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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.

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

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.

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.

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 ...

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...

Dear Editors,We read with interest the comments by Han et al. [1] on our network meta-analysis [2] concerning the impact of triple ICS/LABA/LAMA therapy in COPD patients, and we also thank all auth...

Introduction: Allergic asthma is a Th2-driven inflammatory process characterized by the infiltration of eosinophils into the airways. IL-5 is a key trigger for eosinophil expansion and release from the bone marrow and plays a crucial role in the entire life span of eosinophils from differentiation to maturation and survival. IL-5 can be considered among the most obvious targets to selectively inhibit eosinophilic airway inflammation. Areas covered: The preclinical and clinical development of reslizumab, a humanized mAb against IL-5 that has been developed to block IL-5 bioactivity and reduce biologically available IL-5, are described with a particular focus on its pharmacodynamics (PK)/pharmacokinetic (PD) profile. Expert opinion: Although pivotal trials have documented that reslizumab can be recommended as add-on therapy for the treatment of patients with severe eosinophilic asthma, there is still important information that is lacking and some PK and PD properties of reslizumab are still not fully understood.

The aim of this research project was to test an incremental bipolar radiofrequency generator with open and laparoscopic inline electrode probe for partial renal resection without vascular clamping.Sixteen polar resections with clamping and six without were performed in four pigs in the acute phase. Three pigs underwent laparoscopic polar resection and were live housed for ten days and reoperated to verify the presence of hematic and urinary collection and the condition of the renal edge. Five pigs underwent laparoscopic polar resection without clamping, and two of these were live housed and reoperated after ten days.Polar renal resection by our system (LaparoNewPro) turned out to be effective and safe, without cardio-respiratory complications or damage to the remaining parenchyma. Coagulation of the renal parenchyma before resection is effective and safe; at the reoperation, no complications were observed. The laparoscopic version of the probe is ergonomic and safe, with effective coagulation and a small amount of smoke produced. No complications occurred in the housed animals. No damage, local or to residual parenchyma, or thrombosis of the renal vessels were found.LaparoNewPro is able to deliver coagulation of the resection line effectively and independently of clamping of the vessels both in the open and laparoscopic approaches. Coagulation times are short, the automatism of the generator is reliable, and the open and laparoscopic probes are ergonomic.

The pharmacokinetic (PK) and pharmacodynamic (PD) effects of long-acting β2-agonists and mostly inhaled corticosteroids (ICSs) shape the efficacy and safety of these agents in the treatment of asthma. In fact, the PK and PD characteristics of the drug largely determine the degree of pulmonary targeting Areas covered. In this review, we summarize the PK and PD properties of inhaled fluticasone furoate (FF) and vilanterol trifenatate (VI) and their fixed-dose combination (FDC) for the treatment of asthma Expert opinion. It is difficult to interpret the data that we have described because the preclinical and clinical development of FF/VI FDC was not really based on solid information on quantitative PK/PD approach. Unfortunately, for both FF and VI we only know concentrations in systemic blood, a compartment that is downstream of both target and non-target respiratory tissue. This lack of information does not allow us to understand the temporal relationship between the delivered dose and the drug concentration at the sites of action within the lungs. In addition, all studies performed with FF and VI did not address the fundamental issue that asthma can significantly alter lung deposition, absorption and also clearance of inhaled medicines.

Oxidative stress is an important trait in the pathogenesis of chronic obstructive pulmonary disease (COPD). Consequently, targeting oxidative stress is likely to be beneficial as a treatment in COPD. Glutathione (GSH) is an intracellular antioxidant that protects against a variety of different antioxidant species. The increase of lung GSH in COPD is an attempt to counter excess oxidant production but it is inadequate during exacerbations due to the excessive production of ROS. N-acetyl-l-cysteine (NAC) acts as a precursor for the substrate cysteine in synthesis of GSH and also as a mucolytic and anti-inflammatory agent. NAC prevents COPD exacerbations at high dosage (≥1200 mg daily), while a regular treatment with 600 mg daily is enough in chronic bronchitis. Nonetheless, we must still establish whether the level of bronchial obstruction may influence its effects, the effect of high-dose NAC in Caucasian patients with COPD, and the role of NAC in the escalation and de-escalation of therapy in COPD.

Umeclidinium is a novel inhaled long-acting muscarinic receptor antagonist (LAMA) approved for treatment of chronic obstructive pulmonary disease (COPD). It provides a bronchodilation of at least 24 h, is well tolerated and has a safe profile. In this article, we describe its pharmacokinetic and pharmacodynamic characteristics. Moreover, we present a meta-analysis of randomized clinical trials carried out in COPD patients, in which the change of forced expiratory volume in 1 s (FEV1) induced by umeclidinium has been compared with that elicited by placebo or the active compound tiotropium. The data generated by the pivotal trials indicate that umeclidinium bromide delivered once-daily via the Ellipta™ inhaler is an effective and well-tolerated treatment for COPD. Therefore, it could to be used as an alternative to LAMAs already in the market, although substantial information is still lacking. It is likely that in the future, umeclidinium will be used frequently, mainly in combination with vilanterol, which is a new once-daily long-acting β2-agonist (LABA).

We aimed to explore whether the acute bronchodilation induced by indacaterol 150 μg and glycopyrronium bromide 50 μg is additive or synergistic with respect to monocomponents by testing the type of effect ex vivo on isolated human bronchi and then in vivo in COPD patients. Both indacaterol and glycopyrronium caused a concentration-dependent relaxation of human isolated bronchial tissues sub-maximally pre-contracted with acetylcholine; glycopyrronium was significantly more potent than indacaterol. The analysis of data using the Bliss Independence (BI) criterion indicated that glycopyrronium plus indacaterol produced an additive interaction at the isoeffective concentrations inducing EC20 and a significant synergistic relaxant effect at isoeffective concentrations inducing EC30. In COPD patients, the inhalation of indacaterol and glycopyrronium in combination significantly anticipated at 15 min post-administration the mean peak of bronchodilatory effect compared to the two drugs administered alone. The study of interaction between indacaterol and glycopyrronium by BI analysis evidenced an additive effect for FEV1 between 5 min and 180 min post-inhalation, with synergistic interaction at 15 min post-administration, compared to the bronchodilation induced by these drugs administered alone. This study suggests that the combination ensures a broncholytic effect that is greater than that induced by the single monocomponents.

Anticholinergic agents are of noteworthy value in the treatment of chronic obstructive pulmonary disease (COPD), but concerns have been raised about a possible association between their use and cardiovascular (CV) morbidity and mortality. In this review, we have examined whether and why an anticholinergic agent, and in particular tiotropium, might cause CV risks.We first examine the potential pharmacological mechanisms that justify the CV risk with an anticholinergic agent, and then the main clinical trials, observational (cohort or case-control) studies, descriptive reviews and meta-analyses that have looked at the CV risks associated with long-term tiotropium, which are available in MEDLINE, EMBASE and Cochrane Controlled Trials Register databases, using the following MeSH, full text and keyword terms: tiotropium bromide OR Spiriva AND COPD OR chronic obstructive pulmonary disease.The almost absolute confidence that there is no real increased risk for death or CV morbidity during treatment with this inhaled anticholinergic agent in patients with COPD because of the results of a large 4-year trial and a robust and extensive analysis of19,000 patients participating in placebo-controlled tiotropium clinical trials. Nonetheless, because high-risk patients such as those with coronary artery disease, heart failure, cardiac arrhythmia, hypoxemia requiring daytime oxygen therapy and a creatinine2 mg/dl were excluded from Phase III clinical trials, it is impossible to exclude these patients from an increased risk of drug-related cardiac events in a real-world setting.Despite the recently raised concerns about an excess risk of CV adverse events with inhaled short-acting anticholinergic agents, the risk:benefit ratio of tiotropium bromide appears still favorable, although it is not known whether high-risk patients are at an increased risk of drug-related CV events.

Roberto Lipsi,1 Paola Rogliani,1 Luigino Calzetta,2 Andrea Segreti,1Mario Cazzola1 1Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; 2Department of Pulmonary Rehabilitation, San Raffaele Pisana Hospital, Istituti di Ricovero e Cura a Carattere Scientifico, Rome, Italy Abstract: Regenerative or stem cell therapy is an emerging field of treatment based on stimulation of endogenous resident stem cells or administration of exogenous stem cells to treat diseases or injury and to replace malfunctioning or damaged tissues. Current evidence suggests that in the lung, these cells may participate in tissue homeostasis and regeneration after injury. Animal and human studies have demonstrated that tissue-specific stem cells and bone marrow-derived cells contribute to lung tissue regeneration and protection, and thus administration of exogenous stem/progenitor cells or humoral factors responsible for the activation of endogenous stem/progenitor cells may be a potent next-generation therapy for chronic obstructive pulmonary disease. The use of bone marrow-derived stem cells could allow repairing and regenerate the damaged tissue present in chronic obstructive pulmonary disease by means of their engraftment into the lung. Another approach could be the stimulation of resident stem cells by means of humoral factors or photobiostimulation. Keywords: chronic obstructive pulmonary disease, stem cells, regenerative therapy, all-trans retinoic acid, photobiostimulation