Spontaneous Ventilation Thoracoscopic Lung Biopsy in Undetermined Interstitial Lung Disease: Systematic Review and Meta-Analysis.

Thoracoscopic surgical biopsy has shown excellent histological characterization of undetermined interstitial lung diseases, although the morbidity rates reported are not negligible. In delicate patients, interstitial lung disease and restrictive ventilatory impairment morbidity are thought to be due at least in part to tracheal intubation with single-lung mechanical ventilation; therefore, spontaneous ventilation thoracoscopic lung biopsy (SVTLB) has been proposed as a potentially less invasive surgical option. This systematic review summarizes the results of SVTLB, focusing on diagnostic yield and operative morbidity. A systematic search for original studies regarding SVTLB published between 2010 to 2023 was performed. In addition, articles comparing SVTLB to mechanical ventilation thoracoscopic lung biopsy (MVTLB) were selected for a meta-analysis. Overall, 13 studies (two before 2017 and eleven between 2018 and 2023) entailing 675 patients were included. Diagnostic yield ranged from 84.6% to 100%. There were 64 (9.5%) complications, most of which were minor. There was no 30-day operative mortality. When comparing SVTLB to MVTLB, the former group showed a significantly lower risk of complications (p < 0.001), whereas no differences were found in diagnostic accuracy. The results of this review suggest that SVTLB is being increasingly adopted worldwide and has proven to be a safe procedure with excellent diagnostic accuracy.

Delivering monoclonal antibodies via inhalation: a systematic review of clinical trials in asthma and COPD.

INTRODUCTION: Advances in understanding the pathophysiology of asthma and chronic obstructive pulmonary disease (COPD) led to investigation of biologic drugs targeting specific inflammatory pathways. No biologics are licensed for COPD while all the approved monoclonal antibodies (mAbs) for severe asthma treatment are systemically administered. Systemic administration is associated with low target tissue exposure and risk of systemic adverse events. Thus, delivering mAbs via inhalation may be an attractive approach for asthma and COPD treatment due to direct targeting of the airways. AREAS COVERED: This systematic review of randomized control trials (RCTs) evaluated the potential role of delivering mAbs via inhalation in asthma and COPD treatment. Five RCTs were deemed eligible for a qualitative analysis. EXPERT OPINION: Compared to systemic administration, delivering mAbs via inhalation is associated with rapid onset of action, greater efficacy at lower doses, minimal systemic exposure, and lower risk of adverse events. Although some of the inhaled mAbs included in this study showed a certain level of efficacy and safety in asthmatic patients, delivering mAbs via inhalation is still challenging and controversial. Further adequately powered and well-designed RCTs are needed to assess the potential role of inhaled mAbs in the treatment of asthma and COPD.

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.

Comparing the Efficacy and Safety Profile of Triple Fixed-Dose Combinations in COPD: A Meta-Analysis and IBiS Score.

Background: Triple fixed-dose combination (FDC) therapy is recommended in severe chronic obstructive pulmonary disease (COPD) patients experiencing frequent exacerbations and/or symptoms not controlled by dual FDCs. Since no randomized controlled trials (RCTs) have directly compared the different inhaled corticosteroid/long-acting ß2-adrenoceptor agonist/long-acting muscarinic antagonist (ICS/LABA/LAMA) FDCs, we performed a meta-analysis to compare the impact of the current available ICS/LABA/LAMA FDCs in COPD. Methods: A meta-analysis was performed by connecting beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide or glycopyrrolate (BDP/FOR/GLY), budesonide (BUD)/GLY/FOR, and fluticasone furoate/umeclidinium bromide/vilanterol (FF/UMEC/VI) FDCs via ICS/LABA or LABA/LAMA FDCs arms. The safety and efficacy profiles were investigated, and the Implemented Bidimensional Surface under the cumulative ranking curve analysis (IBiS) was carried out. Protocol registration: CRD42022301189. Results: Data from 21,809 COPD patients were extracted from the ETHOS, IMPACT, KRONOS, and TRILOGY studies. No significant (p > 0.05) differences were detected across the triple FDCs with respect to the risk of exacerbation, trough forced expiratory volume in the first second (FEV1), transition dyspnea index (TDI), St. George's Respiratory Questionnaire (SGRQ), risk of serious adverse events (SAEs), cardiovascular (CV) SAEs, pneumonia, and all-cause mortality. According to IBiS score, BDP/FOR/GLY 200/12/25 µg twice daily (BID) was the FDC reporting the best combined efficacy/safety profile (area 41.41%), although FF/UMEC/VI 100/62.5/25 µg once daily (QD) showed the greatest efficacy profile (50.54%). The protection against mortality related to the dose of ICS. Conclusions: All triple FDCs are effective and safe in COPD regardless of the regimen of administration (twice daily vs. once daily), with no relevant difference in the risk of CV SAEs and pneumonia.

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.

Lifestyle and Dietary Habits Affect Plasma Levels of Specific Cytokines in Healthy Subjects.

Low-grade chronic inflammation (LGCI) is a common feature of non-communicable diseases. Cytokines play a crucial role in LGCI. This study aimed to assess how LGCI risk factors [e.g., age, body mass index (BMI), smoke, physical activity, and diet] may impact on specific cytokine levels in a healthy population. In total, 150 healthy volunteers were recruited and subjected to questionnaires about the last 7-day lifestyle, including smoking habit, physical activity, and food frequency. A panel of circulating cytokines, chemokines, and growth factors was analyzed by multiplex ELISA. BMI showed the heaviest impact on the correlation between LGCI-related risk factors and cytokines and was significantly associated with CRP levels. Aging was characterized by an increase in IL-1b, eotaxin, MCP-1, and MIP-1α. Smoking was related to higher levels of IL-1b and CCL5/RANTES, while physical activity was related to MIP-1α. Within the different eating habits, CRP levels were modulated by eggs, red meat, shelled fruits, and greens consumption; however, these associations were not confirmed in a multivariate model after adjusting for BMI. Nevertheless, red meat consumption was associated with an inflammatory pattern, characterized by an increase in IL-6 and IL-8. IL-8 levels were also increased with the frequent intake of sweets, while a higher intake of shelled fruits correlated with lower levels of IL-6. Moreover, IL-6 and IL-8 formed a cluster that also included IL-1b and TNF-α. In conclusion, age, BMI, smoke, physical activity, and dietary habits are associated with specific cytokines that may represent potential markers for LGCI.

Road Toward a New Model of Care for Idiopathic Pulmonary Fibrosis in the Lazio Region.

A timely, confirmed diagnosis of Idiopathic Pulmonary Fibrosis (IPF) has a significant impact on the evolution of the disease. The current model of care in the Lazio region (in Italy) was assessed on the basis of real-world data provided by the four reference centers responsible for diagnosing and treating IPF. The 5-year, population-based, retrospective longitudinal study provided the data that is at the basis of the current proposal for a new clinical and therapeutic pathway (DTCP) and has been shared with regional decision makers. A DTCP must be defined and based on four pillars: GPs, pulmonologists, IPF centers, and telemedicine. Each must play a role within a sort of hub-and-spoke model. IPF centers remain the hubs, while spokes are identified in trained GPs and pulmonologists.

Potential Drawbacks of ICS/LABA/LAMA Triple Fixed-Dose Combination Therapy in the Treatment of Asthma: A Quantitative Synthesis of Safety Profile.

Introduction: Inhaled corticosteroid/long-acting ß2-adrenoceptor agonist/long-acting muscarinic antagonist (ICS/LABA/LAMA) fixed-dose combination (FDC) is currently recommended as controller option at asthma Step 4 and as preferred treatment at asthma Step 5, but no research investigated the potential drawbacks of this therapeutic option in a large asthmatic population. Thus, the aim of this study was to quantify the potential drawbacks of triple FDC therapy in asthma. Methods: A 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. Results: 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, P<0.05). 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. Conclusion: 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.

Synergy across the drugs approved for the treatment of asthma.

INTRODUCTION: Inhaled corticosteroids are the cornerstone for the treatment of stable asthma, however, when disease severity increases, escalating therapy to combinations of drugs acting on distinct signalling pathways is required. It is advantageous to providing evidence of a synergistic interaction across drug combinations, as it allows optimizing bronchodilation while lowering the dose of single agents. In the respiratory pharmacology field, two statistical models are accepted as gold standard to characterize drug interactions, namely the Bliss Independence criterion and the Unified Theory. In this review, pharmacological interactions across drugs approved for the treatment of asthma have been systematically assessed. EVIDENCE ACQUISITION: A comprehensive literature search was performed in MEDLINE for studies that used a validated pharmacological method for assessing drug interaction. The results were extracted and reported via qualitative synthesis. EVIDENCE SYNTHESIS: Overall, 45 studies were identified from literature search and 5 met the inclusion criteria. Current evidence coming from ex-vivo models of asthma indicates that drug combinations modulating bronchial contractility induce a synergistic bronchorelaxant effect. In murine models of lung inflammation, the combination between inhaled corticosteroids and ß2-adrenoceptor agonists synergistically improve lung function and the inflammatory profile. CONCLUSIONS: There is still limited knowledge regarding the mechanistic basis underlying pharmacological interactions across drugs approved for asthma. The synergism elicited by combined agents is an effect of class. Specifically designed clinical trials are needed to confirm the results coming from preclinical evidence, but also to establish the minimal dose for combined agents to induce a synergistic interaction and maximize bronchodilation.

An Overview of the Safety and Efficacy of Monoclonal Antibodies for the Chronic Obstructive Pulmonary Disease.

Several mAbs have been tested or are currently under clinical evaluation for the treatment of COPD. They can be subdivided into those that aim to block specific pro-inflammatory and pro-neutrophilic cytokines and chemokines, such as TNF-α, IL-1ß, CXCL8 and IL-1ß, and those that act on T2-mediated inflammation, respectively, by blocking IL-5 and/or its receptor, preventing IL-4 and IL-13 signaling, affecting IL-33 pathway and blocking TSLP. None of these approaches has proved to be effective, probably because in COPD there is no dominant cytokine or chemokine and, therefore, a single mAb cannot be effective on all pathways. With a more in-depth understanding of the numerous pheno/endotypic pathways that play a role in COPD, it may eventually be possible to identify those specific patients in whom some of these cytokines or chemokines might predominate. In this case, it will be possible to implement a personalized treatment, but the use of each mAb will only be reserved for a very limited number of subjects.

New Avenues for Phosphodiesterase Inhibitors in Asthma.

INTRODUCTION: Phosphodiesterases (PDEs) are isoenzymes ubiquitously expressed in the lungs where they catalyse cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (GMP), which are fundamental second messengers in asthma, thereby regulating the intracellular concentrations of these cyclic nucleotides, their signaling pathways and, consequently, myriad biological responses. The superfamily of PDEs is composed of 11 families with a distinct substrate specificity, molecular structure and subcellular localization. Experimental studies indicate a possible role in asthma mainly for PDE3, PDE4, PDE5 and PDE7. Consequently, drugs that inhibit PDEs may offer novel therapeutic options for the treatment of this disease. AREAS COVERED: In this article, we describe the progress made in recent years regarding the possibility of using PDE inhibitors in the treatment of asthma. EXPERT OPINION: Many data indicate the potential benefits of PDE inhibitors as an add-on treatment especially in severe asthma due to their bronchodilator and/or anti-inflammatory activity, but no compound has yet reached the market as asthma treatment mainly because of their limited tolerability. Therefore, there is a growing interest in developing new PDE inhibitors with an improved safety profile. In particular, the research is focused on the development of drugs capable of interacting simultaneously with different PDEs, or to be administered by inhalation. CHF 6001 and RPL554 are the only molecules that currently are under clinical development but there are several new agents with interesting pharmacological profiles. It will be stimulating to assess the impact of such agents on individual treatable traits in specially designed studies.

Treatable Mechanisms in Asthma.

Asthma is a heterogeneous condition, but firm identification of heterogeneity-focused treatments is still lacking. Dividing patients into subgroups of asthma pheno-/endotypes based on combined clinical and cellular biological characteristics and linking them to targeted treatments could be a potentially useful approach to personalize therapy for better outcomes. Nonetheless, there are still many problems related to the identification and validation of asthma phenotypes and endotypes. Alternatively, a precision-medicine strategy for the management of patients with airways disease that is free from the traditional diagnostic labels and based on identifying "treatable traits" in each patient might be preferable. However, it would represent a quite unsophisticated approach because the definition of a treatable trait is too imprecise. In fact, there is still no understanding of the mechanisms underlying treatable traits that allow directing any targeted therapies against any particular treatable trait. Fortunately, in-depth identification of underlying molecular pathways to guide targeted treatment in individual patients is in progress thanks to the improvement in big data management obtained from '-omic' sciences that is greatly increasing knowledge concerning asthma.

Advances in pulmonary drug delivery devices for the treatment of chronic obstructive pulmonary disease.

Introduction: Proper device selection is crucial for the clinical results of inhalation therapy. However, none of the available devices fully conforms to the requirements for delivering drug with increased patient adherence, and we are still looking for the ideal inhaler. For this reason, there are several ongoing technical innovations to improve inhaler devices.Areas covered: Progress in pulmonary drug delivery device technology is examined, focusing on innovations in pressurized metered dose inhalers, dry powder inhalers, nebulizers, and soft mist inhalers.Expert opinion: Both formulation improvements and new device technologies have been developed over the last couple of decades through an improved understanding of the mechanisms of aerosolization and lung deposition. Digital health is offering the potential to produce inhalers with a wider range of monitoring capabilities, but further studies are needed, in particular as regards the analysis of cost-effectiveness. Furthermore, there are still substantial issues that must be overcome in order to continually innovate and improve targeted inhaled drug delivery to the lungs. In any case, there are other potential therapeutic possibilities for COPD in development that may be administered by inhalation, whose clinical use requires advances and improvements in the devices used for administration.

Nonintubated surgical biopsy of undetermined interstitial lung disease: a multicentre outcome analysis.

OBJECTIVES: Nonintubated surgical biopsy (NISB) of interstitial lung disease (ILD) has shown promise in unicentre reports as a reliable method to achieve pathological diagnosis with low morbidity. The aim of this study was to investigate for the first time early outcomes of NISB of ILD using a multicentre retrospective analysis. METHODS: Seven European and extra-European institutions participated in the study. Overall, 112 procedures were included. The mean age was 60 ± 12 years (65 men and 47 women). Preoperative total lung capacity and diffusion capacity of carbon monoxide were 74 ± 16% predicted and 57 ± 18% predicted, respectively. Forty-five patients had 1 or more associated comorbidities. NISB of ILD were performed under spontaneous ventilation by intercostal block (n = 84) or epidural anaesthesia (n = 28) with (n = 58) or without (n = 54) sedation and by thoracoscopic surgery (n = 88) or minithoracotomy (n = 24). RESULTS: Mean anaesthesia time, operative time and global time spent in the operating room were 31 ± 31 min, 29 ± 15 min and 89 ± 156 min, respectively. Feasibility was scored as excellent, good, satisfactory or unsatisfactory requiring conversion to general anaesthesia with intubation in 92, 12, 2 and 6 instances, respectively. There were no deaths. Morbidity was 7.1% and included prolonged air leaks in 4 patients and pneumonia, atelectasis, anaemia and gastric bleeding in 1 patient each. A precise pathological diagnosis was achieved in 108 patients (96%). The mean hospital stay was 2.5 ± 2.7 days. Comparisons of results achieved in the largest single-centre series (group A, 60 patients operated on) versus those resulting from the sum of the patients operated on in the other centres (group B, 52 patients operated on) showed no differences in feasibility (P = 0.10) and morbidity (P = 0.10) whereas hospital stay was shorter in group A (1.3 ± 0.5 days vs 3.9 ± 3.4 days, P < 0.001). CONCLUSIONS: Results of this multicentre study confirm the satisfactory feasibility of NISB of ILD in 82% of patients with no deaths and a low morbidity rate. Intergroup comparisons indicated that the hospital stay was shorter in group A whereas there were no differences in feasibility and morbidity rates.

Effect of adding roflumilast or ciclesonide to glycopyrronium on lung volumes and exercise tolerance in patients with severe COPD: A pilot study.

COPD is a chronic inflammatory disease characterized by partially reversible airflow limitation. Currently, phosphodiesterase4 inhibitors and inhaled corticosteroids are anti-inflammatory agents that can be used in patients with severe COPD, always added to at least one bronchodilator. In this prospective interventional pilot study, we investigated the effect of adding oral roflumilast 500 µg once-daily or inhaled ciclesonide 160 µg once-daily to glycopyrronium 44 µg once-daily on lung volumes and exercise tolerance in 16 patients with severe COPD, of which 8 received roflumilast and 8 ciclesonide for 8 weeks. Detailed pulmonary function and endurance shuttle tests were performed at time 0, after 2 weeks of glycopyrronium and after 8 weeks of add-on of either roflumilast or ciclesonide. Glycopyrronium increased significantly (p < .05) FEV1, and IC at rest and at the peak of exercise and improved the walking distance. In particular, it induced a bronchodilation similar to that elicited by salbutamol 800 µg. After 8 weeks of combination therapy, both the trough and the post bronchodilator FEV1 further improved but the increase was very small and not significant. Furthermore, adding either roflumilast or ciclesonide did not provide a further improvement in IC and walking distance. This study provides further evidence of the efficacy of glycopyrronium 44 µg once daily, confirming that improvements in airflow are associated with increases in IC and improvements in exercise tolerance. The addition of anti-inflammatory drugs, regardless of class used, does not seem to add benefits on lung function and exercise tolerance, likely because of the large effect induced by glycopyrronium.

Impact of LABA/LAMA combination on exercise endurance and lung hyperinflation in COPD: A pair-wise and network meta-analysis.

BACKGROUND: The ability to exercise is an important clinical outcome in COPD, and the improvement in exercise capacity is recognized to be an important goal in the management of COPD. Therefore, since the current interest in the use of bronchodilators in COPD is gradually shifting towards the dual bronchodilation, we carried out a meta-analysis to evaluate the impact of LABA/LAMA combination on exercise capacity and lung hyperinflation in COPD. METHODS: RCTs were identified after a search in different databases of published and unpublished trials. The aim of this study was to assess the influence of LABA/LAMA combinations on endurance time (ET) and inspiratory capacity (IC), vs. monocomponents. RESULTS: Eight RCTs including 1632 COPD patients were meta-analysed. LABA/LAMA combinations were significantly (P < 0.05) more effective than the LABA or LAMA alone in terms of the improvement in ET (+43 s and +22 s, respectively) and IC (+107 ml and +87 ml, respectively). LABA/LAMA combinations showed the highest probability of being the best therapy with regard of both ET and IC (100% and 100%, respectively), followed by LAMA (66% and 64%, respectively) and LABA (32% and 36%, respectively), as indicated by the analysis of surface under the cumulative ranking curve (SUCRA). No publication bias was detected in this meta-analysis. CONCLUSIONS: This meta-analysis clearly demonstrates that if the goal of the therapy is to enhance exercise capacity in patients with COPD, LABA/LAMA combinations consistently meet the putative clinically meaningful differences for both ET and IC and, in this respect, are superior to their monocomponents.

Optimizing drug delivery in COPD: The role of inhaler devices.

BACKGROUND: Inhaled medication is the cornerstone of the pharmacological treatment for patients with asthma and chronic obstructive pulmonary disease (COPD). Several inhaler devices exist, and each device has specific characteristics to achieve the optimal inhalation of drugs. The correct use of inhaler devices is not granted and patients may incur in mistakes when using pressurized metered-dose inhalers (pMDIs) or dry-powder inhaler (DPIs). The incorrect use of inhaler devices can lead to a poorly controlled disease status. Unfortunately, guidelines provide limited guidance regarding the choice of devices. This article presents a review of the literature on different inhaler device requirements. Data from literature (PubMed and Google Scholar) on the commercially available inhaler devices have been evaluated and the history of inhaler medicine described. Furthermore, advantages and disadvantages of each type of device have been analyzed. The evaluation of literature indicated the availability of robust data on the devices characteristics and factors influencing selection of delivery devices. Each type of device has its own pro and cons. The age, cognitive status, visual acuity, manual dexterity, manual strength and ability to coordinate the inhaler actuation with inhalation may be as important as the disease severity in determining the correct approach to delivery of respiratory medication. The administration of effective therapies via a device that is simple to use and accepted by patients may help to improve treatment outcomes in patients with COPD.