Mucus clearance is crucial for airway protection, and its dysfunction leads to chronic obstructive pulmonary disease (COPD) characterized by mucus hypersecretion (MHS) and impaired clearance. MUC5AC and MUC5B mucin proteins are key components of airway mucus, with MUC5AC being particularly responsive to environmental stimuli, making it a potential COPD biomarker. N-acetylcysteine (NAC) is a mucolytic agent with known effects on mucus viscosity and clearance, but its precise mechanisms in COPD remain unclear. This systematic review evaluated the impact of NAC on MHS in the airways, reporting significant inhibitory effects on MUC5AC and MUC5B gene and protein expression, as well as a reduction in the number of goblet cells. NAC has demonstrated efficacy in vitro and in animal models of MHS, including COPD models, but data on human bronchial tissue are lacking. This systematic review suggests that NAC acts as a mucolytic and a mucoregulator, directly inhibiting mucus secretion and goblet cell hyperplasia. Given the critical role of MHS in COPD progression, exacerbations, and mortality, these findings highlight the potential of NAC as a targeted therapy for hypersecretion COPD phenotypes. However, further studies are needed to confirm the results of this systematic review, even in human bronchial tissue, to provide translatable evidence in clinical settings. Understanding the intimate mechanism of NAC versus MHS regulation may pave the way for more effective treatments targeting airway mucus dysfunction in COPD, ultimately improving patient outcomes and reducing morbidity and mortality associated with chronic mucus hypersecretion.

Purpose: Clinically important deterioration (CID) is a composite endpoint developed to quantify the impact of pharmacological treatment in clinical trials for Chronic Obstructive Pulmonary Disease (COPD), also showing a prognostic value. CID is defined as any of the following condition: forced expiratory volume in 1 s decrease ≥ 100 mL from baseline, and/or St. George’s Respiratory Questionnaire total score increase ≥ 4-unit from baseline, and/or the occurrence of a moderate-to-severe exacerbation of COPD. Although most COPD patients experience a clinical worsening as they get older, to date, no specific studies assessed the correlation between ageing and CID in COPD. Therefore, the aim of this study was to investigate the impact of ageing on CID in COPD patients. Patients and Methods: Data obtained from 55219 COPD patients were extracted from 17 papers, mostly post-hoc analyses. A pairwise meta-analysis and a meta-regression analysis were performed according to PRISMA-P guidelines to quantify the impact of pharmacological therapy on CID and to determine whether ageing might modulate the risk of CID in COPD patients. Results: Inhaled treatments resulted generally effective in reducing the risk of CID in COPD (relative risk: 0.81, 95% confidence interval 0.79– 0.84; P < 0.001). The meta-regression analysis indicated a trend toward significance (P = 0.063) in the linear relationship between age and the risk of CID. Of note, age significantly (P < 0.05) increased the risk of CID when associated with lower post-bronchodilator FEV₁. These results were not affected by a significant risk of bias. Conclusion: This quantitative synthesis suggests that inhaled therapy is effective in reducing the risk of CID in COPD, although such a protective effect may be affected in older patients with impaired lung function. Further studies specifically designed on CID in COPD are needed to confirm these results.

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been shown to cause long-term pulmonary sequelae. Objects: The aim of this study was to evaluate the consequences of the SARS-CoV-2 infection on pulmonary function and on the 6-min walk test related to the severity of the disease. Methods: A cross-sectional study was conducted at the “Policlinico Tor Vergata” Academic Hospital (Rome, Italy), including 75 patients evaluated in post-COVID clinics at the Respiratory Units between November 2020 and September 2021. Complete pulmonary function tests, 6-min walk tests and persistence of symptoms were performed. Results: Of the 75 subjects, 23 had mild, 16 moderate, 26 severe and 10 very severe COVID-19, classified according to WHO. Very severe patients had a lower FVC (100 ± 10%pr) compared to the other groups (116 ± 16%pr, 116 ± 13%pr, 122 ± 20%pr from mild to severe; p < 0.05) and a lower TLC (94 ± 13%pr) compared to the others (102 ± 10%pr, 108 ± 15%pr, 108 ± 12%pr from mild to severe; p < 0.05). DLco and DLco/VA were similar among groups. At the 6MWT, distance, rest and nadir SpO₂ were similar among groups, but all groups presented a significant decrease in SpO₂ from rest to nadir (Rest SpO₂: 97.0 ± 1.0% vs. Nadir SpO₂: 93.6 ± 2.7%, p < 0.01). A positive correlation was found between desaturation and delta SpO₂ (rest—nadir) (R: 0.29, p < 0.05) and the Distance Desaturation Product (R: 0.39, p < 0.01). Conclusions: These results showed that, although the PFTs are within the normal range, there is still a mild restrictive spirometric pattern after six months in very severe subjects. Moreover, the only persistent pathological sequalae of SARS-CoV-2 infection were a mild desaturation at 6MWT, despite the severity of the infection.

Introduction: Chronic obstructive pulmonary disease (COPD) is a significant global health issue characterized by persistent airflow limitation and inflammation. Triple fixed-dose combinations (FDCs) of inhaled corticosteroids (ICS), long-acting β 2-agonists (LABA), and long-acting muscarinic antagonists (LAMA) show promise by potentially enhancing bronchodilation and anti-inflammatory effects. Although randomized controlled trials (RCTs) provide efficacy data, they may not fully represent real-world clinical practice, highlighting the value of real-world evidence (RWE). Methods: This study conducted a systematic review and meta-analysis of prospective observational multicenter studies to evaluate the real-world effectiveness of a triple extrafine FDC containing beclomethasone dipropionate (BDP), formoterol fumarate (FF), and glycopyrronium (G) in moderate-to-severe COPD patients. Databases MEDLINE and SCOPUS were searched for relevant studies reporting on the COPD Assessment Test (CAT) score and forced expiratory volume in one second (FEV₁). Results: The meta-analysis included seven studies with 5952 patients, indicating high methodological quality with Newcastle–Ottawa Scale scores ≥ 7. Results showed significant improvement in CAT scores (− 5.82 95% CI − 7.61 - − 4.03; P < 0.001) and FEV₁ (127 mL 95% CI 42– 212; P < 0.001) for extrafine BDP/FF/G FDC compared to any prior treatments (ICS/LABA, ICS+LABA, LABA/LAMA, LABA+LAMA, multiple-inhaler triple therapy, single-inhaler triple therapy), exceeding minimal clinically important differences. Heterogeneity was significant, but Egger’s test suggested no significant publication bias. Conclusion: The triple extrafine BDP/FF/G FDC effectively improves health status and lung function in real-world COPD patients, supporting its use as a viable therapeutic strategy. Further research should explore long-term outcomes and investigate specific patient subgroups to optimize individualized treatment approaches.

Ambulatory oxygen therapy (AOT) is commonly prescribed in Interstitial Lung Disease (ILD) patients, with the aim of reducing dyspnea and increasing exercise tolerance. Despite its frequent use and a reasonable physiological rationale, there is a lack of evidence supporting the effect of AOT on improving dyspnea during exercise. Moreover, dyspnea encompasses distinct sensory (intensity, quality) and affective (anxiety, fear) components with different underlying neurophysiological mechanisms. The aim of this study was to evaluate the effect of oxygen supplementation on exercise tolerance and dyspnea in ILD patients with exercise induced hypoxia (EIH). Forty-seven ILD patients performed a six minute walk test (6MWT) on room air (RA) and with oxygen supplementation (Ox). The 6MWT distance (6MWD) was significantly greater with oxygen supplementation (RA: 242±143 m vs Ox: 345±106 m p<0,01). With oxygen supplementation, the overall dyspnea and anxiety significantly decreased both at rest (1,1±1,4 Borg Unit (BU) vs 0,4±0,9BU , p.<0.01, and 1,1±1,6BU vs 0,5±1,3 BU, p.<0.05, respectively) and at the end of exercise (5,1±2,6 BU vs 3,7±2,5 BU, p.<0.001 and 3,4 ±2,9 vs 2,5 ±2,8, p.<0.01, respectively) despite a greater walked distance. In ILD patients with EIH, oxygen supplementation increases the exercise tolerance and reduces overall dyspnea perception and the anxiety component of breathlessness.

Asthma is a heterogeneous disorder characterized by chronic airway inflammation and airway hyperresponsiveness (AHR). Inhaled corticosteroids (ICS) combined with long-acting β₂-agonists (LABA) remain the mainstay of therapy, yet a subset of patients with difficult-to-treat or severe disease remains uncontrolled and requires high-intensity treatment. Recommendations support adding a long-acting muscarinic antagonist (LAMA) (i.e., tiotropium, glycopyrronium, umeclidinium) as part of triple therapy for these patients. Robust clinical evidence from randomized controlled trials and meta-analyses indicates that open and fixed-dose triple combinations improve lung function and reduce exacerbation risk vs. ICS/LABA, although effects on moderate exacerbations are inconsistent. The established mechanism of action of LAMA is bronchodilation through antagonism of M₃ muscarinic acetylcholine (ACh) receptors (mAChR) on airway smooth muscle. However, evidence for anti-inflammatory effects derives mainly from preclinical investigations. These studies suggest that mAChR expressed on airway epithelial and immune cells may contribute to inflammation and remodeling via non-neuronal ACh signaling. In experimental models, LAMA reduce pro-inflammatory mediator release, limit neutrophil recruitment, and modulate tissue remodeling pathways, with potential synergistic effects when combined with ICS and LABA. Additional indirect anti-inflammatory mechanisms, including reduced airway stretch and potential antiviral activity, have been described. Overall, while clinical benefits of adding a LAMA in difficult-to-treat and severe asthma are well established, the evidence of anti-inflammatory effect of LAMA remains preliminary and requires confirmation in targeted ex vivo studies and further clinical trials.