The Extra Cost Due to Non-Adherence to Inhaled Treatments in Adolescents with Mild-to-Moderate Persistent Asthma.

Bronchial asthma has a high socio-economic impact in Western countries. Low adherence to prescribed inhalation treatments contributes to poor asthma control and the higher utilization of healthcare resources. Although adolescents usually do not comply with long-term inhaled treatments prescribed on a regular basis, the related economic consequences still are poorly investigated in Italy. AIM: A 12-month estimation of the economic impact of non-adherence to inhalation treatments in adolescents with mild-to-moderate atopic asthma. METHODS: Non-smoking adolescents aged 12-19 years, without any significant comorbidity, prescribed with inhaled cortico-steroids (ICS) or ICS/long-acting beta(2)-adrenergics (LABA) via dry powder inhalers (DPIs) on a regular basis were automatically selected from the institutional database. Spirometric lung function, clinical outcomes, and pharmacological information were collected. The adolescents' adherence to their prescribed regimen was calculated monthly. Adolescents were divided in two sub-groups based on their adherence to prescriptions: ≤70% (not adherent) or >70% (adherent), and statistically compared (Wilcoxon test, assuming p < 0.05). RESULTS: Overall, 155 adolescents fulfilled the inclusion criteria (males, 49.0%; mean age, 15.6 years ± 2.9 SD; mean BMI, 19.1 ± 1.3 SD). Mean values of lung function were: FEV1 = 84.9% pred. ± 14.8 SD, FEV1/FVC = 87.9 ± 12.5 SD; MMEF = 74.8% pred. ± 15.1 SD and V25 = 68.4% pred. ± 14.9 SD. ICS had been prescribed in 57.4% of subjects and ICS/LABA in 42.6%. Mean adherence to original prescriptions was 46.6% ± 9.2 SD in non-adherent and 80.3% ± 6.6 SD in adherent adolescents, respectively (p < 0.001). The mean rates of hospitalizations, exacerbations, and GP visits; the average duration of absenteeism; the frequency of systemic steroids and antibiotics courses needed over the study period were significantly and substantially lower in adolescents adherent to prescriptions (all p < 0.001). The mean total annual extra cost calculated in the two sub-groups was EUR 705.8 ± 420.9 SD in non-adherent adolescents and EUR 192.1 ± 68.1 SD in adherent adolescents, respectively (p < 0.001), which was 3.7 times higher than in non-adherent adolescents. CONCLUSIONS: In adolescents, the clinical control of mild-to-moderate atopic asthma is directly and strictly related to the degree of adherence to prescribed inhalation therapies. All clinical and economic outcomes prove dramatically poor when adherence is low, and treatable asthma can be frequently mistaken for refractory asthma in these cases. Adolescents' non-adherence impacts the burden of the disease quite substantially. Much more effective strategies centered specifically on adolescents' asthma are needed.

Coughing Can Be Modulated by the Hydration Status in Adolescents with Asthma.

A lower thirst sensitivity frequently characterizes children and adolescents. The daily water intake can be frequently insufficient for the homeostasis and the integrity of their airway epithelium. Little is known about the real-life relationship between dehydration and coughing in young students with asthma. The aim was to investigate the effect of dehydration on coughing in asthmatic students aged ≤16 years. A validated questionnaire aimed to investigate their respiratory history and cough incidence was used. Urine samples were also collected for assessing osmolality. Wilcoxon test, the Pearson Chi Square and the Fisher Exact Test were used; p < 0.05 was assumed as significant. Valid data were obtained from 305 healthy and 56 asthmatic students. Mean urine osmolality was significantly higher in asthmatic than in healthy students (1012 ± 197.7 vs. 863.0 ± 223.0 mOsm/kg, respectively; p < 0.001), particularly in symptomatic asthmatic students (1025 ± 191.6 mOsm/kg, p < 0.01). Both the incidence and duration of coughing episodes were directly related to the degree of urine osmolality (both p < 0.001). Dehydration affects the prevalence and the duration of a cough in asthmatic students aged ≤16 years. Adequate daily water intake should be stimulated in these subjects in order to contain their basic cough attitude.

Lung Function Can Predict the Expected Inspiratory Airflow Rate through Dry Powder Inhalers in Asthmatic Adolescents.

Several factors affect drug delivery from dry powder inhalers (DPIs). Some are related to patient's physiological characteristics, while others depend on DPIs' technical aspects. The patient's inspiratory airflow rate (IAR) affects the pressure drop and the turbulence needed to disaggregate the powder inside a DPI. The present study investigated whether lung function limitations occurring in asthmatic adolescents affect their IAR when inhaling through a DPI simulator. Eighteen consecutive adolescents with asthma were recruited, and IAR was randomly assessed at low-, mid-, and high-resistance regimens. A multiple logistic model was developed to evaluate the association of patients' lung function characteristics and devices' resistance with the probability to achieve the expected IAR (E-IAR). The mean value of E-IAR achieved seemed to be sex- and age-independent. Low- and high-resistance regimens were less likely to consent the E-IAR level (odds ratio [OR] = 0.035 and OR = 0.004, respectively). Only the basal residual volume and the inspiratory resistance, but not the Forced Expiratory Volume in 1 s (FEV1), seemed to affect the extent of IAR in asthmatic adolescents (OR = 1.131 and OR = 0.290, respectively). The results suggest that the assessment of current lung function is crucial for choosing the proper DPI for asthmatic adolescents.

The Emotional Response to Pandemic of Middle- and High-School Students of an Italian Northern Province: The ERP Study.

The COVID-19 outbreak variably affected people's mental reactions worldwide but was only episodically investigated in healthy Italian teenagers. Our aim was to investigate the emotional responses of Italian middle and high school students to the pandemic. An anonymous 10-item questionnaire was distributed in pre-selected school samples. Responders had to score their perceived extent for each reaction from 0 (lowest perception) to 10 (highest perception). A group of adults was selected as control. Generalized linear models were used to estimate differences among adults and students, high school (HS) and middle school (MS) students, and urban (U) and rural (R) MS students. Comparisons were presented as mean difference (Δ) with a 95% confidence interval (CI). A total of 1512 questionnaires (635 adults, 744 HS, 67 UMS, and 66 RMS) were analyzed. Students appeared more indifferent (Δ = 1.97, 1.52-2.41), anxious (Δ = 0.56, 0.07-1.04), aggressive (Δ = 2.21, 1.72-2.70), and depressed (Δ = 1.87, 1.40-2.34) than adults did, and claimed a higher loss of interest in their activities (Δ = 1.21, 0.72-1.70). Students were less disbelieving (Δ = -0.93, -1.50-0.35) and feared for their loved ones (Δ = -0.89, -1.40-0.39). MS students were less affected by the outbreak than HS students were. Furthermore, R-MS students were significantly less aggressive and depressed, but more indifferent and disbelieving than U-MS. Female sex was an independent factor associated to almost all the questionnaire domains. The pattern of the psychological responses to the pandemic in Italian students proved multifaceted. In addition to anxiety, loss of interest in activities, and depression, aggressiveness emerged as the most characterizing mental attitude in response to the pandemic.

Validation of a Novel Compact System for the Measurement of Lung Volumes.

BACKGROUND: Current techniques for measuring absolute lung volumes rely on bulky and expensive equipment and are complicated to use for the operator and the patient. A novel method for measurement of absolute lung volumes, the MiniBox method, is presented. RESEARCH QUESTION: Across a population of patients and healthy participants, do values for total lung capacity (TLC) determined by the novel compact device (MiniBox, PulmOne Advanced Medical Devices, Ltd.) compare favorably with measurements determined by traditional whole body plethysmography? STUDY DESIGN AND METHODS: A total of 266 participants (130 men) and respiratory patients were recruited from five global centers (three in Europe and two in the United States). The study population comprised individuals with obstructive (n = 197) and restrictive (n = 33) disorders as well as healthy participants (n = 36). TLC measured by conventional plethysmography (TLCPleth) was compared with TLC measured by the MiniBox (TLCMB). RESULTS: TLC values ranged between 2.7 and 10.9 L. The normalized root mean square difference (NSD) between TLCPleth and TLCMB was 7.0% in healthy participants. In obstructed patients, the NSD was 7.9% in mild obstruction and 9.1% in severe obstruction. In restricted patients, the NSD was 7.8% in mild restriction and 13.9% in moderate and severe restriction. No significant differences were found between TLC values obtained by the two measurement techniques. Also no significant differences were found in results obtained among the five centers. INTERPRETATION: TLC as measured by the novel MiniBox system is not significantly different from TLC measured by conventional whole body plethysmography, thus validating the MiniBox method as a reliable method to measure absolute lung volumes.

A Bayesian Framework to Assess the Usability of Dry Powder Inhalers in a Cohort of Asthma Adolescents in Italy.

The useability of DPIs (dry powder inhalers) depends on several factors that are influenced by the patients' subjectivity and objectivity. The short-form global usability score (S-GUS), a specific tool for the quick ranking and comparison in real life of an inhaler's usability, was used to investigate six of the most prescribed DPIs (Breezhaler, Diskus, Ellipta, Nexthaler, Spiromax, and Turbohaler) in consecutive asthma patients aged <18 years. A Bayesian indirect comparison (IC) was carried out to merge all pairwise comparisons between the six DPIs. Thirty-three subjects participated: eighteen tested Breezhaler, Spiromax, Nexthaler, and Ellipta simultaneously, while fifteen tested Breezhaler, Spiromax, Diskus, and Turbohaler. The estimates of the S-GUS, by the IC model, allowed us to rank the DPIs by their degree of usability: Ellipta, Diskus, and Spiromax were classified as "good to pretty good" (S-GUS > 15), while Spiromax, Turbohaler, and Breezhaler were classified as "insufficient" (S-GUS < 15). The multidomain assessment is recommended in asthma adolescents in order to approximate the effective usability of different DPIs as best as possible. The S-GUS proves particularly suitable in current clinical practice because of the short time required for its use in adolescents.

The first, holistic immunological model of COVID-19: Implications for prevention, diagnosis, and public health measures.

The natural history of COVID-19 caused by SARS-CoV-2 is extremely variable, ranging from asymptomatic or mild infection, mainly in children, to multi-organ failure, eventually fatal, mainly in the eldest. We propose here the first model explaining how the outcome of first, crucial 10-15 days after infection, depends on the balance between the cumulative dose of viral exposure and the efficacy of the local innate immune response (natural IgA and IgM antibodies, mannose-binding lectin). If SARS-CoV-2 runs the blockade of this innate immunity and spreads from the upper airways to the alveoli in the early phases of the infections, it can replicate with no local resistance, causing pneumonia and releasing high amounts of antigens. The delayed and strong adaptive immune response (high-affinity IgM and IgG antibodies) that follows, causes severe inflammation and triggers mediator cascades (complement, coagulation, and cytokine storm), leading to complications often requiring intensive therapy and being, in some patients, fatal. Low-moderate physical activity can still be recommended. However, extreme physical activity and oral breathing with hyperventilation during the incubation days and early stages of COVID-19 facilitates re-inhalation and early direct penetration of high numbers of own virus particles in the lower airways and the alveoli, without impacting on the airway's mucosae covered by neutralizing antibodies ("viral auto-inhalation" phenomenon). This allows the virus to bypass the efficient immune barrier of the upper airway mucosa in already infected, young, and otherwise healthy athletes. In conclusion, whether the virus or the adaptive immune response reaches the lungs first is a crucial factor deciding the fate of the patient. This "quantitative and time-/sequence-dependent" model has several implications for prevention, diagnosis, and therapy of COVID-19 at all ages.

Galectin-3: an early predictive biomarker of modulation of airway remodeling in patients with severe asthma treated with omalizumab for 36 months.

BACKGROUND: Bronchial asthma is a heterogeneous disease characterized by three cardinal features: chronic inflammation, variable airflow obstruction, and airway hyperresponsiveness. Asthma has traditionally been defined using nonspecific clinical and physiologic variables that encompass multiple phenotypes and are treated with nonspecific anti-inflammatory therapies. Based on the modulation of airway remodeling after 12 months of anti-immunoglobulin E (IgE) treatment, we identified two phenotypes (omalizumab responder, OR; and non-omalizumab responder, NOR) and performed morphometric analysis of bronchial biopsy specimens. We also found that these two phenotypes were correlated with the presence/absence of galectin-3 (Gal-3) at baseline (i.e., before treatment). The aims of the present study were to investigate the histological and molecular effects of long-term treatment (36 months) with anti-IgE and to analyze the behavior of OR and NOR patients. METHODS: All patients were treated with the monoclonal antibody anti-IgE omalizumab for 36 months. The bronchial biopsy specimens were evaluated using morphometric, eosinophilic, and proteomic analysis (MudPIT). New data were compared with previous data, and unsupervised cluster analysis of protein profiles was performed. RESULTS: After 36 months of treatment with omalizumab, reduction of reticular basement membrane (RBM) thickness was confirmed in OR patients (Gal-3-positive at baseline); similarly, the protein profiles (over 500 proteins identified) revealed that, in the OR group, levels of proteins specifically related to fibrosis and inflammation (e.g., smooth muscle and extracellular matrix proteins (including periostin), Gal-3, and keratins decreased by between 5- and 50-fold. Eosinophil levels were consistent with molecular data and decreased by about tenfold less in ORs and increased by twofold to tenfold more in NORs. This tendency was confirmed (p < 0.05) based on both fold change and DAVE algorithms, thus indicating a clear response to anti-IgE treatment in Gal-3-positive patients. CONCLUSIONS: Our results showed that omalizumab can be considered a disease-modifying treatment in OR. The proteomic signatures confirmed the presence of Gal-3 at baseline to be a biomarker of long-term reduction in bronchial RBM thickness, eosinophilic inflammation, and muscular and fibrotic components in omalizumab-treated patients with severe asthma. Our findings suggest a possible relationship between Gal-3 positivity and improved pulmonary function.

Proteomics of bronchial biopsies: galectin-3 as a predictive biomarker of airway remodelling modulation in omalizumab-treated severe asthma patients.

Asthma is a chronic inflammatory disease. Reticular basement membrane (RBM) thickening is considered feature of airway remodelling (AR) particularly in severe asthma (SA). Omalizumab, mAb to IgE is effective in SA and can modulate AR. Herein we describe protein profiles of bronchial biopsies to detect biomarkers of anti-IgE effects on AR and to explain potential mechanisms/pathways. We defined the bronchial biopsy protein profiles, before and after treatment. Unsupervised clustering of baseline proteomes resulted in very good agreement with the morphometric analysis of AR. Protein profiles of omalizumab responders (ORs) were significantly different from those of non-omalizumab responders (NORs). The major differences between ORs and NORs lied to smooth muscle and extra cellular matrix proteins. Notably, an IgE-binding protein (galectin-3) was reliable, stable and predictive biomarker of AR modulation. Omalizumab down-regulated bronchial smooth muscle proteins in SA. These findings suggest that omalizumab may exert disease-modifying effects on remodelling components.

A 36-month study on the cost/utility of add-on omalizumab in persistent difficult-to-treat atopic asthma in Italy.

OBJECTIVE: Omalizumab is a biological treatment for difficult-to-treat allergic asthma. Its mechanism of action relies on impeding the binding of immunoglobulin E (IgE) to specific cellular receptors, thus blocking the inflammatory cascade. At present, no long-term data are available on its cost/effectiveness. The aim of this study is to assess long-term clinical outcomes and to measure the cost/utility of long-term omalizumab use in difficult-to-treat allergic asthmatics. METHODS: The clinical, economic, and quality-of-life (QoL) outcomes of 36-month add-on omalizumab therapy were compared to equivalent outcomes for the year before the therapy's introduction in a cohort (n = 16) of adults with severe uncontrolled atopic asthma on chronic high-dose antiasthma treatments. The variables considered were lung function, IgE levels, health status, Asthma Control Test (ACT) score, QoL (St. George Questionnaire), general practitioner (GP) and specialist visits, number and duration of hospitalizations, emergency room admission, and pharmacological treatment (both dose and duration). Derived calculated indicators were changes in health-related QoL, total healthcare costs, and incremental cost/utility. Data from the two periods were tested for statistically significant differences according to Student's t test and p < .05 was accepted. RESULTS: Add-on omalizumab significantly and progressively improved asthma control and patient health-related QoL. Symptomatic drug and hospital care costs for these patients dropped significantly. A €450 increase in overall monthly costs was observed; however, when health benefits were considered, this cost increase translated into an incremental cost/utility ratio of €23,880 per quality-adjusted life year gained, which is quite a favorable and convenient figure in terms of the willingness to pay for health benefits in industrialized countries. CONCLUSIONS: The 36-month add-on omalizumab therapy persistently improved all clinical outcomes in difficult-to-treat asthmatic patients. Costs were also optimized and related to the extent of long-term health benefits achieved.

Effects of tiotropium and formoterol on quiet breathing pattern assessed by optoelectronic plethysmography in COPD patients: a pilot study.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a disease characterized by an airflow limitation that is not fully reversible. ß(2)-agonists and anticholinergics represent the most effective therapeutic options. Optoelectronic plethysmography (OEP) is a novel technology, which provides noninvasive steady-state measurements of chest wall kinematics, together with the assessment of the relative contribution of all different thoracic and abdominal compartments to tidal volume. OBJECTIVES: The aim of this pilot study was to investigate the changes in quiet breathing due to different long-acting bronchodilators (namely, formoterol and tiotropium) administered to COPD patients of different severity. METHODS: Eight moderate-to-severe COPD patients were studied according to a randomized crossover design. All subjects received both the long-acting bronchodilators: formoterol (long-acting ß(2)-agonist, 24 µg) and tiotropium (long-acting anticholinergic bronchodilator, 18 µg). The effect of bronchodilators on quiet breathing was evaluated by means of OEP at base conditions, and 2 and 7 hours after inhalation. RESULTS: Both bronchodilators caused changes in the quiet breathing pattern in COPD patients that had previously reported only negligible changes in FEV(1) (ΔFEV(1) = 2.6% after salbutamol). The main changes were observed in increased ventilation per minute, inspiratory and expiratory flow, and decreased breath-by-breath variability. Formoterol induced its main effects during the first 2 hours after inhalation, while tiotropium caused improvements between 2 and 7 hours. CONCLUSION: Even though a greater cohort of COPD patients is needed in order to confirm the present results, this pilot study reports a novel piece of evidence concerning the effects of bronchodilators on quiet breathing pattern in severe and very severe COPD patients.

A MCh test pre-post esophageal acidification in detecting GER-related asthma.

The direct effect of gastro-esophageal reflux (GER) on lung function is still debated. Objective. To investigate the role of esophageal acidification in affecting airway response to MCh in GER-related versus atopic asthmatics and to assess specificity and sensitivity of events. Subjects. A total of 56 never-smoking, mild asthmatics: 27 non-atopic asthmatics and acid GER (GER+ve) and 29 atopic asthmatics without any GER (GER-ve). Methods. Each subject performed an MCh challenge in baseline (MCh(b)), and 30 minutes after an acid drink (125 mL at pH = 2; MCh(ac)), one day apart. PD(20)FEV(1) MCh(b) and MCh(ac) were compared by estimating the area under the ROC curve (AU-ROC). Results. GER+ve and GER-ve subjects (well matched in baseline) had a different duration of esophageal acid contact (24-hour monitoring; pH-24h AU(4)), and PD(20)FEV(1) MCh(ac) (both p < 0.001). AU-ROC was 86.3% (76% to 97%, 95%CI). Sensitivity and specificity of changes were 82.8% (72.9% to 92.7%, 95%CI) and 85.2% (75.9% to 94.5%, 95%CI), respectively. The difference in MCh threshold that maximized both the sensitivity and specificity level was 100 mu g. Conclusions. The esophageal acidification identified GER-related asthma with a good level of both sensitivity and specificity by enhancing the MCh response only in the presence of acid GER. Data are supporting the effectiveness of this procedure for clinical purposes.

Clinical and pharmacoeconomic profile of COPD patients with FEV1 50--60% predicted: pilot study on the impact of the extended indication of ICS/LABA.

BACKGROUND: The use of inhaled corticosteroids (ICS) and long-acting beta(2) adrenergics (LABA) in fixed combination (ICS/LABA) was recently extended to COPD patients with a baseline FEV(1) 50-60% predicted, thus broadening the original guideline indications (GOLD 2006) that limited their use only to stages III and IV. METHOD: The present study was carried out to assess the clinical profile of this new subset of patients, with a view to providing data for future studies on the impact of this novel extension of ICS/LABA use in COPD. RESULTS: Data from the present observational cross-sectional study suggest that COPD patients with FEV(1) 50-60% predicted depict a dichotomic condition: actually, even though resembling milder patients in terms of frequency and severity of their respiratory symptoms, they are much more similar to severer patients in terms of rate of hospital admissions and resource consumption (p50.01). In other words, this subset of patients seems to represent a peculiar condition in the evolutional phase of COPD during which therapeutic treatment should be intensified in order to slow down the disease progression effectively. Nevertheless, independently of the severity, the general therapeutic approach to COPD was found to be greatly inadequate when compared to GOLD guidelines, particularly in terms of appropriateness. CONCLUSIONS: These findings should pave the way for future studies aimed to long-term monitoring of main outcomes and to evaluate the overall impact of earlier ICS/LABA use on disease progression and lung function decline in COPD.

Cost analysis of GER-induced asthma: a controlled study vs. atopic asthma of comparable severity.

Bronchial asthma is a costly disease: while the role of pharmaceutical strategies was greatly emphasised in order to alleviate its economic burden, the aetiological approach to asthma has received much less attention from this point of view. The impact of gastro-oesophageal reflux (GER)-related asthma was assessed in comparison to atopic asthma in 262 matched patients, and the corresponding direct and indirect annual costs calculated. All subjects were screened by means of a 95-item self-questionnaire. The overall resource utilisation was calculated for the last 12 months. Drug-induced annual costs were euro 290.4 (interquartile range-iqr 32.8) in atopic and euro 438.4 (iqr 27.8) in GER-related asthma (p<0.001); expenditure for medical consultations and diagnostics were euro 166.1 (iqr 14.8) vs. euro 71.6 (iqr 11.0) (p<0.001), and euro 338.4 (20.0) vs. 186.9 (iqr 26.5) (p<0.001), respectively. Direct costs due to hospital admissions and indirect costs due to absenteeism were also higher in GER-related asthmatics: 2.201.7+/-90.0 vs. euro 567.1+/-11.0 (p<0.001), and euro 748.7+/-94.7 vs. euro 103.6+/-33.9 (p<0.001), respectively. The total annual cost per patient was euro 1246.7 (iqr 1979.6) in atopic and euro 3967.1 (iqr 3751.5) in GER-related asthma, p<0.001. In conclusion, GER-induced asthma has a more relevant economic impact on healthcare resources than atopic asthma. Although further studies are needed, present data tend to demonstrate that when facing difficult asthma (GER-related asthma in this case), the aetiological assessment of the disease plays a critical role in optimising the approach to patients' needs.

Salmeterol & fluticasone 50 microg/250 microg bid in combination provides a better long-term control than salmeterol 50 microg bid alone and placebo in COPD patients already treated with theophylline.

UNLABELLED: Bronchodilator agents are central to the symptomatic management of Chronic Obstructive Pulmonary Disease (COPD), and long-acting inhaled bronchodilators are regarded as more convenient. The role of inhaled corticosteroids still remains controversial, but there is increasing evidence that they may improve FEV(1) and symptoms in the long-term. AIM: of the present small pilot study was to compare Salmeterol & Fluticasone (SM&FP) 50/250 microg bid via a single Diskus inhaler with SM 50 microg bid alone, and with placebo (P) in the treatment of moderate COPD. METHODS: Eighteen moderate COPD patients (53-77 yr, mean basal FEV(1)=49.1% pred.+/-5.0 s.d.; mean FEV(1) reversibility=3.6% bsln+/-3.8 s.d.) treated with theophylline 400 mg/day and beta(2) short acting prn, were divided into three matched groups of six subjects according to a double-blind design, and treated with SM&FP 50/250 microcg, or SM 50 microcg alone, or P via Diskus inhaler bid for 52 weeks. In bsln, after 4, 12, 24, 36 and 52 weeks, FEV(1) (% pred), morning PEF (l/s), the daily symptom score, and the number of exacerbations (compared with the previous year) were considered. Statistics. t-test, anova in each treatment group, and anova among basal values and among the 52 week values were used, being p<0.05 accepted. Also changes (DeltaFEV(1)) from baseline were compared at different control times. RESULTS: The mean number of exacerbations/yr decreased from 3.5+/-0.8 to 1.16+/-0.75 s.d. exacerbation/yr in the SM&FP group (t-test p<0.001); from 3.0+/-0.89 to 2.3+/-0.81 s.d. in the SM group (t-test p=ns); and from 3.16+/-1.16 to 4.16+/-0.75 s.d. in the P group (t-test p=ns). Patients receiving SM&FP showed the highest mean improvement in FEV(1) (+7.3%+/-3.3 s.d.) over the baseline pre-treatment value after 36 weeks of treatment (anova p<0.001), being FEV(1) unchanged after 52 weeks of treatment in SM group (+0.33%+/-2.4 s.d.) and with a substantial decrease following P (-2.6%+/-1.2 s.d.) (anova p<0.001). Morning PEF (l/min) increased in subjects treated with SM&FP (anova p<0.001), while it remained unchanged in SM and P group (in both, anova p=ns). After 52 weeks of treatment, only subjects treated with SM&FP showed a reduction of the daily symptoms score from 3.6+/-0.7 to 2.0+/-0.2 s.d. (anova p=0.008). Daily beta(2) short acting prn consumption was reduced only in SM&FP group from 4.2+/-0.81 to 2.2+/-1.2 s.d. after 52 weeks (anova p<0.001). CONCLUSIONS: SM&FP 50/250 microcg regularly assumed in combination via a single Diskus inhaler for a 52 week period improves respiratory function (such as FEV(1), morning PEF), and and symptom score significantly in moderate COPD previously treated with theophylline, and at an higher extent than SM alone or P. The use of beta(2) short acting prn is also reduced, together with the number of exacerbations.