Respiratory muscle training with normocapnic hyperpnea improves ventilatory pattern and thoracoabdominal coordination, and reduces oxygen desaturation during endurance exercise testing in COPD patients

Background: Few data are available about the effects of respiratory muscle training with normocapnic hyperpnea (NH) in COPD. The aim is to evaluate the effects of 4 weeks of NH (Spirotiger®) on ventilatory pattern, exercise capacity, and quality of life (QoL) in COPD patients. Methods: Twenty-six COPD patients (three females), ages 49-82 years, were included in this study. Spirometry and maximal inspiratory pressure, St George Respiratory Questionnaire, 6-minute walk test, and symptom-limited endurance exercise test (endurance test to the limit of tolerance [tLim]) at 75%-80% of peak work rate up to a Borg Score of 8-9/10 were performed before and after NH. Patients were equipped with ambulatory inductive plethysmography (LifeShirt®) to evaluate ventilatory pattern and thoracoabdominal coordination (phase angle [PhA]) during tLim. After four supervised sessions, subjects trained at home for 4 weeks 10 minutes twice a day at 50% of maximal voluntary ventilation. The workload was adjusted during the training period to maintain a Borg Score of 5-6/10. Results: Twenty subjects completed the study. After NH, maximal inspiratory pressure significantly increased (81.5±31.6 vs 91.8±30.6 cmH2O, P<0.01); exercise endurance time (+150 seconds, P=0.04), 6-minute walk test (+30 meters, P=0.03), and QoL (-8, P<0.01) all increased. During tLim, the ventilatory pattern changed significantly (lower ventilation, lower respiratory rate, higher tidal volume); oxygen desaturation, PhA, and dyspnea Borg Score were lower for the same work intensity (P<0.01, P=0.02, and P<0.01, respectively; one-way ANOVA). The improvement in tidal volume and oxygen saturation after NH were significantly related (R2=0.65, P<0.01). Conclusion: As expected, NH improves inspiratory muscle performance, exercise capacity, and QoL. New results are significant change in ventilatory pattern, which improves oxygen saturation, and an improvement in thoracoabdominal coordination (lower PhA). These two facts could explain the reduced dyspnea during the endurance test. All these results together may play a role in improving exercise capacity after NH training

Inflammatory and immunological mechanisms of virus induced asthma and chronic obstructive pulmonary disease (COPD) exacerbations

Asthma and chronic obstructive pulmonary disease (COPD) are the two most prevalent chronic airway diseases. Much of the morbidity, mortality and health care costs of the diseases are associated with exacerbations. Exacerbations are acute episodes that punctuated the natural history of the disease characterized by increased symptoms and airflow obstruction determining quality of life impairment and with possible effect on long term history of the disease. Thus, the prevention and the treatment of exacerbations are major tasks in the management of both asthma and COPD. However currently available treatment are only partially effective in reducing the incidence of such events. Over the last decade evidence has emerged implicating virus respiratory tract infections as a major cause of exacerbations both in asthma and in COPD. In particular, rhinovirus (i.e. the etiologic cause of the common cold) is the most frequently identify virus during exacerbations of both asthma and COPD. The comprehension of the inflammatory and immunological mechanisms that pave the way for exacerbation following respiratory tract infection in asthmatic and COPD patients will give the opportunity to highlight novel potential targets for pharmacological intervention. The recent development of in vivo experimental models of rhinovirus induced asthma and COPD exacerbations represents the unique tool to evaluate pathogenetic mechanisms and novel pharmacological pathways for treating and preventing COPD and asthma exacerbations. The aim of the present thesis is to review the data available on inflammatory and immunological mechanisms of virus induced exacerbations of asthma and COPD and to present the results of the studies conducted by the Candidate to enlighten the emerging field of virus induced asthma and COPD exacerbations

Inhaled corticosteroids and the lung microbiome in copd

The Global Initiative for Chronic Obstructive Lung Disease 2021 Report recommends inhaled corticosteroid (ICS)-containing regimens as part of pharmacological treatment in patients with chronic obstructive lung disease (COPD) and frequent exacerbations, particularly with eosinophilic inflammation. However, real-world studies reveal overprescription of ICS in COPD, irrespective of disease presentation and inflammatory endotype, leading to increased risk of side effects, mainly respiratory infections. The optimal use of ICS in COPD therefore remains an area of intensive research, and additional biomarkers of benefit and risk are needed. Although the interplay between inflammation and infection in COPD is widely acknowledged, the role of the microbiome in shaping lower airway inflammation has only recently been explored. Next-generation sequencing has revealed that COPD disease progression and exacerbation frequency are associated with changes in the composition of the lung microbiome, and that the immunosuppressive effects of ICS can contribute to potentially deleterious airway microbiota changes by increasing bacterial load and the abundance of potentially pathogenic taxa such as Streptococcus and Haemophilus. Here, we explore the relationship between microbiome, inflammation, ICS use and disease phenotype. This relationship may inform the benefit:risk assessment of ICS use in patients with COPD and lead to more personalised pharmacological management

Symptom variability and control in COPD: Advantages of dual bronchodilation therapy

Abstract Background Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder characterized by usually progressive development of airflow obstruction that is not fully reversible. While most patients will experience symptoms throughout the day or in the morning upon awakening, many patients do not experience their symptoms as constant but report variability in symptoms during the course of the day or over time. Symptom variability adversely affects patients' health status and increases the risk of COPD exacerbations. Methods We examined data from the literature on symptom variability and control in patients with COPD, with focus on the use of inhaled bronchodilator therapy with long-acting muscarinic antagonist agents (LAMA) plus long-acting β 2 -agonists (LABA); in particular twice-daily fixed-dose combination LAMA/LABA therapy with aclidinium/formoterol. Results Correct diagnosis and assessment of COPD requires comprehensive clinical and functional evaluation and consideration of individual needs to support the clinical decisions necessary for effective long-term management. Combining bronchodilators from different and complementary pharmacological classes with distinct mechanisms of action can increase the magnitude of bronchodilation as opposed to increasing the dose of a single bronchodilator. Conclusions The use of inhaled bronchodilator therapy with LAMA/LABA fixed-dose combinations in patients with stable COPD is supported by current evidence. This treatment approach provides robust effects on lung function and symptom control and may improve patients' adherence to treatment. Administration of the long-acting bronchodilators aclidinium and formoterol as twice daily fixed-dose aclidinium/formoterol 400/12 μg has the potential to control symptoms throughout the 24 h in patients with stable moderate-to-severe COPD

Sars-CoV-2 Infection Prompts IL-1β-Mediated Inflammation and Reduces IFN-λ Expression in Human Lung Tissue

Two years after its spreading, the severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) is still responsible for more than 2000 deaths per day worldwide, despite vaccines and monoclonal antibody countermeasures. Therefore, there is a need to understand the immune–inflammatory pathways that prompt the manifestation of the disease to identify a novel potential target for pharmacological intervention. In this context, the characterization of the main players in the SARS-CoV-2-induced cytokine storm is mandatory. To date, the most characterized have been IL-6 and the class I and II interferons, while less is known about the proinflammatory cytokine IL-1β and class III interferons. Here, we report a preliminary study aimed at the characterization of the lung inflammatory context in COVID-19 patients, with a special focus on IFN-λ and IL-1β. By investigating IFN and inflammatory cytokine patterns by IHC in 10 deceased patients due to COVID-19 infection, compared to 10 control subjects, we reveal that while IFN-β production was increased in COVID-19 patients, IFN-λ was almost abolished. At the same time, the levels of IL-1β were dramatically improved, while IL-6 lung levels seem to be unaffected by the infection. Our findings highlight a central role of IL-1β in prompting lung inflammation after SARS-CoV-2 infection. Together, we show that IFN-λ is negatively affected by viral infection, supporting the idea that IFN-λ administration together with the pharmaceutical blockage of IL-1β represents a promising approach to revert the COVID-19-induced cytokine storm

Real-world, long-term effectiveness of allergy immunotherapy in allergic rhinitis: Subgroup analyses of the REACT study

Background: Randomized controlled trials have demonstrated the efficacy of allergy immunotherapy (AIT) in allergic rhinitis (AR) and the disease-modifying effects of the SQ grass sublingual immunotherapy (SLIT) tablet. // Objective: We sought to assess real-world, long-term effectiveness and safety across AIT subgroups: route of administration, therapeutic allergen, persistence to AIT, and SQ grass SLIT tablet. // Methods: The primary outcome of AR prescriptions from a retrospective cohort study (REAl-world effeCtiveness in allergy immunoTherapy; 2007-2017) was assessed across prespecified AIT subgroups in subjects with AR with and without AIT prescriptions (controls). Safety was assessed as anaphylaxis for 2 days or less of the first AIT prescription. Subgroup follow-up continued until samples were fewer than 200 subjects. // Results: Subcutaneous immunotherapy (SCIT) and SLIT tablets showed similarly greater reductions in AR prescriptions than controls (SCIT vs SLIT tablets: year 3, P = .15; year 5, P = .43). Comparably greater reductions in AR prescriptions were observed for grass- and house dust mite–specific AIT than for controls, but significantly smaller reductions were observed for tree-specific AIT (tree vs house dust mite, and vs grass: years 3 and 5, P < .0001). Persistence to AIT was associated with greater reductions in AR prescriptions versus nonpersistence (persistence vs nonpersistence: year 3, P = .09; year 5, P = .006). SQ grass SLIT tablet showed sustained reductions versus controls for up to 7 years (year 3, P = .002; year 5, P = .03). Rates of anaphylactic shock were low (0.000%-0.092%), with no events for SQ SLIT tablets. // Conclusions: These results demonstrate real-world, long-term effectiveness of AIT, complement disease-modifying effects observed in SQ grass SLIT-tablet randomized controlled trials, and highlight the importance of using newer evidence-based AIT products for tree pollen AR

Long-term real-world effectiveness of allergy immunotherapy in patients with allergic rhinitis and asthma: Results from the REACT study, a retrospective cohort study

Summary Background Allergen immunotherapy (AIT) is the only causal treatment for respiratory allergy. Long-term real-life effectiveness of AIT remains to be demonstrated beyond the evidence from randomised controlled trials (RCTs). Methods REACT (Real world effectiveness in allergy immunotherapy) is a retrospective cohort study using claims data between 2007 and 2017. Study eligibility was a confirmed diagnosis of allergic rhinitis (AR), with or without asthma, and AIT. To ensure comparable groups, AIT-treated subjects were propensity score matched 1:1 with control subjects, using characteristic and potential confounding variables. Outcomes were analysed as within (pre vs post AIT) and between (AIT vs control) group differences across 9 years of follow-up (ClinicalTrial.gov: NCT04125888). Findings 46,024 AIT-treated subjects were matched with control subjects and 14,614 were included in the pre-existing asthma cohort. AIT-treated subjects were 29·5 (16·3) years and 53% were male. Compared to pre-index year, AIT was consistently associated with greater reductions compared to control subjects in AR and asthma prescriptions, including both asthma controller and reliever prescriptions. Additionally, the AIT group had significantly greater likelihood of stepping down asthma treatment (P <0·0001). In addition to the reduction in asthma treatment in the AIT group, a greater reduction in severe asthma exacerbations was demonstrated (P<0·05). Reductions in pneumonia with antibiotic prescriptions, hospitalisations, and duration of inpatients stays were all in favour of AIT. Interpretation The study extends the existing RCT evidence for AIT by demonstrating longer-term and sustained effectiveness of AIT in the real world. Additionally, in patients with concurrent asthma, AIT was associated with reduced likelihood of asthma exacerbations and pneumonia

Satisfaction with chronic obstructive pulmonary disease treatment: results from a multicenter, observational study

Background: Understanding the level of patients\u2019 satisfaction with treatment and its determinants have the potential to impact therapeutic management and clinical outcome in chronic conditions such as chronic obstructive pulmonary disease (COPD). Methods: A national, multicenter, longitudinal, observational study of COPD from 20 Italian pulmonary centers to explore patients\u2019 satisfaction to treatment [assessed by the Treatment Satisfaction Questionnaire, 9 items (TSQM-9)] and association with clinical parameters [including dyspnea score, COPD Assessment Test (CAT) score, exacerbation rate], adherence to treatment [Morisky Medication-Taking Adherence Scale (MMAS-4)], illness perception [evaluated by Brief Illness Perception Questionnaire (B-IPQ)] in a 1-year follow up. Results: A total of 401 COPD patients were enrolled [69.4% group B Global Initiative for COPD (GOLD), considering 366 patients with available GOLD 2017 classification at enrollment]. At enrollment, satisfaction with treatment was moderate, being TSQM-9 mean scores for effectiveness 64.2 [95% confidence interval (CI) 62.5\u201365.9], for convenience 75.8 (95% CI 74.2\u201377.3), and for global satisfaction 65.7 (95% CI 64.0\u201367.4). Global satisfaction was negatively associated with disease perception (\u3b2 = 120.4709, p &lt; 0.0001), and grade of dyspnea (\u3b2 = 124.2564, p = 0.009). Satisfaction with treatment was lower in patients with poor compared with optimal adherence to treatment (\u3b2 = 124.5608, p = 0.002). Changes in inhalation regimens during follow up did not modify the satisfaction with treatment. Conclusions: The results of this real-life study showed that the patients\u2019 satisfaction with treatments is only moderate in COPD. A high grade of patients\u2019 satisfaction is associated mainly with a low perception of the disease, high adherence to treatment and lower level of dyspnea

Long-term, real-world effects of allergy immunotherapy in children with allergic rhinitis and pre-existing asthma - a subgroup analysis of the REACT study

Background: Randomised controlled trials (RCTs) have demonstrated the efficacy of allergy immunotherapy (AIT) in allergic rhinitis (AR) and the disease-modifying effects of the SQ grass sublingual immunotherapy (SLIT)-tablet.// Objective: To assess real-world, long-term effectiveness and safety across AIT subgroups: route of administration, therapeutic allergen, persistence to AIT, and SQ grass SLIT-tablet.// Methods: The primary outcome of AR prescriptions from a retrospective cohort study (REACT; 2007–2017) was assessed across pre-specified AIT subgroups in AR subjects with, and without AIT prescriptions (controls). Safety was assessed as anaphylaxis ≤2 days of the first AIT prescription. Subgroup follow-up continued until samples were <200 subjects.// Results: Subcutaneous immunotherapy (SCIT) and SLIT-tablets showed similarly greater reductions in AR prescriptions than controls (SCIT versus SLIT-tablets: Year 3, p=0.15; Year 5, p=0.43). Comparably greater reductions in AR prescriptions were observed for grass- and house dust mite (HDM)-specific AIT than controls, but significantly smaller reductions were observed for tree-specific AIT (tree versus HDM, and versus grass: Years 3 and 5, p<0.0001). Persistence to AIT was associated with greater reductions in AR prescriptions versus non-persistence (persistence versus nonpersistence: Year 3, p=0.09; Year 5, p=0.006). SQ grass SLIT-tablet showed sustained reductions versus controls for up to 7 years (Year 3, p=0.002; Year 5, p=0.03). Rates of anaphylactic shock were low (0.000–0.092%), with no events for SQ SLIT-tablets.// Conclusion: These results demonstrate real-world, long-term effectiveness of AIT, complement disease-modifying effects observed in SQ grass SLIT-tablet RCTs, and highlight the importance of using newer evidence-based AIT products for tree pollen AR