Influence of allergic status and nasal polyposis on long-term Benralizumab response in eosinophilic severe asthma.

Objective: It is unclear whether Benralizumab effectiveness in severe eosinophilic asthma can be influenced by nasal polyposis (NP) or allergic status associations. We evaluated whether Benralizumab long-term efficacy in asthma outcomes could be different in subjects with atopy (SAEA) compared to the effectiveness in those without allergies (SNAEA) and in individuals with NP compared to those without NP. Methods: This observational retrospective study considered 95 consecutive patients divided into allergic (SAEA; n:65[68.4%]; skin prick tests positive [SPT] and/or IgE values ≥100 UI/mL), and non-allergic (SNAEA; n:30[31.6%], SPT negative and normal IgE levels<100 UI/mL). Overall population was also divided into two groups according to NP presence (NP+:39[41%] and NP-:56[59%]). Benralizumab treatment mean was19.7±7.2 months (range 12-35). Results: No differences in Benralizumab effectiveness were found in asthma outcomes in patients with/without NP. SNOT-22 improvement was higher in NP+ (-22±24) compared to NP- groups (6.33±15.5;p=0.055). FEV1 (16.33±19.22%), ACT(7.45±3.95) increases and frequency of SABA use (3.37±4.99) reduction were higher in SAEA compared to what obtained in non-allergic subjects (FEV1:8.15±15.6%,p=0.043; ACT:4.89±3.57,p=0.005; SABA use:-1.16±1.84;p=0.015). 93.8% of SAEA patients whereas only 72.2% of SNAEA individuals reduced OC doses at least half after Benralizumab (p=0.035). These results were partially confirmed by linear regression models showing associations between allergic status and FEV1, ACT and SABA use changes (ß=8.37;p=0.048, ß=2.056;p=0.033 and ß=-2.184;p=0.042 respectively). Conclusion: Benralizumab effectiveness in asthma appears to be independent of NP presence. The allergic eosinophilic disease, compared to just eosinophilic asthma, may be a more severe phenotype. Benralizumab may have greater efficacy in SAEA on some outcomes.

Oxidative stress and viral Infections: rationale, experiences, and perspectives on N-acetylcysteine.

This article explores current evidence on the role of oxidative stress in viral infections, and on the use of antioxidant drugs as adjunctive treatment. MEDLINE/PubMed was searched for appropriate keywords, and preclinical and clinical studies with reviews were retrieved and examined by authors. Old and current evidence shows that GSH content reduction is the main mechanism of redox imbalance in viral-infected cells. Clinical studies found that GSH levels are depleted in patients with viral infections such as HIV and SARS-CoV. Viral infections activate inflammation through different pathways, and several of these mechanisms are related to oxidative stress. NAC is a precursor of GSH, and many of its intracellular effects are mediated by GSH replenishment, but it also activates some anti-inflammatory mechanisms. NAC has an excellent safety profile and better oral and topical bioavailability than GSH. These characteristics make NAC a suitable option as a repurposed drug. Adjunctive antioxidant treatment may improve the outcomes of antiviral therapies. Current evidence supports the rationale for this practice and some clinical experience showed encouraging results.

Severe asthma and long-term Benralizumab effectiveness in real-life.

OBJECTIVE: Long-term efficacy of Benralizumab in real life is not clearly known. We assessed the long-term effectiveness persistence to anti-IL-5R treatment in a group of severe eosinophilic asthmatics. PATIENTS AND METHODS: We retrospectively analyzed 95 individuals affected by severe asthma (36 males  ̶ 37.9%; mean age 58.1 ± 12.2) treated with Benralizumab (mean time 19.7 ± 7.2 months, range 12-35). Outcomes were evaluated at the beginning and at the end of patients' treatment periods. RESULTS: Mean baseline blood eosinophils were 897.5 ± 720.1 cells/µL (11 ± 5.6%) decreasing to 7.4 ± 20.6 cells/µL (0.97 ± 0.26%; p < 0.0001) after Benralizumab. FENO likewise decreased from 63.9 ± 68.4 to 28.4 ± 23.6 ppb, while FEV1% significantly improved (p < 0.0001). Mean FEF25-75 also increased from 45.8 ± 24.6% to 60.7 ± 24.6%, whereas RAW dropped from 202.15 ± 109.6% to 135.2 ± 54.75% (p < 0.0001). Also, lung volumes greatly decreased. ACT/ACQ significantly improved, while exacerbations number fell from 4.1 ± 2.4, before anti-IL-5R, to 0.33 ± 0.77, after treatment (p < 0.0001). Rhinitis severity levels and SNOT-22 also changed favorably. Patients that took long-term OCs were 71.6% before treatment, decreasing to 23.2% after Benralizumab (p < 0.0001), with an OCs dose reduction from 14.8 ± 8.9 to 1.45 ± 2.8 mg/day (p < 0.0001). 51.6% of subjects used SABA as needed before Benralizumab, falling to 4.2% after treatment. Several patients showed a reduction of ICS doses, SABA use and maintenance therapy step-down. Clinical/biological response with anti-IL-5R remained constant or even improved in terms of exacerbations or maintenance therapy reductions over time. On the contrary, FEF25-75% improvement slowed down in the long-term. No relationship was found between baseline blood eosinophil number and therapeutic response. CONCLUSIONS: Long-term Benralizumab effectiveness persistence in all outcomes in real life was confirmed.

The prevalence of sleep impairments and predictors of sleep quality among patients with asthma.

BACKGROUND: Sleep is a significant dimension of daily life. However, only a few studies have examined the sleep quality of asthmatics in a real-world clinical settings. OBJECTIVE: This study is aimed to estimate the prevalence of sleep impairments among asthmatic patients and examine the relationship between sleep quality, asthma control, rhinitis symptoms, and sociodemographic characteristics. METHODS: The present study adopted the observational cross-sectional research design that has been designed by the Italian Respiratory Society and used valid assessments to measure the study variables. RESULTS: Data from 1150 asthmatic patients (mean age 51.01 years ± 16.03) were subjected to analysis. 58.3% of the patients had impaired sleep quality (Pittsburgh Sleep Quality Index [PSQI] total scores > 5), and their mean PSQI score was 5.68 (SD = 3.4). A significant correlation emerged between sleep quality and asthma control (p = 0.0001) and a significant albeit weak correlation emerged between PSQI total scores and Total 5 Symptoms Score (r = 0.24, p = 0.0001). Sleep quality was significantly associated health-related quality of life [HRQoL]. (r = 0.50, p < 0.001). After exclusion of patients at risk for Obstructive Sleep Apnea Syndrome (OSAS) and Gastro Esophageal Reflux Disease (GERD), the most important determinants of PSQI score were HRQoL, In the entire sample asthma control is the strongest predictor of both sleep quality and HRQoL. CONCLUSIONS: The results of this real-world study highlight the prevalence, impact and predictors of sleep disturbances in asthmatic patients and suggest the need for physicians to detect poor sleep quality.

Balancing evidence and frontline experience in the early phases of the COVID-19 pandemic: current position of the Italian Society of Anti-infective Therapy (SITA) and the Italian Society of Pulmonology (SIP).

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), which has rapidly become epidemic in Italy and other European countries. The disease spectrum ranges from asymptomatic/mildly symptomatic presentations to acute respiratory failure. At the present time the absolute number of severe cases requiring ventilator support is reaching or even surpassing the intensive care unit bed capacity in the most affected regions and countries. OBJECTIVES: To narratively summarize the available literature on the management of COVID-19 in order to combine current evidence and frontline opinions and to provide balanced answers to pressing clinical questions. SOURCES: Inductive PubMed search for publications relevant to the topic. CONTENT: The available literature and the authors' frontline-based opinion are summarized in brief narrative answers to selected clinical questions, with a conclusive statement provided for each answer. IMPLICATIONS: Many off-label antiviral and anti-inflammatory drugs are currently being administered to patients with COVID-19. Physicians must be aware that, as they are not supported by high-level evidence, these treatments may often be ethically justifiable only in those worsening patients unlikely to improve only with supportive care, and who cannot be enrolled onto randomized clinical trials. Access to well-designed randomized controlled trials should be expanded as much as possible because it is the most secure way to change for the better our approach to COVID-19 patients.

What drives inhaler prescription for asthma patients? Results from a real-life retrospective analysis.

BACKGROUND: The choice of inhaler device for asthma patients depends upon multiple attributes. We investigated factors that may drive general practitioners (GPs) and respiratory specialists in the prescription of inhaler devices for asthma patients who initiated inhalation therapy. METHODS: We retrospectively analysed prescriptions by GPs and respiratory specialists to asthma patients commencing inhaled corticosteroid/long-acting ß2-agonist combination therapy available as both pressurised metered-dose inhalers (pMDIs) and dry powder inhalers (DPIs). Patient characteristics were compared by device and multivariate analysis was used to model the likelihood of receiving a pMDI as opposed to a DPI in order to identify drivers for prescription. A sample of the respiratory specialists completed an ad-hoc survey of their perceived success in achieving asthma control in their patients and barriers to attaining full control. RESULTS: Prescription of a particular inhaler device was unrelated to the characteristics of the patients. Multivariate analysis revealed that the main driver for the choice of inhaler device was the medication (Odds Ratio and 95% Confidence Interval, respectively for GPs and specialists: 0.19 [0.16-0.23]; 0.17 [0.08-0.37]). Specialists perceived asthma as being inadequately controlled in 41% of their patients, and considered patients' difficulties in using DPIs and pMDIs as instrumental in this, citing a need for a novel, more effective inhaler technology. CONCLUSION: Physicians choose inhaler devices according to the prescribed drugs and not to the characteristics of the individual patient. This may reflect a lack of confidence in existing inhaler devices and underlines the need for technologies, which are more reliable and easier to use by patients.

Factors reducing omalizumab response in severe asthma.

BACKGROUND: Despite adding Omalizumab to conventional therapy, several severe asthmatics still show poor disease control. We investigated the factors that may affect a reduced Omalizumab response in a large population of severe asthmatics. METHODS: 340 patients were retrospectively evaluated. FEV1%, FVC%, Asthma Control Test (ACT), fractional exhaled nitric oxide (FENO), possible step-downs/step-ups of concomitant therapies, exacerbations, disease control levels, ICS doses and SABA use, observed at the end of treatment, were considered as a response to Omalizumab. RESULTS: Age was an independent risk factor for a reduced response concerning FEV1%, FVC%, ACT and for a lower asthma control. Obesity (vs normal weight) was a determinant condition for exacerbations (OR:3.114[1.509-6.424], p = 0.002), for a disease partial/no control (OR:2.665[1.064-6.680], p = 0.036), for excessive SABA use (OR:4.448[1.837-10.768], p = 0.002) and for an unchanged/increased level of concomitant asthma medications. Furthermore, obesity also reduced the response in FEV1 (ß = -6.981,p = 0.04), FVC (ß = -11.689,p = 0.014) and ACT (ß = -2.585, p = 0.027) and was associated with a higher FENO level (ß = 49.045,p = 0.040). Having at least one comorbidity was a risk factor for exacerbations (OR:1.383[1.128-1.697], p = 0.008) and for an ACT <20 (OR:2.410[1.071-3.690], p = 0.008). Specifically, chronic heart disease was associated with both a lower ACT and FVC% whereas gastroesophageal reflux with a partial/no asthma control. Nasal polyps were a predisposing factor leading both to exacerbations and to the use of higher inhaled corticosteroids doses. Moreover, smoking habits, pollen or dog/cat dander co-sensitizations may negatively influence Omalizumab response. CONCLUSION: Age, obesity, comorbidities, smoking habits, nasal polyps, allergic poly-sensitization might reduce Omalizumab effectiveness independently to other asthma-influencing factors.

Asymmetric dimethylarginine (ADMA): will be or will not be a new revolutionary biomarker of bronchial asthma.

Carraro et al. measured asymmetric dimethylarginine (ADMA) in the exhaled breath condensate (EBC) obtained from children with asthma and from healthy subjects. The authors demonstrated higher levels of ADMA in EBC of asthmatics compared to controls. ADMA levels in EBC did not correlate with serum levels, lung function parameters, and fractional exhaled nitric oxide. ADMA levels in EBC did not significantly differ between asthmatic patients regularly treated with inhaled steroids and those who were steroid naïve. Further studies are necessary in order to evaluate the role of this biomarker in the characterization of phenotypes of severe bronchial asthma.

Choose the best route: ultrasound-guided transbronchial and transesophageal needle aspiration with echobronchoscope in the diagnosis of mediastinal and pulmonary lesions.

Nodal mediastinal staging is a crucial part of the diagnostic workup of patients with nonsmall- cell lung cancer (NSCLC) for planning optimal treatment. Transesophageal endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) and real-time endobronchial ultrasounds transbronchial needle aspiration (EBUS-TBNA) are accurate, minimally invasive and safe diagnostic techniques for mediastinal staging. Because of the different accessibility to the mediastinum, they are considered complementary and their combination increases the diagnostic yield as compared with the either alone. Recent studies have shown that endosonography represents the best initial test for invasive mediastinal evaluation in NSCLC. Endoscopic ultrasound (with bronchoscope)-guided fine needle aspiration (EUS-B-FNA) is a recently introduced procedure consisting of a transesophageal needle aspiration using an ultrasound bronchoscope. It allows to perform both transbronchial and transesophageal needle sampling with the same instrument, in the same session and by one operator only, thus maximizing time and costs savings. In a recent study Oki et al. randomized 110 patients with hilar/mediastinal adenopathies or lung abnormalities adjoining both the esophagus and the bronchi, to undergo EBUSTBNA or EUS-FNA performed by pulmonologists with an echobronchoscope. The Authors demonstrated that both procedures provide a high diagnostic yield, without any difference in the number of adverse events and a good comparable tolerance. Nevertheless, the transesophageal approach guaranteed a significantly lower dose of anesthetics and sedatives, a shorter procedural time, fewer oxygen desaturations, a significantly lower cough score and a higher operator satisfaction. In this review our aim was to discuss the findings by Oki et al. in the context of medical literature, highlighting the importance of the EUS-B needle aspiration technique in diagnosing mediastinal and lung lesions, when EBUS-TBNA is deemed less suitable. Finally, we pointed out the importance of interventional pulmonologists being trained to perform mediastinal sampling by the esophageal route, to choose the best solution in every technical and clinical occurence.

Why use long acting bronchodilators in chronic obstructive lung diseases? An extensive review on formoterol and salmeterol.

Long-acting ß2-adrenoceptor agonists, formoterol and salmeterol, represent a milestone in the treatments of chronic obstructive lung diseases. Although no specific indications concerning the choice of one molecule rather than another are provided by asthma and COPD guidelines, they present different pharmacological properties resulting in distinct clinical employment possibilities. In particular, salmeterol has a low intrinsic efficacy working as a partial receptor agonist, while formoterol is a full agonist with high intrinsic efficacy. From a clinical perspective, in the presence of low ß2-adrenoceptors availability, like in inflamed airways, a full agonist can maintain its bronchodilatory and non-smooth muscle activities while a partial agonist may be less effective. Furthermore, formoterol presents a faster onset of action than salmeterol. This phenomenon, combined with the molecule safety profile, leads to a prompt amelioration of the symptoms, and allows using this drug in asthma as an "as needed" treatment in patients already on regular treatment. The fast onset of action and the full agonism of formoterol need to be considered in order to select the best pharmacological treatment of asthma and COPD.

Bronchoscopy in sarcoidosis: union is strength.

Sarcoidosis is a benign disease of unknown etiology that is characterized by the formation of noncaseating epithelioid cell granulomas. Although a multisystemic disease, it primarily affects the lung and the lymphatic system of the body. When a histological diagnosis is required, bronchoscopy is frequently employed because allows tissue sampling from several anatomic sources, such as airways, lung parenchyma and hilar/mediastinal nodes. Transbronchial lung biopsies (TBLB), endobronchial biopsies (EBB) and conventional transbronchial needle aspiration (cTBNA) have long been the only bronchoscopic techniques to diagnose sarcoid granulomas, until the advent of endobronchial ultrasound guided needle aspiration (EBUS-TBNA). This technique shows excellent yield in sampling mediastinal adenopathies with a higher sensitivity than the conventional technique in sarcoidosis as well. Furthermore, non controlled studies, demonstrated its diagnostic superiority than EBB and TBLB in stages I (hilar adenopathies only) and II (hilar lymph nodes and parenchymal infiltrations) thoracic sarcoidosis. In a recent study, Gupta et al., randomized 130 patients with suspected stage I and II disease to undergo EBUS-TBNA or cTBNA in conjunction with transbronchial and endobronchial biopsies. The Authors demonstrated that the yield of cTBNA added to EBB and TBLB is similar to EBUS-TBNA plus transbronchial biopsies, although ultrasound guided transbronchial needle aspiration shows the best single diagnostic efficacy. In this review article we aimed to discuss the findings by Gupta in the context of medical literature, highlighting the importance of adding nodal aspirations (with or without ultrasound guidance) with bronchial and transbronchial samples to gain the optimal sensitivity in obtaining histological confirmation. We finally pointed out the need for future studies to evaluate the potential role of rapid on-site evaluation (ROSE) of needle aspirates in reducing additional sampling and related costs and complications.

Asymmetric dimethylarginine (ADMA): will be or will not be a new revolutionary biomarker of bronchial asthma?

Carraro et al. measured asymmetric dimethylarginine (ADMA) in the exhaled breath condensate (EBC) obtained from children with asthma and from healthy subjects. The authors demonstrated higher levels of ADMA in EBC of asthmatics compared to controls. ADMA levels in EBC did not correlate with serum levels, lung function parameters, and fractional exhaled nitric oxide. ADMA levels in EBC did not significantly differ between asthmatic patients regularly treated with inhaled steroids and those who were steroid naïve. Further studies are necessary in order to evaluate the role of this biomarker in the characterization of phenotypes of severe bronchial asthma.

Choose the best route: ultrasound-guided transbronchial and transesophageal needle aspiration with echobronchoscope in the diagnosis of mediastinal and pulmonary lesions.

Nodal mediastinal staging is a crucial part of the diagnostic workup of patients with non-small-cell lung cancer (NSCLC) for planning optimal treatment. Transesophageal endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) and real-time endobronchial ultrasounds transbronchial needle aspiration (EBUS-TBNA) are accurate, minimally invasive and safe diagnostic techniques for mediastinal staging. Because of the different accessibility to the mediastinum, they are considered complementary and their combination increases the diagnostic yield as compared with the either alone. Recent studies have shown that endosonography represents the best initial test for invasive mediastinal evaluation in NSCLC. Endoscopic ultrasound (with bronchoscope)-guided fine needle aspiration (EUS-B-FNA) is a recently introduced procedure consisting of a transesophageal needle aspiration using an ultrasound bronchoscope. It allows to perform both transbronchial and transesophageal needle sampling with the same instrument, in the same session and by one operator only, thus maximizing time and costs savings. In a recent study Oki et al. randomized 110 patients with hilar/mediastinal adenopathies or lung abnormalities adjoining both the esophagus and the bronchi, to undergo EBUS-TBNA or EUS-FNA performed by pulmonologists with an echobronchoscope. The Authors demonstrated that both procedures provide a high diagnostic yield, without any difference in the number of adverse events and a good comparable tolerance. Nevertheless, the transesophageal approach guaranteed a significantly lower dose of anesthetics and sedatives, a shorter procedural time, fewer oxygen desaturations, a significantly lower cough score and a higher operator satisfaction. In this review our aim was to discuss the findings by Oki et al. in the context of medical literature, highlighting the importance of the EUS-B needle aspiration technique in diagnosing mediastinal and lung lesions, when EBUS-TBNA is deemed less suitable. Finally, we pointed out the importance of interventional pulmonologists being trained to perform mediastinal sampling by the esophageal route, to choose the best solution in every technical and clinical occurence.

Differences in the efficacy and safety among inhaled corticosteroids (ICS)/long-acting beta2-agonists (LABA) combinations in the treatment of chronic obstructive pulmonary disease (COPD): Role of ICS.

Inhaled corticosteroids (ICS) are frequently recommended for the treatment of asthma and COPD, often in combination with long-acting beta2-agonists (LABA), depending on the severity of the disease and/or on the specific phenotype. Several ICS/LABA combinations are currently available that differ in their pharmacokinetic characteristics and dose of both components. Thus, this review assesses differences in the efficacy and the safety profiles of the ICS components in the two more frequently used ICS/LABA combinations (budesonide/formoterol and fluticasone/salmeterol) for the management of COPD. Whereas the basic mechanism of action is similar for all ICS (binding with the intracellular glucocorticoid receptor, which mediates both genomic and non genomic effects), the pharmacokinetic and characteristics of ICS are quite different in terms of receptor affinity, bioavailability, lipophilicity and drug persistence in the airways. Fluticasone persists longer in airway mucus and requires more time to dissolve in the lining fluid and then enter the airway wall, whereas budesonide is cleared more quickly from the airways. Comparative efficacy of the two major ICS/LABA combinations recommended for the treatment of COPD show similar efficacy in terms of reduction of exacerbations, improvement in forced expiratory volume in the first second (FEV1) and quality of life. One retrospective cohort study suggested a greater efficacy for the budesonide/formoterol combination on hospital or emergency department admissions, oral corticosteroid courses, and addition of tiotropium, and an observational real-life study reported a greater reduction of COPD exacerbations with budesonide/formoterol than with fluticasom/salmeterol combination. Among the potential side effects of chronic ICS treatment in patients with COPD, recently the use of fluticasone or fluticasone/salmeterol combination has been associated with a higher prevalence of pneumonia in the major long-term studies. On the other hand, no similar increased risk of pneumonia has been reported in patients with COPD treated with the budesonide/formoterol combination. A recent population-based cohort study from the Quebec database showed that the adjusted odds ratio for having severe pneumonia was higher for fluticasone (2.1) than for budesonide (1.17) or other ICS (1.41). Of the ICS studied, only fluticasone demonstrated a dose-related increase in risk of pneumonia in patients with COPD. This difference between fluticasone and budesonide may be explained by the longer retention of fluticasone in the airways, with potentially greater inhibition of type-1 innate immunity. Therefore, the risk:benefit ratio should be evaluated thoroughly when choosing an ICS/LABA combination for patients with COPD.

Is mild asthma in real life always in the Green Zone?

Asthma is a chronic inflammatory disease of the airways that is characterized by variable narrowing of the airways and symptoms of intermittent dyspnea, wheezing, and nighttime or early-morning coughing. Asthma is a major health problem throughout the world, affecting an estimated 315 million persons of all ages. Asthma is clinically heterogeneous, and its pathophysiology is complex. For convenience, asthma action plans are often broken down into three zones, usually based on peak flow meter recordings: green, yellow, and red according to the level of lung function impairment. Recent evidence shows that every asthmatic is potentially at risk for severe exacerbation independently of his/her zone, including the green zone. Furthermore, in real life scenario asthmatic patients can have poor perception of their symptoms or/and overestimate their level of asthma control, and this can obviously confound the clinical picture and favor sudden worsening of symptoms. To understand how to treat these patients, as well as how to assess their future risk, can make a difference in terms of clinical outcomes and prognosis. Following the suggestions and concerns recently published, who recently focused on the clinical management of mild asthma, we aimed at exploring strengthens and gaps in the daily management of the mildest forms of the disease, with a focus on alternative diagnostic and therapeutic strategies in approaching the "green" patient in clinical practice.

The role of cefditoren in the treatment of lower community-acquired respiratory tract infections (LRTIs): from bacterial eradication to reduced lung inflammation and epithelial damage.

OBJECTIVES: Lower respiratory tract infections (LRTIs), including pneumonia and acute exacerbations of Chronic Obstructive Pulmonary Disease (COPD), are among the most common diagnoses in both outpatient and inpatient settings. Due to the burden of LRTIs healthcare providers must adopt practices focused on improving outcomes with the aim to reduce treatment failure and antibiotic resistances. Moreover, the role of acute and chronic infection in the pathogenesis of COPD has received considerable attention, since chronic infection can contribute to airways inflammation and COPD progression. This review discusses the role of cefditoren for the treatment of LRTIs, compared with the definition of "appropriate" of the WHO as "the cost-effective use of antimicrobials which maximizes clinical therapeutic effect while minimizing both drug-related toxicity and the development of antimicrobial resistance". RESULTS AND CONCLUSIONS: Cefditoren appears to meet the definition of "appropriate" for the treatment of LRTIs. In fact, this molecule shows an adequate pharmacokinetic profile without the need for any adjustment also in aged patients with mild renal impairment or mild-to-moderate hepatic dysfunction. The low drug-drug interaction potential of cefditoren can be an advantage also in poly-treated patients. The antimicrobial spectrum of cefditoren includes both Gram+ and Gram- bacteria, with high activity against Streptococcus pneumoniae, including drug-resistant strains, Haemophilus infuenzae and Moraxella chatarrhalis. Last, recent findings suggested that cefditoren can be a valid alternative to levofloxacin in outpatients with acute exacerbation of COPD; in this setting a treatment with cefditoren showed to be associated with a significant reduction of some key inflammatory markers involved in epithelial damage, including KL-6 and IL-6.

Randomized Controlled Trials and real life studies. Approaches and methodologies: a clinical point of view.

Randomized Controlled Trials (RCTs) are the "gold standard" for evaluating treatment outcomes providing information on treatments "efficacy". They are designed to test a therapeutic hypothesis under optimal setting in the absence of confounding factors. For this reason they have high internal validity. The strict and controlled conditions in which they are conducted, leads to low generalizability because they are performed in conditions very different from real life usual care. Conversely, real life studies inform on the "effectiveness" of a treatment, that is, the measure of the extent to which an intervention does what is intended to do in routine circumstances. At variance to RCTs, real life trials have high generalizability, but low internal validity. Recently the number of real life studies has been rapidly growing in different areas of respiratory medicine, particularly in asthma and COPD. The role of such studies is becoming a hot topic in respiratory medicine, attracting research interest and debate. In the first part of this review we discuss some of the advantages and disadvantages of different types of RCTs and analyze the strengths and weaknesses of real life trials, considering the recent examples of some studies conducted in COPD. We then discuss methodological approaches and options to overcome some of the limitations of real life studies. Comparing the conclusions of effectiveness and efficacy trials can provide important pieces of information. Indeed, these approaches can result complementary, and they can guide the interpretation of each other results.

COPD classification methods and informativeness on mortality: contrasting evidences.

Understanding whether the ABCD GOLD classification method is informative with respect to the spirometric classification of severity in predicting mortality of patients with chronic obstructive pulmonary disease (COPD) is subject of debate. The results of a study performed on a sample of the Norwegian population (HUNT2) were recently published. Such data showed the inferiority of ABCD classification in predicting mortality compared to the spirometric classification, which was considered the gold standard up to the 2011 version of GOLD guidelines. This result is not in line with the results of other studies that have shown the equivalence of the two classifications. The new GOLD classification seemed to be a step forward for what concerns understanding patient's needs, but it seems clear that the insertion of a single clinical variable to the spirometric data may not be exhaustive in describing all the phenomena related to a heterogeneous disease such as COPD. The publication of the HUNT study provides an opportunity to analyze how the evidence has been produced, which scientific speculations it offers, what considerations could be drawn and what further research would be appropriate.