Sex differences in adult asthma and COPD therapy: a systematic review.

BACKGROUND: Although asthma is more prevalent in women and the prevalence of COPD is increasing in women, the current international recommendations for the management and prevention of asthma and COPD provide no sex-related indication for the treatment of these diseases. Therefore, we systematically reviewed the evidence across literature on the sex-related effectiveness of asthma and COPD therapy. METHODS: This systematic review has been registered in PROSPERO and performed according to PRISMA-P. The PICO framework was applied for the literature search strategy: "patient problem" included adult patients suffering from asthma or COPD, "Intervention" regarded the pharmacological treatments for asthma or COPD, "Comparison" was vs. baseline, active controls, or placebo, "Outcome" was any difference sex-related in the effectiveness of interventions. RESULTS: In asthma 44% of the evidence reported that men responded better than women to the therapy, whereas this percentage was 28% in COPD. ICS was generally less effective in women than in men to treat asthma, and consistent evidence suggests that in asthmatic patients ICS/LABA/LAMA combination may be equally effective in both men and women. Due to the inconsistent available evidence, it is not possible to identify specific treatments whose effectiveness is related to sex difference in COPD patients. CONCLUSIONS: There is a strong need of investigating the sex-related impact of asthma and COPD treatments. Pre-specified analyses in men and women should be planned in future trial protocols, a necessary condition that should be requested also by the regulatory agencies to overcome the anachronistic "one-size-fits-all" approach to therapeutics associated with suboptimal outcomes for patients.

Inflammatory and contractile profile in LPS-challenged equine isolated bronchi: Evidence for IL-6 as a potential target against AHR in equine asthma.

BACKGROUND: Airway inflammation and airway hyperresponsiveness (AHR) are pivotal characteristics of equine asthma. Lipopolysaccharide (LPS) may have a central role in modulating airway inflammation and dysfunction. Therefore, the aim of this study was to match the inflammatory and contractile profile in LPS-challenged equine isolated bronchi to identify molecular targets potentially suitable to counteract AHR in asthmatic horses. METHODS: Equine isolated bronchi were incubated overnight with LPS (0.1-100 ng/ml). The contractile response to electrical field stimulation (EFS) and the levels of cytokines, chemokines, and neurokinin A (NKA) were quantified. The role of capsaicin sensitive-sensory nerves, neurokinin-2 (NK2) receptor, transient receptor potential vanilloid type 1 receptors (TRPV1), and epithelium were also investigated. RESULTS: LPS 1 ng/ml elicited AHR to EFS (+238.17 ± 25.20% P < 0.001 vs. control). LPS significantly (P < 0.05 vs. control) increased the levels of IL-4 (+36.08 ± 1.62%), IL-5 (+38.60 ± 3.58%), IL-6 (+33.79 ± 2.59%), IL-13 (+40.91 ± 1.93%), IL-1ß (+1650.16 ± 71.16%), IL-33 (+88.14 ± 8.93%), TGF-ß (22.29 ± 1.03%), TNF-α (+56.13 ± 4.61%), CXCL-8 (+98.49 ± 17.70%), EOTAXIN (+32.26 ± 2.27%), MCP-1 (+49.63 ± 4.59%), RANTES (+36.38 ± 2.24%), and NKA (+112.81 ± 6.42%). Capsaicin sensitive-sensory nerves, NK2 receptor, and TRPV1 were generally involved in the LPS-mediated inflammation. Epithelium removal modulated the release of IL-1ß, IL-33, and TGF-ß. Only the levels of IL-6 fitted with AHR to a wide range of EFS frequencies, an effect significantly (P < 0.05) inhibited by anti-IL-6 antibody; exogenous IL-6 induced significant (P < 0.05) AHR to EFS similar to that elicited by LPS. CONCLUSION: Targeting IL-6 with specific antibody may represent an effective strategy to treat equine asthma, especially in those animals suffering from severe forms of this disease.

Pulmonary Rehabilitation in Noncystic Fibrosis Bronchiectasis.

BACKGROUND: Current guidelines for the treatment of noncystic fibrosis bronchiectasis (NCFB) recommend pulmonary rehabilitation (PR), but to date, there are few studies that have proven its effectiveness. OBJECTIVE: The main objective of this study was to examine the effect of PR on pulmonary function tests and exercise capacity. METHOD: The aim of this study was to systematically review the effects of PR in NCFB on (1) forced expiratory volume in the first second (FEV1) and (2) exercise capacity evaluated by the 6-min walk test (6MWT) and the incremental shuttle walk test (ISWT). This meta-analysis was undertaken according to PRISMA recommendations. RESULTS: This pair-wise meta-analysis included data obtained from studies that enrolled 529 NCFB patients. The FEV1 assessment after PR between the active and control group did not show any significant increase (FEV1 difference 0.084 mL; CI: -0.064, +0.233; p = 0.264), and there was an increasing trend (188 mL; CI: -0 to 0.009, +0.384) at the limits of statistical significance (p = 0.061). Walked distance showed a significant increase in the PR group compared to the control group (ISWT distance difference 070.0 m; CI: 55.2, 84.8; p < 0.001), and this finding was confirmed before and after PR both by the ISWT (68.85 m greater than baseline; CI: 40.52, 97.18; p < 0.001) and by the 6MWT (37.7 m greater than baseline; CI: 20.22, 55.25; p < 0.001). CONCLUSIONS: PR improves exercise tolerance in NCFB patients, but it has a modest impact on respiratory function.

Triple therapy in uncontrolled asthma: a network meta-analysis of phase III studies.

Conflicting evidence is currently available concerning the impact on asthma exacerbation of triple inhaled corticosteroid (ICS)/long-acting ß2-adrenoceptor agonist (LABA)/long-acting muscarinic receptor antagonist (LAMA) fixed-dose combination (FDC).Since meta-analyses allow settling controversies of apparently inconsistent results, we performed a network meta-analysis of phase III randomised controlled trials including 9535 patients to assess the effect of ICS/LABA/LAMA combinations in uncontrolled asthma.Triple combination therapies with an ICS administered at high dose (HD) were more effective (p<0.05) than medium-dose (MD) ICS/LABA/LAMA FDC and both MD and HD ICS/LABA FDCs against moderate to severe exacerbation (relative risk 0.61-0.80) and increasing trough forced expiratory volume in 1 s (from +33 to +114 mL). Triple combination therapies including HD ICS were superior (p<0.05) to MD ICS/LABA/LAMA FDC in preventing severe exacerbation (relative risk 0.46-0.65), but not with respect to moderate exacerbation (p>0.05). Triple combination therapies were equally effective on asthma control, with no safety concerns.This quantitative synthesis suggests that ICS/LABA/LAMA FDCs are effective and safe in uncontrolled asthma, and that the dose of ICS in the combination represents the discriminating factor to treat patients with a history of moderate or severe exacerbation.

Indacaterol, glycopyrronium, and mometasone: Pharmacological interaction and anti-inflammatory profile in hyperresponsive airways.

LABA/ICS and LABA/LAMA/ICS combinations elicit beneficial effects in asthma. Specific evidence concerning the impact of combining indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF) on human airway hyperresponsiveness (AHR) and airway inflammation is still missing. The aim of this study was to characterize the synergy of IND/MF and IND/GLY/MF combinations, both once-daily treatments for asthma, in hyperresponsive airways. Passively sensitized human medium and small airways were stimulated by histamine and treated with IND/MF (molar ratio: 100/45, 100/90) and IND/GLY/MF (molar ratio: 100/37/45, 100/37/90). The effect on contractility and airway inflammation was tested. Drug interaction was assessed by Bliss Independence equation and Unified Theory. IND/MF 100/90 elicited middle-to-very strong synergistic relaxation in medium and small airways (+≈20-30% vs. additive effect, P < 0.05), for IND/MF 100/45 the synergy was middle-to-very strong in small airways (+≈20% vs. additive effect, P < 0.05), and additive in medium bronchi (P > 0.05 vs. additive effect). IND/GLY/MF 100/37/45 and 100/37/90 induced very strong synergistic relaxation in medium and small airways (+≈30-50% vs. additive effect, P < 0.05). Synergy was related with significant (P < 0.05) reduction in IL-4, IL-5, IL-6, IL-9, IL-13, TNF-α, TSLP, NKA, SP, and non-neuronal ACh, and enhancement in cAMP. IND/MF and IND/GLY/MF combinations synergistically interact in hyperresponsive medium and small airways and modulate the levels of cytokines, neurokinins, ACh, and intracellular cAMP. The concentrations of MF in the combinations modulate the effects in the target tissue.

SMART and as-needed therapies in mild-to-severe asthma: a network meta-analysis.

To date, there are no network meta-analyses comparing the impact of as-needed treatments in asthma, including the single maintenance and reliever therapy (known as "SMART" or "MART"; for simplicity, SMART will be used hereafter) and the use of inhaled corticosteroid (ICS)/long-acting ß2-agonist (LABA) combination exclusively on an as-needed basis. Therefore, we performed a systematic review and network meta-analysis concerning the efficacy and safety of SMART and as-needed therapies in asthma. Data from 32 096 asthmatic patients were extracted from 21 studies, lasting from 6 to 12 months. In adult mild-to-moderate asthmatic patients low-dose SMART and as-needed low-dose ICS/LABA combination were significantly (relative effect <0.78; p<0.05) more effective than the other as-needed therapies in reducing the risk of exacerbation, and both were ranked as the first treatment option reaching the first quartile of the surface under the cumulative ranking curve analysis (SUCRA). In adult moderate-to-severe asthmatic patients, low-dose to medium-dose SMART and high-dose ICS/LABA+as-needed short-acting ß2-agonist were equally effective in reducing the risk of severe asthma exacerbation (p>0.05), although only low- to medium-dose SMART was ranked as the first treatment option (first SUCRA quartile). Overall, these treatments were well tolerated, and effective also on lung function and disease control. This study supports SMART and as-needed therapies as a suitable therapeutic option for asthma, by providing the most effective positioning of each specific treatment according to the disease severity.

Adding a Second Bronchodilator in COPD: A Meta-Analysis on the Risk of Specific Cardiovascular Serious Adverse Events of Tiotropium/Olodaterol Fixed-Dose Combination.

Dual bronchodilation therapy represents the cornerstone for the treatment of COPD. A large retrospective study reports that adding a second long-acting bronchodilator in patients with COPD significantly increases the risk of heart failure. Nevertheless, retrospective studies are characterized by limitations including misdiagnosis and inaccuracy of recordkeeping. This study aimed to ascertain whether tiotropium/olodaterol (T/O) 5/5 µg fixed-dose combination (FDC) may modulate the risk of main cardiovascular outcomes in COPD patients enrolled in randomized controlled trials (RCTs). A meta-analysis (CRD42017070100) was performed by selecting RCTs reporting raw data from the ClinicalTrials.gov database concerning the impact of T/O 5/5 µg FDC vs. monocomponents on the occurrence of specific cardiovascular serious adverse events: arrhythmia, heart failure, myocardial infarction, and stroke. Data were reported as relative risk and 95% Confidence Interval, and the risk of publication bias assessed via Egger's test. Eighty six full text articles were identified, and 10 RCTs published in 7 studies between 2015 and 2018 were included into the analysis. Data obtained from 12,690 COPD patients (44.47% T/O FDC, 55.53% monocomponents) were extracted. T/O 5/5 µg FDCs did not significantly modulate (p-value > 0.05) the risk of arrhythmia (1.02, 0.55 - 1.92), heart failure (0.88, 0.41 - 1.92), myocardial infarction (1.15, 0.70 - 1.87), and stroke (0.98, 0.44 - 2.16) vs. monocomponents. No significant publication bias affected the effect estimates of this meta-analysis. The results of this quantitative synthesis indicate that dual bronchodilation with T/O 5/5 µg FDC is characterized by an acceptable cardiovascular safety profile in COPD patients.

Isolated airways in equine respiratory pharmacology: They never lie.

Pre-clinical studies on human isolated bronchi have relevant translational value in human in vivo, conversely no investigation has been performed to assess whether data resulting from equine isolated airways can have any translational application in asthmatic horses. Thus, a meta-regression analysis via random-effect method was carried out to correlate the pharmacological characteristics of bronchodilators resulting from experiments performed in equine isolated bronchi with their impact on the lung function outcomes in asthmatic horses. Data on the potency of different bronchodilators were extracted from four ex vivo studies involving 68 horses, and related with the maximum change in transpulmonary pressure (ΔPplmax), pulmonary resistance (RL), and dynamic lung compliance (Cdyn) resulting from the meta-analysis of clinical trials aimed to assess the effect of different bronchodilator classes, namely antimuscarinic agents and ß2-adrenoreceptor (ß2-AR) agonists, on lung function of asthmatic horses. The potency (pEC50) detected in equine isolated bronchi for each specific bronchodilator did not significantly (P > 0.05) influence the bronchorelaxant effect resulting from clinical trials. RL was characterized by a flatter meta-regression line (slope 0.01, 95%CI -0.25 - 0.28) with respect to ΔPplmax (slope 0.90, 95%CI -4.06 - 2.26) and Cdyn (slope 0.09, 95%CI -0.21 - 0.04). The quality of evidence was moderate for RL and ΔPplmax and low for Cdyn. This quantitative synthesis provides the indirect evidence that pre-clinical investigations performed by using equine isolated airways may produce useful data to predict the impact of bronchodilators on the RL of asthmatic horses. Further translational studies are needed to directly confirm the results of this research.

Efficacy and cardiovascular safety profile of dual bronchodilation therapy in chronic obstructive pulmonary disease: A bidimensional comparative analysis across fixed-dose combinations.

Despite several long-acting ß2-adrenoceptor agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combinations (FDCs) are currently approved for the treatment of chronic obstructive pulmonary disease (COPD), there are limited findings concerning the direct comparison across the different LABA/LAMA FDCs. The aim of this study was to compare the efficacy/safety profile of approved LABA/LAMA FDCs in COPD. A network meta-analysis was performed by linking the efficacy (forced expiratory volume in 1 s, St' George Respiratory Questionnaire, transitional dyspnea index) and safety (cardiovascular serious adverse events) outcomes resulting from randomized controlled trials that directly compared LABA/LAMA FDCs with placebo and/or each other. The Surface Under the Cumulative Ranking Curve Analysis (SUCRA) was performed for each single outcome (SUCRA: 1 = best, 0 = worst). The combined efficacy/safety profile was reported via the novel Improved Bidimensional SUCRA score (IBiS: the higher the value the better the treatment). Data obtained from 12,136 COPD patients (79.50% LABA/LAMA FDCs vs. placebo; 20.50% direct comparison between different LABA/LAMA FDCs) were extracted from 22 studies published between 2013 and 2019. The IBiS score showed the following rank of efficacy/safety profile: tiotropium/olodaterol 5/5 µg (area 66.83%) ¼ glycopyrronium/indacaterol 15.6/27.5 µg (area 40.43%)  >  umeclidinium/vilanterol 62.5/25 µg (area 30.48%)  ≈  aclidinium/formoterol 400/12 µg (area 28.44%)  >  glycopyrronium/indacaterol 50/110 µg (area 19.95%)  >  glycopyrronium/formoterol 14.4/9.6 µg (area 11.50%). Each available LABA/LAMA FDC has a specific efficacy/safety profile that needs to be considered for personalized therapy in COPD. Head-to-head studies aimed to assess the impact of different LABA/LAMA FDCs on the risk of COPD exacerbation are needed to further improve the information provided by this quantitative synthesis.

Investigational Treatments in Phase I and II Clinical Trials: A Systematic Review in Asthma.

Inhaled corticosteroids (ICS) remain the mainstay of asthma treatment, along with bronchodilators serving as control agents in combination with ICS or reliever therapy. Although current pharmacological treatments improve symptom control, health status, and the frequency and severity of exacerbations, they do not really change the natural course of asthma, including disease remission. Considering the highly heterogeneous nature of asthma, there is a strong need for innovative medications that selectively target components of the inflammatory cascade. The aim of this review was to systematically assess current investigational agents in Phase I and II randomised controlled trials (RCTs) over the last five years. Sixteen classes of novel therapeutic options were identified from 19 RCTs. Drugs belonging to different classes, such as the anti-interleukin (IL)-4Rα inhibitors, anti-IL-5 monoclonal antibodies (mAbs), anti-IL-17A mAbs, anti-thymic stromal lymphopoietin (TSLP) mAbs, epithelial sodium channel (ENaC) inhibitors, bifunctional M3 receptor muscarinic antagonists/ß2-adrenoceptor agonists (MABAs), and anti-Fel d 1 mAbs, were found to be effective in the treatment of asthma, with lung function being the main assessed outcome across the RCTs. Several novel investigational molecules, particularly biologics, seem promising as future disease-modifying agents; nevertheless, further larger studies are required to confirm positive results from Phase I and II RCTs.

Impact of Sex on Proper Use of Inhaler Devices in Asthma and COPD: A Systematic Review and Meta-Analysis.

Despite females being more often affected by asthma than males and the prevalence of COPD rising in females, conflicting evidence exists as to whether sex may modulate the correct inhaler technique. The aim of this study was to assess the impact of sex on the proper use of inhaler devices in asthma and COPD. A pairwise meta-analysis was performed on studies enrolling adult males and females with asthma or COPD and reporting data of patients making at least one error by inhaler device type (DPI, MDI, and SMI). The data of 6,571 patients with asthma or COPD were extracted from 12 studies. A moderate quality of evidence (GRADE +++) indicated that sex may influence the correct use of inhaler device in both asthma and COPD. The critical error rate was higher in females with asthma (OR 1.31, 95%CI 1.14−1.50) and COPD (OR 1.80, 95%CI 1.22−2.67) using DPI vs. males (p < 0.01). In addition, the use of SMI in COPD was associated with a greater rate of critical errors in females vs. males (OR 5.36, 95%CI 1.48−19.32; p < 0.05). No significant difference resulted for MDI. In conclusion, choosing the right inhaler device in agreement with sex may optimize the pharmacological treatment of asthma and COPD.

Muscarinic receptor antagonists and airway inflammation: A systematic review on pharmacological models.

Airway inflammation is crucial in the pathogenesis of many respiratory diseases, including chronic obstructive pulmonary disease (COPD) and asthma. Current evidence supports the beneficial impact of muscarinic receptor antagonists against airway inflammation from bench-to-bedside. Considering the numerous sampling approaches and the ethical implications required to study inflammation in vivo in patients, the use of pre-clinical models is inevitable. Starting from our recently published systematic review concerning the impact of muscarinic antagonists, we have systematically assessed the current pharmacological models of airway inflammation and provided an overview on the advances in in vitro and ex vivo approaches. The purpose of in vitro models is to recapitulate selected pathophysiological parameters or processes that are crucial to the development of new drugs within a controlled environment. Nevertheless, immortalized cell lines or primary airway cells present major limitations, including the inability to fully replicate the conditions of the corresponding cell types within a whole organism. Induced animal models are extensively used in research in the attempt to replicate a respiratory condition reflective of a human pathological state, although considering animal models with spontaneously occurring respiratory diseases may be more appropriate since most of the clinical features are accompanied by lung pathology resembling that of the human condition. In recent years, three-dimensional organoids have become an alternative to animal experiments, also because animal models are unable to fully mimic the complexity of human pulmonary diseases. Ex vivo studies performed on human isolated airways have a superior translational value compared to in vitro and animal models, as they retain the morphology and the microenvironment of the lung in vivo. In the foreseeable future, greater effort should be undertaken to rely on more physiologically relevant models, that provide translational value into clinic and have a direct impact on patient outcomes.

Medium-dose ICS-containing FDCs reduce all-cause mortality in COPD patients: an in-depth analysis of dual and triple therapies.

OBJECTIVES: The recent publication of additional data retrieval for patients missing week 52 vital status in the original analyses of the ETHOS study provides the urgent need of updating previous network meta-analyses (NMA) to produce stronger evidence on mortality in patients receiving dual and triple FDCs according with the level of ICS dose. METHODS: A NMA was performed to compare the effect of ICS/LABA/LAMA, ICS/LABA, and LABA/LAMA FDCs administered via the same inhaler device in COPD patients. The number need to treat (NNT) was also calculated. RESULTS: When considering on-treatment all-cause of death (analyzed patients: 18,864), MD ICS/LABA/LAMA and MD ICS/LABA FDCs significantly reduced the risk of mortality vs. LABA/LAMA FDC (RR 0.59 95%CrI 0.35-0.97 and 0.61 95%CrI 0.38-0.99 respectively, P < 0.05); NNT ranged between 123 and 129. MD ICS/LABA/LAMA FDC also significantly reduced the risk of adjudicated cardiovascular mortality vs. LABA/LAMA FDC (RR 0.44 95%CI 0.19-0.97, P < 0.05). Low-dose (LD) ICS/LABA FDC did not significantly modulate mortality. CONCLUSION: MD ICS/LABA/LAMA and MD ICS/LABA FDCs were effective in reducing on-treatment all-cause of death, with MD ICS/LABA/LAMA FDC being effective also against adjudicated cardiovascular mortality. The protection against mortality was related with the level of ICS dose in the FDCs.

The impact of long-acting muscarinic antagonists on mucus hypersecretion and cough in chronic obstructive pulmonary disease: a systematic review.

Patients suffering from chronic obstructive pulmonary disease (COPD) clinically manifest airway mucus hypersecretion as sputum expectoration and cough. Evidence accumulated in the past decade has shown that the cholinergic system not only regulates airway smooth muscle contraction but also the activity of inflammatory and airway epithelial cells, including goblet cells, and submucosal gland activity. Long-acting muscarinic antagonists (LAMAs) with the most favourable M3/M2 muscarinic acetylcholine (ACh) receptors residency properties are not only excellent bronchodilators but potentially also mucus-modifying agents, able to positively impact on mucus hypersecretion and cough. The aim of this systematic review was to investigate the impact of LAMAs on mucus hypersecretion and cough in COPD patients. The evidence confirmed that LAMAs, mainly tiotropium and aclidinium, improved sputum production and cough in moderate to severe COPD. Thus, LAMAs not only antagonise the ACh-induced bronchoconstriction of the airways but also appear to limit the production of mucus secreted in response to ACh by airway goblet cells and/or submucosal glands. Further clinical studies are necessary to evaluate the impact of LAMAs exclusively on sputum symptoms and cough as primary end-points and to investigate whether LAMAs have a modulatory action on the rheological properties of mucus.

Impact of long-acting muscarinic antagonists on small airways in asthma and COPD: A systematic review.

Small airway disease is recognized as a cardinal pathological process of chronic obstructive pulmonary disease (COPD), and recently small airways have been recognized as a major site of airflow obstruction also in asthmatic patients. The transversal involvement of small airways in COPD and asthma has warranted research efforts to identify therapeutic strategies able to unlock the small airway compartment. The mainstay of COPD treatment is represented by long-acting ß2-adrenoceptor agonists (LABAs) and long-acting muscarinic antagonists (LAMAs). In asthma, the efficacy of LAMAs administered add-on to inhaled corticosteroids (ICSs) or ICS/LABA combinations has been investigated only in recent years. The aim of this systematic review was to examine the current literature concerning the impact of LAMAs on small airways and their lung deposition in both COPD and asthma. LAMAs administered either alone or in combination induced an effective bronchorelaxant effect of small airways, however the effectiveness of respiratory medications not only relies on the selected drug, but also on the employed inhalation device and patient's adherence. Tiotropium delivered via Respimat® SMI achieved a superior drug deposition in the peripheral lung compared to HandiHaler® dry powder inhaler and metered-dose inhalers (MDIs). The use of co-suspension™ delivery technology for MDIs and the introduction of the eFlow® nebulizer to deliver glycopyrronium improved aerosol drug delivery to the peripheral lung, by achieving uniform distribution of drug particles. This systematic review provides a synthesis of current literature concerning the impact of LAMAs on small airways and an insight on LAMAs distribution within the lung.

Advances in understanding of mechanisms related to increased cardiovascular risk in COPD.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) represents a serious global health issue that is commonly associated with cardiovascular (CV) disease (CVD). The close relationship between COPD and CVD could be explained by different factors, first and foremost a chronic low-grade systemic inflammation implicated in the pathogenesis of both diseases and several stimuli enhancing the inflammatory processes and causing a mixed condition with worse outcomes than either disorder alone. AREAS COVERED: The present narrative review considers the mechanisms underlying the increased CV risk in COPD, and it provides insights on biomarkers and predictive models to predict CVD in COPD patients. EXPERT OPINION: COPD patients often remain asymptomatic of CVD, with respiratory symptoms generally attributed to the preexisting pulmonary disease. It is fundamental to understand the mechanistic pathways that underpin the intimate relationship between the two disorders. However, it is still not clear what is the origin of the common background of low-grade systemic inflammation, it could be a 'spillover' or a general inflammatory state. Primary prevention, cross-collaboration between specialists and early detection via predictive biomarkers and validated models are fundamental to stratify COPD patients according to CV risk.

Efficacy and safety of triple combination therapy for treating chronic obstructive pulmonary disease: an expert review.

Introduction: The current recommendations of chronic obstructive pulmonary disease (COPD) suggest to escalate from inhaled corticosteroid/long-acting ß2-adrenoceptor agonist (ICS/LABA) treatment to triple therapy in patients experiencing persistent breathlessness, exercise limitation, or exacerbation. The addition of an ICS to LABA/long-acting muscarinic antagonist (LAMA) combination is recommended for frequently exacerbating patients with high levels of blood eosinophils. Nowadays, three triple therapies have been approved as fixed-dose combinations (FDCs) for the treatment of COPD: beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FOR/GLY), fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI), and budesonide/glycopyrronium bromide/formoterol fumarate (BUD/GLY/FOR).Areas covered: This narrative review evaluates the efficacy and safety profile of triple FDC therapy for the treatment of COPD, by evaluating the data originating from pivotal randomized-controlled trials (RCTs).Expert opinion: The currently approved triple FDCs exert a protective effect against the risk of COPD exacerbation compared to ICS/LABA and LABA/LAMA, with some concerns regarding the risk of pneumonia for some specific FDCs. Since the assessed RCTs were characterized by important confounders, the obtained results should be interpreted with caution. Indeed, FDCs provide advantages in terms of improved adherence to treatment and lower errors in COPD management; however, direct head-to-head comparisons are needed to establish real differences between the currently approved triple FDCs.

The Impact of Muscarinic Receptor Antagonists on Airway Inflammation: A Systematic Review.

Long-acting muscarinic receptor antagonists (LAMAs) are the cornerstone for the treatment of chronic obstructive pulmonary disease (COPD); furthermore, tiotropium is approved as add-on therapy in severe asthmatic patients. Accumulating evidence suggests that LAMAs may modulate airway contractility and airway hyperresponsiveness not only by blocking muscarinic acetylcholine receptors (mAchRs) expressed on airway smooth muscle but also via anti-inflammatory mechanisms by blocking mAchRs expressed on inflammatory cells, submucosal glands, and epithelial cells. The aim of this systematic review, performed according to the PRISMA-P guidelines, was to provide a synthesis of the literature on the anti-inflammatory impact of muscarinic receptor antagonists in the airways. Most of the current evidence originates from studies on tiotropium, that demonstrated a reduction in synthesis and release of cytokines and chemokines, as well as the number of total and differential inflammatory cells, induced by different pro-inflammatory stimuli. Conversely, few data are currently available for aclidinium and glycopyrronium, whereas no studies on the potential anti-inflammatory effect of umeclidinium have been reported. Overall, a large body of evidence supports the beneficial impact of tiotropium against airway inflammation. Further well-designed randomized controlled trials are needed to better elucidate the anti-inflammatory mechanisms leading to the protective effect of LAMAs against exacerbations via identifying suitable biomarkers.

Current long-acting muscarinic antagonists for the treatment of asthma.

INTRODUCTION: The role of long-acting muscarinic antagonists (LAMAs) is well established in uncontrolled asthma, but not in milder stages. AREAS COVERED: This review examines the main randomized controlled trials (RCTs) that have investigated LAMAs administered as monotherapy or in combination to asthmatic patients, according to the different phenotypes. It offers an overview of the role of LAMAs or their fixed dose combinations (FDCs) in the treatment across all the different stages of asthma. EXPERT OPINION: Tiotropium is now widely recognized as treatment for moderate to severe uncontrolled asthma (step 4-5) in adults and children. The most recent new evidence is: a) in adults, three different LAMA/long-acting ß2-agonist (LABA)/inhaled corticosteroid (ICS) FDCs have been recently approved, extending the treatment options for these patients; b) therapy with LAMAs does not depend on patient's Th2 status and justifies the indication regardless of patient's phenotyping; c) in the milder stages, the high variability of response to LAMAs and the lack of a good phenotyping of patients represents the main obstacle in prescribing LAMAs. A better characterization of parasympathetic tone activity could improve LAMAs prescription.

Factors Influencing the Efficacy of COVID-19 Vaccines: A Quantitative Synthesis of Phase III Trials.

To date, there is still a paucity of data from Phase III trials concerning the efficacy of vaccines against COVID-19. Furthermore, no studies investigated the variables that may modulate the efficacy of vaccination. The aim of this analysis was to assess whether there are modifying factors that may potentially influence the clinical efficacy of COVID-19 vaccines. A quantitative synthesis of data from Phase III trials was performed via pairwise and network meta-analyses, along with meta-regression analysis. Data from Phase III trials are currently available only for AZD1222, BNT162b2, mRNA-1237, and Sputnik V. Vaccination resulted to be generally effective (90.0%, 95%CI 72.6-96.4; p < 0.001), although the efficacy of AZD1222 (62.1%) introduced a significant level of heterogeneity in the meta-analysis (I2 92.17%, p < 0.001). No significant modifying factors resulted from the meta-regression analysis. However, considering the mRNA-based vaccines, a trend toward significance (p = 0.081) resulted for age. The network meta-analysis provided the following rank of effectiveness: BNT162b2 ≃ mRNA-1273 > Sputnik V >> AZD1222. In conclusion, no modifying factors seem to modulate the efficacy of vaccines against COVID-19. This quantitative synthesis will need to be updated as soon as further clinical results on the efficacy profile are available from Phase III trials for further licensed COVID-19 vaccines.