Long-term inhaled corticosteroid treatment in patients with chronic obstructive pulmonary disease, cardiovascular disease, and a recent hospitalised exacerbation: The ICSLIFE pragmatic, randomised controlled study.

INTRODUCTION: Patients with chronic obstructive pulmonary disease (COPD) frequently have cardiovascular comorbidities, increasing the risk of hospitalised COPD exacerbations (H-ECOPDs) or death. This pragmatic study examined the effects of adding an inhaled corticosteroid (ICS) to long-acting bronchodilator(s) (LABDs) in patients with COPD and cardiac comorbidities who had a recent H-ECOPD. METHODS: Patients >60 years of age with COPD and ≥1 cardiac comorbidity, within 6 months after discharge following an H-ECOPD, were randomised to receive LABD(s) with or without ICS, and were followed for 1 year. The primary outcome was the time to first rehospitalisation and/or all-cause death. RESULTS: The planned number of patients was not recruited (803/1032), limiting the strength of the conclusions. In the intention-to-treat population, 89/403 patients (22.1 %) were rehospitalised or died in the LABD group (probability 0.257 [95 % confidence interval 0.206, 0.318]), vs 85/400 (21.3 %) in the LABD+ICS group (0.249 [0.198, 0.310]), with no difference between groups in time-to-event (hazard ratio 1.116 [0.827, 1.504]; p = 0.473). All-cause and cardiovascular mortality were lower in patients receiving LABD(s)+ICS, with relative reductions of 19.7 % and 27.4 %, respectively (9.8 % vs 12.2 % and 4.5 % vs 6.2 %), although the groups were not formally statistically compared for these endpoints. Fewer patients had adverse events in the LABD+ICS group (43.0 % vs 50.4 %; p = 0.013), with 4.9 % vs 5.4 % reporting pneumonia adverse events. CONCLUSIONS: Results suggest addition of ICS to LABDs did not reduce the time-to-combined rehospitalisation/death, although it decreased all-cause and cardiovascular mortality. ICS use was not associated with an increased risk of adverse events, particularly pneumonia.

Endotyping Chronic Respiratory Diseases: T2 Inflammation in the United Airways Model.

Over the past 15 years, the paradigm of viewing the upper and lower airways as a unified system has progressively shifted the approach to chronic respiratory diseases (CRDs). As the global prevalence of CRDs continues to increase, it becomes evident that acknowledging the presence of airway pathology as an integrated entity could profoundly impact healthcare resource allocation and guide the implementation of pharmacological and rehabilitation strategies. In the era of precision medicine, endotyping has emerged as another novel approach to CRDs, whereby pathologies are categorized into distinct subtypes based on specific molecular mechanisms. This has contributed to the growing acknowledgment of a group of conditions that, in both the upper and lower airways, share a common type 2 (T2) inflammatory signature. These diverse pathologies, ranging from allergic rhinitis to severe asthma, frequently coexist and share diagnostic and prognostic biomarkers, as well as therapeutic strategies targeting common molecular pathways. Thus, T2 inflammation may serve as a unifying endotypic trait for the upper and lower airways, reinforcing the practical significance of the united airways model. This review aims to summarize the literature on the role of T2 inflammation in major CRDs, emphasizing the value of common biomarkers and integrated treatment strategies targeting shared molecular mechanisms.

A clinician's guide to single vs multiple inhaler therapy for COPD.

INTRODUCTION: In the management of chronic obstructive pulmonary disease (COPD), inhalation therapy plays a pivotal role. However, clinicians often face the dilemma of choosing between single and multiple inhaler therapies for their patients. This choice is critical because it can affect treatment efficacy, patient adherence, and overall disease management. AREAS COVERED: This article examines the advantages and factors to be taken into consideration when selecting between single and multiple inhaler therapies for COPD. EXPERT OPINION: Both single and multiple inhaler therapies must be considered in COPD management. While single inhaler therapy offers simplicity and convenience, multiple inhaler therapy provides greater flexibility and customization. Clinicians must carefully evaluate individual patient needs and preferences to determine the most appropriate inhaler therapy regimen. Through personalized treatment approaches and shared decision-making, clinicians can optimize COPD management and improve patient well-being. Nevertheless, further research is required to compare the effectiveness of single versus multiple inhaler strategies through rigorous clinical trials, free from industry bias, to determine the optimal inhaler strategy. Smart inhaler technology appears to have the potential to enhance adherence and personalized management, but the relative merits of smart inhalers in single inhaler regimens versus multiple inhaler regimens remain to be determined.

Is the Rehabilitation Complexity Scale useful in individuals undergoing in-hospital pulmonary rehabilitation?

OBJECTIVE: To assess validity and responsiveness of the Extended Rehabilitation Complexity Scale (RCS-Ev13) to in-hospital pulmonary rehabilitation (PR) in individuals with chronic respiratory diseases (CRD). DESIGN: cross-sectional multicentric study. Assessments in individuals attending units on two non-consecutive days. SETTING: 14 Italian in-hospital PR units. PARTICIPANTS: Five hundred forty-seventh individuals (59.2% male, age 72 [65-78] years): 317 with Chronic Respiratory Failure due to various causes (CRF group); 96 with chronic obstructive pulmonary disease without CRF (COPD), 39 Tracheostomized and Ventilated (Tx/V), and 95 with other diseases (Miscellaneous). INTERVENTION: Assessment of RCS-Ev13 before and after the PR program. MAIN OUTCOME MEASURES: RCS-Ev13 and outcome measures: Barthel Index (BI), Barthel Index Dyspnoea (BiD), Medical Research Council Scale for dyspnoea (MRC), COPD Assessment Test (CAT), Short Physical Performance Battery (SPPB), Six-Minute Walking Test (6MWT). RESULTS: The highest RCS-Ev13 admission values (median; IQR) were found in TX/V (17; 15-18) as compared to other groups (8; 7-10, 10; 9-12, 8; 8-10 in COPD, CRF and Miscellaneous respectively, p<0.001). At admission and discharge, RCS-Ev13 correlated strongly with BI, 6MWT, and SPPB and moderately with MRC and BiD (r: 0.43 to 0.60). After the program RCS-Ev13 as well as all outcome measures improved significantly in all groups (p< 0.001 for all). The size of improvement was different among groups according to the different variables. In the overall group the effect size was high for changes in RCS-E v13 (Cohen's d = -2.0984), CAT = (-1.1937), MRC (- 1.0505), BiD (- 0.9364) and SPPB (0.9231) while moderate for 6MWT (0.7670) and BI (0.6574). CONCLUSIONS: RCS-E v13 varies according to different CRDs, is responsive to PR, has good construct and concurrent validity, and correlates with most of the accepted outcome measures of PR. Its scoring may provide useful information on the care burden of individuals undergoing PR.

Autoimmunity against Nucleus Ambiguous Is Putatively Possible in Both Long-COVID-19 and Vaccinated Subjects: Scientific Evidence and Working Hypothesis.

As reported by the World Health Organization (WHO), about 10-20% of people have experienced mid- to long-term effects following SARS-CoV-2 infection, collectively referred to as post-COVID-19 condition or long-COVID, including some neurovegetative symptoms. Numerous findings have suggested that the onset of these neurovegetative symptoms upon viral infection may be caused by the production of autoantibodies through molecular mimicry phenomena. Accordingly, we had previously demonstrated that 22 of the human proteins sharing putatively immunogenic peptides with SARS-CoV-2 proteins are expressed in the dorsal motor nucleus and nucleus ambiguous. Therefore, if molecular mimicry occurs following severe forms of COVID-19, there could be transitory or permanent damage in some vagal structures, resulting in a lower vagal tone and all the related clinical signs. We investigated the presence of autoantibodies against two proteins of vagal nuclei sharing a peptide with SARS-CoV-2 spike glycoprotein using an immunoassay test on blood obtained from patients with cardiorespiratory symptoms in patients affected by ongoing symptomatic COVID-19 (long-COVID), subjects vaccinated without a history of SARS-CoV-2 infection, and subjects not vaccinated without a history of SARS-CoV-2 infection. Interestingly, putative autoantibodies were present in both long-COVID-19 and vaccinated groups, opening interesting questions about pathogenic mechanisms of the disease.

Exploring novel perspectives on eosinophilic inflammation in severe asthma.

Two recent articles by the same research group documented that patients with severe eosinophilic asthma exhibit an increased proportion of a subtype of eosinophils, namely CD62Llow inflammatory eosinophils (iEos) and identified an intriguing correlation between such iEos and asthma control scores. Moreover, CD62Llow iEos were reduced after treatment with the anti-IL-5 monoclonal antibody mepolizumab. In the future, we believe that eosinophil subtypes could represent a useful biomarker in severe eosinophilic asthma, helping clinicians characterize patient endotypes and monitoring the response to biological drugs.

Patients with severe eosinophilic asthma (SEA) have an increased proportion of a subtype of eosinophils, CD62L^low inflammatory eosinophils (iEos), which are reduced after mepolizumab treatment. iEos might represent a novel useful biomarker in SEA.

The Beneficial Impact of Pulmonary Rehabilitation in Idiopathic Pulmonary Fibrosis: A Review of the Current Literature.

Idiopathic pulmonary fibrosis (IPF) is a chronic and irreversible fibrotic disease whose natural history is characterised by a progressive worsening of the pulmonary function, exertional dyspnoea, exercise intolerance, reduced physical activity, and health-related quality of life (HRQOL) impairment. Pulmonary rehabilitation (PR) is a comprehensive, multi-disciplinary programme that uses a combination of strength training, teaching, counselling, and behaviour modification techniques to reduce symptoms and optimise functional capacity in patients with chronic lung disease. Based on the well-documented effectiveness of PR in chronic obstructive pulmonary disease (COPD), over the years supportive evidence of its benefits for other respiratory diseases has been emerging. Although the latest rehabilitation guidelines recognised PR's efficacy for interstitial lung disease (ILD) and IPF in particular, this comprehensive approach remains underused and under-resourced. In this review, we will discuss the advantages and beneficial effects of PR on IPF, analysing its impact on exercise capacity, disease-related symptoms, cardiovascular outcomes, body composition, and HRQOL.

Upregulation of Notch Signaling and Cell-Differentiation Inhibitory Transcription Factors in Stable Chronic Obstructive Pulmonary Disease Patients.

Notch signaling is involved in the prevention of cell differentiation and cell fate in various organs, including the lungs. We aimed to determine the transcriptomic and protein expression of Notch receptors, their ligands, and related transcription factors in stable COPD. The expression and localization of Notch receptors, their ligands, and related transcription factors were measured in bronchial biopsies of individuals with stable mild/moderate (MCOPD) (n = 18) or severe/very severe (SCOPD) (n = 16) COPD, control smokers (CSs) (n = 13), and control nonsmokers (CNSs) (n = 11), and in the lung parenchyma of those with MCOPD (n = 13), CSs (n = 10), and CNSs (n = 10) using immunohistochemistry, ELISA tests, and transcriptome analyses. In the bronchial biopsies, Notch4 and HES7 significantly increased in the lamina propria of those with SCOPD compared to those with MCOPD, CSs, and CNSs. In the peripheral lung bronchiolar epithelium, Notch1 significantly increased in those with MCOPD and CSs compared to CNSs. ELISA tests of lung parenchyma homogenates showed significantly increased Notch2 in those with MCOPD compared to CSs and CNSs. Transcriptomic data in lung parenchyma showed increased DLL4 and HES1 mRNA levels in those with MCOPD and CSs compared to CNSs. These data show the increased expression of the Notch pathway in the lungs of those with stable COPD. These alterations may play a role in impairing the regenerative-reparative responses of diseased bronchioles and lung parenchyma.

Impact of biologics on lung hyperinflation in patients with severe asthma.

BACKGROUND: In asthma, inflammation affects both the proximal and distal airways and can cause significant hyperinflation, which is thought to be a major cause of dyspnea. METHODS: This is a retrospective observational study evaluating the effect of three months of treatment with different biologic drugs (benralizumab, dupilumab and omalizumab) on pulmonary hyperinflation in a cohort of patients with severe asthma already receiving regular triple inhaled therapy. Changes in RV, RV/TLC ratio, FRC and FRC/TLC ratio were the primary efficacy measures. Secondary outcomes included FEV1, FVC, FEV1/FVC ratio, IC, IC/TLC ratio, asthma control test, the percentage of eosinophils in the blood and fractional FENO. RESULTS: Benralizumab led to significant changes (p < 0.001) in RV, RV/TLC, FRC, and FRC/TLC. Dupilumab demonstrated a notable reduction in RV (p = 0.017) and RV/TLC (p = 0.002), but the decreases in FRC and FRC/TLC were merely numerical and not as pronounced as those induced by benralizumab. Omalizumab's positive impact on RV (p = 0.057) and RV/TLC (p = 0.085), as well as FRC (p = 0.202) and FRC/TLC (p = 0.096), was also predominantly numerical, with a tendency towards efficacy, albeit excluding the effect on FRC. Treatment with biologics resulted in improvements in all other lung function parameters assessed and a decrease in FENO levels. CONCLUSION: This study, although limited by small sample size, lack of a placebo control, and unbalanced group sizes, suggests that biological agents are effective in reducing lung hyperinflation even after a relatively short treatment.

Quality of life and work functionality in severe asthma patients: the impact of biological therapies.

BACKGROUND: Severe asthma can cause poor health status, poor health-related quality of life (HRQoL) and an impaired functioning at work. However, to date, limited data are available on the impact of the biological therapies on such outcomes. Therefore, aim of the present study was to prospectively assess the clinical, quality of life and work functionality issues in severe asthma patients both at baseline and after 6 months of biological therapies and determine which individual, pathological and occupational factors can influence such parameters. METHODS: Fifty-two patients were enrolled between December 2022 and June 2023. Patients' personal, clinical, functional and occupational features were assessed. The Short Form Health Survey (SF-12), the Work Productivity and Activity Impairment (WPAI) questionnaire and the Work Ability Index (WAI) were employed to assess HRQoL, the employee's productivity and perception of work ability, respectively. RESULTS: Among the enrolled patients, 30 (57.70%) were employed. Biological therapy induced a significant improvement in clinical and functional parameters, e.g., FEV1% (72 ± 12 vs.87 ± 13%; 72 ± 14 vs. 86 ± 14%), FVC% (92 ± 11 vs. 101 ± 11%; 90 ± 13 vs. 98 ± 14%) and FEV1/FVC (62 ± 11 vs. 71 ± 8%; 64 ± 9 vs. 70 ± 8%) in workers and non-workers, respectively (P < 0.001). Comparably, the perception of life quality significantly improved, as physical and mental health scores, in the overall cohort, increased from 40.7 ± 10.3 and 48.5 ± 8.5 to 46.8 ± 8.6 and 51.6 ± 6.4, respectively (P < 0.001). The work ability perception significantly improved from a moderate to a good one (34 ± 6 vs. 40 ± 6, P = 0.001). A significant reduction in the absenteeism (19 ± 15 vs. 3 ± 11%; P < 0.001) and presenteeism rate (53 ± 24 vs. 29 ± 26%; P < 0.001), and an improvement in daily (40 ± 27.5% vs. 28.9 ± 24.7%, P < 0.001, in the overall population) and work activities (57 ± 25 vs. 29 ± 27%, P < 0.001) was determined. Gender, age, symptoms control and pulmonary functionality were correlated with the physical and mental health perception, daily activity impairment and work ability. CONCLUSIONS: Our study pointed out that biological therapies improved clinical, general life and occupational outcomes in patients with severe asthma. The correlation between clinical aspects and psychological and occupational issues suggest the relevance for a multidisciplinary management of the disease for an effective participation of patients in the world of work.

The biomarkers' landscape of post-COVID-19 patients can suggest selective clinical interventions.

In COVID-19 clinical symptoms can persist even after negativization also in individuals who have had mild or moderate disease. We here investigated the biomarkers that define the post-COVID-19 clinical state analyzing the exhaled breath condensate (EBC) of 38 post COVID-19 patients and 38 sex and age-matched healthy controls via nuclear magnetic resonance (NMR)-based metabolomics. Predicted gene-modulated microRNAs (miRNAs) related to COVID-19 were quantified from EBC of 10 patients and 10 controls. Finally, clinical parameters from all post-COVID-19 patients were correlated with metabolomic data. Post-COVID-19 patients and controls showed different metabolic phenotype ("metabotype"). From the metabolites, by using enrichment analysis we identified miRNAs that resulted up-regulated (hsa-miR146a-5p) and down-regulated (hsa-miR-126-3p and hsa-miR-223-3p) in post-COVID-19. Taken together, our multiomics data indicate that post-COVID-19 patients before rehabilitation are characterized by persistent inflammation, dysregulation of liver, endovascular thrombotic and pulmonary processes, and physical impairment, which should be the primary clinical targets to contrast the post-acute sequelae of COVID-19.

Exhaled Nitric Oxide as Biomarker of Type 2 Diseases.

Nitric oxide (NO) is a short-lived gas molecule which has been studied for its role as a signaling molecule in the vasculature and later, in a broader view, as a cellular messenger in many other biological processes such as immunity and inflammation, cell survival, apoptosis, and aging. Fractional exhaled nitric oxide (FeNO) is a convenient, easy-to-obtain, and non-invasive method for assessing active, mainly Th2-driven, airway inflammation, which is sensitive to treatment with standard anti-inflammatory therapy. Consequently, FeNO serves as a valued tool to aid the diagnosis and monitoring of several asthma phenotypes. More recently, FeNO has been evaluated in several other respiratory and/or immunological conditions, including allergic rhinitis, chronic rhinosinusitis with/without nasal polyps, atopic dermatitis, eosinophilic esophagitis, and food allergy. In this review, we aim to provide an extensive overview of the current state of knowledge about FeNO as a biomarker in type 2 inflammation, outlining past and recent data on the application of its measurement in patients affected by a broad variety of atopic/allergic disorders.

Bone Morphogenic Proteins and Their Antagonists in the Lower Airways of Stable COPD Patients.

BACKGROUND: Bone morphogenic proteins (BMPs) and their antagonists are involved in the tissue development and homeostasis of various organs. OBJECTIVE: To determine transcriptomic and protein expression of BMPs and their antagonists in stable COPD. METHODS: We measured the expression and localization of BMPs and some relevant antagonists in bronchial biopsies of stable mild/moderate COPD (MCOPD) (n = 18), severe/very severe COPD (SCOPD) (n = 16), control smokers (CS) (n = 13), and control non-smokers (CNS) (n = 11), and in lung parenchyma of MCOPD (n = 9), CS (n = 11), and CNS (n = 9) using immunohistochemistry and transcriptome analysis, in vitro after the stimulation of the 16HBE cells. RESULTS: In bronchial biopsies, BMP4 antagonists CRIM1 and chordin were increased in the bronchial epithelium and lamina propria of COPD patients. BMP4 expression was decreased in the bronchial epithelium of SCOPD and MCOPD compared to CNS. Lung transcriptomic data showed non-significant changes between groups. CRIM1 and chordin were significantly decreased in the alveolar macrophages and alveolar septa in COPD patients. External 16HBE treatment with BMP4 protein reduced the bronchial epithelial cell proliferation. CONCLUSIONS: These data show an imbalance between BMP proteins and their antagonists in the lungs of stable COPD. This imbalance may play a role in the remodeling of the airways, altering the regenerative-reparative responses of the diseased bronchioles and lung parenchyma.

Flow-mediated dilation as a marker of endothelial dysfunction in pulmonary diseases: A narrative review.

The endothelium is an active and crucial component of vessels and produces several key regulatory factors for the homeostasis of the entire organism. Endothelial function can be investigated invasively or non-invasively, both in the coronary and peripheral circulation. A widely accepted method for the assessment of endothelial function is measurement of flow-mediated dilation (FMD), which evaluates the vascular response to changes in blood flow. In this current review, we describe FMD applications in the clinical setting of different respiratory diseases: acute SARS-COV2 infection, pulmonary embolism; post-acute SARS-COV2 infection, Chronic Obstructive Pulmonary Disease, Obstructive Sleep Apneas Syndrome, Pulmonary Hypertension, Interstitial Lung Diseases. Emerging evidence shows that FMD might be an effective tool to assess the cardiovascular risk in patients suffering from the undermentioned respiratory diseases as well as an independent predictive factor of disease severity and/or recovery.

The Clinical Application of Established and Emerging Biomarkers for Chronic Respiratory Diseases.

Biomarkers are indicators of a pathological or physiological state, and they are essential for facilitating the diagnosis of a subclinical condition, understanding the origin or progression of a disease, stratifying the risk, and assessing the response to a specific therapeutic approach [...].

Cardiovascular Risk Associated with Alpha-1 Antitrypsin Deficiency (AATD) Genotypes: A Meta-Analysis with Meta-Regressions.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) can result in severe liver and respiratory disorders. The uninhibited elastase activity on the elastic tissue of arterial walls suggests that AATD may also impact vascular health. Thus, we performed a meta-analysis of the studies evaluating cardiovascular risk in individuals with AATD and non-AATD controls. METHODS: A systematic literature search was conducted in the main scientific databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Differences between cases and controls were expressed as odds ratios (OR) with 95% confidence intervals (95%CI). The protocol was registered on PROSPERO under the identification number CRD42023429756. RESULTS: The analysis of eight studies showed that, with a prevented fraction of disease of 15.0% and a corresponding OR of 0.779 (95%CI: 0.665-0.912; p = 0.002), a total of 24,428 individuals with AATD exhibited a significantly lower risk of ischemic heart disease compared to 534,654 non-AATD controls. Accordingly, given a prevented fraction of disease of 19.5%, a lower risk of acute myocardial infarction was documented when analyzing four studies on 21,741 cases and 513,733 controls (OR: 0.774; 95%CI: 0.599-0.999; p = 0.049). Sensitivity and subgroup analyses substantially confirmed results. Meta-regression models suggested that these findings were not influenced by AATD genotypes or prevalence of chronic obstructive pulmonary disease (COPD) among cases and controls, while higher differences in the prevalence of male sex (Z-score: 3.40; p < 0.001), hypertension (Z-score: 2.31; p = 0.021), and diabetes (Z-score: 4.25; p < 0.001) were associated with a lower effect size. CONCLUSIONS: Individuals with AATD may exhibit a reduced risk of ischemic heart disease, even in the presence of mild deficiency of the serine protease inhibitor. Although caution is warranted due to the observational nature of the data, future pharmacological and rehabilitation strategies should also take this controversial relationship into account.

Effects of pulmonary rehabilitation in survivors of severe acute respiratory syndrome coronavirus 2. Role of vaccination.

Survivors of severe COVID-19 requiring hospital admission may suffer from short- and long-term sequelae, including disability and reduced physical performance. Vaccination and pulmonary rehabilitation (PR) are effective tools against COVID-19 effects. While the beneficial effect of each of these treatments is known, there are no data about their combined effect. In people admitted to PR hospitals after severe COVID-19 disease, we retrospectively analyzed whether PR outcome might be influenced by vaccination status. Ninety-six individuals were studied (46 vaccinated, 50 unvaccinated). Unvaccinated individuals were younger and less comorbid than vaccinated ones and had needed more intensive care support during the previous hospitalization. Measures of disability and physical performance did not differ between groups at the beginning and at the end of the PR program. However, each group showed a statistically significant improvement in all outcome measures (6-minute walking test, short physical performance battery, Barthel Index). We conclude that vaccination status does not influence the outcome of in-patient PR programs for survivors of severe COVID-19.