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Chronic obstructive pulmonary disease (COPD) is a disorder characterized by a complicated chronic inflammatory response that is resistant to corticosteroid therapy. As a result, there is a critical need for effective anti-inflammatory medications to treat people with COPD. Using monoclonal antibodies (mAbs) to inhibit cytokines and chemokines or their receptors could be a potential approach to treating the inflammatory component of COPD.The therapeutic potential that some of these mAbs might have in COPD is reviewed.No mAb directed against cytokines or chemokines has shown any therapeutic impact in COPD patients, apart from mAbs targeting the IL-5 pathway that appear to have statistically significant, albeit weak, effect in patients with eosinophilic COPD. This may reflect the complexity of COPD, in which no single cytokine or chemokine has a dominant role. Because the umbrella term COPD encompasses several endotypes with diverse underlying processes, mAbs targeting specific cytokines or chemokines should most likely be evaluated in limited and focused populations.

Introduction: The value of treating asthma with the triple regimen of inhaled corticosteroid (ICS), long-acting β2-agonist (LABA), and long-acting muscarinic antagonist (LAMA) delivered using multiple inhalers (MITT), or a single inhaler (SITT) is supported by a growing body of evidence, although research is still limited regarding the use of MITT. Areas covered: Clinical characteristics, treatment patterns, disease burden, and persistence/adherence associated with MITT use in asthma. The MEDLINE database was searched to identify references from inception until October 2022. Expert opinion: The use of MITT is not very frequent in asthma patients, although it improves lung function and reduces the incidence of severe exacerbations. This may be due to existing concerns about using different devices on adherence and persistence to treatment, with a negative influence on outcomes, and to the fear that the patient will discontinue ICS/LABA but not LAMA. Nevertheless, although the current trend favors the SITT approach, some physicians may be induced to prescribe MITT over SITT because it allows the titration of individual components of triple therapy to be increased or decreased. Therefore, there is an evident need for pragmatic real-life studies to document when to prefer SITT and when MITT should be used.

As of today, there is still a need to determine which COPD patients may benefit from ICS therapy, whether ICSs are useful in COPD patients without chronic bronchitis, and whether long-acting bronchodilators can reduce the risk of exacerbations in frequent exacerbators even if ICSs are not used, and whether combination therapy including ICSs is helpful in infrequent exacerbators to optimize the use of ICSs in COPD.Herein, the authors provide an overview of use of ICS in COPD, discuss their value to the current treatment armamentarium and focus on emerged aspects on which there is no consensus.There is growing agreement on why, in whom, and when ICS therapy can be used in COPD, although the consensus is still lacking because of the heterogeneity of COPD. The use of BECs is only helpful in T2 inflammation, while there is a lack of biomarkers indicating the presence of T1 and T17 immunity, which is poorly responsive to ICS. Identifying ICS-sensitive endotypes using specific biomarkers that have yet to be identified and validated is likely to demonstrate that ICSs can influence the natural course of COPD in at least a subset of patients.

Single inhaler triple therapy (SITT) with an inhaled corticosteroid, a long-acting βThe preclinical and clinical development in COPD of fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) SITT and its use in the real world.Findings from phase III/IV trials and the use of FF/UMEC/VI in the real-world setting support the view that it may be a useful, safe, and cost-effective option for the maintenance treatment of COPD, especially when dealing with patients who are not adequately controlled with dual ICS/LABA or LAMA/LABA therapy. Only direct head-to-head comparisons will be able to establish whether FF/UMEC/VI may be preferable to the other SITTs approved for COPD due to its pharmacokinetic and pharmacodynamic characteristics and especially the fact that it is the only one that can be taken once-daily. In addition, there is a need for further studies, especially in the real world, to optimize the positioning of FF/UMEC/VI in the treatment of COPD, also considering the availability of FF/VI and UMEC/VI and the need for better differentiation between the three treatments.

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Long-COVID is the condition characterised by the permanence of symptoms beyond 4 weeks after initial infection. It affects 1 out of 5 people and is loosely related to the severity of acute infection and pathological mechanisms which are yet to be understood.This article looks at currently available or under-study therapies for long-COVID syndrome. It particularly gives focus to ongoing trials and review the underlying mechanisms. A comprehensive literature search was performed on PubMed and clincaltrial.gov of clinical trials concerning the management of long-COVID syndrome."Long-COVID" syndrome is a new emergency characterized by several symptoms such as fatigue, dyspnoea, cognitive and attention disorders, sleep disorders, post-traumatic stress disorder, muscle pain, and concentration problems. Despite the many guidelines available to date, there are no established treatments of long-COVID. Pharmacological research is studying known drugs that act on the reduction or modulation of systemic inflammation, or innovative drugs used in similar pathologies. Rehabilitation now seems to be the safest treatment to offer, whereas we will have to wait for the pharmacological research trials in progress as well as plan new trials based on a better understanding of the pathogenic mechanisms.

Roberta Pisi,1 Marina Aiello,1 Annalisa Frizzelli,1 Luigino Calzetta,1 Laura Marchi,1 Giuseppina Bertorelli,1 Giovanna Pisi,2 Alfredo Chetta1 1Department of Medicine and Surgery, Respiratory Disease and Lung Function Unit, University of Parma, Parma, Italy; 2Department of Pediatrics, Cystic Fibrosis Center, University Hospital, Parma, ItalyCorrespondence: Luigino CalzettaDepartment of Medicine and Surgery, Respiratory Disease and Lung Function Unit, University of Parma, Viale A. Gramsci, 14, Parma, 43126, ItalyEmail luigino.calzetta@unipr.itPurpose: Smoking-induced bronchiolitis with progressive small airway dysfunction (SAD) is a leading cause of chronic obstructive pulmonary disease. We investigated the value of using the impulse oscillometry system (IOS) to detect SAD in asymptomatic smokers with preserved spirometry.Patients and Methods: We included 75 asymptomatic smokers (37 females, mean age 47± 12 years, 26± 17 pack/year) with preserved spirometry [forced expiratory volume at 1st second (FEV1)/forced vital capacity (FVC) ≥ 0.70 and normal FVC] and 34 never-smokers (19 females, mean age 42± 15 years).Results: In smokers, pack/years were significantly related to spirometry and IOS parameters (p < 0.05). The values of the fall in resistance from 5 Hz to 20 Hz (R5 – R20) were significantly and inversely related to the values of the ratio of forced expiratory volume in 3 and in 6 seconds (FEV3/FEV6) (p < 0.05). In addition, the percentage of heavy smokers (≥ 30 pack/year) with R5 – R20 > 0.07 kPa·s·L− 1, considered as IOS index of SAD, but not with FEV3/FEV6 less than a lower limit of normal, a spirometry index of SAD, was significantly higher than that of mild smokers (< 30 pack/year) and never-smokers (p < 0.05).Conclusion: This study demonstrates that IOS has the potential to detect SAD in asymptomatic heavy smokers with preserved spirometry and with FEV3/FEV6 values in the normal range. We confirm that IOS provides parameters which can complement traditional measurements of pulmonary function.Keywords: small airway dysfunction, impulse oscillometry system, spirometry, smokers, COPD

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

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.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 (NKLPS 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-1β (+1650.16 ± 71.16%), IL-33 (+88.14 ± 8.93%), TGF-β (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, NKTargeting 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.

ntroduction: The treatment of uncontrolled asthma has improved because of triple therapy that includes a long-acting muscarinic antagonist (LAMA) and biological drugs, but several patients are resistant to corticosteroids and/or cannot achieve adequate asthma control using such therapies. Areas covered: Herein, the authors review the current and emerging synthetic pharmacotherapy for uncontrolled asthma to overcome obstacles and limitations of biological therapies. The authors also provide their expert perspectives and opinion on the treatment of uncontrolled asthma. Expert opinion: LAMAs should be added to inhaled corticosteroid/long-acting β2-agonist combinations much earlier than currently recommended by the Global Initiative for Asthma strategy because they can influence the course of small airways disease, reducing lung hyperinflation and improving asthma control. Biological therapies are a major advance in the treatment of severe asthma, but their use is still very limited for several reasons. An alternative to overcome the use of biological therapies is to synthesize compounds that target inflammation-signaling pathways. Several pathways have been identified as potential targets to design either therapeutic or prophylactic drugs against asthma. Some new compounds have already been tested in humans, but results have often been disappointing probably because existing phenotypic and endotypic variants may unpredictably limit the therapeutic value of blocking a specific pathway in most asthmatics, although there may be a substantial benefit for a subgroup of patients.

Introduction: A growing body of evidence indicates that prevalence of chronic obstructive pulmonary disease (COPD) has been increasing more rapidly among women compared to men, but the available data on the differences between the sexes in the responses to the various COPD therapies are still scarce. Areas covered: The aim of this narrative review is to provide an overview of current knowledge on sex differences in COPD management. Expert opinion: There is no solid evidence of sex differences in response to usual COPD treatments but there are sex-related differences in management of patients with a clinical diagnosis of COPD. It is difficult to explain the reason for these differences, but most likely they are due to local prescribing habits, rather than solid scientific reasons. However, there are also signals of different sex-related responses, the qualification and quantification of which is difficult with the information currently available. These signals should lead to the inclusion of more women in clinical trials, but also to the design of prospective clinical studies to assess the possible differences linked to sex in COPD treatment responses, whose identification is an important step toward the definition of personalized COPD therapy.

Luigino Calzetta,1 Angelo Coppola,2 Beatrice Ludovica Ritondo,3 Matteo Matino,3 Alfredo Chetta,1 Paola Rogliani2,3 1Department of Medicine and Surgery, Respiratory Disease and Lung Function Unit, University of Parma, Parma, Italy; 2Division of Respiratory Medicine, University Hospital “Policlinico Tor Vergata”, Rome, Italy; 3Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome “Tor Vergata”, Rome, ItalyCorrespondence: Paola Rogliani Department of Experimental MedicineUniversity of Rome “Tor Vergata”, Via Montpellier 1, Rome 00133, ItalyTel +39 06 2090 4656Email paola.rogliani@uniroma2.itAbstract: 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.Keywords: muscarinic receptor antagonist, LAMA, tiotropium, inflammation, systematic review

BackgroundThe strength of association between comorbidities and asthma has never been ranked in relation to the prevalence of the comorbidity in the nonasthma population. We investigated the strength of association between comorbidities and asthma.MethodsA comprehensive literature search was performed for observational studies reporting data on comorbidities in asthma and nonasthma populations. A pairwise meta-analysis was performed and the strength of association calculated by anchoring odds ratios and 95% confidence intervals with the rate of comorbidities in nonasthma populationsviaCohen'sdmethod. Cohen'sd=0.2, 0.5 and 0.8 were cut-off values for small, medium and large effect sizes, respectively; very large effect size resulted for Cohen'sd >0.8. The review was registered in the PROSPERO database; identifier number CRD42022295657.ResultsData from 5 493 776 subjects were analysed. Allergic rhinitis (OR 4.24, 95% CI 3.82–4.71), allergic conjunctivitis (OR 2.63, 95% CI 2.22–3.11), bronchiectasis (OR 4.89, 95% CI 4.48–5.34), hypertensive cardiomyopathy (OR 4.24, 95% CI 2.06–8.90) and nasal congestion (OR 3.30, 95% CI 2.96–3.67) were strongly associated with asthma (Cohen'sd>0.5 and ≤0.8); COPD (OR 6.23, 95% CI 4.43–8.77) and other chronic respiratory diseases (OR 12.85, 95% CI 10.14–16.29) were very strongly associated with asthma (Cohen'sd>0.8). Stronger associations were detected between comorbidities and severe asthma. No bias resulted according to funnel plots and Egger's test.ConclusionThis meta-analysis supports the relevance of individualised strategies for disease management that look beyond asthma. A multidimensional approach should be used to assess whether poor symptom control is related to uncontrolled asthma or to uncontrolled underlying comorbidities.

Introduction Bronchodilators are the cornerstone of chronic obstructive pulmonary disease (COPD) therapy and long-acting muscarinic antagonists (LAMAs) as a mono or combination treatment play a pivotal role. Several LAMAs are already available on the market in different formulations, but developing a new compound with a higher M3 receptor selectivity and a lower affinity to M2 receptors to increase the therapeutic effect and minimize the adverse effects is still a goal. Moreover, new formulations could improve adherence to therapy. Areas covered This systematic review assesses investigational long-acting muscarinic antagonist in Phase I and II clinical trials over the last decade. It offers insights on whether LAMAs and/or their new formulations in clinical development can become effective treatments for COPD in the future. Expert opinion Research on LAMA seems to have come to a standstill, the few new molecules under study do not show distinctive characteristics compared to the previous ones. Muscarinic antagonist/β2-agonist (MABAs) appear to be the major innovation currently under investigation, and they could theoretically open new research frontiers on the effect between adrenergic and muscarinic interaction in the same cell.

Introduction: The current recommendations of chronic obstructive pulmonary disease (COPD) suggest to escalate from inhaled corticosteroid/long-acting β2-adrenoceptor agonist (ICS/LABA) treatment to...

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.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.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.

Because there is a solid pharmacological rationale based on positive interactions between long-acting muscarinic receptor antagonists (LAMAs) and long-acting β-agonists (LABAs) for their ability to relax human airway smooth muscle in vitro alongside several randomised controlled trials (RCTs) and real-world observational studies that support the use of LAMA/LABA fixed-dose combinations (FDCs) for the treatment of patients with chronic obstructive pulmonary disease (COPD), in this narrative review we discuss the preclinical and clinical proofs supporting the use of LAMA + LABA therapy in COPD and why this therapeutic approach optimises bronchodilation. Robust evidence indicates that all LAMA/LABA FDCs are consistently more effective than LAMA or LABA administered alone in improving lung function, dyspnoea, quality of life and exercise capacity in patients with COPD. However, the ability of dual bronchodilation with FDCs of LAMA/LABA to prevent or reduce the risk of COPD exacerbations remains unclear due to conflicting data from large RCTs, despite several mechanisms explaining why such combinations should be of value in decreasing the frequency of COPD exacerbations. Both LABAs and LAMAs mechanistically can affect the cardiovascular system, but from clinical studies to date, LAMA/LABA FDCs have an acceptable cardiovascular safety profile, at least in the COPD population enrolled in RCTs. Indirect evidence suggests that some FDCs may even exert a protective role against serious cardiovascular adverse events compared to monotherapies. Consequently, several LAMA/LABA FDCs have been developed and approved for clinical use as treatments for patients with COPD. However, to date, there are unfortunately very few head-to-head studies comparing the safety and efficacy of different LAMA/LABA FDCs, making it difficult to choose the most appropriate combination, although the use of meta-analyses has provided some information in this regard. Endurance time Exercise time until exhaustion measured by a standard endurance test. Inspiratory capacity The maximum volume of air that can be inspired after reaching the end of a normal, quiet expiration. It is the sum of the tidal volume and the inspiratory reserve volume. St George's Respiratory Questionnaire (SGRQ) A tool to measure health status in patients with respiratory disease. It has three domains: symptoms, activity and impacts. A total score is also calculated. A minimal important difference (range) of ∼4 (2.4-5.6) units in the SGRQ total score is supported by published studies. Surface under the cumulative ranking curve analysis (SUCRA) A numerical representation of the overall rating that displays a single value for each treatment. SUCRA levels vary from 0% to 100%. The higher the SUCRA value and the closer it is to 100%, the more likely therapy is in the top rank or one of the top rankings; the lower the SUCRA value and the closer it is to 0%, the more likely therapy is in the bottom rank or one of the bottom ranks. Transition dyspnoea index (TDI) Widely used in clinical studies of COPD to measure shortness of breath, indicating change in response to an intervention. The total score ranges from -9 to 9; the negative value indicates deterioration, whereas a positive value indicates improvement. There is sufficient evidence to suggest that the minimal important difference for the TDI score is 1 unit. Trough FEV

Introduction Historically, asthma was considered a disease predominantly of the large airways, but gradually small airways have been recognized as the major site of airflow obstruction. Small airway dysfunction (SAD) significantly contributes to the pathophysiology of asthma and it is present across all asthma severities. Promising pre-clinical findings documented enhanced beneficial effects of combination therapies on small airways compared to monocomponents, thus it was questioned whether this could translate into further clinical implications from bench-to-bedside. The aim of this review was to systematically assess the state of the art of small airway involvement in asthma, especially in response to different pharmacological treatments acting on the respiratory system. Evidence acquisition A comprehensive literature search was performed in MEDLINE for randomized controlled trials (RCTs) characterizing the impact on small airways of different pharmacological treatments acting on the respiratory system. The results were extracted and reported via qualitative synthesis. Evidence synthesis Overall, 63 studies were identified from the literature search, whereas 23 RCTs met the inclusion criteria. Evidence confirms that both drug particle size and the type of inhalation devices represent two of the most important variables for an effective peripheral lung distribution. Conclusions Despite the numerous methodological tools to detect SAD, there is still no gold standard diagnostic method to assess small airways, especially in severe asthma. Further research should be directed to improve primary and secondary prevention strategies by supporting the combined approach of different non-invasive techniques for an early detection of peripheral abnormalities and optimization of asthma therapy.

Chronic Obstructive Pulmonary Disease and Diabetes Mellitus are common and chronic disorders. Chronic Obstructive Pulmonary Disease is characterized by persistent respiratory symptoms and airflow limitation due to airway and/or alveolar abnormalities and it is considered currently the fourth leading cause of death worldwide. Diabetes Mellitus is a systemic disease characterized by a chronic hyperglycemia associated with inflammation and oxidative stress. The relationship between the two conditions is not completely understood and conflicting results are reported in the literature. Many studies have investigated the mechanisms through with the respiratory disease is associated with an increased risk of metabolic condition or whether the incidence risk of Chronic Obstructive Pulmonary Disease in individuals affected by Diabetes Mellitus is higher. The link between the two chronic conditions has relevant implications in the management of patients affected by the both of them. Respiratory patients should be screened for Diabetes Mellitus as a frequent comorbidity of lung disease since therapeutic options should be assessed about risk-to-benefit ratios associated with the indication for the steroid use. Furthermore, the role of hyperglycemia on pulmonary function (e.g. infection or inflammatory processes) should be evaluated in Diabetes Mellitus. Finally, in presence of both diseases potential treatment interactions should be considered. In this overview we explored the common aspects of both clinical chronic illnesses and investigated the interplay between the two conditions.

Leishmania (L.) infantum is a vector-borne parasite currently endemic in several Southern countries of European Union (EU), and dogs represent the main reservoir and hosts. Data from clinical trials are inconsistent with respect to the efficacy of vaccination against L. infantum infection. Therefore, a quantitative synthesis via pairwise meta-analysis was performed in agreement with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) to increase the strength of evidence and assess the real efficacy profile of vaccines against L. infantum currently approved in EU. Data obtained from 1,394 dogs were extracted from 10 studies. The overall analysis indicated that vaccination is significantly effective in protecting against L. infantum infection (RR 0.40, 95%CI 0.23–0.72; I2 70%; P

To date, there is solid evidence from randomized controlled trials (RCTs) supporting the rationale for withdrawal from inhaled corticosteroids (ICSs) in most patients suffering from chronic obstructive pulmonary disease (COPD). However, the populations selected for RCTs only partially represent the real-life population of COPD patients.In this review, a systematic synthesis of data useful in the daily clinical practice was provided in order to guide clinicians toward the optimal approach for the de-escalation of ICSs in COPD.De-escalation to ICS is a procedure that allows optimizing the pharmacological therapy of stable COPD patients. While only a minority of severe COPD patients that are symptomatic and/or at high risk of exacerbation may really need of triple therapy, most patients should be de-escalated/switched from ICS-containing regimen toward dual bronchodilator therapy, or even to single bronchodilator regimen in patients affected by less severe form of COPD.

There is a large interindividual variability in response to ICSs in asthma. About 70% of the variance in ICS response is likely due at least partially to genetically determined characteristics of target genes. In this article, we examine the effects on the ICS response of gene variations in the corticosteroid pathway, and in the pharmacokinetics of corticosteroids, and also those outside the corticosteroid pathway, which have the potential to influence corticosteroid activity. Although the available evidence indicates that responses to ICSs in asthma are influenced by different genetic variants, there are still deep uncertainties as to whether a real association between these genetic variants and corticosteroid response could also possibly exist because there are difficulties in reproducing pharmacogenetic findings. This explains at least partly the insufficient use of pharmacogenomic data when treating asthmatic patients, which creates a real limitation to the proper use of ICSs in an era of precision medicine that links the right patient to the right treatment. Knowing and dealing with the genetic factors that influence the therapeutic ICS response is a fundamental condition for prescribing the right dose of ICS to the right patient at the right time.

Inhaled corticosteroids (ICSs) are considered the cornerstone of asthma treatment. Despite the solid evidence documenting the efficacy and safety of ICSs at the level of the airways, their use can be affected by pulmonary and systemic adverse events (AEs) when administered chronically and/or at high doses. Thus, there is a pharmacological and medical need for new glucocorticoid (GC) receptor (GR) ligands with a more favorable therapeutic index, in order to overcome the shortcomings of currently available ICSs. The therapeutic profile of GCs can be improved by enhancing genomic mechanisms mediated by transrepression, which is assumed to be responsible for several anti-inflammatory and immunomodulatory actions, rather than transactivation, which causes most of the GC-associated AEs. It was assumed that an independent modulation of the molecular mechanisms underlying transactivation and transrepression could translate into the dissociation of beneficial effects from AEs. Therefore, current research is looking for GCs that are able to elicit prevalently transrepression with negligible transactivating activity. These compounds are known as selective glucocorticoid receptor agonists (SEGRAs). In this review, experimental GR agonists currently in pre-clinical and clinical development for the treatment of asthma have been systematically assessed. Several compounds are currently under pre-clinical development, but only three novel experimental GR agonists (GW870086X, AZD5423, AZD7594) seem to have some potential therapeutic relevance and have entered clinical trials for the treatment of asthma. Since data from pre-clinical studies have not always been confirmed in clinical investigations, well-designed randomized controlled trials are needed in asthmatic patients to confirm the potentially positive benefit/risk ratio of each specific SEGRA and to optimize the development strategy of these agents in respiratory medicine.

Triple therapy in COPD is becoming increasingly important with the cumulative documentation of its ability to reduce the risk of AECOPD. However, it must be established which patients benefit most from it compared to other treatments.We critically review the literature to determine, if possible, the real role of triple therapy in the treatment of COPD. We have identified studies from several databases and selected the information thought to be more significant.It is still unclear whether and when addition of an ICS to the LAMA/LABA combination provides real additional clinical value, regardless of a preventive effect on exacerbations. There are many doubts about the value of the blood eosinophil count as a valid biomarker to predict AECOPD risk and the clinical response to ICS, also because no association was found in observational studies. In any case, before starting a therapy involving ICS, the risk factors for the development of pneumonia must always be evaluated. Adding a LAMA to an ICS/LABA combination seems to be less problematic. However, each LABA/LAMA combination has a specific efficacy/safety profile that needs to be considered for personalized therapy in COPD even in the context of triple therapy.

Introduction. The current pharmacological treatments for the management of stable COPD permit the reduction of symptoms and frequency and severity of exacerbations, and the improvement of exercise ...

BACKGROUND AND PURPOSE: Combining inhaled corticosteroids (ICSs), long‐acting β(2)‐adrenoceptor agonists (LABAs) and long‐acting muscarinic antagonists (LAMAs) is recommended to treat severe forms of asthma and chronic obstructive pulmonary disease (COPD). Clinical benefits have been demonstrated for ICS/LABA/LAMA combinations. This study characterized the interaction between the ICS beclomethasone dipropionate, the LABA formoterol fumarate and the LAMA glycopyrronium bromide in human airways. EXPERIMENTAL APPROACH: Human passively sensitized airways and bronchi from COPD donors were stimulated with histamine or carbachol. Tissues were incubated overnight with beclomethasone and then treated with formoterol and glycopyrronium, alone or in triple combination. The interaction was assessed by using Bliss Independence and Unified Theory theorems. KEY RESULTS: Beclomethasone/formoterol/glycopyrronium combination synergistically relaxed medium bronchi and small airways. Beclomethasone/formoterol/glycopyrronium combination at 100:6:12.5 combination ratio was a balanced drug mixture leading to very strong synergistic effect on relaxation of medium bronchi (Combination Index: from 0.042 to 0.96) and middle to very strong synergy in small airways (Combination Index: from 0.018 to 0.310). The synergy was related with the activation of intracellular glucocorticoid receptors and G(sα) subunit G‐protein of β(2)‐adrenoceptors, leading to the modulation of cyclic AMP‐dependent PKA pathway. CONCLUSION: Triple beclomethasone/formoterol/glycopyrronium combination induces synergistic bronchorelaxant effect in medium and small human airways, at least in ex vivo experiments. Further research is needed to confirm these findings in clinical studies in patients with asthma or COPD.

Severe asthma is often associated with numerous comorbidities that complicate disease management and affect patient's outcomes. They contribute to poor disease control and mimic asthma symptoms. Although some comorbidities such as obstructive sleep apnea, bronchiectasis, and chronic obstructive pulmonary disease are generally well recognized, many other may remain undiagnosed but may be detected in an expert specialist setting. The management of comorbidities seems to improve asthma outcomes, and optimizes therapy by avoiding overtreatment. The present review provides recent knowledge regarding the most common comorbidities which are associated with severe asthma.Comorbidities are more prevalent in severe asthma than in mild-to-moderate disease or in the general population. They can be grouped into two large domains: the pulmonary domain and the extrapulmonary domain. Pulmonary comorbidities include upper respiratory tract disorders (obstructive sleep apnea, allergic and nonallergic rhinitis, chronic rhinosinusitis, nasal polyposis) and middle/lower respiratory tract disorders (chronic obstructive pulmonary disease, allergic bronchopulmonary aspergillosis and fungal sensitization, bronchiectasis, dysfunctional breathing). Extrapulmonary comorbidities include anxiety, depression, gastro-esophageal reflux disease, obesity, cardiovascular, and metabolic diseases.The identification of comorbidities via multidimensional approach is needed to initiate appropriate multidisciplinary management of patients with severe asthma.

Inhaled corticosteroid/long-acting βA pairwise meta-analysis was performed according to PRISMA-P guidelines to assess the risk of overall serious adverse events (SAEs), cardiovascular SAEs, and pneumonia reported as SAE in asthmatic patients treated with ICS/LABA/LAMA FDC vs ICS/LABA FDC. A pooled analysis was performed to calculate the frequency of SAEs.Data from 7204 asthmatic patients were extracted from the CAPTAIN, IRIDIUM, TRIMARAN, and TRIGGER studies. Triple FDC vs ICS/LABA FDC did not increase the risk of total SAEs (RR 0.99 95% CI 0.83-1.18) and cardiac SAEs (RR 0.74 95% CI 0.39-1.40), whereas the sensitivity analysis performed to resolve heterogeneity resulted in increased risk of vascular SAEs (RR 3.23 95% CI 1.05-9.90, P0.05). The level of ICS dose did not modulate the risk of pneumonia, in any case pneumonia was the most frequent SAE (0.57%). These results were not affected by significant risk of bias.Triple FDC is a safe pharmacological therapy in severe asthmatic patients; it is characterized by a favourable safety profile and few potential drawbacks, namely, the increased risk of vascular SAEs, that certainly are worthy of future investigations.

Asthma is a heterogeneous chronic inflammatory disease of the airways that affects approximately 300 million people worldwide. About 5–10% of all asthmatics suffer from severe or uncontrolled asthma, associated with increased mortality and hospitalization, reduced quality of life, and increased health care costs. In recent years, new treatments have become available, and different asthma phenotypes characterized by specific biomarkers have been identified. Biological drugs are currently indicated for patients with severe asthma that is not controlled with recommended treatments. They are mostly directed against inflammatory molecules of the type 2 inflammatory pathway and are effective at reducing exacerbations, maintaining control over asthma symptoms, and reducing systemic steroid use, which is associated with well-known adverse events. Although biological drugs for severe asthma have had a major impact on the management of the disease, there is still a need for head-to-head comparison studies of biologics and to identify new biomarkers for asthma diagnosis, prognosis, and response to treatment. Identifying novel biomarkers could facilitate the development of therapeutic strategies that are precisely tailored to each patient’s requirements.

Background: Alpha 1 antitrypsin deficiency (AATD) is an autosomal codominant genetic condition that affects Caucasians of the European population due to the presence of a deficient allele of the SERPINA1 gene. A frequency of about 1/5,000 individuals has been estimated in Italy. Objectives: The aim of the study was to evaluate the distribution of the clinical manifestations of severe and intermediate genetic AATD in the geographic area around Parma in Northern Italy. Method: 238 subjects were submitted to molecular analysis of the SERPINA1 gene, and data on anthropometric variables, smoking habits, number of packs per year, AAT serum concentration, and clinical manifestations were recorded and presented as mean ± SD or median values (1st quartile; 3rd quartile). Results: The results show a distribution of genetic AATD of 4.1% of the screened population in the area encompassing the city of Parma. PI*MS and PI*MZ were the most common genotypes at 40.9% and 28.2% of the population with genetic AATD, and asthma and emphysema were the most represented clinical manifestations. Conclusion: Our study allowed to increase the knowledge of the distribution of genetic AATD in Northern Italy providing information regarding frequencies of genotypes and clinical manifestations of the disorder.

Dear Editors,We read with interest the comments by Barnes et al. [1] on our expert review concerning the effect of triple inhaled corticosteroid (ICS)/long-acting β2 adrenoceptor agonist (LABA)/lon...

Pulmonary rehabilitation (PR) is a proven and effective intervention for chronic obstructive pulmonary disease (COPD). The recent pandemic has raised interest on new services, such as telerehabilitation (Tele-R). The aim of this study was to systematically review the effects of Tele-R in COPD on: 1) exercise capacity evaluated by the 6-minute walk test (6MWT); 2) dyspnea (modified Medical Research Council – mMRC); 3) COPD control (the COPD assessment test - CAT). The analysis compared Tele-R versus no rehabilitation and Tele-R versus center-based rehabilitation. This meta-analysis was undertaken according to PRISMA recommendations. This pair-wise meta-analysis included data obtained from studies that enrolled 758 COPD patients. The tele-R compared to no rehabilitation improved the 6MWT distance of 48 m (CI: 24, 72; p

OBJECTIVES The potential of multi-walled carbon nanotubes (MWCNTs) in inducing airway hyperresponsiveness (AHR) was investigated in human airways. METHODS Human isolated bronchi were exposed to MWCNTs and the contractility to electrical field stimulation (EFS) was measured. Neuronal acetylcholine (ACh) and cyclic adenosine monophosphate (cAMP) were quantified. Some tissues were desensitized by consecutive administrations of capsaicin. RESULTS MWCNTs (100 ng/ml - 100 µg/ml) induced AHR (overall contractile tone vs. negative control: +83.43 ± 11.13%, P