Modeled small airways lung deposition of two fixed-dose triple therapy combinations assessed with in silico functional respiratory imaging.

BACKGROUND: Small airways disease plays a key role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and is a major cause of obstruction; therefore, it is a critical pharmacotherapy target. This study evaluated lung deposition of two inhaled corticosteroid (ICS)/long-acting ß2-agonist/long-acting muscarinic antagonist single-inhaler triple therapies using in silico functional respiratory imaging (FRI). Deposition was assessed using real-world inhalation profiles simulating everyday use where optimal inhalation may be compromised. METHODS: Three-dimensional airway models were produced from 20 patients with moderate-to-very severe COPD. Total, central, and regional small airways deposition as a percentage of delivered dose of budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) 160/7.2/5 µg per actuation and fluticasone furoate/umeclidinium/vilanterol (FF/UM/VI) 100/62.5/25 µg were evaluated using in silico FRI based on in vitro aerodynamic particle size distributions of each device. Simulations were performed using multiple inhalation profiles of varying durations and flow rates representing patterns suited for a pressurized metered-dose inhaler or dry-powder inhaler (four for BGF, two for FF/UM/VI, with one common profile). For the common profile, deposition for BGF versus FF/UM/VI was compared post-hoc using paired t-tests. RESULTS: Across inhalation profiles, mean total lung deposition was consistently higher with BGF (47.0-54.1%) versus FF/UM/VI (20.8-22.7%) and for each treatment component, with greater deposition for BGF also seen in the central large airways. Mean regional small airways deposition was also greater across inhalation profiles with BGF (16.9-23.6%) versus FF/UM/VI (6.8-8.7%) and for each treatment component. For the common profile, total, central, and regional small airways deposition were significantly greater for BGF versus FF/UM/VI (nominal p < 0.001), overall and for treatment components; notably, regional small airways deposition of the ICS components was approximately five-fold greater with budesonide versus fluticasone furoate (16.1% vs. 3.3%). CONCLUSIONS: BGF was associated with greater total, central, and small airways deposition for all components versus FF/UM/VI. Importantly, using an identical inhalation profile, there was an approximately five-fold difference in small airways deposition for the ICS components, with only a small percentage of the ICS from FF/UM/VI reaching the small airways. Further research is needed to understand if the enhanced delivery of BGF translates to clinical benefits.

Effect of long-term medium to high-dose inhaled budesonide on bone mineral density in children with asthma: a cross-sectional study.

OBJECTIVE: The objective of this study was to examine the impact of long-term medium to high-dose inhaled budesonide on bone mineral density in children with asthma. METHODS: We conducted a cross-sectional study in children aged 7-17 years with asthma, who received long-term (≥2 years), medium to high-dose inhaled budesonide (≥400µg/day in 6-11 years old; ≥800 µg/day in >11 years old). We measured bone mineral density (BMD) using dual-energy X-ray absorptiometry and compared it with reference Indian normative values. RESULTS: Thirty-five children with moderate to severe asthma receiving long-term medium to high-dose inhaled budesonide, were included in the study. We found a significantly low lumbar-spine BMD in the study population compared to reference Indian values (p-value 0.002). Eight cases had short stature. Despite the adjustment for height-age in these short-stature cases, lumbar-spine BMD remained significantly low in the study population (p-value 0.020). No significant difference was found in 25-hydroxy vitamin D levels between subjects with "low BMD" and "BMD z-score > -2". CONCLUSIONS: The findings of this study suggest that long-term medium to high-dose inhaled budesonide treatment in children with asthma is associated with decreased BMD. However, further investigation with a larger sample size is necessary to confirm this relationship.

Design of Multitarget Inhibitors as Tracheal Smooth Muscle Relaxants.

INTRODUCTION: Asthma complications and adverse effects associated with steroidal therapy highlight the need for non-steroidal compounds intercepting asthmatic pathophysiology at multiple targets. The present investigation was carried out to evaluate the tracheal smooth muscle relaxant effect of virtually designed, combinatorially synthesized polyfunctional N-heteroarylamides. METHODS: Virtual screening and molecular docking studies of designed compounds were performed using PyRx and AUTODOCK 4.2 software against molecular targets viz. FLAP, LTB4, and H1 receptor. Cross-validation of virtual screening results and active site, confirmation was performedusingVlife MDS software version 3.5. The combinatorial approach was used to synthesize designed compounds in which heterocyclic amines were reacted with substituted aromatic acid chlorides by nucleophilic substitution reaction to obtain a 5x5 mini-library. The structures of synthesized leads were confirmed by infrared and proton magnetic resonance spectroscopic analysis. Synthesized compounds were evaluated for their smooth muscle relaxation effect on isolated goat tracheal smooth muscle. RESULTS: Results were calculated as a percent decrease in contraction response observed using histamine and LTB4. The tested compounds produced anticipated tracheal smooth muscle relaxant activity. Based on the results of screening the structure-activity relationships (SAR) have been reported. CONCLUSION: Present study concluded that synthesized polyfunctional N-heteroarylamides have a tracheal smooth muscle relaxant effect. The mode of action is predicted from the analysis of virtual screening results. A good correlation was observed between virtual screenings and biological activities of lead molecules suggesting the rationale used to optimize the structural requirements of a ligand for selected targets is appropriate.

Clinical Characteristics, Treatment Persistence, and Outcomes Among Patients With COPD Treated With Single- or Multiple-Inhaler Triple Therapy: A Retrospective Analysis in Spain.

BACKGROUND: COPD is a leading cause of death and disability. COPD therapy goals include reducing exacerbations and improving symptom control. Single-inhaler triple therapy (SITT) or multiple-inhaler triple therapy (MITT) is indicated for patients with frequent exacerbations despite bronchodilator therapy. No available evidence compares SITT vs MITT in Spain in terms of treatment persistence, exacerbations, and other outcomes. RESEARCH QUESTION: Do COPD patients in Spain initiating SITT vs MITT have improved persistence, exacerbations, and health care resource utilization? STUDY DESIGN AND METHODS: This real-world, observational, retrospective cohort study analyzed electronic health records in the Spanish National Healthcare System BIG-PAC database to identify COPD patients aged ≥ 40 years initiating SITT or MITT (using two or three inhalers) between June 1, 2018 and December 31, 2019. Comparative data on persistence (allowing up to 60 days without prescription refill), exacerbation rates, and health care resource utilization and costs during 12-month follow-up were analyzed. Multivariate adjusted analyses were performed. RESULTS: Eligible patients (N = 4,625) initiating SITT (n = 1,011) or MITT (n = 3,614) had a mean age of 70.9 years; most were male (73.9%) with mainly moderate (62.0%) or severe (26.5%) airflow limitation. Between-cohort baseline characteristics were similar. At 12-month follow-up, SITT patients had higher persistence (hazard ratio [HR] = 1.37; 95% CI = 1.22-1.53; P < .001), reduced risk of exacerbations (HR = 0.68; 95% CI = 0.61-0.77; P = .001), and lower all-cause mortality risk (HR = 0.67; 95% CI = 0.63-0.71, P = .027), compared with MITT patients. SITT was associated with significantly reduced health care resource use (mean annual cost savings: €403 vs MITT). For both SITT and MITT, persistence was associated with improved exacerbation rates vs nonpersistence, and substantial adjusted mean annual cost savings (€2,115 and €2,700, respectively). INTERPRETATION: Patients initiating SITT had a clinically relevant improvement in persistence leading to reductions in mortality, incidence of exacerbations, and health care resource use with consequent mean cost savings.

Effects of inhaled corticosteroids (ICS) on lung microbiota and local immune response in long-term treatment of chronic obstructive pulmonary disease (COPD): utility of titration and therapeutic index.

Administration of inhaled corticosteroids (ICS) is one of the most controversial issues in the treatment of stable chronic obstructive pulmonary disease (COPD). Associations between these drugs and increased incidence of severe pneumonia and other respiratory infections have already been reported in literature, as well as effects on the immune system and on the lung microbiota. ICS vary in their pharmacodynamic and pharmacokinetic properties, despite being widely considered therapeutically similar. The use of ICS requires, therefore, a deep knowledge of their pharmacokinetics and pharmacodynamics to obtain the maximum benefit and the least side effects. Defining new phenotypes-endotypes of COPD may lead to novel pharmacological and therapeutic scenarios while define the correct indications for prescription of ICS. Titration is certainly an important means by which these objectives can be achieved.

Triple Therapy in COPD: Time for Adaptive Selection Trials.

Recent trials reported significant reductions in all-cause mortality with single-inhaler triple therapy for chronic obstructive pulmonary disease (COPD). However, reviews of these trials identified inconsistencies in the findings and methodological issues with the design and analysis, including the "adverse impact of inhaled corticosteroid (ICS) withdrawal rather than the addition" of the triple therapy. Indeed, ICS were discontinued in over 70% of the patients in these trials and 40% already using triple therapy, muddying the interpretation of the data. The "adaptive" clinical trial design is an efficient approach that allows continual modification of the study treatment allocation during follow-up. In this article, we propose the "adaptive selection" trial design, which applies the adaptive concept to the selection of patients into the trial by adapting the randomization choices to the treatment already used by the patients. With such a design, patients already on triple therapy would be excluded outright from trials of triple therapy effectiveness, while the others are randomly allocated to specific treatment arms according to their current treatment, avoiding issues of treatment withdrawal effects. Adaptive selection trials should be the norm for studies of COPD therapies. This approach would avoid the vexing effects of treatment withdrawal that have afflicted the recent triple therapy trials. This concept of adaptive selection has been applied in COPD to the question of whether patients can be safely de-escalated from ICS. It is time to also apply it to studies of the effectiveness of treatment escalation.

Risk factors for nontuberculous mycobacterial pulmonary disease (NTM-PD) in Croatia.

BACKGROUND: The incidence, geographical distribution and clinical relevance of different nontuberculous mycobacteria (NTM) in Croatia are well described. There are few data on the risk factors for developing NTM pulmonary disease (NTM-PD) in this setting. METHODS: We conducted a retrospective cohort study on all Croatian residents with NTM isolated from respiratory samples in the period from 2006 to 2015 with follow-up to 2018. The American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines were used to establish NTM-PD diagnosis. Clinical, radiological and treatment data were collected from hospital records. RESULTS: Risk analysis calculations were made on the 439 isolation episodes that were classified as definitive NTM-PD (n = 137) or no disease (n = 302). Female gender, presence of bronchiectasis, low BMI and long-term systemic corticosteroid treatment were independent risk factors associated with NTM-PD. Hemoptysis and malaise were presenting symptoms independently associated with NTM-PD. Chronic obstructive pulmonary disease (COPD) and low/moderate dose inhaled corticosteroid (ICS) treatment were not associated with NTM-PD. High dose ICS treatment was a significant risk factor for developing NTM-PD (aOR = 4.73, CI 1.69-13.23 p = 0.003). CONCLUSION: The NTM-PD patients in Croatia are similar to those in other published cohorts in terms of their characteristics and risk factors. The significant dose-dependent association between ICS use and NTM-PD adds to the body of evidence suggesting that high dose ICS use is associated with NTM-PD.

Cardiovascular safety of mometasone/indacaterol and mometasone/indacaterol/glycopyrronium once-daily fixed-dose combinations in asthma: pooled analysis of phase 3 trials.

OBJECTIVE: To evaluate cardiovascular safety of two new inhaled fixed-dose combinations for treatment of asthma: (i) the inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) mometasone furoate/indacaterol acetate (MF/IND), (ii) the ICS/LABA/long-acting muscarinic antagonist (LAMA) MF/IND/glycopyrronium bromide (GLY). METHODS: Patient-level data were pooled from four randomized trials, including 52-week studies PALLADIUM (n = 2216) and IRIDIUM (n = 3092), 24-week study ARGON (n = 1426), and 12-week study QUARTZ (n = 802). Cardio-/cerebrovascular (CCV) event frequencies were examined in the following comparisons: (1) LABA effect: pooled-dose MF/IND vs. pooled-dose MF; (2) LAMA effect: pooled-dose MF/IND/GLY vs. pooled-dose MF/IND; (3) ICS-dose effects: (a) high-dose MF/IND vs. medium-dose MF/IND, (b) high-dose MF/IND/GLY vs. medium-dose MF/IND/GLY; (4) intra-class effects: (a) high-dose MF/IND vs. Fluticasone/Salmeterol (F/S), (b) high-dose MF/IND/GLY vs. F/S + Tiotropium (TIO). Risk estimates (percentage of patients with ≥1 CCV event) and risk differences (RDs) with 95% confidence intervals (CIs) were calculated for each comparison. RESULTS: The frequency of CCV events was low, without notable differences between comparison groups. Risk estimates and corresponding RDs (95% CIs) were as follows: (1) pooled-dose MF/IND = 2.35%, pooled-dose MF = 2.18%, RD = 0.17% (-1.00%, 1.34%); (2) pooled-dose MF/IND/GLY = 3.65%, pooled-dose MF/IND = 3.77%, RD = -0.12% (-1.63%, 1.39%); (3a) high-dose MF/IND = 3.69%, medium-dose MF/IND = 3.35%, RD = 0.34% (-1.25%, 1.94%); (3b) high-dose MF/IND/GLY = 2.84%, medium-dose MF/IND/GLY = 2.02%, RD = 0.82% (-0.49%, 2.13%); (4a) high-dose MF/IND = 3.69%, F/S = 2.82%, RD = 0.87% (-0.66%, 2.40%); (4b) high-dose MF/IND/GLY = 1.26%, F/S + TIO = 1.05%, RD = 0.21% (-1.26%, 1.68%). CONCLUSIONS: There was no evidence of increased cardiovascular risk attributable to the addition of IND to MF or addition of GLY to MF/IND. Similarly, no evidence of increased cardiovascular risk was observed with an increase in the ICS-dose or relative to F/S ± TIO.

Is Blood Eosinophil Count a Biomarker for Chronic Obstructive Pulmonary Disease in a Real-World Clinical Setting? Predictive Property and Longitudinal Stability in Japanese Patients.

The authors examined predictive properties and the longitudinal stability of blood eosinophil count (BEC) or three strata (<100 cells/mm3, 100-299 cells/mm3 and ≥300 cells/mm3) in patients with chronic obstructive pulmonary disease (COPD) for up to six and a half years as part of a hospital-based cohort study. Of the 135 patients enrolled, 21 (15.6%) were confirmed to have died during the follow-up period. Episodes of acute exacerbation of COPD (AECOPD) were identified in 74 out of 130 available patients (56.9%), and admission due to AECOPD in 35 out of 132 (26.5%). Univariate Cox proportional hazards analyses revealed that almost all the age, forced expiratory volume in 1 s (FEV1) and health status measures using St. George's Respiratory Questionnaire (SGRQ) Total and COPD Assessment Test (CAT) Score were significantly related to these types of events, but the relationship between age and AECOPD did not reach statistical significance (p = 0.05). Neither BEC nor the three different groups stratified by BEC were significant predictors of any subsequent events. There were no significant differences in the BEC between Visits 1-3 (p = 0.127, Friedman test). The ICC value was 0.755 using log-transformed data, indicating excellent repeatability. In the case of assigning to strata, Fleiss' kappa was calculated to be 0.464, indicating moderate agreement. The predictive properties of BEC may be limited in a real-world Japanese clinical setting. Attention must be paid to the fact that the longitudinal stability of the three strata is regarded as moderate.

Respiratory Adherence Care Enhancer Questionnaire: Identifying Self-Management Barriers of Inhalation Corticosteroids in Asthma.

Introduction: Suboptimal self-management of inhaled corticosteroids (ICS) in asthma patients is frequently observed in clinical practice and associated with poor asthma control. Driving factors for suboptimal self-management are complex and consist of a range of behavioral barriers (cognitive, affective and practical) with a considerable inter-individual variability. Identification of individual barriers facilitates the use of corresponding behavior change techniques and tailored care to improve asthma treatment outcomes. Objective: This study describes the development and validation of the 'Respiratory Adherence Care Enhancer' (RACE) questionnaire to identify individual barriers to self-management of ICS therapy in asthma patients. Methods: The development included: 1) an inventory of self-management barriers based on a literature review, 2) expert assessment on relevance and completeness of this set, linking these barriers to behavioral domains of the Theoretical Domains Framework (TDF) and 3) the formulation of corresponding questions assessing each of the barriers. A cross-sectional study was performed for validation. Primary care asthma patients were invited to fill out the RACE-questionnaire prior to a semi-structured telephonic interview as golden standard. Barriers detected from the questionnaire were compared to those mentioned in the interview. Results: The developed questionnaire is made up of 6 TDF-domains, covering 10 self-management barriers with 23 questions. For the validation 64 patients completed the questionnaire, of whom 61 patients were interviewed. Cronbach's alpha for the consistency of questions within the barriers ranged from 0.58 to 0.90. Optimal cut-off values for the presence of barriers were determined at a specificity between 67 and 92% with a sensitivity between 41 and 83%. Significant Areas Under the Receiver Operating Curves values were observed for 9 barriers with values between 0.69 and 0.86 (p-value <0.05), except for 'Knowledge of ICS medication' with an insignificant value of 0.53. Conclusion: The RACE-questionnaire yields adequate psychometric characteristics to identify individual barriers to self-management of ICS therapy in asthma patients, facilitating tailored care.

ACE2 expression in allergic airway disease may decrease the risk and severity of COVID-19.

The coronavirus disease (COVID-19) is caused by Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and presents with respiratory symptoms which can be life threatening in severe cases. At the start of the pandemic, allergy, asthma, and chronic obstructive pulmonary disease (COPD) were considered as risk factors for COVID-19 as they tend to exacerbate during respiratory viral infections. Recent literature has not shown that airway allergic diseases is a high-risk factor or that it increases the severity of COVID-19. This is due to a decrease in Angiotensin-converting enzyme 2 (ACE2) gene expression in the nose and bronchial cells of allergic airway diseases. Conventional asthma treatment includes inhaled corticosteroids (ICS), allergen immunotherapy (AIT), and biologics, and should be continued as they might reduce the risks of asthmatics for coronavirus infection by enhancing antiviral defence and alleviating inflammation.

Inhaled corticosteroids and risk of influenza in patients with asthma: a meta-analysis of randomized controlled trials.

BACKGROUND: It was reported that inhaled corticosteroids (ICS) treatment may affect local immunity and microbial community of the airway. However, whether ICS treatment increases the risk of influenza in patients with asthma remains unclear. This meta-analysis aimed to compare the risk of influenza between ICS and non-ICS treatment in patients with asthma. METHODS: PubMed, Embase, Cochrane Library and Clinical Trials.gov were searched from inception until November 2019. Randomized controlled trials (RCTs) were included that compared ICS treatment with non-ICS treatment on the risk of influenza in patients with asthma. Meta-analyses were conducted by the Peto approach and Mantel-Haenszel approach with corresponding 95% CIs. RESULTS: Nine trials involving 6486 patients were included in this meta-analysis. The risk of influenza was not different between ICS treatment and the control groups (Peto OR: 1.01, 95% CI 0.74-1.37, P = 0.95). The results of subgroup analyses based on durations (long-term and short-term treatment), doses (high-, medium- and low-dose treatment) and types (fluticasone and budesonide treatment) of ICS were consistent with the above pooled results. Moreover, subgroup analysis based on patients' age also revealed that use of ICS did not increase the risk of influenza. Results of the two meta-analysis approaches were similar. CONCLUSIONS: Use of ICS does not increase the risk of influenza in patients with asthma. This study adds to safety evidence of ICS as a regular controller treatment for patients with asthma.

Association between inhaled corticosteroids and upper respiratory tract infection in patients with chronic obstructive pulmonary disease: a meta-analysis of randomized controlled trials.

BACKGROUND: We aimed to assess the association between inhaled corticosteroids (ICSs) and the risk of upper respiratory tract infection (URTI) in patients with chronic obstructive pulmonary disease (COPD). METHODS: PubMed, Embase, Cochrane Library and Clinical Trials.gov were searched from inception to October 2019. Randomized controlled trials (RCTs) of any ICSs vs control for COPD with reporting of URTI as an adverse event were included. The study was registered with PROSPERO prospectively (#CRD42020153134). RESULTS: Seventeen RCTs (20,478 patients) were included. ICSs significantly increased the risk of URTI in COPD patients (RR, 1.13; 95% CI 1.03-1.24; P = 0.01; heterogeneity: I2 = 7%). Futher subgroup analyses suggested that short-term use of ICSs increased the risk of URTI (RR, 1.29; 95% CI 1.06-1.56; P = 0.01; heterogeneity: I2 = 14%) but not for long-term use (RR, 1.08; 95% CI 0.97-1.2; P = 0.14; heterogeneity: I2 = 0%). Short-term use of high-dose fluticasone increased the risk of URTI (RR, 1.33; 95% CI 1.03-1.71; P = 0.03; heterogeneity: I2 = 0%) but not for long-term use (RR, 1.12; 95% CI 0.97-1.29; P = 0.13; heterogeneity: I2 = 50%). Medium-dose (RR, 0.97; 95% CI 0.71-1.32; P = 0.84; heterogeneity: I2 = 0%) and low-dose (RR, 1.39; 95% CI 0.92-2.1; P = 0.12; heterogeneity: I2 = 30%) fluticasone did not increase the risk of URTI regardless of duration. Neither mometasone (RR, 1.05; 95% CI 0.87-1.26; P = 0.61; heterogeneity: I2 = 0%) nor budesonide (RR, 1.08; 95% CI 0.77-1.5; P = 0.67; heterogeneity: I2 = 46%) increased the risk of URTI, regardless of dosage or duration. CONCLUSIONS: Long-term use of ICSs does not increase the risk of URTI in patients with COPD. Short-term use of high-dose fluticasone increases the risk of URTI in patients with COPD, but not mometasone or budesonide.

Brief report: inhaled corticosteroid use and the risk of checkpoint inhibitor pneumonitis in patients with advanced cancer.

BACKGROUND: Checkpoint inhibitor pneumonitis (CIP) is an immune-related adverse event that may complicate treatment with immune checkpoint inhibitors (ICI) and can cause significant morbidity. We sought to identify predictors for the development of CIP, and whether the use of inhaled corticosteroids (ICS) at time of ICI may be protective. METHODS: Patients with advanced cancer treated with ICI from 2011 and 2018 were included in this study. CIP attribution to ICI was determined by treating physician at time of diagnosis. Predictors were assessed by univariate and multivariable Cox proportional hazard models. RESULTS: We identified 837 pts treated with ICI, of whom 30 (3.6%) developed grade 2 or higher CIP. 82 patients (9.8%) were receiving ICS at time of ICI and had increased risk of developing CIP with hazard ration (HR) of 4.22 (95% CI 1.93-9.21, p < 0.001) compared to those patients not receiving ICS. Patients with age ≥ 65 years had increased risk of developing CIP (HR 2.12, 95% CI 1.02-4.40, p = 0.044), as did 209 patients with lung cancer (198 NSCLC and 11 SCLC) compared to other types of cancers (HR 3.15, 95% CI 1.54-6.46, p = 0.002). In multivariable analysis, age ≥ 65 years, lung cancer diagnosis, and ICS use remained statistically associated with the development of CIP, with adjusted HR for ICS 3.09 (95% CI 1.32-7.24, p = 0.009). CONCLUSIONS: Patients treated with ICS at time of ICI initiation had an increased risk of developing CIP. We further identified older adults with age ≥ 65 years and lung cancers as independent risk factors for CIP.

Comparison of Characteristics Between ICS-Treated COPD Patients and ICS-Treated COPD Patients with Concomitant Asthma: A Study in Primary Care.

Background and Objective: Inhaled corticosteroids (ICS) for COPD has been much debated. Our aim was to identify characteristics associated with prescribing ICS for patients with COPD alone compared to those with concomitant asthma in general practice. Patients and Methods: Participating general practitioners (GPs) (n=144) recruited patients with COPD (ICPC 2nd ed. code R95) currently prescribed ICS (ACT code R03AK and R03BA). Data, if available, on demographics, smoking habits, spirometry, COPD medication, dyspnea score, and exacerbation history were retrieved from the medical records. Logistic regression analysis was used to identify possible differences in characteristics between patients with COPD alone compared to those having a concomitant diagnosis of asthma. Results: A total of 2.289 (45% males) COPD patients on ICS were recruited. Compared to patients with COPD alone (n=1.749), those with COPD and concomitant asthma (n=540) were younger (p<0.001), had higher BMI, higher FEV1/FVC ratio, higher blood eosinophil count and less life-time tobacco exposure (36 and 26 pack-years, respectively). Compared to COPD alone, logistic regression analysis showed that COPD with concomitant asthma was significantly associated to age (OR 0.94; CI 0.92 to 0.97; p<0.001), pack-years of smoking (OR 0.98; CI 0.97 to 0.99; p<0.001), %pred (OR 1.02; CI 1.00 to 1.03; p=0.005), and doctor-diagnosed depression (OR 2.59; CI 1.20 to 5.58; p=0.015). Conclusion: In COPD patients currently prescribed ICS, the presence of concomitant asthma was associated with being younger, having less tobacco exposure, more preserved lung function and a higher likelihood of doctor-diagnosed depression compared to COPD alone.

Inhaled corticosteroids and risk of pneumonia in patients with chronic obstructive pulmonary disease: A meta-analysis of randomized controlled trials.

OBJECTIVE: Inhaled corticosteroids (ICS) are generally used to treat patients with chronic obstructive pulmonary disease (COPD) who suffer from repeated exacerbations. Recently, it was reported that ICS treatment increased the risk of pneumonia in COPD patients. But it is controversial.The objective of this paper is to clarify the associations between ICS treatment and the risk of pneumonia in COPD patients. METHODS: PubMed, Cochrane Library, Clinical Trials.gov, and Embase were searched from February 2019 to June 2019. Randomized clinical trials (RCTs) were incorporatedthat compared ICS with non-ICS treatment on the risk of pneumonia in COPD patients. Meta-analyses were conducted by the Peto and Mantel-Haenszel approaches with corresponding 95% CIs. RESULTS: Twenty-five trials (N = 49,982 subjects) were included. Pooled results demonstrated a significantly increased risk of pneumonia with ICS use in COPD patients (RR, 1.59, 95% CI, 1.33-1.90; I2 = 51%). ICS treatment also increased the risk of severe pneumonia (RR, 2.17, 95% CI, 1.47-3.22; I2 = 29%). The results of subgroup analysis based on doses of ICS were consistent with the above. However, subgroup analyses based on types of ICS revealed that fluticasone therapy was associated with an increased risk of pneumonia but not budesonide. In addition, medium- and low-doses of budesonide treatment also did not increase the risk of pneumonia. CONCLUSIONS: Use of ICS increases the risk of pneumonia in patients with COPD. The above is prominent for fluticasone-containing ICSs but not for budesonide-containing ICSs.

Elevated serum OX40L is a biomarker for identifying corticosteroid resistance in pediatric asthmatic patients.

BACKGROUND: Corticosteroids are widely used to control asthma symptoms, but steroid resistance (SR) is a common adverse reaction. Therefore, it is important to accurately predict the corticosteroid response of asthmatic patients. This study aims to evaluate the serum OX40 ligand (OX40L) in pediatric asthmatic patients, and to investigated its correlations with clinical characteristics and corticosteroid response. METHODS: A total of 192 pediatric asthmatic patients with inhaled corticosteroid (ICS) therapy and 130 healthy controls were selected. Clinical data were collected, and the serum levels of immunoglobulin (IgE), interleukin-6 (IL-6), thymic stromal lymphopoietin (TSLP), and OX40L were measured by enzyme-linked immunosorbent assay (ELISA). The level of serum OX40L was compared between the steroid-sensitive asthma (SSA) and steroid-resistant asthma (SRA) groups. RESULTS: The serum OX40L level in asthmatic patients (713.5 ± 165.7 pg/mL) was significantly higher than that of the healthy controls (238.6 ± 27.8 pg/mL) (P < 0.001), and significantly higher in SRA group (791.2 ± 167.9 pg/mL) than in SSA group (655.6 ± 138.8 pg/mL) (P < 0.001). The serum OX40L level showed a significant positive correlation with serum IgE, blood percentages of eosinophils and neutrophils, serum IL-6 and TSLP, and showed a negative correlation with asthma control test (ACT) score and forced expiratory volume in first second (FEV1%). Receiver operating characteristics (ROC) curve was performed to obtain a cutoff value of serum OX40L as 780 pg/mL (sensitivity = 58.5%; specificity = 86.4%), which can identify SRA in asthmatic patients. Multivariate logistic regression analysis showed that elevated serum OX40L (≥780 pg/mL), as well as lymphocytes (%), ACT score, serum IL-6 and TSLP, were independent predictors of SRA (OX40L ≥ 780 pg/mL: odds ratio = 4.188; 95% CI = 1.800-9.746; P = 0.001). The serum OX40L level was decreased after ICS treatment in asthmatic patients, and the reduction in serum OX40L was significant higher in SSA group compared with SRA group. CONCLUSION: High serum OX40L can be used as a biomarker to identify asthmatic patients with corticosteroid resistance, and the change in OX40L level also reflects the response to ICS treatment. These results suggest an association of OX40L with the pathophysiology, inflammation, and clinical outcomes of asthma. New agents targeting OX40L can provide more precise and personalized therapy for asthma.

Inhaled corticosteroids and risk of upper respiratory tract infection in patients with asthma: a meta-analysis.

BACKGROUND: Recent studies have suggested a possible association between respiratory infection and the use of inhaled corticosteroids (ICS). We aimed to ascertain the risk of upper respiratory tract infection (URTI) with long-term inhaled corticosteroid use among patients with asthma. METHODS: Through a comprehensive literature search of PubMed, Cochrane Library, EMBASE, and Google Scholar from inception to May 2018, we included randomized controlled trials of any ICS vs. a control treatment for asthma, with reporting of URTI as an adverse event. We conducted meta-analyses by the Peto approaches to generate summary estimates comparing ICS with non-ICS treatment on the risk of URTI. RESULTS: Seventeen trials (15,336 subjects) were included. Compared with non-ICS treatment, ICSs were associated with a significantly increased risk of URTI (Peto OR, 1.24; 95% CI 1.08-1.42; I2 = 5%, p = 0.002). Subgroup analyses were performed for different dose, both high- and low-dose ICSs were associated with a significantly increased risk of URTI (high dose: Peto OR, 1.46; 95% CI 1.05-2.03; I2 = 0%; p = 0.03) (low dose: Peto OR, 1.20; 95% CI 1.04-1.39; I2 = 25%; p = 0.01). Moreover, fluticasone was observed with an increased risk of URTI (Peto OR, 1.18; 95% CI 1.02-1.38; p = 0.03; heterogeneity: I2 = 21%) but not budesonide, low-dose fluticasone treatment was associated with a significantly higher risk of URTI but not high dose. CONCLUSIONS: This study raises safety concerns about the risk of URTI associated with ICS use in patients with asthma, but it should be further investigated.

Growth perturbations from stimulant medications and inhaled corticosteroids.

Stimulant medications for the treatment of attention deficit hyperactivity disorder (ADHD) and inhaled corticosteroids (ICS) for the treatment of asthma are two classes of medications that are commonly prescribed in pediatrics. Among other adverse effects of these medications, growth attenuation has long been a focus of investigation. With stimulants, growth deficits of 1-1.4 cm/year have been observed in the short term, mainly in the first 2 years of treatment, in a dose-dependent manner. Long-term studies on stimulants have reported divergent effects on growth, with many studies showing no clinically significant height deficits by adulthood. The study that followed the largest cohort of children on stimulants, however, reported an overall adult height deficit of 1.29 cm in subjects who had received stimulant medications, with mean adult height deficit of 4.7 cm among those taking the medication consistently. With ICS use, mild growth suppression is seen in the short term (particularly in the first year of therapy) with growth rates reduced by 0.4-1.5 cm/year. Available current evidence indicates that the impact of ICS use on adult height is not clinically significant, with effects limited to 1.2 cm or less. There is significant individual variability in growth suppression with ICS use, with the specific pharmacologic agent, formulation, dose exposure, age, puberty, medication adherence, and timing of administration being important modifying factors. Based on currently available evidence, the therapeutic benefits of ICS for management of asthma and stimulant medications for management of ADHD outweigh the potential risk for growth suppression. Strategies to minimize growth attenuation and other potential adverse effects of these medications include using the lowest efficacious dose, frequent assessments and dose titration. Particular vigilance is essential with concomitant use of multiple medications that can attenuate growth and to evaluate for potential adrenal insufficiency from ICS use.