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Cough variant asthma (CVA), a common asthma phenotype characterized by nonproductive cough and bronchial hyperreactivity (BHR), is usually detected by bronchial provocation tests (BPTs) which are time-consuming, expensive, and unsafe. The primary study objective was to provide proof of concept for the use of fractional exhaled nitric oxide (FENO), eosinophil count percentage in induced sputum (sEOS%), forced expiratory flow between 25 and 75% of forced vital capacity (FEF25–75%) % predicted value, and FEF25–75% z-scores as surrogate markers predicting BHR in young adults with suspected CVA; the secondary objective was to compare the diagnostic performance of the various techniques. Three hundred and ten subjects (median age 24 years) were included in a cross-sectional study. Subjects were characterized as BHR positive (POS) (n = 147) or BHR negative (NEG) (n = 163) according to methacholine BPT. Classification accuracies were expressed as areas under the receiver operator characteristic curves (AUC). Compared with BHR NEG, FEF25–75% % predicted value and FEF25–75% z-scores were lower in the BHR POS group (p < 0.001), whereas FENO (p < 0.001) and sEOS% were higher (p < 0.001). AUC values for detecting BHR were as follows: FENO, 0.98 (SD = 0.02); sEOS%, 0.98 (SD = 0.02); FEF25–75% % pred, 0.93 (SD = 0.05); FEF25–75% z scores, 0.92 (SD = 0.05). Optimal cutoff values (OCV) for BHR prediction were as follows: FENO, 32.7 ppb (sensitivity = 0.93, specificity = 0.96), sEOS%, 3.80% (sensitivity = 0.94, specificity = 0.94), FEF25–75% % predicted value, 80.0% (sensitivity = 0.90, specificity = 0.87), and FEF25–75% z-score, −0.87 (sensitivity = 0.89, specificity = 0.87). Non-invasive/semi-invasive airway inflammatory or small airway functional measures might be used as surrogate markers predicting BHR in young adults with suspected CVA.

Background. Pulmonary hypertension (PH) is a progressive fatal disease thus, noninvasive prognostic tools are needed to follow these patients. The aim of our study was to evaluate fractional exhaled nitric oxide (FeNO) and exhaled breath temperature (EBT) values in patients with PH from different causes and to correlate them with respiratory functional data. Methods. Twenty-four PH patients underwent spirometry, carbon monoxide diffusion (DLCO) test, transthoracic echocardiography, right-heart catheterization, and FeNO and EBT measurements. Results. We studied 3 groups according to the type of PH: 10 patients with pulmonary arterial hypertension (PAH) (group A), 11 patients with PH due to chronic obstructive pulmonary disease (COPD) (group B), and 3 patients with PH associated with left heart disease (group C). Mean FeNO values tend to be higher in group B (15.0 ± 9.3ppb) compared with other groups (respectively, 9.9 ± 5.7 and 8.5 ± 5.2 ppb in groups A and C; p = 0.271) but no statistical significance has been reached. Mean values of alveolar NO concentration (CANO) were higher in groups A and B compared to group C (respectively, 16.9 ± 12.6; 13.9 ± 6.8; and 6.7 ± 2.0 ppb) (p = 0.045). EBT mean values were significantly lower in group C when compared with other groups (group C: 29.0 +- 1.3°C, groups A and B: 30.9 ± 1.3 and 31.2 ± 1.2°C, respectively: p = 0.041). EBT levels were inversely correlated to mean pulmonary artery pressure (PAPm) levels (Spearman coefficient -0.481; p = 0.017). Conclusions. eNO, CANO, and EBT have been evaluated in three groups of PH patients. Interestingly EBT reduction was correlated with PAPm increase, whereas FeNO was higher in COPD patients and CANO in PAH and COPD groups. Further studies are needed to clarify EBT, FeNO, and CANO roles as biomarkers in the monitoring of patients with PH.

Introduction Patients with chronic obstructive pulmonary disease (COPD) have an increased risk of cardiovascular disease. The endothelial dysfunction likely plays a central role in increasing cardiovascular risk. Objectives This cross-sectional, study investigated the prevalence and extent of endothelial dysfunction in patients with stable COPD. Methods Peripheral arterial tonometry (PAT) was measured by post-ischemic reactive hyperemia index (RHI) in 16 COPD patients, 16 healthy controls and 16 subjects with treated systemic arterial hypertension (AH) and analysed with covariates condition (dyslipidemia, and medications). Results The prevalence of endothelial dysfunction was significantly higher in COPD group than in the other groups. Mean RHI was significantly lower in COPD patients compared with the other groups. At linear regression FEV1 and RHI were directly correlated (Spearman index = 0.553; P = .026). COPD patients in groups C and D according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages showed lower RHI compared with patients classified as A and B (P

The identification of determinants of attempts to quit smoking and quitting smoking success is crucial for effective smoking prevention and/or cessation programs. Thus, here we have conducted a survey to determine the sociodemographic characteristics of tobacco use and the potential determinants of quitting smoking among a population of 140 subjects&mdash, 101 smokers and 39 ex-smokers&mdash, referred to our clinic for respiratory diseases. Subject characteristics included demographic data, employment and education status, respiratory disease family history, smoking habits, life habits, diet, alcohol intake, and physical activity. In comparison with former smokers, active smokers were younger, lived with at least one smoking family member, and were more frequently exposed to passive smoke. They also displayed a higher coffee consumption, a higher frequency of in-between-meal snacks, and a lower chronic obstructive pulmonary disease (COPD) prevalence. In comparison with subjects who had never attempted to quit smoking, individuals who had attempted to quit smoking were younger, had a lower pack-year median, consumed a higher amount of coffee and alcohol, and conducted regular physical activity. Determinants of successful smoking cessation were older age, lower passive smoking exposure and daily coffee intake, and COPD diagnosis. Overall, our findings underscore the importance of health education in fostering successful smoking cessation in respiratory disease patients.

Chronic obstructive pulmonary disease (COPD) is a common disabling disease characterized by progressive airflow obstruction. Great efforts were spent in the development of drugs able to improve symptoms, quality of life, reduce exacerbations, hospitalizations and the frequency of death of patients with COPD. The cornerstones of treatment are bronchodilator drugs of two different classes: beta agonists and muscarinic antagonists. Currently the Global initiative for COPD suggests the use of long acting beta agonists (LABAs) and long acting muscarinic antagonists (LAMAs) in combination for the majority of COPD patients, thus great interest is associated with the developing of LAMA/LABA fixed combination in the maintenance treatment of stable COPD. Many LAMA/LABA fixed dose combinations have been licensed in different countries and the clinical use of these drugs stimulated the performance of many clinical trials. The purpose of this review is a complete criticism of pharmacological and clinical aspects related to the use of LAMA/LABA single inhalers for the maintenance treatment of stable COPD, with particular mention to the most debated topics and future prospects in the field.

Maintenance pharmacological treatment for stable chronic obstructive pulmonary disease (COPD) is based on inhaled drugs, including long-acting muscarinic receptor antagonists (LAMA), long-acting β2-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.

Chronic obstructive pulmonary disease (COPD) is characterized by poorly reversible airflow limitation, with an abnormal pulmonary and systemic inflammatory response to tobacco smoking. Systemic inflammation promotes atherosclerosis, to treat the complications of which beta-blockers are paramount. In the COPD setting, however, the use of beta-blockers has been limited by fears that they could adversely affect lung function. However, by controlling adrenergic drive and reducing the heart rate, beta-blockers could reduce the risk of arrhythmias and sudden death among COPD patients. Thus, beta-blocker use is strongly supported by evidence in COPD patients with history of myocardial infarction, but warrants consideration in other cardiovascular comorbidities. Studies specifically designed to ascertain the role of beta-blockers in patients with COPD with cardiovascular conditions are still needed, because the majority of the current evidence is based on retrospective observational studies.

Chronic Obstructive Pulmonary Disease (COPD) is defined as a disease characterized by persistent, progressive airflow limitation. Recent studies have underlined that COPD is correlated to many systemic manifestations, probably due to an underlying pattern of systemic inflammation. In COPD fractional exhaled Nitric Oxide (FeNO) levels are related to smoking habits and disease severity, showing a positive relationship with respiratory functional parameters. Moreover FeNO is increased in patients with COPD exacerbation, compared with stable ones. In alpha-1 antitrypsin deficiency, a possible cause of COPD, FeNO levels may be monitored to early detect a disease progression. FeNO measurements may be useful in clinical setting to identify the level of airway inflammation,per seand in relation to comorbidities, such as pulmonary arterial hypertension and cardiovascular diseases, either in basal conditions or during treatment. Finally, some systemic inflammatory diseases, such as psoriasis, have been associated with higher FeNO levels and potentially with an increased risk of developing COPD. In these systemic inflammatory diseases, FeNO monitoring may be a useful biomarker for early diagnosis of COPD development.

Objective Platelet activation in COPD patients is associated with an increased risk of cardiovascular events. We aimed at assessing the mean platelet volume (MPV), as an index of platelet activation, in COPD patients both when stable or during acute exacerbation (AE). Research design and methods A total of 478 patients (75 with AE) and 72 age-matched healthy controls were enrolled. Medical history, comorbidities, medications, pulmonary function tests, MPV and blood cell count, erythrocyte sedimentation rate (ERS) and C-reactive protein (CRP) were recorded. Results MPV was higher in COPD than in controls (8.7 ± 1.1 fL and 8.4 ± 0.8 fL respectively, p = 0.025) and increased with the severity of the disease as assessed by post-bronchodilator forced expiratory volume in the first second (FEV1) categorized I to IV (p > 0.05). MPV was higher in COPD patients during AE compared with stable condition (8.7 ± 1.0 fL and 8.9 ± 1.0 fL, p = 0.021). MPV ≥10.5 fL correlated with the presence of at least one co-existing cardiovascular disease (p = 0.008). No correlation was observed between MPV and CRP or ERS in patients or in controls. A negative correlation was found between platelet count and MPV in COPD patients. Limitations The retrospective design did not allow the assessment of a clear cause-effect relationship between MPV and all the pathophysiological factors considered. Conclusions Elevated MPV is associated with lower platelet count and with cardiovascular comorbidity in COPD patients. MPV is higher in more severe COPD and during AE. Present findings warrant future studies to confirm a possible clinically relevant role for platelet activation in cardiovascular risk in the COPD population.

Ageing population is constantly increasing due to rising life expectancy; consequently, the percentage of the elderly patients with asthma is increasing, as well. Fractional exhaled nitric oxide (FeNO) is a biomarker of lung inflammation, and currently it is widely used in clinical practice for asthma diagnosis and monitoring. Yet, there are no data about normal values of FeNO in patients of more than 65 years of age with normal lung function. The aim of this study was to establish adult FeNO reference values for subjects older than 65 years, according to the international guidelines. FeNO was measured in 303 healthy, nonsmoking adults more than 65 years of age, with normal spirometry values measured using the online single-breath technique. The results were analyzed by chemiluminescent detection. The FeNO levels obtained range from 5.00 to 29.9 ppb, with a mean value of 12.48 ± 2.80 ppb. A significant association of FeNO levels with age (p

Background: Forced expiratory flow at 25 and 75% of the pulmonary volume (FEF25-75%) might be considered as a marker of early airway obstruction. FEF25-75% impairment might suggest earlier asthma recognition in symptomatic subjects even in the absence of other abnormal spirometry values. Objectives: The study was designed in order to verify whether FEF25-75% impairment in a cohort of subjects with asthma-like symptoms could be associated with the risk of bronchial hyperresponsiveness (BHR) and with airway inflammation expressed as fractional exhaled nitric oxide (FeNO) and eosinophil counts in induced sputum. Methods: Four hundred adults with a history of asthma-like symptoms (10.5% allergic) underwent spirometry, determination of BHR to methacholine (PD20FEV1), FeNO analysis and sputum induction. FEF25-75% Results: All subjects had normal FVC, FEV1 and FEV1/FVC, while FEF25-75% was abnormal in 27.5% of them. FEF25-75% (z-score) was associated with PD20FEV1 (p < 0.001), FeNO (p < 0.001) and sputum eosinophils (p < 0.001). Patients with abnormal FEF25-75% showed higher levels of FeNO and eosinophils in induced sputum than did patients with normal FEF25-75% (p < 0.01 and p < 0.01, respectively). Subjects with abnormal FEF25-75% had an increased probability of being BHR positive (OR = 13.38; 95% CI: 6.7-26.7; p < 0.001). Conclusions: Our data show that abnormal FEF25-75% might be considered an early marker of airflow limitation associated with eosinophilic inflammation and BHR in subjects with asthma-like symptoms, indicating a role for FEF25-75% as a predictive marker of newly diagnosed asthma.

Crohn's Disease is an inflammatory bowel disease associated with a variety of systemic manifestations, including large and small airway involvement. The latter is most often a subclinical one, and requires expensive and invasive diagnostic approaches. Nitric Oxide (NO) can be detected non-invasively in the exhaled air (eNO) and be considered as a surrogate marker of airway inflammation. eNO tested at multiple expiratory flows can be used to distinguish the alveolar concentration of NO (CalvNO) from the total amount of fractional eNO (FeNO). The aim of our study is to compare FeNO and concentration of alveolar nitric oxide (CalvNO) levels and to assess their relationship with pulmonary involvement in Crohn's patients differing in clinical stage and therapeutic regimens versus a group of healthy subjects. Thirty Crohn's patients not showing clinical evidence of pulmonary diseases and 21 non-smoking, non-atopic healthy controls were enrolled. FeNO (14.9±10.2 ppb vs 10.1±6.3 ppb, p=0.049) and CaIvNO (4.4±2.2 ppb vs 2.6±1.9; p=0.006) values were found to be significantly higher in Crohn's patients than in healthy controls. Both FeNO and CaIvNO correlated positively with the Crohn's Disease Activity Index. In conclusion, our results for FeNO and CaIvNO confirm the presence of subclinical pulmonary involvement in Crohn's disease. eNO measurement may be of clinical value in the follow-up of Crohn's patients.

Patients with chronic obstructive pulmonary disease (COPD) are prone to clinical exacerbations that are associated with increased airway inflammation, a potent pro-thrombotic stimulus. Limited information is available on the mechanisms underlying the putative alterations of the endothelial-coagulative system during acute exacerbations. The aim was to investigate whether the activation of the endothelial-coagulative system occurs in association with the acute inflammatory response of COPD exacerbation. We monitored the blood levels of surrogate markers of inflammation: interleukin-6 (IL-6); endothelium damage: von Willebrand’s factor (vWF); clotting activation: D-dimer (D-D), and prothrombin fragment 1+2 (F1+2); fibrinolytic response: plasminogen activator inhibitor 1 (PAI-1), in COPD subjects, during hospital admission and after clinical resolution. In 30 COPD subjects, IL-6, vWF, D-D and F1+2 levels were elevated during exacerbation and decreased significantly at clinical stability (IL-6, p = 0.005; vWF, p < 0.001; D-D, p < 0.001; F1+2, p < 0.001). PAI-1 levels did not change at exacerbation compared to clinically stable situations. Positive correlations were observed between several of the markers measured. Elevation of IL-6, vWF, D-D and F1+2 levels during COPD exacerbations implies a strict association between acute inflammation, endothelial activation and clotting initiation. This was not associated with a change in PAI-1, implying an increase in the fibrinolytic response to inflammation. The pro-thrombotic nature of COPD exacerbations sustained by enhanced clotting activation appears to be mitigated by excessive fibrinolysis.

Systemic sclerosis (SSc) is a connective tissue disorder of unknown etiology that is often complicated by pulmonary involvement, with pulmonary hypertension (PH) and interstitial lung disease (ILD) being the major causes of death. It has been suggested that the amount of nitric oxide (NO) in exhaled air may predict the onset of complications. The aim of the study was to measure exhaled NO in SSc patients and investigate its relationship with pulmonary involvement with and without PH.Fifty patients (5 men and 45 women; mean age, 59.1 +/- 11.7 years [+/- SD]) with a diagnosis of SSc based on the preliminary criteria of the American Rheumatism Association, and 40 healthy control subjects (5 men and 35 women; mean age, 58.3 +/- 12.2 years) underwent exhaled NO measurements by means of a chemiluminescence analyzer, pulmonary function tests, high-resolution thorax CT, and Doppler echocardiography.Exhaled NO concentrations were significantly higher in SSc patients than control subjects (p = 0.02), and significantly lower in the patients with ILD and/or PH than in those without PH (p0.01). There was a significant inverse correlation between pulmonary artery systolic pressure and exhaled NO concentration in all of the studied patients (r = - 0.5, p0.001).Our results indicate that exhaled air NO concentrations are lower in SSc patients with lung involvement than in those without, and that SSc patients without ILD or PH have higher exhaled NO values than healthy subjects.

Background. Andolast is a new airway specific anti-inflammatory agent. The aim of the present multicentered, randomized, placebo controlled study is to investigate whether andolast produces a therapeutic response greater than placebo in asthmatic adult patients. Methods. 549 symptomatic patients with mild or moderate asthma were randomized to receive andolast at three different doses (2, 4, or 8 mg t.i.d.) or placebo for 12 weeks. Efficacy and safety were evaluated during scheduled visits with pulmonary function tests, peak expiratory flow rate (PEFR), symptoms diary and quality of life questionnaire. The primary outcome included the changes (expressed as percent variation) from baseline of the forced expiratory volume in one second (FEV1) absolute values after 12 weeks of treatment. Findings. One hundred and thirty one (131) patients were treated with andolast at the dose of 2 mg t.i.d., 128 patients at the dose of 4 mg t.i.d., 144 at the dose of 8 mg t.i.d. and 146 with placebo. Andolast produced a dose dependent significant improvement over placebo on airflow obstruction, as shown by the changes in FEV1 (andolast 2, 4, 8 mg vs. placebo: p = 0.011), especially in a subgroup of patients showing moderate airways obstruction (FEV1

The objective of this prospective, randomized, double-blind, placebo-controlled, multicenter parallel-group study was to evaluate the effect of long-term ambroxol treatment in preventing exacerbations of chronic obstructive pulmonary disease (COPD). Two hundred and forty-two outpatients with COPD defined by ATS criteria with value of FEV1 between > or =60 and 80% of predicted and history of one or more exacerbations in the previous year were recruited by 26 Respiratory Medicine Centers in Italy and treated for 1 year with one ambroxol retard capsule of 75 mg twice daily or placebo. The percentage of patients free from exacerbation at 6 months was 63% with ambroxol and 60% with placebo (p=0.366) and at 12 months 56% with ambroxol and 53% with placebo (p=0.363). In a subset of 45 patients with more severe baseline symptoms, ambroxol therapy was associated with a significant higher percentage of patients free from exacerbation compared to placebo: 63 vs. 38% (p=0.038). In conclusion, we did not find a significant difference between long-term ambroxol therapy and placebo, in preventing exacerbations in patients with COPD. In patients with more severe respiratory symptoms at baseline, however, we observed a significant difference in the cumulative exacerbation-free persistence between ambroxol and placebo, suggesting that long-term muco-regulatory therapy with ambroxol could be useful in highly symptomatic patients with COPD.

Study objectives: During a bronchial provocation test (BPT), the performance of maximal inspiratory-expiratory maneuvers, causing abrupt and marked shifts in intrathoracic pressure, may increase the risk of cardiac arrhythmias. Moreover, the inhalation of methacholine (MCh), a cholinergic agonist agent, could favor the development of unwelcome cardiovascular events, namely, cardiac arrhythmias. Subjects and methods: We studied the number and severity of cardiac arrhythmias by ECG-Holter monitoring before, during, and after BPTs with MCh challenge in a group of 46 consecutive nonselected subjects (28 men and 18 women) with clinical indications for BPT, without preexisting cardiovascular diseases, and not receiving arrhythmogenic drugs. The subjects performed a routine pulmonary function test (PFT), followed by BPT, during ECG-Holter monitoring. Determination of the serum potassium concentration, a baseline arterial blood gas analysis, and monitoring of oxyhemoglobin saturation also were performed. Results: We found no significant increase in the number of supraventricular and ventricular arrhythmias during the performance of PFTs and of BPTs with MCh in the subjects, either with or without bronchial hyperresponsiveness (BHR). However, during the performance of BPTs, we observed a significant reduction in mean heart rate. Conclusions: Our results indicate that the performance of PFTs and BPTs with MCh does not increase the cardiac arrhythmogenic risk in subjects without cardiovascular diseases, as well as in those with BHR, suggesting that these tests are safe to perform in most subjects.

Chronic Obstructive Pulmonary Disease (COPD) has been recently recognized as a condition involving more than the lungs. The presence of common factors in COPD and in other chronic extra-pulmonary diseases, as well as the co-existence of these conditions in the same adult individual, supports the hypothesis of a shared pathogenetic pathway. We will here review the interplay between coexisting COPD and the metabolic syndrome (MS), based on the most updated knowledge. We will discuss this clinical condition from the definition, to the pathophysiology and to the clinical implications. Basically, MS is more likely to be present in a COPD patients, and increased levels of circulatory pro-inflammatory proteins from both the lung and adipose tissue coincide in these patients. The relative impact of the coexisting COPD and MS may depend on several factors: the presence of physical inactivity and of systemic inflammation related to a smoking habit, sedentary lifestyle, airway inflammation and obstruction, adipose tissue and inflammatory marker activation. More studies will be required to elucidate the association between COPD and MS and to formulate individualized management approaches for this specific disease phenotype.

Current approaches to control asthma do not involve direct assessment of airway inflammation. The aim of this study is to assess whether the therapeutic adjustments of steroid treatment according to a stepwise algorithm based on sputum Eosinophils (sEos) and fractioned exhaled Nitric Oxide (FeNO) were effective in maintaining the stability of a group of stable asthmatic patients during a twelvemonth follow-up. Fourteen asthmatic patients, treated for asthma according to a previously published protocol, were enrolled in the study. The patients underwent clinical evaluation, pulmonary function tests, measuring of airway hyperresponsiveness to methacholine, and determination of FeNO and sEos at visit 1. These procedures were repeated after 6 and 12 months (Visits 2 and 3, respectively). Symptoms score gradually improved during the study (p=0.008), no changes were observed in the frequency of clinical asthma exacerbations or in airway hyperresponsiveness to methacholine. At the end of the study both sEos and FeNO were significantly improved (p=0.011 and p=0.003, respectively) and at visit 3 the median steroid dose was reduced (p=0.039) in accordance with the improving of symptoms score, FeNO and sEos values. A direct relationship was observed between the difference of FeNO values and the difference of sEos registered between visits 1 and 2 (r2=609, p0.001) and between visits 2 and 3 (r2=646, p

Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow limitation. In moderate-to-severe COPD, long-acting bronchodilators are the basis of therapy. Inhaled long-acting β(2)-agonists (LABAs) are used for the treatment of COPD. LABAs have been in use since the 1990s enabling persistent bronchodilation for 12 hours; however, sustained bronchodilation is desirable. Compared with twice-daily LABAs, new LABAs with ultra-long duration (ultra-LABAs) could provide improvements in efficacy and compliance with fast onset of action, 24-hour bronchodilation and a good safety profile. Several novel ultra-LABAs showing once-daily delivery profiles are in development. In this article, we discuss these novel agents' properties and clinical trials of their efficacy and safety, including the only licensed ultra-LABA, indacaterol.

Although an influence of advancing age on lung cellularity in healthy subjects has already been described, induced sputum reference values for cell counts in older healthy adults are not available. The aim of the present study was to evaluate the influence of age on the variation of sputum cell distribution in a considerable number of healthy subjects. A total of 70 nonatopic, nonsmoker healthy subjects aged ≥50 years underwent sputum induction and blood cell count. Sputum samples were processed and then were analyzed by optical microscopy. Differential cell counts were reported as percentages and amount of cells/mg.Sputum cell distribution of healthy subjects aged ≥50 years was mainly composed of neutrophils. Both the percentage and the amount of sputum neutrophils correlated with the subjects' age, r=0.5, p=0.00001 and r=0.32, p=0.007, respectively. This correlation was more evident in women (n=35) than in men (n=35). No correlation was found between blood neutrophils and age. The increase in sputum neutrophils was not secondary to an increase in blood neutrophils.In the studied subjects, aging was associated, particularly in women, with an increase in sputum neutrophils not related to an increase of blood neutrophils. These results could be useful in clinical and experimental settings as reference values to compare with data from subjects aged over 50 years. These data showed that sputum neutrophila can be dissociated from airway symptoms and could create a favorable background for the development of age-related lung diseases.

Chronic plaque psoriasis is associated to an increased risk of cardiovascular events. The aim of our study is to test patients with psoriasis for common markers of acquired and inherited thrombophilia. A cross-sectional study on 172 patients with psoriasis and 198 controls was carried out. The plasma levels of coagulation protein C, coagulation protein S, homocysteine, folic acid, C-reactive protein (CRP) and fibrinogen as well as activated protein C resistance and antithrombin III activity, were measured. CRP and homocysteine levels were higher in patients with psoriasis than in controls (5.9 ± 7.1 vs 3.1 ± 2.4 mg/L, p=0.0003 and 16.3 ± 12.8 vs 10.4 ± 4.6 umol/L, p=0.0001; mean ± SD) whereas folic acid was lower in psoriatic patients compared to controls (4.3 ± 7.2 vs 12.6 ± 7.9 p=0.006). Levels of coagulation protein C, coagulation protein S, fibrinogen as well as activated protein C resistance, antithrombin III activity were within normal ranges both in cases and controls. In a multivariate regression analysis, psoriasis severity was an independent predictor of higher CRP. In conclusion, high levels of serum CRP and homocysteine were found in patients with psoriasis, related to the severity of the disease. These data suggest that the increased risk of thrombotic cardiovascular events observed in psoriasis patients should be ascribed to an acquired rather than inherited thrombophilic status.

Objectives. Although the likelihood of intermediate alpha-1-antitrypsin deficiency (PiMZ) patients developing chronic obstructive pulmonary disease (COPD) remains uncertain, several investigators have suggested that a lack of antiprotease inhibitor activity may favour the development of airway inflammation with subsequent pulmonary tissue damage. The levels of exhaled nitric oxide (FeNO) in PiMZ subjects are unknown and polymorphisms in nitric oxide synthase have been linked to lung disease susceptibility in subjects with alpha-1-antitrypsin (AAT) deficiency. This study was aimed at assessing FeNO levels in a group of PiMZ subjects and comparing it with the concentrations found amongst groups of COPD and control patients. Design. A group of 31 PiMZ subjects, 31 COPD patients and 30 controls underwent pulmonary function tests, AAT assay and phenotyping, and FeNO measurement in an ambulatory setting. Results. FeNO values observed in the group of PiMZ subjects (21.6 ± 8.9 ppb) showed a significant increase compared with COPD (14.5 ± 8.7 ppb; P

The aim of the present study was to treat unstable asthma according to exhaled nitric oxide (eNO) and induced-sputum eosinophils (sEos) levels to assess if this strategy is better than the conventional approach based on symptoms and function to achieve asthma control.Fourteen patients with mild-to-moderate persistent asthma (6 men, 8 women) were recruited. During the recruitment visit, the patients, previously treated for asthma following Global Initiative for Asthma recommendations, underwent clinical evaluation and pulmonary function tests (PFTs). Then, after 4 weeks of washout from inhaled antiinflammatory treatment, the patients underwent a basal visit performing PFTs, challenge test to methacholine, and determination of eNO and sEos counts. These procedures were repeated after 3, 6, and 12 months while the patients were treated with inhaled steroids in a stepwise fashion according to eNO and sEos values.At the end of the study, a significant decrease in eNO and sEos was observed (57.2 +/- 32.8 parts per billion [ppb] vs 22.1 +/- 10.8 ppb, p0.01; and 27.1 +/- 27.1% vs 3.7 +/- 3.5%, p0.01, respectively). A close correlation (r2 = 0.41, p0.01) between the percentage change of eNO and sEos was observed only after 6 months. Patients treated according to the levels of these inflammatory markers had fewer symptoms and fewer exacerbations compared to those the year before when they were conventionally treated.Our results show the usefulness of eNO and sEos for titrating treatment in asthmatic patients in order to achieve better long-term control of the disease. The eNO decrease reflects adequately the reduction of sEos only after 6 months.

Background: Severe alpha-1-antitrypsin deficiency (AATD), due to homozygosity for the protease inhibitor (Pi) Z allele, is a genetic risk factor for chronic obstructive pulmonary disease (COPD). In a previous study the sputum of severe AATD subjects with airflow obstruction showed a pattern of cellular inflammation similar to COPD patients. It is uncertain whether heterozygotes for the Z allele or intermediate deficiency (PiMZ) have an increased risk of developing COPD. Methods: Sputum cell counts and the supernatant level of the neutrophil chemoattractant interleukin (IL)-8 were investigated by sputum induction in 10 non-smoker asymptomatic PiMZ subjects with normal pulmonary function, 10 patients with stable COPD, and 10 age matched normal subjects. Data are expressed as mean (SD). Results: The mean (SD) number of neutrophils was significantly higher (p 4 /ml) and patients with COPD (126.9 (18.8) ×10 4 /ml) than in matched normal subjects (55.0 (8.7) ×10 4 /ml). IL-8 levels were increased in PiMZ subjects (828.5 (490.6) ng/ml; median 1003.0 ng/ml; range 1260–100 ng/ml) and in COPD patients (882.5 (524.3) ng/ml; median 934.9 ng/ml; range 1506–258 mg/ml) compared with normal subjects (3.5 (0.5) ng/ml; median 3.5 ng/ml; range 4.5–2.5 ng/ml). There was a significant positive correlation between IL-8 supernatant concentration and neutrophil count in PiMZ subjects (p = 0.036; r = 0.66). An inverse correlation was observed between the percentage of neutrophils and forced expiratory volume in 1 second (% predicted) in patients with COPD (p = 0.04; r = −0.43). Conclusions: These findings indicate that PiMZ subjects without airflow obstruction may have an IL-8 related neutrophilic inflammation in the airways, similar to stable COPD patients, suggesting an increased risk of developing pulmonary changes.

Quantitative ultrasound bone densitometry (QUBD) is a new method to assess bone mineral density and bone microarchitecture. Corticosteroid (CS) therapy may diminish bone mass, alter bone quality and may influence growth hormone (GH) secretion and bone metabolism markers. Therefore, the aim of this study was to evaluate the effects of long-term therapy with inhaled CSs (ICSs) on structural bone characteristics and their correlations with GH secretion and bone markers in asthmatic patients.In a cross-sectional study, we enrolled 60 adult patients with mild to moderate persistent asthma: 22 on chronic (1 year) ICS therapy, 10 naive to ICSs treatment and 28 healthy control subjects. The groups were matched for age and BMI. Each subject underwent to QUBD at the phalanxes to assess bone microarchitecture by ultrasound bone profile index (UBPI), bone density by amplitude-dependent speed of sound (AdSos); test with GH-releasing hormone (GHRH) injection with calculation of peak GH and the Delta GH (peak GH-basal GH); and hormonal and bone markers measurements.Asthmatics treated with long-term ICS therapy showed a lower UBPI (P0.01) compared to controls (49.8 +/- 19.3 vs. 77.0 +/- 10.1, respectively) and to asthmatics never taking ICSs (73.2 +/- 9.6). In ICS-treated asthmatics, DeltaGH and GH-peak showed a significant correlation with UBPI. A significant difference was observed comparing asthmatics treated with ICSs to controls and asthmatics naive to ICSs in GH response to GHRH iv bolus. Serum osteocalcin was significantly reduced in asthmatic patients treated with ICSs.In asthmatic patients, long-term ICSs treatment produces negative effects on bone quality assessed by QUBD, and such effects are associated to an impaired GH secretion.

Some studies have demonstrated that the function of the growth hormone (GH)-insulin-like growth factor (IGF)-1 axis is significantly impaired in patients with oral corticosteroid (CS)-induced osteoporosis. The aim of study was to investigate the effects of long-term therapy with inhaled CSs (ICSs) on the hypothalamic-pituitary-GH axis by the GH response to GH-releasing hormone (GHRH), as well as bone turnover, in adult asthmatic patients.Cross-sectional study.Twenty-seven adult subjects with mild-to-moderate persistent asthma (long-term ICS therapy [ie,1 year], 20 patients; naive to ICS treatment, 7 patients) and 10 control subjects.Each subject underwent testing with an IV bolus (1 mug/kg) injection of human GHRH, and samples of GH were taken 15 min before the GHRH injection, at 0 min (ie, at the time of GHRH injection), and at 15, 30, 45, 60, and 90 min after injection to obtain values for peak GH and DeltaGH. At baseline, samples of serum IGF-1 and blood-urine were collected for bone turnover markers.The GH response to GHRH was significantly reduced in asthmatic patients receiving ICSs (peak GH, p0.05; and DeltaGH, p0.01) in comparison with control subjects and asthmatic patients who were naive to ICS therapy (peak GH and DeltaGH, p0.01). Baseline IGF-1 levels were similar in the three groups. Serum osteocalcin, a marker of bone formation, was significantly reduced (p0.01) and correlated with GH peak (r(2) = 0.34; p = 0.007) in asthmatic patients who were treated with ICSs.We conclude that GH secretion in response to GHRH is significantly reduced in adult asthmatic patients receiving therapy with ICS and that such inhibition could play a negative role in bone metabolism.

Malerba M, Radaeli A, Ceriani L, Tantucci C, Grassi V (University of Brescia, Brescia, Italy). Airway hyperresponsiveness in a large group of subjects with α1-antitrypsin deficiency: a cross-sectional controlled study. J Intern Med 2003; 253: 351–358. Background. It has been suggested that subjects with α1-antitrypsin (AAT) deficiency, lacking a major antiprotease defence against airway inflammation, might be more susceptible of development of airway hyperresponsiveness (AHR). Moreover, lower AAT blood levels might also be able to influence the severity of AHR. Objectives. This study was aimed to investigate the prevalence of AHR in a large group of subjects with AAT deficiency included in the Italian Registry and to evaluate the relationship between AAT blood levels and the severity of AHR in this population. Design. Cross-sectional controlled study. Setting. Regional Reference Centre for AAT deficiency in Brescia, Italy. Methods. A total of 114 subjects with AAT deficiency underwent pulmonary function tests. Eighty-six were eligible to perform a bronchial provocation test with methacholine (MCh) (baseline FEV1 > 60% predicted) to assess the provocative dose producing a 20% fall of FEV1 (PD20FEV1). Similar measurements were performed in a control group of 27 age-matched normal subjects. Results. The prevalence of AHR (PD20FEV1

Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease characterized by airflow limitation that is not fully reversible. Bronchodilator therapy is the cornerstone in COPD treatment. Bronchodilation in COPD is mainly achieved via administration of long- and ultralong-acting β2-agonists and with long-acting muscarinic antagonists. New combinations of bronchodilators with dual-acting muscarinic antagonist and β2-agonist properties have been licensed, and others are currently being developed with the aim of achieving once-daily dosing, and therefore may improve the likelihood of treatment compliance. These combination bronchodilators include glycopyrronium bromide/indacaterol maleate, umeclidinium (UMEC) bromide/vilanterol trifenatate (VI), aclidinium bromide/formoterol and tiotropium bromide/olodaterol (Boehringer Ingelheim, Germany). This review will focus mainly on studies and clinical trials involving the novel fixed-dose combination of UMEC/VI at doses of 125/25 μg and 62.5/25 μg in patients with COPD. Data from large clinical trials involving more than 4,500 COPD patients indicate that UMEC/VI is an effective once-daily treatment in COPD with improved pulmonary function. Future studies assessing the impact of this combination on exacerbations, delay in disease progression, and health status in patients with COPD are warranted.

Background: Inhaled corticosteroids (ICS) treatment for asthma control is generally focused on lung function and symptoms, but inadequately correlated with airway inflammation. Objective: To compare asthma control in a group of patients whose treatment was based on fraction of exhaled nitric oxide (FENO) and sputum eosinophils (intervention group) with a group in whom treatment was based on clinical score (control group). Study design and primary outcome: Randomized parallel-group longitudinal 24-month study including 5 visits every 6 months. A combination of asthma exacerbation rate and symptom score at 24 months was the primary outcome. Participants: Fourteen patients with eosinophilic asthma per group were included. Results: In the intervention group, exacerbation rate/patient/year was reduced at 12 months (0.82) (-73%) and, to a greater extent at 24 months (0.5) (-84%) compared with baseline (3.21, p