Inhaled Corticosteroids Particle Size and Risk of Hospitalization Due to Exacerbations and All-Cause Mortality in Patients with Chronic Obstructive Pulmonary Disease. A Nationwide Cohort Study.

Background: Extra-fine particle inhaled corticosteroids (ICS) improve peripheral airway distribution, but their effect on risk of exacerbations and all-cause mortality in patients with chronic obstructive pulmonary disease (COPD) is unclear. Methods: This observational cohort study compares patients with COPD who received extra-fine particle ICS to those who received standard particle size ICS from 2010 to 2017 while followed in outpatient clinics. The primary outcome was the time to a COPD exacerbation that required hospitalization, with all-cause mortality as a secondary outcome. Data were analyzed using an adjusted Cox proportional hazards model and a competing risk analysis. Two predefined subgroup analyses of patients treated with pressurised metered dose inhalers (pMDIs) and patients with a previous exacerbation history, was carried out. Lastly, we created a propensity score matched cohort as a sensitivity analysis. Results: Of the 40,489 patients included, 38,802 (95.8%) received stand particle size ICS and 1,687 (4.2%) received extra-fine particle ICS. In total 7,058 were hospitalized with a COPD exacerbation, and 4,346 died. No significant protective effect of extra-fine particle ICS against hospitalization due to COPD exacerbations (HR 0.93, 95% CI 0.82-1.05, p=0.23) or all-cause mortality (HR 1.00, 95% CI 0.85-1.17, p=0.99) was found when compared to standard particle size ICS. However, in the subgroup analysis of patients treated with pMDIs, extra-fine particle ICS was associated with reduction in risk of exacerbations (HR 0.72, 95% CI 0.63-0.82, p<0.001) and all-cause mortality (HR 0.72, 95% CI 0.61-0.86, p<0.001). Conclusion: The administration of extra-fine particle ICS was not associated with reduced risk of exacerbations or all-cause mortality in our primary analysis. A subgroup consisting of patients treated with pMDIs suggested potential protective benefits.

Comparative Risk of Neuropsychiatric Adverse Events Associated With Leukotriene-Receptor Antagonists Versus Inhaled Corticosteroids.

BACKGROUND: Leukotriene-receptor antagonists (LTRA) and inhaled corticosteroids (ICS) are common controller medications for asthma, but limited studies examine their comparative risks on neuropsychiatric adverse events (NAEs) in asthma patients. OBJECTIVE: To investigate the comparative risks of LTRA versus ICS on seven distinct categories of NAEs in asthma patients at a nationwide level. METHODS: We conducted a nationwide cohort study during 2010-2021. Incident NAEs and its clinical subgroups (e.g., psychotic disorders, anxiety disorders, movement disorders, behavioral and emotional disorders, mood disorders, sleep-related disorders, and personality disorders) were assessed. Cox proportional hazards regressions were employed to quantify the comparative risks. RESULTS: There were 1,249,897 asthma patients aged 6-64 years. Incidence rates for NAEs were 25.10 per 1000 person-years among patients treated with LTRA, and 23.46 per 1000 person-years among those treated with ICS. The incidence rate difference was 1.64 [95%CI: 0.30-2.98] per 1000 person-years. Positive associations of NAEs and three clinical subgroups were found in patients treated with LTRA compared to ICS (hazard ratios (HR): 1.06 [95%CI: 1.00-1.12] for NAEs; HR: 1.88 [95%CI: 1.24-2.84] for psychotic disorders; HR: 1.10 [95%CI: 1.01-1.20] for anxiety disorders; and HR: 1.27 [95%CI: 1.02-1.58] for behavioral and emotional disorders), but not for movement disorders, mood disorders, sleep-related disorders, and personality disorders. CONCLUSIONS: This nationwide cohort study identified heightened risks, ranging from 6% to 88%, of NAEs and three clinical subgroups in asthma patients treated with LTRA compared to ICS. These findings underscore the necessity for clinicians to communicate with patients regarding potential neuropsychiatric harms when prescribing LTRA.

A New Process for the Synthesis of Budesonide 21-Phosphate and Evaluation in a Murine Model of Inflammation.

In this study, a new and straightforward process for the preparation of budesonide 21-phosphate (Bud-21P) and its disodium salt (Bud-21P-Na2) is described. The method results in a yield comparable to those obtained by diphosphoryl chloride, but it is more manageable, less expensive, and safer. The new compounds are characterized by better water solubility compared to the parent compound. Moreover, they have been evaluated for their anti-inflammatory activity and the obtained results clearly evidence that Bud-21P and Bud-21P-Na2 retained anti-inflammatory activity like the parent compound budesonide (Bud) in mice with cutaneous induced edema.

Reducing the risk of death - a possible outcome in COPD patients.

INTRODUCTION: COPD is a leading cause of global mortality, particularly under-recognized and under-diagnosed. In 2020, it was the sixth leading cause of death in the US and has contributed to 4.72% of all-cause mortality (ACM) according to the Global Burden of Disease Study 2017. Factors influencing COPD-related mortality include smoking, aging populations, comorbidities, sarcopenia, physical capacity, and lack of effective treatments. AREAS COVERED: This review discusses various factors influencing COPD-related mortality and analyzes observational studies and pivotal RCTs evaluating the impact of different therapies on ACM. EXPERT OPINION: COPD significantly impacts ACM, necessitating effective management strategies. Smoking cessation is crucial in reducing mortality risk. Exacerbation management and comorbidity treatment are essential to improve patient outcomes. Various therapeutic interventions, such as smoking cessation, vaccination, long-term oxygen therapy, and lung volume reduction surgery, have shown benefits in reducing mortality. Pharmacotherapies might reduce the risk of mortality, although the current scientific evidences remain inconclusive. Advances in pharmacological interventions, tailored treatment plans, and physical activity programs are vital. More robust and long-term studies, focusing on real-world data and addressing biases in treatment allocation, are needed to conclusively determine the efficacy of different therapies in reducing ACM in COPD patients.

Nebulized Budesonide Prevents Airway Inflammation in Children with High Total IgE Levels After Open Heart Surgery with Cardiopulmonary Bypass: A Prospective Randomized Controlled Trial.

Cardiopulmonary bypass (CPB) is a crucial technique used to repair congenital heart defects (CHD); however, it may induce inflammatory response, leading to airway inflammation and need for prolonged mechanical ventilation. In this study, we aimed to evaluate the effect of budesonide nebulization in children with high serum total immunoglobulin E (tIgE) levels undergoing surgical repair of CHD via CPB. We conducted a randomized, single-center, controlled trial at a tertiary teaching hospital. One-hundred and one children with high tIgE were enrolled and randomized into the budesonide nebulization group (BUD group, n = 50) or the normal saline nebulization group (NS group, n = 51) between January 2020 and December 2020. Budesonide or normal saline was administered through a vibrating mesh nebulizer during mechanical ventilation every 8 h. Blood and bronchoalveolar lavage fluid (BALF) samples were examined and data on airway mechanics and clinical outcomes were recorded. IL-6 and IL-8 levels in the blood and BALF samples significantly increased after CPB in both groups. Budesonide inhalation reduced IL-6 and IL-8 levels in the blood and BALF samples in children with high tIgE (P < 0.05). The mean airway pressure, PCO2, and oxygen index in the BUD group were significantly lower than those in the NS group after the first inhalation dose and persisted until almost 24 h after surgery. The peak inspiratory pressure and drive pressure were lower in the BUD group than in the NS group at nearly 24 h after surgery, with no significant difference at other time points. Additionally, the duration of mechanical ventilation, number of noninvasive ventilations after extubation, and number of patients using aerosol-inhaled bronchodilators after CICU in the BUD group were significantly lower than those in the NS group (P < 0.05). Children with high preoperative tIgE levels are at risk of airway inflammation after cardiopulmonary bypass. Inhaling budesonide during postoperative mechanical ventilation can reduce the intensity of inflammatory reactions, shorten the duration of mechanical ventilation, reduce airway pressure and the utilization of NIV after extubation.

Inhaled Medications for Maintenance Therapy in Pediatric Noncystic Fibrosis Bronchiectasis.

OBJECTIVE: This review focuses on evaluating literature for the use of inhaled mucolytics (hypertonic saline, mannitol, and dornase alfa), inhaled antibiotics (tobramycin, aztreonam, colistin, and amikacin), and inhaled corticosteroids in pediatric noncystic fibrosis bronchiectasis. DATA SOURCES: A literature search via PubMed was conducted using the search terms "non-cystic fibrosis bronchiectasis," "primary ciliary dyskinesia," and "bronchiectasis" in combination with each inhaled agent of interest. STUDY SELECTION AND DATA EXTRACTION: Studies were included if they were specific to patients with a clinical diagnosis of noncystic fibrosis bronchiectasis published from 1998 to July 2024. DATA SYNTHESIS: Several inhaled medications can be considered as maintenance therapies for pediatric patients with noncystic fibrosis bronchiectasis. Hypertonic saline could be considered for its potential airway clearance benefits and low risk of causing harm. Inhaled antipseudomonal antibiotics should be considered in patients who are colonized with Pseudomonas aeruginosa. Inhaled corticosteroid therapy should be reserved for patients with concomitant asthma. Dornase alfa has shown worse outcomes in adults with noncystic fibrosis bronchiectasis and should be used with caution. Risks and benefits should be carefully considered when evaluating these therapies for use in noncystic fibrosis bronchiectasis, and patient-specific treatment regimens should be developed. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Chronic management of pediatric noncystic fibrosis bronchiectasis remains challenging due to paucity of applicable literature. Risks and benefits of different agents are discussed in this article with recommendations for application to clinical practice based on studies performed in both adult and pediatric patients with noncystic fibrosis bronchiectasis. CONCLUSION: Several inhaled medications could be considered as maintenance therapies for pediatric patients with noncystic fibrosis bronchiectasis, with more robust evidence to support use of inhaled antipseudomonal antibiotics and hypertonic saline compared with other available agents. Further investigation is needed to identify a clear place in therapy for inhaled therapies in pediatric noncystic fibrosis bronchiectasis.

Inhaled Corticosteroids Use Before Hospitalization May Be Protective in Children With Direct Lung Injury.

BACKGROUND: Systemic corticosteroid use in acute respiratory failure has yielded uncertain benefits, partially because of off-target side effects. Inhaled corticosteroids (ICSs) confer localized antiinflammatory benefits and may protect adults with direct lung injury (DLI) from developing respiratory failure. To our knowledge, this relationship has not been studied in children. RESEARCH QUESTION: Do children with DLI who are prescribed ICSs before hospitalization have lower odds of progressing to respiratory failure? STUDY DESIGN AND METHODS: This retrospective, single-center cohort identified children seeking treatment at the ED with DLI and medication records before hospitalization. The primary outcome was intubation; secondary outcomes included noninvasive respiratory support (NRS). We tested the association of ICSs with intubation and NRS, adjusting for confounders. We stratified analyses on history of asthma and performed a sensitivity analysis adjusting for systemic corticosteroid use to account for status asthmaticus. RESULTS: Of 35,220 patients, 17,649 patients (50%) were prescribed ICSs. Intubation occurred in 169 patients (73 patients receiving ICSs) and NRS was used in 3,582 patients (1,336 patients receiving ICS). ICS use was associated with lower intubation (adjusted OR, 0.46; 95% CI, 0.31-0.67) and NRS (aOR, 0.45; 95% CI, 0.40-0.49). The association between ICS and NRS differed according to history of asthma (P = .04 for interaction), with ICS exposure remaining protective only for patients with a history of asthma. Results held true in sensitivity analyses. INTERPRETATION: ICS use prior to hospitalization may protect children with DLI from progressing to respiratory failure, with possible differential efficacy according to history of asthma.

Comparative effectiveness of dupilumab and omalizumab on asthma exacerbations and systemic corticosteroid prescriptions: Real-world US ADVANTAGE study.

BACKGROUND: In the United States, dupilumab is approved for moderate-to-severe eosinophilic or oral corticosteroid-dependent asthma, and omalizumab is approved for managing moderate-to-severe allergic asthma uncontrolled by inhaled corticosteroids. However, limited comparative effectiveness data exist for these biologics due to differing patient characteristics and treatment histories. OBJECTIVE: This study assessed the real-world effectiveness of dupilumab and omalizumab for asthma in patients in the United States. METHODS: In this retrospective observational study, TriNetX Dataworks electronic medical record data were used to identify patients with asthma age ≥12 years who initiated (index) dupilumab or omalizumab between November 2018 and September 2020 and who had at least 12 months of pre- and post-index clinical information. Inverse probability of treatment weighting was applied to balance potential confounding in treatment groups. Asthma exacerbation rates and systemic corticosteroid (SCS) prescriptions were compared using a doubly robust negative binomial regression model, adjusting for baseline exacerbation/SCS rates and patient characteristics with ≥10% standardized differences after inverse probability of treatment weighting. RESULTS: All inclusion and exclusion criteria were met by 2138 dupilumab patients and 1313 omalizumab patients. After weighting, the majority of baseline characteristics were balanced (standard difference <10%) between the 2 groups. Dupilumab was associated with a 44% lower asthma exacerbation rate (P < .0001) versus omalizumab. Additionally, dupilumab treatment significantly (P < .05) reduced SCS prescriptions by 28% during the follow-up period compared with omalizumab treatment. CONCLUSIONS: The US ADVANTAGE real-world study demonstrated a significant reduction in severe asthma exacerbations and SCS prescriptions for patients prescribed dupilumab compared with patients prescribed omalizumab during 12 months of follow-up.

Systemic Adverse Events Associated with Locally Administered Corticosteroids.

Topical corticosteroids are a mainstay in the treatment of many pediatric disorders. While they have proven beneficial therapeutic effects and are generally considered safe, systemic adverse events may occur. This study presents four cases of children who experienced systemic adverse events after using inhaled and intranasal topical corticosteroids, as well as topical corticosteroids in other forms. A comprehensive literature review was performed to explore the existing evidence on this topic. The aim of this study is to raise awareness among healthcare providers about the possibility of systemic adverse events associated with the use of locally administered corticosteroids in pediatric patients. This information underscores the importance of careful monitoring, individualized treatment plans, and further research to better understand and mitigate the risks associated with corticosteroids, even those not given systemically.

Dupilumab Efficacy in Children With Type 2 Asthma Receiving High/Medium-Dose ICS (VOYAGE).

BACKGROUND: In phase 3 VOYAGE (NCT02948959), dupilumab showed clinical efficacy with an acceptable safety profile in children (6-11 years) with uncontrolled, moderate-to-severe type 2 asthma (blood eosinophils ≥150 cells/µL or fractional exhaled nitric oxide ≥20 ppb). OBJECTIVE: We analyzed dupilumab's efficacy in children with type 2 asthma by high- or medium-dose inhaled corticosteroids (ICS) at baseline. METHODS: Children were randomized to receive add-on dupilumab 100/200 mg (by body-weight ≤30 kg/>30 kg) every 2 weeks or placebo for 52 weeks and stratified by high- or medium-dose ICS at baseline. Endpoints were annualized severe exacerbation rate, changes from baseline in percent-predicted forced expiratory volume in 1 second (ppFEV1) and 7-item Asthma Control Questionnaire - Interviewer Administered (ACQ-7-IA) score, proportions of ACQ-7-IA responders (improvement ≥0.5), and biomarker changes. RESULTS: In children receiving high- (n = 152) or medium- (n = 195) dose ICS at baseline, dupilumab versus placebo reduced severe exacerbation rates by 63% (P < .001) and 59% (P = .003), respectively. At week 52, dupilumab improved ppFEV1 by least squares mean difference versus placebo of 5.7 percentage points (P = .02) and 9.35 points (P < .001), and reduced ACQ-7-IA scores by 0.53 points (P < .001) and 0.40 points (P < .001), respectively. No significant treatment interactions between ICS subgroups were detected at week 52. Significant improvements were observed in ACQ-7-IA responder rates and most type 2 biomarker levels. CONCLUSION: Dupilumab reduced severe exacerbation rates and improved lung function and asthma control in children with uncontrolled, moderate-to-severe type 2 asthma, regardless of ICS dose at baseline.

Elevated Fracture Risks in Patients Using Inhaled Corticosteroids: A Korean Nationwide Study.

Background: In this comprehensive retrospective nationwide cohort study, we examined the relationships between various asthma medications and bone health, utilizing data from the National Health Insurance Service database of South Korea. Methods: From 2015 to 2019, the relevant dataset included 168,611 individuals aged 66 years, among whom 8,747 were diagnosed with asthma. We focused on a subset of 6,173 patients, all 66-year-old women. Participants were categorized into four groups: nonusers of asthma medication (n=2,868), leukotriene antagonist users (n=2,281), inhaled corticosteroid (ICS) users (n=517), and those using a combination of ICS and long-acting beta-agonist (ICS+LABA) medication (n=507). The primary outcomes measured were the incidences of major osteoporotic fractures and hip fractures during the follow-up period. Results: Over 2.7 years of follow-up, 615 cases of major osteoporotic fractures and 96 cases of hip fractures were recorded. ICS users exhibited a heightened risk of both injuries, with hazard ratios of 1.38 (95% confidence interval [CI], 1.18 to 1.63; P<0.001) for major osteoporotic fractures and 1.56 (95% CI, 1.33 to 1.83; P<0.001) for hip fractures. Similarly elevated risks were observed in the ICS+LABA group. Notably, the risk associated with ICS was particularly pronounced among patients with osteopenia for both fracture types. Overall, the use of ICS, alone or in combination with LABA, in patients with asthma is associated with significantly increased risks of osteoporotic fractures, especially among those with osteopenia. Conclusion: These findings underscore the importance of considering bone health when managing asthma, especially in older patients and those with existing bone density issues.

Impact of Ongoing Treatment With Inhaled Corticosteroids During Specific Inhalation Challenges for Diagnosing Occupational Asthma.

BACKGROUND: Specific inhalation challenge (SIC) tests are still the reference test for diagnosing sensitizer-induced occupational asthma (SIOA). The European Respiratory Society recommends the cessation of inhaled corticosteroids (ICS) 72 hours before SIC. OBJECTIVE: To assess the effect of an ongoing ICS treatment during SIC on the maximum fall in forced expiratory volume in 1 second (FEV1), the change in methacholine provocative concentration of methacholine inducing a 20% fall in FEV1 (PC20), and sputum eosinophil counts after exposure to the suspected agent. METHODS: We performed a retrospective analysis using a database of cases referred to our center for suspected SIOA from 1999 to 2022. The results of the SIC were compared between subjects treated with ICS during SIC and steroid-naïve subjects. RESULTS: Six hundred and seventy-one individuals underwent SIC in the laboratory. Three hundred and eighteen were treated with ICS, whereas 353 were steroid naïve. The proportion of subjects with a positive SIC was greater among ICS-treated subjects (39. 6%) compared with steroid-naïve subjects (27.5%, P < .001). A treatment with ICS did not influence the outcome of the SIC. There was no difference in the change in PC20 or the percentage of sputum eosinophils after SIC between steroid-treated and steroid-naïve subjects. CONCLUSIONS: An ongoing ICS treatment during an SIC did not affect the occurrence of an asthmatic reaction, the change in airway responsiveness, or eosinophilic inflammation after exposure to the suspected agent in subjects who have been treated with ICS for a long period of time.

Increased Pneumonia Risk Associated with Concomitant Use of Inhaled Corticosteroids and Benzodiazepines: A Pharmacovigilance Analysis.

BACKGROUND: Inhaled corticosteroids (ICS) are effective in managing asthma and chronic obstructive pulmonary disease (COPD) but increase the risk of pneumonia. Benzodiazepines (BZD), commonly prescribed for comorbid psychiatric disorders in asthma or COPD patients, are also associated with pneumonia. This study investigates the risk of pneumonia associated with the concomitant use of ICS and BZD. METHODS: Data from the FDA Adverse Event Reporting System from Q4 2013 to Q3 2023 were extracted. Reports involving asthma or COPD patients were included. Disproportionality analysis and logistic regression analysis were performed to assess the risk of pneumonia associated with the combined use of ICS and BZD. Additive and multiplicative models were used to further confirm the results. Additionally, subgroup analyses were conducted based on gender, age, and disease type. RESULTS: A total of 238,411 reports were included. The combined use of ICS and BZD was associated with a higher reporting of pneumonia (ROR: 2.41, 95% CI 2.25-2.58). Using additive and multiplicative methods, the results remained significant. The strongest risk signals were observed in specific drug combinations, such as mometasone with clonazepam, budesonide with temazepam, and mometasone with zopiclone. Subgroup analyses showed higher pneumonia risks in females, patients over 60 years old, and those with asthma. CONCLUSION: Our findings identified a significantly elevated pneumonia risk with the combined use of ICS and BZD. These results highlighted the necessity for cautious co-prescription of ICS and BZD and suggested the need for more comprehensive clinical studies to assess this interaction.

Prescriptions of respiratory medications in children aged 0-10 years: A longitudinal drug utilization study in the POMME database.

INTRODUCTION: Respiratory tract disorders are common in children. However, there is no available data on the prescription of respiratory medications for children in France. This study aimed to provide an overview of medications for obstructive airway diseases prescriptions for children during the initial ten years of their lives within POMME, a French population-based cohort of children. MATERIAL AND METHODS: This longitudinal, population-based study used data from the French POMME birth cohort, comprising children born in Haute Garonne between July 2010 and June 2011. Anonymous medical information, including medication reimbursement data, was collected between ages 0 and 10 years. Exposure was defined as at least one prescription for respiratory medications (ATC code R03*), focusing on specific subclasses. Data were analyzed by age, season, and prescribing physicians' specialties. RESULTS: Out of 5956 children, 4951 (83.1 %) received respiratory medication prescriptions. Inhaled corticosteroids (ICSs) were the most prescribed (95.3 %), followed by short-acting ß2-agonists (68.8 %). The number of prescriptions increased with age, except for ICSs alone, which peaked between 6 months and 2 years. The average number of prescriptions per child was relatively low. DISCUSSION: This study highlighted high prescription rates of respiratory medications in children under 10 years, with ICSs being the most prevalent. While these medications are primarily intended for asthma management, the findings suggested a significant proportion of off-label prescriptions, especially in young children. Further research and clinical guidance are warranted to ensure appropriate medication use in the pediatric population.

Rethinking Blood Eosinophils for Assessing Inhaled Corticosteroids Response in COPD: A Post Hoc Analysis From the FLAME Trial.

BACKGROUND: The varied treatment response to inhaled corticosteroids (ICS) in patients with COPD and the associated increased risk of pneumonia necessitate a personalized ICS therapeutic approach. This is informed by blood eosinophil count (BEC), which predicts ICS treatment response. However, BEC appears to change in response to ICS treatment. RESEARCH QUESTION: Does (1) BEC measured on ICS treatmen (2) BEC measured off ICS treatment, or (3) the change in BEC during ICS treatment best predict treatment response to ICS in COPD? STUDY DESIGN AND METHODS: Fluticasone Salmeterol on COPD Exacerbations Trial (FLAME), a 52-week, double-blind randomized controlled trial compared long-acting beta-2 agonist (LABA)/long-acting muscarinic antagonist (LAMA) with LABA/ICS. Corticosteroids were prohibited during a 4-week run-in period. We chose patients previously on ICS, thereby allowing BEC before and after the run-in period to represent BEC on and off ICS, respectively. In this post hoc analysis, we revisited outcome data, exploring how the three BEC biomarkers interacted with treatment response to the ICS-containing regimen. RESULTS: Our study confirms that LABA/LAMA combination is superior, or at least noninferior, to LABA/ICS in curbing exacerbations for most FLAME participants. However, higher BEC off ICS, higher BEC on ICS, and significant BEC suppression during ICS treatment corresponded to superior response to LABA/ICS in terms of exacerbation rate, time to first exacerbation, and time to first pneumonia. In a subgroup, including 9% of participants, BEC changed significantly during ICS treatment (≥ 200 cells/µL), and higher BEC on ICS did not predict ICS treatment response. For these patients, BEC off ICS and BEC change proved more predictive. Excess pneumonia risk associated with ICS appeared to be confined to patients who do not benefit from this treatment. BEC was not predictive of treatment effects on lung function and health status. INTERPRETATION: This exploratory analysis advocates preferentially using BEC off ICS or BEC change during ICS treatment for guiding ICS treatment decisions. BEC measured on ICS is less predictive of treatment response. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT01782326; URL: www. CLINICALTRIALS: gov.