthy individuals. Breathomics has also been reported to identify patients affected by different types of respiratory diseases. Patterns of breath volatile compounds detected by e-nose and EBC metabolic profiles have been associated with asthma phenotypes. In combination with other -omics platforms, breathomics might provide a molecular approach to respiratory disease phenotyping and a molecular basis to tailored pharmacotherapeutic strategies. Breathomics might also contribute to identify new surrogate markers of respiratory inflammation, thus, facilitating drug discovery. Validation in newly recruited, prospective independent cohorts is essential for development of e-nose and EBC NMRbased metabolomics techniques.

Pharmacological treatment of chronic obstructive pulmonary disease: from evidence-based medicine to phenotyping.

Chronic obstructive pulmonary disease (COPD) is characterized by large phenotype variability, reflected by a highly variable response to pharmacological treatment. Nevertheless, current guidelines suggest that patients with COPD of similar severity should be treated in the same way. The phenotype-based pharmacotherapeutic approach proposes bronchodilators alone in the nonfrequent exacerbator phenotype and a combination of bronchodilators and inhaled corticosteroids in patients with asthma-COPD overlap syndrome (ACOS) and moderate-to-severe exacerbator phenotype. The clinical importance of phenotypes is changing the paradigm of COPD management from evidence-based to personalized medicine. However, the personalized pharmacological strategy of COPD has to be validated in future clinical studies.