Evaluation of COVID-19 impact on DELAYing diagnostic-therapeutic pathways of lung cancer patients in Italy (COVID-DELAY study): fewer cases and higher stages from a real-world scenario.

INTRODUCTION: COVID-19 has disrupted the global health care system since March 2020. Lung cancer (LC) patients (pts) represent a vulnerable population highly affected by the pandemic. This multicenter Italian study aimed to evaluate whether the COVID-19 outbreak had an impact on access to cancer diagnosis and treatment of LC pts compared with pre-pandemic time. METHODS: Consecutive newly diagnosed LC pts referred to 25 Italian Oncology Departments between March and December 2020 were included. Access rate and temporal intervals between date of symptoms onset and diagnostic and therapeutic services were compared with the same period in 2019. Differences between the 2 years were analyzed using the chi-square test for categorical variables and the Mann-Whitney U test for continuous variables. RESULTS: A slight reduction (-6.9%) in newly diagnosed LC cases was observed in 2020 compared with 2019 (1523 versus 1637, P = 0.09). Newly diagnosed LC pts in 2020 were more likely to be diagnosed with stage IV disease (P < 0.01) and to be current smokers (someone who has smoked more than 100 cigarettes, including hand-rolled cigarettes, cigars, cigarillos, in their lifetime and has smoked in the last 28 days) (P < 0.01). The drop in terms of new diagnoses was greater in the lockdown period (percentage drop -12% versus -3.2%) compared with the other months included. More LC pts were referred to a low/medium volume hospital in 2020 compared with 2019 (P = 0.01). No differences emerged in terms of interval between symptoms onset and radiological diagnosis (P = 0.94), symptoms onset and cytohistological diagnosis (P = 0.92), symptoms onset and treatment start (P = 0.40), and treatment start and first radiological revaluation (P = 0.36). CONCLUSIONS: Our study pointed out a reduction of new diagnoses with a shift towards higher stage at diagnosis for LC pts in 2020. Despite this, the measures adopted by Italian Oncology Departments ensured the maintenance of the diagnostic-therapeutic pathways of LC pts.

The lung immuno-oncology prognostic score (LIPS-3): a prognostic classification of patients receiving first-line pembrolizumab for PD-L1 ≥ 50% advanced non-small-cell lung cancer.

BACKGROUND: To stratify the prognosis of patients with programmed cell death-ligand 1 (PD-L1) ≥ 50% advanced non-small-cell lung cancer (aNSCLC) treated with first-line immunotherapy. METHODS: Baseline clinical prognostic factors, the neutrophil-to-lymphocyte ratio (NLR), PD-L1 tumour cell expression level, lactate dehydrogenase (LDH) and their combination were investigated by a retrospective analysis of 784 patients divided between statistically powered training (n = 201) and validation (n = 583) cohorts. Cut-offs were explored by receiver operating characteristic (ROC) curves and a risk model built with validated independent factors by multivariate analysis. RESULTS: NLR < 4 was a significant prognostic factor in both cohorts (P < 0.001). It represented 53% of patients in the validation cohort, with 1-year overall survival (OS) of 76.6% versus 44.8% with NLR > 4, in the validation series. The addition of PD-L1 ≥ 80% (21% of patients) or LDH < 252 U/l (25%) to NLR < 4 did not result in better 1-year OS (of 72.6% and 74.1%, respectively, in the validation cohort). Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 [P < 0.001, hazard ratio (HR) 2.04], pretreatment steroids (P < 0.001, HR 1.67) and NLR < 4 (P < 0.001, HR 2.29) resulted in independent prognostic factors. A risk model with these three factors, namely, the lung immuno-oncology prognostic score (LIPS)-3, accurately stratified three OS risk-validated categories of patients: favourable (0 risk factors, 40%, 1-year OS of 78.2% in the whole series), intermediate (1 or 2 risk factors, 54%, 1-year OS 53.8%) and poor (>2 risk factors, 5%, 1-year OS 10.7%) prognosis. CONCLUSIONS: We advocate the use of LIPS-3 as an easy-to-assess and inexpensive adjuvant prognostic tool for patients with PD-L1 ≥ 50% aNSCLC.

Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy.

BACKGROUND: Resistance to BRAF inhibitors is an emerging problem in the melanoma field. Strategies to prevent and overcome resistance are urgently required. METHODS: The dynamics of cell signalling, BrdU incorporation and cell-cycle entry after BRAF inhibition was measured using flow cytometry and western blot. The ability of combined BRAF/MEK inhibition to prevent the emergence of resistance was demonstrated by apoptosis and colony formation assays and in 3D organotypic cell culture. RESULTS: BRAF inhibition led to a rapid recovery of phospho-ERK (pERK) signalling. Although most of the cells remained growth arrested in the presence of drug, a minor population of cells retained their proliferative potential and escaped from BRAF inhibitor therapy. A function for the rebound pERK signalling in therapy escape was demonstrated by the ability of combined BRAF/MEK inhibition to enhance the levels of apoptosis and abrogate the onset of resistance. CONCLUSION: Combined BRAF/MEK inhibition may be one strategy to prevent the emergence of drug resistance in BRAF-V600E-mutated melanomas.

Clinical studies in asthmatics with a new non-extra fine HFA formulation of beclometasone dipropionate (BDP Modulite).

The main objective of the clinical development programme for BDP Modulite, a new non-extra fine formulation of beclometasone dipropionate (BDP) in hydrofluoroalkane (HFA), has been to demonstrate therapeutic equivalence compared with standard BDP chlorofluorocarbon (CFC) products at the recommended posology (delivered dose and patient population). A total of 1158 asthmatic patients were included in five clinical studies and 658 patients were treated with BDP Modulite. Four studies were undertaken in mild or moderate-to-severe asthmatic adults, while one study was carried out in children. The duration of treatment was 12 weeks in three studies and 6 weeks in the other two studies. A range of doses of BDP Modulite from 200 micrograms bid up to 1500 micrograms bid was evaluated against CFC comparators. The primary efficacy variable in all studies was morning PEFR while secondary variables included other lung function parameters, symptom scores and salbutamol use. All studies demonstrated equivalence of efficacy for morning PEFR for BDP Modulite versus BDP-CFC when compared on a microgram for microgram basis. The secondary outcome variables also consistently support similar efficacy of the two products. The safety and tolerability profile for BDP Modulite was similar to BDP-CFC; the incidence of adverse events was comparable between treatments and plasma and urinary cortisol were generally unchanged in patients receiving 1000 micrograms day-1 for 6-12 weeks. In conclusion, the results of the clinical studies with BDP Modulite show that this new HFA formulation allows a seamless transition to CFC-free BDP, thus simplifying the changeover.

A new HFA-134a propellant in the administration of inhaled BDP via the Jet spacer: controlled clinical trial vs the conventional CFC.

This study was carried out with the aim of demonstrating the efficacy and tolerability of beclomethasone dipropionate (BDP) aerosol spray 500 microg b.i.d. via a spacer device (Jet, Chiesi Farmaceutici S.p.A.) using a new HFA-134a formulation or chlorofluorocarbon (CFC) propellant. After having completed a 2-week run-in period, 154 adult patients (77 in each group) with mild-to-moderate persistent asthma were randomised into two groups to receive the study treatment for a duration of 12 weeks in a double-blind, multinational, multicentre, parallel-group design. Morning and evening peak expiratory flow rate (PEFR), use of rescue salbutamol, number of day- and night-time asthma attacks, number of night-time awakenings due to asthma and clinical symptoms were recorded daily by patients on diary cards. Pulmonary function tests (FEV1, FVC, PEFR, FEF25-75%, MEF50 and FEF25) and vital signs were measured at the clinic at study entry, at the start of treatment and every 2 weeks thereafter. Morning serum cortisol (8.00-10.00 a.m.) was measured at the start and at the end of the treatment period. Adverse events were recorded throughout the total study period. Significant improvements over baseline were reported in both groups in terms of lung function, symptoms and use of rescue inhaled salbutamol. Equivalence between groups was demonstrated for the primary end-point morning PEFR, as well as for evening PEFR and FEV1. No statistically significant differences in the comparisons between groups, except for FEF25 (P=0.044), were observed in any of the other efficacy variables. Adverse events were reported in 31% of patients in the BDP-HFA group and in 32% in the CFC group. Adverse drug reactions were 4 and 2 in the two groups, respectively. No drug-related serious adverse events were reported in either of the groups. No signs of relevant adrenal suppression were observed in both groups: 2 patients in each group had final values below the normal range. In conclusion, the BDP-HFA-134a formulation proved to be equivalent in efficacy and comparable in safety to the standard BDP-CFC product over 12 weeks in adult patients with mild-to-moderate persistent asthma.

Equivalent efficacy and safety of a new HFA-134a formulation of BDP compared with the conventional CFC in adult asthmatics.

The present study demonstrates the equivalent efficacy for BDP 500 microg bid given via MDI with the new HFA-134a propellant (Chiesi Farmaceutici S.p.A., Parma) compared to a conventional CFC propellant (Becotide, Allen & Hanburys, UK). One hundred and sixteen adult patients with stable mild to moderate asthma (FEV1 > or = 60% of predicted normal) entered a 2-week run-in period where they maintained their own inhaled corticosteroids and were then assigned to a 12-week treatment with the test drug in a randomized, multicentre, double-blind, double-dummy, parallel-group design. Ninety-one patients completed the study period. Morning and evening peak expiratory flow rate (PEFR), use of rescue salbutamol, number of daytime and nighttime asthma attacks, number of nighttime awakenings, and clinical symptoms were recorded daily by patients on a diary card. Pulmonary function tests (FEV1, FVC, PEFR, MEF50 and FEF25) were completed at study entry, at the start of treatment and every 2 weeks thereafter. Morning (08.00-10.00 AM) serum cortisol was measured at the start and at the end of treatment. Adverse events were collected for the total study period. Equivalence between groups was demonstrated for the primary end-point morning PEFR, as well as for evening PEFR and FEV1 (the 95% CI of the treatments' difference was within the 5% of the LSM of BDP CFC). The other secondary pulmonary function tests measured at the clinic visit showed a satisfactory asthma control, albeit without statistically significant differences between groups. Decreases in the use of rescue salbutamol and in clinical symptoms were also reported in both groups, with no differences between them. Adverse events were reported in 81.4% of patients in the BDP HFA group and in 82.5% in the CFC group. There were 73 and 59 adverse drug reactions in the two groups, respectively; the difference was mainly due to differences in taste. No drug-related serious adverse events were reported in either group. No difference was seen for morning serum cortisol between baseline and end of treatment, or between groups. In conclusion, the BDP-HFA 134a formulation proved to be statistically equivalent to the standard BDP CFC product over 12 weeks in adult patients with mild to moderate asthma.

Effect of inhaled beclomethasone dipropionate and budesonide dry powder on pulmonary function and serum eosinophil cationic protein in adult asthmatics.

The aim of this study was to determine whether the effects of inhaled beclomethasone dipropionate and budesonide dry powder on pulmonary function correlate with those on measurement of serum eosinophil cationic protein (sECP). Thirty-two asthmatic adults in a stable phase, treated daily with 1,000 micrograms beclomethasone dipropionate metered-dose inhaler, completed a 2-week wash-out period and were then randomized to receive a 200 micrograms/dose q.i.d. of either drug, over an 8-week period. Pulmonary function tests (FEV1, FVC, PEFR, FEF25-75% and MEF50) were measured at study entry, before and after every 2 weeks of treatment, while PEFR (morning and evening), symptom scores and salbutamol use PRN were recorded daily on a dairy card. sECP was measured at baseline and after 4 and 8 weeks of treatment. Safety variables included adverse reactions, morning serum cortisol and vital signs (heart rate and blood pressure). FEV1, FVC, PEFR, FEF25-75%, MEF50 and morning PEFR significantly increased (p < 0.05) over baseline in the beclomethasone group, while only FEV1 at week 6 and evening PEFR significantly increased (p < 0.05) in the budesonide group; no significant differences between groups were reported. sECP significantly decreased (p < 0.01) in the beclomethasone group at week 4 and 8 (p < 0.05 between groups). Evidence of statistically significant negative correlation between the FEV1 percent predicted and sECP was assessed at baseline (correlation coefficient r = -0.60, p < 0.05) in the total patient sample, and in the results, expressed as percent change over baseline, obtained at both week 4 and 8 (p < 0.01). A significant decrease in salbutamol use PRN, symptom score and number of daily bronchospasm attacks was also reported in the beclomethasone group (p < 0.05). No adverse reactions or relevant changes in morning cortisol and vital signs were reported in either group. It was concluded that sECP proved to be a reliable marker for monitoring inflammatory events in asthma; inhaled beclomethasone dipropionate dry powder was at least as effective as budesonide in improving lung function and the underlying asthma inflammation.

Efficacy and tolerability of brodimoprim in bacterial otitis media in children. Controlled study versus cefaclor.

78 pediatric patients affected by acute otitis media were selected and randomized into two balanced groups of treatment: brodimoprim, at the dosage of 200 mg once-a-day on the first day and of 100 mg once-a-day on the following days, and cefaclor at a dosage of 40 mg/Kg/day in three doses. Brodimoprim resulted more efficacious in the reduction of symptoms, especially hypoacusis and tinnitus (p < 0.05 between treatments); tympanometry showed a higher number of normalizations in the brodimoprim group, without significant differences between treatments. Both drugs resulted active against most of isolated bacterial strains. Side effects were reported in 4 patients treated with brodimoprim and in 6 patients in the control group.

Efficacy and tolerability of brodimoprim at two different dosage schedules in the treatment of acute uncomplicated bacterial cystitis: comparative study vs. pefloxacin.

In an open study, 172 male and female adult patients with acute uncomplicated bacterial cystitis were randomly allocated to three treatment groups. Two groups received brodimoprim 200 mg tablets as follows: a single dose of two 200 mg tablets on day 1, followed by one tablet per day on days 2 and 3 (58 patients); or a single daily dose of two tablets, for 2 days (63 patients). The third group received a single dose of pefloxacin, as two 400 mg tablets, for 1 day (51 patients). Complete urinalysis, sediment and urine culture examinations were carried out before treatment and 10 days after the last dose. Evaluation also comprised, at the time of enrolment and 48 h after the last dose, measurement of corporal temperature and assessment of symptoms (dysuria, pollakiuria, strangury, suprapubic pain, burning sensation during urination and urgency) on a 4-point scale. The eradication rate for the pathogen concerned was 98.3% and 96.7% in the groups receiving brodimoprim for 3 and 2 days, respectively, and 92.8% in the pefloxacin group (between-group comparison n.s.). There was significant regression of symptoms (P < 0.001) in the three groups (between-groups comparison n.s.). Mainly gastrointestinal adverse events occurred in 3 patients receiving brodimoprim for 2 days and in 4 patients from each of the other two groups.

Platelet and endothelial response with trapidil in patients with peripheral obliterative arteriopathy.

The activity of trapidil, an antiaggregating agent with PDGF antagonist properties, was investigated in order to verify its possible modulating effect in the endothelial and platelet activation. PDGF, t-PA, PAI-1 and ET-1 plasma levels were measured before and after a 2 month treatment period with trapidil 200 mg tablets bid or placebo in 30 patients affected by POA in Fontaine stage II. PDGF and PAI-1 significantly (p < 0.05) increased in the placebo group, and PDGF also in the comparison between treatments (p < 0.05). Aggregation data demonstrate an absence of Ca++ antagonist action of trapidil. The results of this study suggest that trapidil can interfere with the combined vascular and platelet response in atherogenesis.

Treating asthma in children with beclomethasone dipropionate: Pulvinal versus Diskhaler.

Seventy-two children (mean age, 10.1 years) with stable moderate asthma who completed a 7-day run-in period were randomized to receive a 4-week treatment with beclomethasone dipropionate (200 micrograms twice daily) administered through two different powder inhalers (Pulvinal; Chiesi Farmaceutici S.p.A, Parma, Italy and Diskhaler; Glaxo-Wellcome, Evreux, France) in a parallel group design. Sixty-nine patients completed the study. Morning and evening peak expiratory flow values, the use of rescue salbutamol, and the severity of clinical symptoms were recorded daily on a diary card. Pulmonary function tests were performed at baseline and then after 2 and 4 weeks of treatment. Pulmonary function values, daily morning and evening peak expiratory flow, and most of the clinical symptoms significantly improved, although the use of rescue salbutamol significantly decreased from the second week of treatment until the end of the study in both groups. Equivalence of efficacy between groups was demonstrated for both pulmonary function and clinical parameters. We conclude that the Pulvinal inhaler is as efficacious as the Diskhaler in beclomethasone-based therapy of asthmatic children.

Effects on lung function, symptoms, and bronchial hyperreactivity of low-dose inhaled beclomethasone dipropionate given with HFA-134a or CFC propellant.

The aim of this study was to compare the efficacy of BDP 200 microg bid via metered dose inhaler, using HFA-134a (Chiesi Farmaceutici S.p.A., Parma, Italy) versus CFC (Becotide, Allen & Hanburys, U.K.) as a propellant. 172 adult patients (86 in each group) with stable mild persistent asthma who completed a 7-day run-in period were randomized to receive a 6-week treatment in a double-blind, double dummy, parallel-group design; 164 patients completed the study. Morning and evening PEFR, use of rescue salbutamol, number of day-time and night-time asthma attacks, number of night-time awakenings and clinical symptoms were recorded daily on a diary card. Pulmonary function tests (FEV(1), FVC, PEFR, and MEF(50)) were measured at the clinic before and after the 1-week run-in period, and after 3 and 6 weeks of treatment. A challenge test with inhaled methacholine was completed at baseline and at the end of the treatment period to assess potential bronchial hyper-reactivity in a subgroup of subjects (n = 65; 34 HFA, 31 CFC). In accordance with asthma of mild severity (FEV(1) predicted over 90% in both groups), a small improvement in lung function compared to baseline was seen for both treatments, significantly for FEV(1) in BDP HFA and MEF(50) in both groups. The two formulations of BDP had similar efficacy for the primary outcome variable morning PEFR (ITT population mean difference 5.8 L/min; C.I. -4.9 to +16.5) as well as for the secondary outcomes of evening PEFR and clinic FEV(1). There were small improvements in methacholine PD(20) and PC20 in both groups, with no significant difference between treatments. A total of 22 and 19 drug-related adverse events were reported in the BDP HFA and CFC groups, respectively; most events were of seasonal nature or were local effects due to the use of inhaled corticosteroids. It can be concluded that the newly developed formulation of BDP given via HFA-134a seems to provide similar asthma control, compared with the same low daily dose of the active drug delivered via CFC. Further studies are needed using higher doses in moderate to severe asthma to confirm these preliminary findings.

Evidence of adequacy of the performance of the Pulvinal by measuring through-device peak inspiratory flow rate in severe airways obstruction in adults and children.

Pulvinal is a novel DPI designed to deliver inhaled drugs to the airways. Previous in vitro and in vivo data has suggested that the peak inspiratory flow rate (PIFR), measured through Pulvinal, does not depend on the severity of expiratory airflow obstruction and that the lowest PIFR values seem sufficient to deliver an effective bronchodilator dose. To study this further, we have investigated through-Pulvinal PIFR in categories of patients who are likly to generate low inspiratory flow rates. Three different patients' groups were selected (severe asthmatics, n = 52, including elderly) patients with severe chronic obstructive pulmonary disease (COPD, n = 21) and children with asthma (n = 16). This study aimed to measure the through-device PIFR and also to assess whether this correlated with measures of expiratory flow rate. Inspiratory flow measurements were made with a Pulvinal inhaler inserted into the adapted mouthpiece of a pneumotochograph. No significant correlations were seen between through-device PIFR and expiratory volumes or flow rates when expressed as percent predicted normal (forced expiratory volume in 1 sec [FEV1] and peak expiratory flow rate [PEFR]) in any of the three studied populations. A significant correlation was present for FEV1 (when expressed in liters) and through-device PIFR in the adult asthmatic and COPD study groups. In spite of the disease severity in adult populations and the age of children, the lowest generated PIFR values were within the range producing adequate performance of Pulvinal DPI (>20 L/min). We conclude that inspiratory flow rates generated through the Pulvinal inhaler can be adequate in asthma and COPD, including patients at the extremes of severity and age, who may theoretically have a limitation in their inspiratory flow.

A new spacer device for administration of inhaled salbutamol: use in elderly asthmatics.

This randomized, parallel-group study compared the use of a metered-dose inhaler (MDI) equipped with a new spacer device (Jet spacer) with that of a standard actuator in the administration of salbutamol (two puffs, 100 micrograms four times daily) to 36 elderly patients with moderate asthma and poor inhalation technique. After a 1-week run-in period, patients entered the 1-week study. Forced expiratory volume in 1 second (FEV1) and peak expiratory flow rate (PEFR) were measured at screening (both groups using the standard actuator) before and 30, 60, 120, and 240 minutes after administration; these measurements were repeated at the start and end of treatment (patients using the spacer or standard actuator). Ratings of efficacy and tolerability by investigators and of acceptability by patients were recorded at the end of treatment. Increases from baseline (from 0 to 240 minutes) in FEV1 and PEFR were comparable in the two groups at screening visit but proved higher (significantly for FEV1: P < .01) in the Jet group than in the standard-actuator group after both the first and last doses of the 7-day treatment period. the Jet group reported greater acceptability than the standard-actuator group. One patient in each group had tremors. The new spacer device is thus a valid alternative to the conventional actuator in patients with definitely or potentially poor hand-mouth coordination.

Beclomethasone dipropionate given to adult asthmatics through a new spacer device: effects of high-dose administration.

The usefulness of a metered-dose inhaler equipped with a new spacer device (Jet spacer) was evaluated and compared with that of a standard actuator in the administration of high-dose inhaled beclomethasone dipropionate (0.5 mg four times daily) to adults with moderate asthma. After a 2-week run-in period, 36 patients were enrolled in a 4-week study according to a randomized, parallel-group design. Efficacy was assessed by measurements of pulmonary function and daily beta 2-agonist consumption. Morning serum and 24-hour urinary cortisol levels were measured at baseline and after treatment; adrenocorticotropic hormone (ACTH) stress testing was also done. Spirometric parameters significantly improved in both groups; peak expiratory flow rate measured at the final visit was significantly higher (P < .01) in the group using the Jet spacer than in patients using the standard actuator. Beta 2-agonist consumption decreased in both groups. The number of patients with a normal response to ACTH was significantly higher (P < .01) in the Jet group than in the standard actuator group; concomitant urinary cortisol excretion decreased significantly (P < .05) in the standard actuator group. Local irritation was reported by 1 patient in the Jet group and by 2 patients in the standard actuator group. Use of the new Jet spacer was found to reduce the potential for adrenal suppression and increase the efficacy of high-dose inhaled beclomethasone dipropionate given to adults with asthma.

Inhaled beclomethasone dipropionate administered through a new spacer device: a controlled clinical study.

This 4-week, randomized, parallel-group study compared the efficacy and safety of a metered-dose inhaler equipped with a new spacer device (Jet spacer) with those of a standard actuator in the administration of inhaled beclomethasone dipropionate (0.5 mg twice daily) in 66 adults with chronic obstructive pulmonary disease (COPD) who were responsive to beta 2-agonists. Lung function values, symptom scores, and daily consumption of a beta 2-agonist determined efficacy. At baseline and after treatment, levels of morning serum and 24-hour urinary cortisol were measured in half of the patients (one center). Ease of use of the two devices was expressed by patients at the final visit. Lung function values and clinical symptoms improved in both groups (P < .01 at the final visit); the Jet group reported a better outcome (P < .05 between groups) than the standard-actuator group for predicted normal values of forced expiratory volume in 1 second, forced vital capacity, and bronchial noises. Salbutamol consumption decreased in both groups. One patient in the Jet group and 5 patients in the standard-actuator group reported adverse reactions. No significant between-group differences were found in plasma and urinary cortisol levels. The Jet device was judged easier to use (P < .05 between groups) than the standard actuator. In conclusion, the jet device was more effective than a standard actuator in reducing local adverse reactions to inhaled beclomethasone dipropionate in adults with COPD, with a better efficacy profile.

Correlation between strand asymmetry and phylogeny in mitochondrial DNA.

An evolutionary distance is introduced in order to propose an efficient and feasible procedure for phylogeny studies. Our analysis are based on the strand asymmetry property of mitochondrial DNA, but can be applied to other genomes. Comparison of our results with those reported in conventional phylogenetic trees, gives confidence about our approximation. Our findings support the hypotheses about the origin of the skew and its dependence upon evolutionary pressures, and improves previous efforts on using the strand asymmetry property of genomes for phylogeny inference. For the evolutionary distance introduced here, we observe that the more adequate technique for tree reconstructions correspond to an average link method which employs a sequential clustering algorithm.

Assessment of inhaled BDP-dose dependency of exhaled nitric oxide and local and serum eosinophilic markers in steroids-naive nonatopic asthmatics.

The aim of the present study was to assess the dose-dependency from inhaled steroids of changes of airways inflammation [eosinophils count and eosinophil cationic protein (ECP)] measures in induced sputum and in serum, as well as that of exhaled nitric oxide. Twenty steroid-naive patients with nonatopic asthma of mild to moderate degree [forced expiratory volume in 1 s (FEV1) = 70% of predicted] and with negative response to the standard tests for allergy were selected; after a 1-week run-in period they were randomized to receive a 12-week treatment period of inhaled beclomethasone dipropionate dry powder given with the Pulvinal inhaler (Clenil P, Chiesi Farmaceutici S.p.A., Parma, Italy) in two different dose regimens, 400 microg bid (high dose) or 200 microg bid (low dose), over a double blind, parallel groups design. The following outcome measures were assessed in baseline and after 1, 6 and 12 weeks of treatment: FEV1 (l), eosinophils count in sputum (%), is ECP (microg/l), serum eosinophils count (%), serum ECP (microg/l) and exhaled NO (ppb). The results showed that all the considered parameters improved in both groups: the increase over baseline of FEV1 and the decrease of NO were significant at any time in the high-dose group and only at week 12 in the low-dose group (NS between groups), whereas the markers of eosinophilic activity showed more consistent reductions in the high-dose than in the low-dose group when measured in induced sputum (P < 0.05 between groups after 6 and 12 weeks for eosinophils count and after 12 weeks for ECP). Decreases over baseline of markers measured in serum were more rapid in the high-dose group, without differences between groups. A marked trend towards a negative correlation was found between FEV1 and ECP, (r = -0.72, P < 0.05), between FEV1 and eosinophils in sputum (r = -0.31, NS) and between FEV1 and exhaled NO (r = -0.38, NS), all of them only in the high-dose group. The results of the study demonstrate that changes of levels of eosinophilic activity in the airways are dependent from the daily dose of inhaled steroids when measured in induced sputum and that the local assessment can therefore represent a practical and noninvasive method to monitor the extent of airways inflammation.