Critical reappraisal of short-acting bronchodilators for pediatric respiratory diseases.

Short-acting bronchodilators are a class of medications commonly used to treat asthma, chronic obstructive pulmonary disease, and other respiratory conditions. The use of these medications has evolved over time as we have gained a better understanding of their effectiveness and safety in the pediatric population. This comprehensive review synthesizes the current understanding of short-acting ß2-agonists and short-acting anticholinergics in children. It addresses indications, contraindications, safety considerations, and highlights areas where further research is needed to guide the most effective use of short-acting bronchodilators.

SABINA + Hong Kong: a territory wide study of prescribing trends and outcomes associated with the use of short-acting ß2 agonists in the Chinese population.

BACKGROUND: Excessive use of short-acting ß2 agonists (SABA) in patients with asthma continues to be a notable concern due to its link to higher mortality rates. Global relevance of SABA overuse in asthma management cannot be understated, it poses significant health risk to patients with asthma and imposes burden on healthcare systems. This study, as part of global SABINA progamme, aimed to describe the prescribing patterns and clinical outcomes associated with SABA use in the Chinese population. METHODS: Retrospective cohort study was conducted using anonymized electronic healthcare records of Clinical Data Analysis and Reporting System (CDARS) from Hong Kong Hospital Authority (HA). Patients newly diagnosed with asthma between 2011 and 2018 and aged ≥12 years were included, stratified by SABA use (≤2, 3-6, 7-10, or ≥11 canisters/year) during one-year baseline period since asthma diagnosis date. Patients were followed up from one-year post-index until earliest censoring of events: outcome occurrence and end of study period (31 December 2020). Cox proportional regression and negative binomial regression were used to estimate the mortality risk and frequency of hospital admissions associated with SABA use respectively, after adjusting for age, sex, Charlson Comorbidity Index (CCI), and inhaled corticosteroid (ICS) dose. Outcomes include all-cause, asthma-related, and respiratory-related mortality, frequency of hospital admissions for any cause, and frequency of hospital admissions due to asthma. RESULTS: 17,782 patients with asthma (mean age 46.7 years, 40.8% male) were included and 59.1% of patients were overusing SABA (≥ 3 canisters per year). Each patient was prescribed a median of 5.61 SABA canisters/year. SABA overuse during baseline period was associated with higher all-cause mortality risk compared to patients with ≤2 canisters/year. Association was dose-dependent, highest risk in those used ≥11 canisters/year (adjusted hazard ratio: 1.42, 95% CI: 1.13, 1.79) and 3-6 canisters/year (adjusted hazard ratio: 1.22, 95% CI: 1.00, 1.50). Higher SABA prescription volume associated with increased frequency of hospital admissions with greatest risk observed in 7-10 canisters/year subgroup (adjusted rate ratio: 4.81, 95% CI: 3.66, 6.37). CONCLUSIONS: SABA overuse is prevalent and is associated with increased all-cause mortality risk and frequency of hospital admissions among the patients with asthma in Hong Kong.

Development and validation of a claims-based algorithm to identify moderate exacerbations in patients with asthma treated in the US.

INTRODUCTION: Definitions of moderate asthma exacerbation have been inconsistent, making their economic burden difficult to assess. An algorithm to accurately identify moderate exacerbations from claims data is needed. METHODS: A retrospective cohort study of Reliant Medical Group patients aged ≥18 years, with ≥1 prescription claim for inhaled corticosteroid/long-acting ß2-agonist, and ≥1 medical claim with a diagnosis code for asthma was conducted. The objective was to refine current algorithms to identify moderate exacerbations in claims data and assess the refined algorithm's performance. Positive and negative predictive values (PPV and NPV) were assessed via chart review of 150 moderate exacerbations events and 50 patients without exacerbations. Sensitivity analyses assessed alternative algorithms and compared healthcare resource utilization (HRU) between algorithm-identified patients (claims group) and those confirmed by chart review (confirmed group) to have experienced a moderate exacerbation. RESULTS: Algorithm-identified moderate exacerbations were: visit of ≤1 day with an asthma exacerbation diagnosis OR visit of ≤1 day with selected asthma diagnoses AND ≥1 respiratory pharmacy claim, excluding systemic corticosteroids, within 14 days after the first claim. The algorithm's PPV was 42%; the NPV was 78%. HRU was similar for both groups. CONCLUSION: This algorithm identified potential moderate exacerbations from claims data; however, the modest PPV underscores its limitations in identifying moderate exacerbations, although performance was partially due to identification of previously unidentified severe exacerbations. Application of this algorithm in future claims-based studies may help quantify the economic burden of moderate and severe exacerbations in asthma when an algorithm identifying severe exacerbations is applied first.

Frequency and economic burden of exacerbations in inhaled corticosteroid/long-acting beta-agonist-treated patients with asthma: A retrospective US claims study.

INTRODUCTION: Despite adherence to inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA) therapy, many patients with asthma experience moderate exacerbations. Data on the impact of moderate exacerbations on the healthcare system are limited. This study assessed the frequency and economic burden of moderate exacerbations in patients receiving ICS/LABA. METHODS: Retrospective, longitudinal study analyzed data from Optum's de-identified Clinformatics® Data Mart Database recorded between October 1, 2015, and December 31, 2019. Eligibility criteria included patients ≥18 years of age with ≥1 ICS/LABA claim and ≥1 medical claim for asthma in the 12 months pre-index (first ICS/LABA claim). Primary objectives included describing moderate exacerbation frequency, and associated healthcare resource utilization (HRU) and costs. A secondary objective was assessing the relationship between moderate exacerbations and subsequent risk of severe exacerbations. Patients were stratified by moderate exacerbation frequency in the 12 months post index. Moderate exacerbations were identified using a newly developed algorithm. RESULTS: In the first 12 months post index 61.6% of patients experienced ≥1 moderate exacerbation. Mean number of asthma-related visits was 4.1 per person/year and median total asthma-related costs was $3544. HRU and costs increased with increasing exacerbation frequency. Outpatient and inpatient visits accounted for a similar proportion of these costs. Moderate exacerbations were associated with an increased rate and risk of future severe exacerbations (incidence rate ratio, 1.56; hazard ratio, 1.51 [both p < 0.001]). CONCLUSIONS: This study highlighted that a high proportion of patients continue to experience moderate exacerbations despite ICS/LABA therapy and subsequently experience increased economic burden and risk of future severe exacerbations.

Asthma patients' and physicians' perspectives on the burden and management of asthma: Post-hoc analysis of APPaRENT 1 and 2 to assess predictors of treatment adherence.

INTRODUCTION: Patient adherence to maintenance medication is critical for improving clinical outcomes in asthma and is a recommended guiding factor for treatment strategy. Previously, the APPaRENT studies assessed patient and physician perspectives on asthma care; here, a post-hoc analysis aimed to identify patient factors associated with good adherence and treatment prescription patterns. METHODS: APPaRENT 1 and 2 were cross-sectional online surveys of 2866 adults with asthma and 1883 physicians across Argentina, Australia, Brazil, Canada, China, France, Italy, Mexico, and the Philippines in 2020-2021. Combined data assessed adherence to maintenance medication, treatment goals, use of asthma action plans, and physician treatment patterns and preferences. Multivariable logistic regression models assessed associations between patient characteristics and both treatment prescription (by physicians) and patient treatment adherence. RESULTS: Patient and physician assessments of treatment goals and adherence differed, as did reporting of short-acting ß2-agonist (SABA) prescriptions alongside maintenance and reliever therapy (MART). Older age and greater patient-reported severity and reliever use were associated with better adherence. Patient-reported prescription of SABA with MART was associated with household smoking, severe or poorly controlled asthma, and living in China or the Philippines. CONCLUSIONS: Results revealed an important disconnect between patient and physician treatment goals and treatment adherence, suggesting that strategies for improving patient adherence to maintenance medication are needed, focusing on younger patients with milder disease. High reliever use despite good adherence may indicate poor disease control. Personalised care considering patient characteristics alongside physician training in motivational communication and shared decision-making could improve patient management and outcomes.

A network meta-analysis of the association between patient traits and response to regular dosing with ICS plus short-acting ß2-agonist reliever or ICS/formoterol reliever only in mild asthma.

INTRODUCTION/BACKGROUND: Mild asthma treatment recommendations include intermittent inhaled corticosteroid (ICS)/formoterol dosing or regular ICS dosing with short-acting ß2-agonist reliever. Due to the heterogeneity of asthma, identification of traits associated with improved outcomes to specific treatments would be clinically beneficial. AIMS/OBJECTIVES: To assess the impact of patient traits on treatment outcomes of regular ICS dosing compared with intermittent ICS/formoterol dosing, a systematic literature review (SLR) and network meta-analysis (NMA) was conducted. Searches identified randomised controlled trials (RCTs) of patients with asthma aged ≥12 years, containing ≥1 regular ICS dosing or intermittent ICS/formoterol dosing treatment arm, reporting traits and outcomes of interest. RESULTS: The SLR identified 11 RCTs of mild asthma, of 14,516 patients. A total of 11 traits and 11 outcomes of interest were identified. Of these, a feasibility assessment indicated possible assessment of three traits (age, baseline lung function, smoking history) and two outcomes (exacerbation rate, change in lung function). The NMA found no significant association of any trait with any outcome with regular ICS dosing relative to intermittent ICS/formoterol dosing. Inconsistent reporting of traits and outcomes between RCTs limited analysis. CONCLUSIONS: This is the first systematic analysis of associations between patient traits and differential treatment outcomes in mild asthma. Although the traits analysed were not found to significantly interact with relative treatment response, inconsistent reporting from the RCTs prevented assessment of some of the most clinically relevant traits and outcomes, such as adherence. More consistent reporting of respiratory RCTs would provide more comparable data and aid future analyses.

Real-World Effectiveness of Single-Inhaler Triple Therapy for COPD: Impact of Diabetes Comorbidity.

Type 2 diabetes is a frequent comorbidity in chronic obstructive pulmonary disease (COPD) patients, with the GOLD treatment recommendations asserting that the presence of diabetes be disregarded in the choice of treatment.In a cohort of COPD patients with frequent exacerbations, initiators of single-inhaler triple therapy or dual bronchodilators were compared on the incidence of COPD exacerbation and pneumonia over one year, adjusted by propensity score weighting and stratified by type 2 diabetes.The COPD cohort included 1,114 initiators of triple inhalers and 4,233 of dual bronchodilators (28% with type 2 diabetes). The adjusted hazard ratio (HR) of exacerbation with triple therapy was 1.04 (95% CI: 0.86-1.25) among COPD patients with type 2 diabetes and 0.74 (0.65-0.85) in those without. The incidence of severe pneumonia was elevated with triple therapy among patients with type 2 diabetes (HR 1.77; 1.14-2.75).Triple therapy in COPD is effective among those without, but not those with, type 2 diabetes. Future therapeutic trials in COPD should consider diabetes comorbidity.

Triple therapy for frequent COPD exacerbators is effective in patients without type 2 diabetes but not in those with type 2 diabetes. The impact of comorbidities should be considered in future COPD therapeutic trials.

Multidisciplinary Management of Patients With Chronic Obstructive Pulmonary Disease and Cardiovascular Disease.

Chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) frequently coexist, increasing the prevalence of both entities and impacting on symptoms and prognosis. CVD should be suspected in patients with COPD who have high/very high risk scores on validated scales, frequent exacerbations, precordial pain, disproportionate dyspnea, or palpitations. They should be referred to cardiology if they have palpitations of unknown cause or angina pain. COPD should be suspected in patients with CVD if they have recurrent bronchitis, cough and expectoration, or disproportionate dyspnea. They should be referred to a pulmonologist if they have rhonchi or wheezing, air trapping, emphysema, or signs of chronic bronchitis. Treatment of COPD in cardiovascular patients should include long-acting muscarinic receptor antagonists (LAMA) or long-acting beta-agonists (LABA) in low-risk or high-risk non-exacerbators, and LAMA/LABA/inhaled corticosteroids in exacerbators who are not controlled with bronchodilators. Cardioselective beta-blockers should be favored in patients with CVD, the long-term need for amiodarone should be assessed, and antiplatelet drugs should be maintained if indicated.

Baseline Characteristics and ICS/LAMA/LABA Response in Asthma: Analyses From the CAPTAIN Study.

BACKGROUND: Findings from CAPTAIN (NCT02924688) suggest that treatment response to fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) differs according to baseline type 2 inflammation markers in patients with moderate to severe asthma. Understanding how other patient physiologic and clinical characteristics affect response to inhaled therapies may guide physicians toward a personalized approach for asthma management. OBJECTIVE: To investigate, using CAPTAIN data, the predictive value of key demographic and baseline physiologic variables in patients with asthma (lung function, bronchodilator reversibility, age, age at asthma onset) on response to addition of the long-acting muscarinic antagonist UMEC to inhaled corticosteroid/long-acting ß2-agonist combination FF/VI, or doubling the FF dose. METHODS: Prespecified and post hoc analyses of CAPTAIN data were performed using categorical and continuous variables of key baseline characteristics to understand their influence on treatment outcomes (lung function [trough FEV1], annualized rate of moderate/severe exacerbations, and asthma control [Asthma Control Questionnaire]) following addition of UMEC to FF/VI or doubling the FF dose in FF/VI or FF/UMEC/VI. RESULTS: Adding UMEC to FF/VI led to greater improvements in trough FEV1 versus doubling the FF dose across all baseline characteristics assessed. Doubling the FF dose was generally associated with numerically greater reductions in the annualized rate of moderate/severe exacerbations compared with adding UMEC, independent of baseline characteristics. Adding UMEC and/or doubling the FF dose generally led to improvements in Asthma Control Questionnaire scores irrespective of baseline characteristics. CONCLUSIONS: Unlike previous findings with type 2 biomarkers, lung function, bronchodilator reversibility, age and age at asthma onset do not appear to predict response to inhaled therapy.

The effect of combining an inhaled corticosteroid and a long-acting muscarinic antagonist on human airway epithelial cells in vitro.

BACKGROUND: Airway epithelial cells (AECs) are a major component of local airway immune responses. Direct effects of type 2 cytokines on AECs are implicated in type 2 asthma, which is driven by epithelial-derived cytokines and leads to airway obstruction. However, evidence suggests that restoring epithelial health may attenuate asthmatic features. METHODS: We investigated the effects of passive sensitisation on IL-5, NF-κB, HDAC-2, ACh, and ChAT in human bronchial epithelial cells (HBEpCs) and the effects of fluticasone furoate (FF) and umeclidinium (UME) alone and in combination on these responses. RESULTS: IL-5 and NF-κB levels were increased, and that of HDAC-2 reduced in sensitised HEBpCs. Pretreatment with FF reversed the effects of passive sensitisation by concentration-dependent reduction of IL-5, resulting in decreased NF-κB levels and restored HDAC-2 activity. Addition of UME enhanced these effects. Sensitized HEBpCs also exhibited higher ACh and ChAT levels. Pretreatment with UME significantly reduced ACh levels, and addition of FF caused a further small reduction. CONCLUSION: This study confirmed that passive sensitisation of AECs results in an inflammatory response with increased levels of IL-5 and NF-κB, reduced levels of HDAC-2, and higher levels of ACh and ChAT compared to normal cells. Combining FF and UME was found to be more effective in reducing IL-5, NF-κB, and ACh and restoring HDAC-2 compared to the individual components. This finding supports adding a LAMA to established ICS/LABA treatment in asthma and suggests the possibility of using an ICS/LAMA combination when needed.

Long-acting B-2 agonists (LABA) or long-acting muscarinic antagonists (LAMA): which one may be the first option in group A COPD patients?

INTRODUCTION: Long-acting muscarinic antagonists (LAMA) or beta-2 agonists (LABA) have been recommended for symptom control in group A COPD patients as a first-line bronchodilator treatment in GOLD guidelines. However, there is no mention of priority/superiority between the two treatment options. We aimed to compare the effectiveness of these treatments in this group. METHODS: The study cohort was formed of all subjects from six pulmonology clinics with an initial diagnosis of COPD who were new users of a LAMA or LABA from January 2020 to December 2021. Seventy-six group A COPD patients, in whom LABA or LAMA therapy had been started in the last 1 month as a first-line treatment, were included in our study. Participants were evaluated with spirometry, COPD Assessment Test (CAT), mMRC scale, and St. George Respiratory Questionnaire (SGRQ) for three times (baseline, 6-12th months). RESULTS: There were 76 group A COPD patients with LAMA (67.1%) and LABA (32.9%). The number of patients who improved in CAT score at the end of the first year was significantly higher in patients using LAMA than those using LABA (p = 0.022); the improvement at minimum clinically important difference (MCID) in CAT score of LAMA group at 1st year was also significant (p = 0.044). SGRQ total and impact scores were found to be statistically lower at 1st year compared to baseline in patients using LAMA (p = 0.010 and 0.006, respectively). Significant improvement was detected in CAT and SGRQ scores at the 6th month visit in the LAMA group having emphysema (p = 0.032 and 0.002, respectively). CONCLUSION: According to significant improvements in CAT and SGRQ score, LAMA may be preferred over LABA as a bronchodilator agent in group A COPD patients, especially in emphysema-dominant phenotype.

[Medication management of COPD]. / Prise en charge médicamenteuse de la BPCO.

MEDICATION MANAGEMENT OF COPD. The management of chronic obstructive pulmonary disease (COPD) is based on drug and non-drug measures. Inhaled therapies are the major issues including the use of short-acting bronchodilators for respiratory symptoms. If symptoms are daily, such as disabling dyspnea or frequent exacerbations, daily treatment with a long-acting bronchodilator is proposed: anti-muscarinic (LAMA) or ß2-agonist (LABA). If there is no improvement, escalation to dual and then triple therapy is proposed. Another major issue in the management of COPD is de-escalation in the event of ineffectiveness or side effects of inhaled corticosteroids (ICS). Finally, the role of blood eosinophils and other biomarkers is even more important that biotherapies could expand the therapeutic options for some subtypes of COPD patients.

PRISE EN CHARGE MÉDICAMENTEUSE DE LA BPCO. La prise en charge de la bronchopneumopathie chronique obstructive (BPCO) repose sur des mesures médicamenteuses et non médicamenteuses. Le principe des traitements médicamenteux dans la BPCO comprend des traitements inhalés, et notamment l'utilisation de bronchodilatateurs de courte durée d'action en cas de symptômes respiratoires. Si les symptômes sont quotidiens à type de dyspnée invalidante ou en cas d'exacerbations fréquentes, un traitement de fond quotidien par un bronchodilatateur de longue durée d'action est indiqué : antimuscarinique (LAMA) ou ß2-agoniste (LABA). En l'absence d'amélioration, une escalade est proposée par bithérapie puis trithérapie. Un autre enjeu majeur de la prise en charge de la BPCO est la désescalade thérapeutique en cas d'inefficacité ou d'effets indésirables des corticostéroïdes inhalés (CSI). Enfin, la place du dosage des éosinophiles et autres biomarqueurs sanguins est d'autant plus importante que les biothérapies pourraient venir élargir l'arsenal thérapeutique pour certains soustypes de patients atteints de BPCO.

Treatment pathways, economic burden and clinical outcomes in new users of inhaled corticosteroid/long-acting B2-agonist dual therapy with chronic obstructive pulmonary disease in a primary care setting in England: a retrospective cohort study.

OBJECTIVE: Management of chronic obstructive pulmonary disease (COPD) with inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA) improves lung function and health status and reduces COPD exacerbation risk versus monotherapy. This study described treatment use, healthcare resource utilisation (HCRU), healthcare costs and outcomes following initiation of single-device ICS/LABA as initial maintenance therapy (IMT). DESIGN: Retrospective cohort study. SETTING: Primary care, England. DATA SOURCES: Linked data from the Clinical Practice Research Datalink Aurum and Hospital Episode Statistics datasets. PARTICIPANTS: Patients with COPD and ≥1 single-device ICS/LABA prescription between July 2015 and December 2018 were included. PRIMARY AND SECONDARY OUTCOME MEASURES: Treatment pathways, COPD-related HCRU and healthcare costs, COPD exacerbations, time to triple therapy, medication adherence (proportion of days covered ≥80%) and indexed treatment time to discontinuation. Data for patients without prior maintenance therapy history (IMT users) and non-triple users were assessed over a 12-month follow-up period. RESULTS: Of 13 451 new ICS/LABA users, 5162 were IMT users (budesonide/formoterol, n=1056; beclomethasone dipropionate/formoterol, n=2427; other ICS/LABA, n=1679), for whom at 3 and 12 months post-index, 45.6% and 39.4% were still receiving any ICS/LABA. At >6 to ≤12 months, the proportion of IMT users with ≥1 outpatient visit (10.1%) and proportion with ≥1 inpatient stay (12.6%) had increased from those at 3 months (9.0% and 7.4%, respectively). Inpatient stays contributed most to total COPD-related healthcare costs. For non-triple IMT users, at 3 and 12 months post-index, 4.5% and 13.7% had ≥1 moderate-to-severe COPD exacerbation. Time to triple therapy initiation and time to discontinuation of index medication ranged from 45.9 to 50.2 months and 2.3 to 2.8 months between treatments. Adherence was low across all time points (21.5-27.6%). Results were similar across indexed therapies. CONCLUSIONS: In the year following treatment initiation, ICS/LABA adherence was poor and many patients discontinued or switched therapies, suggesting that more consideration and optimisation of treatment is required in England for patients initiating single-device ICS/LABA therapy.

Effects of triple therapy on disease burden in patients of GOLD groups C and D: results from the observational COPD cohort COSYCONET.

BACKGROUND: Randomized controlled trials described beneficial effects of inhaled triple therapy (LABA/LAMA/ICS) in patients with chronic obstructive pulmonary disease (COPD) and high risk of exacerbations. We studied whether such effects were also detectable under continuous treatment in a retrospective observational setting. METHODS: Data from baseline and 18-month follow-up of the COPD cohort COSYCONET were used, including patients categorized as GOLD groups C/D at both visits (n = 258). Therapy groups were defined as triple therapy at both visits (triple always, TA) versus its complement (triple not always, TNA). Comparisons were performed via multiple regression analysis, propensity score matching and inverse probability weighting to adjust for differences between groups. For this purpose, variables were divided into predictors of therapy and outcomes. RESULTS: In total, 258 patients were eligible (TA: n = 162, TNA: n = 96). Without adjustments, TA patients showed significant (p < 0.05) impairments regarding lung function, quality of life and symptom burden. After adjustments, most differences in outcomes were no more significant. Total direct health care costs were reduced but still elevated, with inpatient costs much reduced, while costs of total and respiratory medication only slightly changed. CONCLUSION: Without statistical adjustment, patients with triple therapy showed multiple impairments as well as elevated treatment costs. After adjusting for differences between treatment groups, differences were reduced. These findings are compatible with beneficial effects of triple therapy under continuous, long-term treatment, but also demonstrate the limitations encountered in the comparison of controlled intervention studies with observational studies in patients with severe COPD using different types of devices and compounds.

Real-world treatment trajectories of adults with newly diagnosed asthma or COPD.

BACKGROUND: There is a lack of knowledge on how patients with asthma or chronic obstructive pulmonary disease (COPD) are globally treated in the real world, especially with regard to the initial pharmacological treatment of newly diagnosed patients and the different treatment trajectories. This knowledge is important to monitor and improve clinical practice. METHODS: This retrospective cohort study aims to characterise treatments using data from four claims (drug dispensing) and four electronic health record (EHR; drug prescriptions) databases across six countries and three continents, encompassing 1.3 million patients with asthma or COPD. We analysed treatment trajectories at drug class level from first diagnosis and visualised these in sunburst plots. RESULTS: In four countries (USA, UK, Spain and the Netherlands), most adults with asthma initiate treatment with short-acting ß2 agonists monotherapy (20.8%-47.4% of first-line treatments). For COPD, the most frequent first-line treatment varies by country. The largest percentages of untreated patients (for asthma and COPD) were found in claims databases (14.5%-33.2% for asthma and 27.0%-52.2% for COPD) from the USA as compared with EHR databases (6.9%-15.2% for asthma and 4.4%-17.5% for COPD) from European countries. The treatment trajectories showed step-up as well as step-down in treatments. CONCLUSION: Real-world data from claims and EHRs indicate that first-line treatments of asthma and COPD vary widely across countries. We found evidence of a stepwise approach in the pharmacological treatment of asthma and COPD, suggesting that treatments may be tailored to patients' needs.

ß2-Adrenergic receptor agonists as a treatment for diabetic kidney disease.

We have previously shown that the long-acting ß2-adrenergic receptor (ß2-AR) agonist formoterol induced recovery from acute kidney injury in mice. To determine whether formoterol protected against diabetic nephropathy, the most common cause of end-stage kidney disease (ESKD), we used a high-fat diet (HFD), a murine type 2 diabetes model, and streptozotocin, a murine type 1 diabetes model. Following formoterol treatment, there was a marked recovery from and reversal of diabetic nephropathy in HFD mice compared with those treated with vehicle alone at the ultrastructural, histological, and functional levels. Similar results were seen after formoterol treatment in mice receiving streptozotocin. To investigate effects in humans, we performed a competing risk regression analysis with death as a competing risk to examine the association between Veterans with chronic kidney disease (CKD) and chronic obstructive pulmonary disease (COPD), who use ß2-AR agonists, and Veterans with CKD but no COPD, and progression to ESKD in a large national cohort of Veterans with stage 4 CKD between 2011 and 2013. Veterans were followed until 2016 or death. ESKD was defined as the initiation of dialysis and/or receipt of kidney transplant. We found that COPD was associated with a 25.6% reduction in progression from stage 4 CKD to ESKD compared with no COPD after adjusting for age, diabetes, sex, race-ethnicity, comorbidities, and medication use. Sensitivity analysis showed a 33.2% reduction in ESKD in Veterans with COPD taking long-acting formoterol and a 20.8% reduction in ESKD in Veterans taking other ß2-AR agonists compared with those with no COPD. These data indicate that ß2-AR agonists, especially formoterol, could be a treatment for diabetic nephropathy and perhaps other forms of CKD.NEW & NOTEWORTHY Diabetic nephropathy is the most common cause of ESKD. Formoterol, a long-acting ß2-adrenergic receptor (ß2-AR) agonist, reversed diabetic nephropathy in murine models of type 1 and 2 diabetes. In humans, there was an association with protection from progression of CKD in patients with COPD, by means of ß2-AR agonist intake, compared with those without COPD. These data indicate that ß2-AR agonists, especially formoterol, could be a new treatment for diabetic nephropathy and other forms of CKD.

Inhaled corticosteroids with combination inhaled long-acting beta2-agonists and long-acting muscarinic antagonists for chronic obstructive pulmonary disease.

BACKGROUND: Management of chronic obstructive pulmonary disease (COPD) commonly involves a combination of long-acting bronchodilators including beta2-agonists (LABA) and muscarinic antagonists (LAMA). LABA and LAMA bronchodilators are now available in single-combination inhalers. In individuals with persistent symptoms or frequent exacerbations, inhaled corticosteroids (ICS) are also used with combination LABA and LAMA inhalers. However, the benefits and risks of adding ICS to combination LABA/LAMA inhalers as a triple therapy remain unclear. OBJECTIVES: To assess the effects of adding an ICS to combination LABA/LAMA inhalers for the treatment of stable COPD. SEARCH METHODS: We searched the Cochrane Airways Group Register of Trials, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase up to 30 November 2022. We also searched ClinicalTrials.gov and the WHO ICTRP up to 30 November 2022. SELECTION CRITERIA: We included parallel-group randomised controlled trials of three weeks' duration or longer that compared the treatment of stable COPD with ICS in addition to combination LABA/LAMA inhalers against combination LABA/LAMA inhalers alone. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. The primary outcomes were acute exacerbations of COPD, respiratory health-related quality of life, pneumonia and other serious adverse events. The secondary outcomes were symptom scores, lung function, physical capacity, and mortality. We used GRADE to assess certainty of evidence for studies that contributed data to our prespecified outcomes. MAIN RESULTS: Four studies with a total of 15,412 participants met the inclusion criteria. The mean age of study participants ranged from 64.4 to 65.3 years; the proportion of female participants ranged from 28% to 40%. Most participants had symptomatic COPD (COPD Assessment Test Score ≥ 10) with severe to very severe airflow limitation (forced expiratory volume in one second (FEV1) < 50% predicted) and one or more moderate-to-severe COPD exacerbations in the last 12 months. Trial medications differed amongst studies. The duration of follow-up was 52 weeks in three studies and 24 weeks in one study. We assessed the risk of selection, performance, and detection bias to be low in the included studies; one study was at high risk of attrition bias, and one study was at high risk of reporting bias. Triple therapy may reduce rates of moderate-to-severe COPD exacerbations compared to combination LABA/LAMA inhalers (rate ratio (RR) 0.74, 95% confidence interval (CI) 0.67 to 0.81; n = 15,397; low-certainty evidence). Subgroup analysis stratifying by blood eosinophil counts showed there may be a greater reduction in rate of moderate-to-severe COPD exacerbations with triple therapy in participants with high-eosinophils (RR 0.67, 95% CI 0.60 to 0.75) compared to low-eosinophils (RR 0.87, 95% CI 0.81 to 0.93) (test for subgroup differences: P < 0.01) (high/low cut-offs: 150 eosinophils/µL in three studies; 200 eosinophils/µL in one study). However, moderate-to-substantial heterogeneity was observed in both high- and low-eosinophil subgroups. These subgroup analyses are observational by nature and thus results should be interpreted with caution. Triple therapy may be associated with reduced rates of severe COPD exacerbations (RR 0.75, 95% CI 0.67 to 0.84; n = 14,131; low-certainty evidence). Triple therapy improved health-related quality of life assessed using the St George's Respiratory Questionnaire (SGRQ) by the minimal clinically important difference (MCID) threshold (4-point decrease) (35.3% versus 42.4%, odds ratio (OR) 1.35, 95% CI 1.26 to 1.45; n = 14,070; high-certainty evidence). Triple therapy may result in fewer symptoms measured using the Transition Dyspnoea Index (TDI) (OR 1.33, 95% CI 1.13 to 1.57; n = 3044; moderate-certainty evidence) and improved lung function as measured by change in trough FEV1 (mean difference 38.68 mL, 95% CI 22.58 to 54.77; n = 11,352; low-certainty evidence). However, these benefits fell below MCID thresholds for TDI (1-unit decrease) and trough FEV1 (100 mL), respectively. Triple therapy is probably associated with a higher risk of pneumonia as a serious adverse event compared to combination LABA/LAMA inhalers (3.3% versus 1.9%, OR 1.74, 95% CI 1.39 to 2.18; n = 15,412; moderate-certainty evidence). In contrast, all-cause serious adverse events may be similar between groups (19.7% versus 19.7%, OR 0.95, 95% CI 0.87 to 1.03; n = 15,412; low-certainty evidence). All-cause mortality may be lower with triple therapy (1.4% versus 2.0%, OR 0.70, 95% CI 0.54 to 0.90; n = 15,397; low-certainty evidence). AUTHORS' CONCLUSIONS: The available evidence suggests that triple therapy may reduce rates of COPD exacerbations (low-certainty evidence) and results in an improvement in health-related quality of life (high-certainty evidence) compared to combination LABA/LAMA inhalers, but probably confers an increased pneumonia risk as a serious adverse event (moderate-certainty evidence). Triple therapy probably improves respiratory symptoms and may improve lung function (moderate- and low-certainty evidence, respectively); however, these benefits do not appear to be clinically significant. Triple therapy may reduce the risk of all-cause mortality compared to combination LABA/LAMA inhalers (low-certainty evidence). The certainty of the evidence was downgraded most frequently for inconsistency or indirectness. Across the four included studies, there were important differences in inclusion criteria, trial medications, and duration of follow-up. Investigation of heterogeneity was limited due to the small number of included studies. We found limited data on the effects of triple therapy compared to combination LABA/LAMA inhalers in patients with mild-moderate COPD and those without a recent exacerbation history.

[Perioperative Rehabolotation Usefulness in Preventing Complications].

The number of elderly patients in thoracic surgery is increasing. The percentage of patients over the age of 80 in surgical cases of malignant diseases such as lung cancer and mediastinal tumors is increasing every year. It is also true that the indications for surgery have been expanding as surgery itself has become less invasive, such as thoracoscopic and robotic surgery. However, it is not uncommon for patients over 80 years of age to have some organ dysfunction and many comorbidities. Therefore, when performing surgery for lung cancer and other diseases, it is important to assess the patient's ability to tolerate surgery, including respiratory and cardiac functions, and to perform risk management. To prevent postoperative complications and improve the accuracy of perioperative management, respiratory rehabilitation should be conducted before and after surgery, and not only smoking cessation instruction but also inhalation training using incentive spirometry( IS), breathing exercises, and the use of inhalers such as long-acting ß2 agonist (LABA)/long-acting muscaring antagonist (LAMA) for patients with chronic obstructive pulmonary disease( COPD) are useful.