Interpretazione critica delle "pairwise" e "network" meta-analisi di studi clinici randomizzati in ambito respiratorio

A meta-analysis is a statistical technique used to assess the data of independent studies concerning the same clinical scenario, in order to synthesize results that are reported as effect estimate. The strength of a meta-analysis lies in its potential to combine the results of studies characterized by different size and that may have been underpowered to answer clinically relevant questions. Furthermore, meta-analyses can be used to clarify questions for which large randomized controlled trials have not led to consensus within the scientific community. The effect estimate resulting from a meta-analysis should be interpreted both from a statistical and clinical point of view. The clinical interpretation of the effect estimate must take into consideration the minimal clinically important differences compared to the comparator, which may be placebo and/or other active treatments. In this review we consider the key points needed to correctly and critically interpret the current meta-analyses, and to assess how reliable are the results from a statistical and clinical point of view

Occupational allergy to horse allergens: More than exposure to horses!

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Pharmacological investigation on the anti-oxidant and anti-inflammatory activity of N-acetylcysteine in an ex vivo model of COPD exacerbation

Oxidative stress is recognized to be one of predisposing factor in the pathogenesis of COPD. The oxidant/antioxidant imbalance is significantly pronounced in patients with COPD exacerbation. N-acetylcysteine (NAC) seems to be able to reduce COPD exacerbations by modulating the oxidative stress in addition to its well-known mucolytic activity, but there are discordant findings on the actual anti-oxidant activity of NAC

Optimizing de-escalation of inhaled corticosteroids in COPD: a systematic review of real-world findings.

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

Therapeutic use of heparin and derivatives beyond anticoagulation in patients with bronchial asthma or COPD

In this review, we identify potential targets for the therapeutic effects of heparin in asthma and chronic obstructive pulmonary disease (COPD), consider the safety and delivery modalities of this therapeutic approach. Specifically, we point to the anti-inflammatory, antioxidant and mucolytic effects of unfractionated heparin with potential to modify disease progression in COPD and asthma when administered via the inhaled route. Inhaled heparin may represent an effective add-on therapy in COPD and asthma patient groups, especially when taking into consideration the relative deficiency in endogenous heparin reported in asthma patients

Hyperglycaemia and Chronic Obstructive Pulmonary Disease

: Chronic obstructive pulmonary disease (COPD) may coexist with type 2 diabetes mellitus (T2DM). Patients with COPD have an increased risk of developing T2DM compared with a control but, on the other side, hyperglycaemia and DM have been associated with reduced predicted levels of lung function. The mechanistic relationships between these two diseases are complicated, multifaceted, and little understood, yet they can impact treatment strategy. The potential risks and benefits for patients with T2DM treated with pulmonary drugs and the potential pulmonary risks and benefits for patients with COPD when taking antidiabetic drugs should always be considered. The interaction between the presence and/or treatment of COPD, risk of infection, presence and/or treatment of T2DM and risk of acute exacerbations of COPD (AECOPDs) can be represented as a vicious circle; however, several strategies may help to break this circle. The most effective approach to simultaneously treating T2DM and COPD is to interfere with the shared inflammatory substrate, thus targeting both lung inflammation (COPD) and vascular inflammation (DM). In any case, it is always crucial to establish glycaemic management since the reduction in lung function found in people with diabetes might decrease the threshold for clinical manifestations of COPD. In this article, we examine possible connections between COPD and T2DM as well as pharmacological strategies that could focus on these connections

N-Acetylcysteine protects human bronchi by modulating the release of neurokinin A in an ex vivo model of COPD exacerbation

Abstract Aims N-Acetylcysteine (NAC) reduces the risk of exacerbation of chronic obstructive pulmonary disease (COPD). Although NAC also has anti-inflammatory activity, the detailed mechanism leading to its protective role remains to be elucidated. We tested the impact of NAC against the effects of lipopolysaccharide (LPS) in an ex vivo model of COPD exacerbation, and investigated the role of neurokinin A (NKA) in this context. Main methods Isolated airways from COPD patients were incubated overnight with LPS (100 ng/ml). NAC was tested at concentrations resembling the plasma levels elicited by oral administration of NAC at 200 mg/day (very low dose), 600 mg/day (low dose) and 1.200 mg/day (high dose). Key findings NAC at high concentrations normalized the peroxidase activity, H2O2, malondialdehyde (MDA), nitric oxide, glutathione (GSH), total antioxidant capacity (TAC), and interleukin 6 (IL-6) (overall change 34.32% ± 4.22%, P  Significance This study demonstrates that, along with its well-known antioxidant activity, the protective effect of NAC against the detrimental effect of LPS is due to the modulation of NKA and IL-6 levels

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

LABA/LAMA combination in COPD: a meta-analysis on the duration of treatment

When there are no randomised clinical trials directly comparing all relevant treatment options, an indirect treatment comparison via meta-analysis of the available clinical evidence is an acceptable alternative. However, meta-analyses may be very misleading if not adequately performed. Here, we propose and validate a simple and effective approach to meta-analysis for exploring the effectiveness of long-acting β2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combinations in chronic obstructive pulmonary disease.14 articles with 20 329 patients (combinations n=9292; monocomponents n=11 037) were included in this study. LABA/LAMA combinations were always more effective than the monocomponents in terms of the improvement in trough forced expiratory volume in 1 s, transition dyspnoea index and St George's Respiratory Questionnaire scores after 3, 6 and 12 months of treatment. No significant publication bias was identified. Significant discrepancies with previous network meta-analyses have been found, with overall differences ranging from 26.7% to 43.3%.Results from previous network meta-analyses were misleading because no adequate attention was given to formulating the review question, specifying eligibility criteria, correctly identifying studies, collecting appropriate information and deciding what it would be pharmacologically relevant to analyse. The real gradient of effectiveness of LABA/LAMA fixed-dose combinations remains an unmet medical need; however, it can be investigated indirectly using a high-quality meta-analytic approach