Inhaled Corticosteroids Research Articles

Budesonide Attains Its Wide Clinical Profile by Alternative Kinetics.

The introduction of inhaled corticosteroids (ICSs) changed over a few decades the treatment focus of mild-to-moderate asthma from bronchodilation to reduction in inflammation. This was achieved by inhaling a suitable corticosteroid (CS), giving a high, protracted airway concentration at a low total dose, thereby better combining efficacy and tolerance than oral therapy. Successful trials with the potent, lipophilic "skin" CS beclomethasone dipropionate (BDP) paved the way, suggesting that ICSs require a very low water solubility, prolonging their intraluminal dissolution within airways. The subsequent ICS development, with resulting clinical landmarks, is exemplified here with budesonide (BUD), showing that a similar efficacy/safety relationship is achievable by partly alternative mechanisms. BUD is much less lipophilic, giving it a 100-fold higher water solubility than BDP and later developed ICSs, leading to its more rapid intraluminal dissolution and faster airway and systemic uptake rates. In airway tissue, a BUD fraction is reversibly esterified to intracellular fatty acids, a lipophilic conjugate, which prolongs airway efficacy. Another mechanism is that the rapidly absorbed bulk fraction, via short plasma peaks, adds anti-inflammatory activity at the blood and bone marrow levels. Importantly, these plasma peaks are too short to provoke systemic adverse actions. Controlled clinical trials with BUD changed the use of ICS from a last resort to first-line treatment. Starting ICS treatment immediately after diagnosis ("early intervention") became a landmark for BUD. An established dose response made BUD suitable for the treatment of patients with all degrees of asthma severity. With the development of the budesonide/formoterol combination inhaler (BUD/FORM), BUD contributed to the widely used BUD/FORM maintenance and reliever therapy (MART). Recent studies demonstrated the value of BUD/FORM as a generally recommended as-needed therapy for asthma ("anti-inflammatory reliever", AIR). These abovementioned qualities have all influenced international asthma management and treatment guidelines.

Risk of cardiovascular events following COVID-19 in people with and without pre-existing chronic respiratory disease

Abstract Background COVID-19 is associated with cardiovascular outcomes in the general population, but it is unknown whether people with chronic respiratory disease (CRD) have a higher risk of cardiovascular events post-COVID-19 compared with the general population and, if so, what respiratory-related factors may modify this risk in these people. Methods Primary and secondary care data from the National Health Service England were used to define a population of adults in England with COVID-19 (index date) between 1 January 2020 and 30 November 2021. Adjusted Cox proportional hazard regression was used to quantify the association between CRD, asthma-related factors, chronic obstructive pulmonary disease (COPD)-related factors, and risk of cardiovascular events. Asthma-specific factors included baseline asthma control, exacerbations, and inhaled corticosteroid (ICS) dose. COPD-specific risk factors included baseline ICS and exacerbations. Secondary objectives quantified the impact of COVID-19 hospitalisation and vaccine dose on cardiovascular outcomes. Results Of 3 670 455 people, those with CRD had a higher risk of cardiovascular events [adjusted hazard ratio (HRadj), 1.08; 95% confidence interval (CI) 1.06–1.11], heart failure (HRadj, 1.17; 95% CI, 1.12–1.22), angina (HRadj, 1.13; 95% CI, 1.06–1.20) and pulmonary emboli (HRadj, 1.24; 95% CI, 1.15–1.33) compared with people without CRD. In people with asthma or COPD, baseline exacerbations were associated with a higher risk of cardiovascular outcomes (HRadj, 1.36; 95% CI, 1.27–1.00 and HRadj, 1.35; 95% CI, 1.24–1.46, respectively). Regardless of CRD, the risk of cardiovascular events was lower with increasing COVID-19 vaccine dose. Conclusions Higher risk of cardiovascular events post-COVID-19 might be explained by the underlying severity of the CRD, and COVID-19 vaccines were beneficial to both people with and those without CRD with regards to cardiovascualr events.

Patterns of asthma medication use and hospital discharges in New Zealand

In New Zealand a progressive increase in budesonide/formoterol dispensing, accompanied by a reduction in dispensing of short-acting β2-agonists (SABAs), inhaled corticosteroids (ICSs), and other ICS/long-acting β2-agonists (ICSs/LABAs), occurred in the 18-month period following publication of the 2020 New Zealand asthma guidelines, which recommended budesonide/formoterol anti-inflammatory reliever therapy. Our aim was to investigate more recent trends in asthma medication use and asthma hospital discharges in New Zealand. New Zealand national dispensing data for inhalers for the period from January 2010 to December 2022 were reviewed for patients aged 12 years and older. Monthly rates of dispensing of budesonide/formoterol, ICSs, other ICS/LABAs, and SABAs were displayed graphically by locally weighted scatterplot smoother plots. The rates of dispensing and hospital discharge for asthma were compared between the past 6 months for which dispensing data were available (July-December 2022) and the corresponding period from July to December 2019. There has been a progressive increase in dispensing of budesonide/formoterol since 2019, with a 108% increase between the period from July to December 2019 and the period from July to December 2022 in adolescents and adults. In contrast, there was a reduction in rates of dispensing of other ICS/LABAs, ICSs, and SABAs by 3%, 18%, and 5%, respectively. During this period, there was a 17% reduction in hospital discharges for asthma. There has been a further widespread uptake of ICS/formoterol reliever and/or maintenance therapy in adolescents and adults with asthma in New Zealand. The changes in prescribing practice have been temporally associated with a reduction in hospital admissions for asthma.

EFFECTS OF INHALED CORTICOSTEROIDS IN STABLE CHRONIC OBSTRUCTIVE PULMONARY DISEASE : A COMPREHENSIVE SYSTEMATIC REVIEW

Background: Inhaled corticosteroids aid COPD patients by improving lung function and reducing exacerbations. The combination of ICS and LABA is more effective than LABA alone, indicating that blood eosinophilia influences therapy efficacy. Patients with low peak inspiratory flow may not receive enough delivery, necessitating the use of spacers to enhance inhaler actuation and inspiration timing. This study aims to systematically review the literature on the effects of inhaled corticosteroids in stable COPD in the last 10 years. Methods: This systematic review used the PRISMA 2020 principles and examined full-text English literature published between 2014 and 2024. Submissions without a DOI were not taken into consideration, nor were editorials and review papers from the same publication. Online resources like PubMed, SagePub, and ScienceDirect were used to compile the literature. Result: Initially, our study team gathered over 60,000 papers from reputable websites such as PubMed, SagePub, and ScienceDirect. Only five papers were found to be directly relevant to our ongoing systematic review after a thorough three-level filtering approach. These publications were then selected for further research through full-text reading. Conclusion: ICS is an effective treatment for COPD because it reduces inflammation, improves airway remodelling, and lowers bacterial load. Higher doses are more effective, because budesonide inhalation enhances lung function.

GSDMB/ORMDL3 Rare/Common Variants Are Associated with Inhaled Corticosteroid Response among Children with Asthma.

Inhaled corticosteroids (ICS) are efficacious in the treatment of asthma, which affects more than 300 million people in the world. While genome-wide association studies have identified genes involved in differential treatment responses to ICS in asthma, few studies have evaluated the effects of combined rare and common variants on ICS response among children with asthma. Among children with asthma treated with ICS with whole exome sequencing (WES) data in the PrecisionLink Biobank (91 White and 20 Black children), we examined the effect and contribution of rare and common variants with hospitalizations or emergency department visits. For 12 regions previously associated with asthma and ICS response (DPP10, FBXL7, NDFIP1, TBXT, GLCCI1, HDAC9, TBXAS1, STAT6, GSDMB/ORMDL3, CRHR1, GNGT2, FCER2), we used the combined sum test for the sequence kernel association test (SKAT) adjusting for age, sex, and BMI and stratified by race. Validation was conducted in the Biorepository and Integrative Genomics (BIG) Initiative (83 White and 134 Black children). Using a Bonferroni threshold for the 12 regions tested (i.e., 0.05/12 = 0.004), GSDMB/ORMDL3 was significantly associated with ICS response for the combined effect of rare and common variants (p-value = 0.003) among White children in the PrecisionLink Biobank and replicated in the BIG Initiative (p-value = 0.02). Using WES data, the combined effect of rare and common variants for GSDMB/ORMDL3 was associated with ICS response among asthmatic children in the PrecisionLink Biobank and replicated in the BIG Initiative. This proof-of-concept study demonstrates the power of biobanks of pediatric real-life populations in asthma genomic investigations.

Evaluation of adherence to guideline-directed therapy and risk factors for exacerbation in mild asthma: a retrospective chart review

BackgroundA significant update was made to both the Global Initiative for Asthma (GINA) in 2019 and the National Heart Lung and Blood Institute (NHLBI) asthma guidelines in 2020 for mild asthma. These groups no longer recommend short-acting beta-agonists (SABA) as monotherapy for mild (GINA) or mild-persistent (NHLBI) asthma. With the lag that can occur between guideline or evidence updates and changes in practice, this study sought to evaluate whether guideline adoption had occurred.MethodsIn this retrospective chart review, patient electronic medical records from a large healthcare system were evaluated from July 1 of 2021 to July 1 of 2022 to determine how many patients with mild asthma were prescribed as needed or daily inhaled corticosteroids (ICS) in addition to as needed SABA. The secondary outcome was to evaluate the incidence of exacerbations in patients with mild asthma, comparing those on guideline-directed therapy or not. In addition, we evaluated other patient factors increasing exacerbation risk in mild asthma.ResultsFor the primary outcome, of the 1,107 patients meeting inclusion criteria, 284 patients (26%) did not have documentation of guideline-directed therapy for mild asthma during the study period, while 823 (74%) were on guideline-directed therapy (Diff:48.7%; 95% CI:45.1 to 52.3%, p < 0.001). For the secondary objective, 161 patients had an exacerbation (12% on guideline-directed therapy, 15.4% not on guideline-directed therapy). This difference in incidence of exacerbation between the two treatment groups was not statistically significant (Diff: -3.4%; 95% CI: -8 to 1.1%; p = 0.133). In addition, being female, having GERD, and being obese were all statistically significant factors associated with having asthma exacerbations among our patient population.ConclusionsNearly one-fourth of patients with mild persistent asthma were not on guideline-directed therapy, despite updates in asthma guidelines (GINA 2019, NHLBI 2020). Factors such as being female, having GERD, and being obese were all statistically significant factors associated with having asthma exacerbations among patients with mild persistent asthma.

Pharmacological Basis of Differences in Dose Response, Dose Equivalence, and Duration of Action of Inhaled Corticosteroids.

Asthma treatment guidelines classify inhaled corticosteroid (ICS) regimens as low, medium, or high dose. However, efficacy and safety are not independently assessed accordingly. Moreover, differences in ICS duration of action are not considered when a dose regimen is selected. We investigated the efficacy and safety implications of these limitations for available ICS molecules. Published pharmacodynamic and pharmacokinetic parameters were used, alongside physiological and pharmacological principles, to estimate the efficacy and safety of available ICS molecules. Extent and duration of glucocorticoid receptor (GR) occupancy in the lung (efficacy) and cortisol suppression (systemic exposure and safety) were estimated. Some ICS regimens (e.g., fluticasone furoate, fluticasone propionate, and ciclesonide) rank high for efficacy but low for systemic exposure, contrary to how ICS dose equivalence is currently viewed. Differences in dose-response relationships for efficacy and systemic exposure were unique for each ICS regimen and reflected in their therapeutic indices. Notably, even low doses of most ICSs can generate high GR occupancy (≥ 90%) across the entire dose interval at steady state, which may explain previously reported difficulties in obtaining dose responses within the clinical dose range and observations that most clinical benefit typically occurs at low doses. The estimated post dose duration of lung GR occupancy for ICS molecules was categorized as 4-6h (short), 14-16h (medium), 25-40h (long), or > 80h (ultra-long), suggesting potentially large differences in anti-inflammatory duration of action. In a real-world clinical setting where there may be poor adherence to prescribed therapy, our findings suggest a significant therapeutic advantage for longer-acting ICS molecules in patients with asthma.

Clinical characteristics and effects of inhaled corticosteroid in patients with post-COVID-19 chronic cough during the Omicron variant outbreak

BackgroundChronic cough is a common symptom in patients post the coronavirus disease 2019 (COVID-19). In this study, we aimed to investigate the efficacy of inhaled corticosteroids (ICS) and the clinical characteristics of patients with post-COVID-19 chronic cough during the Omicron era.MethodsAn ambispective, longitudinal cohort study was conducted that included patients with post-COVID-19 who attended the respiratory clinic at our hospital between January 1, 2023, and March 31, 2023 with a complaint of persistent cough lasting more than 8 weeks. At 30 and 60 days after the first clinic visit for post-COVID-19 chronic cough, enrolled patients were prospectively followed up. We compared the changes in symptoms and pulmonary function between patients receiving ICS treatment (ICS group) and those not receiving ICS treatment (NICS group) at the two visits.ResultsA total of 104 patients with post-COVID-19 chronic cough were enrolled in this study (ICS group, n = 51; NICS group, n = 53). The most common symptoms accompanying post-COVID-19 chronic cough were sputum (58.7%, 61/104) and dyspnea (48.1%, 50/104). Seventy-one (82.6%, 71/86) patients had airway hyperresponsiveness, and 49 patients (47.1%, 49/104) were newly diagnosed with asthma. Most patients (95.2%, 99/104) exhibited improvement at 60 days after the first visit. The pulmonary function parameters of the patients in the ICS group were significantly improved compared to the baseline values (P < 0.05), and the improvement in the FEV1/FVC was significantly greater than that in the NICS group (P = 0.003) after 60 days.ConclusionsSevere acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may contribute to the pathogenesis of asthma, which could be the underlying cause of persistent cough post-COVID-19 infection. Post-COVID-19 chronic cough during the Omicron era was often accompanied by sputum, dyspnea, and airway hyperresponsiveness. ICS treatment did not have a significant impact on symptom management of post-COVID-19 chronic cough; however, it can improve impaired lung function in in these individuals.

Airsupra: An inhaled albuterol/budesonide combination for asthma.

The FDA has approved Airsupra (AstraZeneca), a metered-dose inhaler containing the short-acting beta2-agonist (SABA) albuterol and the inhaled corticosteroid (ICS) budesonide, for use as needed for treatment or prevention of bronchoconstriction and to reduce the risk of exacerbations in patients ≥18 years old with asthma. Airsupra is the first combination of a SABA and an ICS to become available in the US. It is not approved for use as maintenance therapy.

Nasopharyngeal microbiota in children is associated with severe asthma exacerbations

BackgroundThe respiratory microbiome has been associated with the etiology and disease course of asthma. ObjectiveThis study assessed the nasopharyngeal microbiota in children with a severe asthma exacerbation and their associations with medication, air quality and viral infection. MethodsA cross-sectional study was performed among children aged 2-18 years admitted to the medium (MCU; n=84) or intensive care (ICU; n=78) with an asthma exacerbation. For case-control analyses, we matched all cases aged 2-6 years (n=87) to controls in a 1:2 ratio. Controls were participants of either a prospective case-control study or a longitudinal birth cohort (n=182). The nasopharyngeal microbiome was characterized by 16S-rRNA-gene sequencing. ResultsCases showed higher Shannon diversity (ICU and MCU combined; p=0.002) and a distinct microbial community composition when compared to controls (PERMANOVA R2=1.9%, p<0.001). We observed significantly higher abundance of Staphylococcus and ‘oral’ taxa, including Neisseria, Veillonella and Streptococcus spp. and lower abundance of Dolosigranulum pigrum, Corynebacterium and Moraxella spp. (MaAsLin2, q<0.25) in cases versus controls. Furthermore, Neisseria abundance was associated with more severe disease (ICU vs MCU MaAslin2 p=0.03, q=0.30). Neisseria spp. abundance was also related with fine particulate matter exposure, whereas Haemophilus and Streptoccocus abundance was related with recent inhalation corticosteroid use. We observed no correlations with viral infection. ConclusionOur results demonstrate that children admitted with asthma exacerbations harbor a microbiome characterized by overgrowth of Staphylococcus and ‘oral’ microbes, and an underrepresentation of beneficial niche-appropriate commensals. Several of these associations may be explained by (environmental or medical) exposures, although cause-consequence relationships remain unclear and requires further investigations.

Association between Increased Risk of Pneumonia with ICS in COPD: A Continuous Variable Analysis of Patient Factors from the IMPACT Study.

Despite the proven benefits of inhaled corticosteroid (ICS)-containing triple therapy for chronic obstructive pulmonary disease (COPD), clinicians limit patient exposure to ICS due to the risk of pneumonia. However, there are multiple factors associated with the risk of pneumonia in patients with COPD. This posthoc analysis of IMPACT trial data aims to set the risks associated with ICS into a context of specific patient-related factors that contribute to the risk of pneumonia. The 52-week, double-blind IMPACT trial randomized patients with symptomatic COPD and ≥1 exacerbation in the prior year 2:2:1 to once-daily fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI), FF/VI or UMEC/VI. Annual rate of on-treatment pneumonias in the intent-to-treat population associated with age, body mass index (BMI), percent predicted forced expiratory volume in 1s (FEV1) and blood eosinophil count (BEC) was evaluated. This analysis revealed that the annual rate of pneumonia showed the lowest risk at the age of 50years. The 95% confidence intervals (CI) between ICS-containing and non-ICS containing treatments diverged in ages > 63years, suggesting a significantly increased ICS-related risk in older patients. In contrast, the annual rate of pneumonia rose in both groups below BMI of 22.5kg/m2, but above that, there was no relationship to pneumonia rate and no differential effect between the two groups. The relationship between BEC and pneumonia was flat up to > 300/µL cells with ICS-containing treatment and then rose. In contrast, the rate of pneumonia with non-ICS containing treatment appeared to increase at a lower level of BEC (~ 200/µL). There was little evidence of a differential effect of older age, lower BMI, lower FEV1 and BEC on the pneumonia rate between ICS-containing and non-ICS containing treatments. This analysis points to the need for a balanced approach to risk versus benefit in the use of ICS-containing treatments in COPD. IMPACT ClinicalTrials.gov number, NCT02164513.

Lack of Association between Inhaled Corticosteroid Use Based on the Exhaled Nitric Oxide and Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

Fractional exhaled nitric oxide (FeNO) is known to useful biomarker for detecting eosinophilic airway inflammation. However, there is a lack of evidence regarding the role of FeNO in chronic obstructive pulmonary disease (COPD). We aimed to assess whether elevated FeNO and its impact on treatment change into an inhaled corticosteroid (ICS)-containing regimen and association with acute exacerbation (AE) in patients with COPD. We retrospectively analyzed 107 COPD patients without a history of asthma from March 2016 to December 2019. The patients whose FeNO value was more than 50 parts per billion (ppb) were defined into the high FeNO group. Multivariable analysis with logistic regression was used to identify factors associated with AE in COPD. The median FeNO value was 32 ppb (interquartile range, 19 to 45) and 34 (20.0%) patients were classified as high FeNO group (median 74 ppb). In the high FeNO group, changes in inhaler treatment into an ICS-containing regimen occurred in 23 of 34 patients after the measurement of FeNO. In multivariate analysis, high FeNO was not a contributing factor for AE, but only the high blood eosinophil count (≥300 cells/μL) was associated with AE (adjusted odds ratio, 2.63; 95% confidence interval, 1.01 to 6.91; p=0.049). High FeNO value had a significant impact on the prescription of ICSs in COPD patients, but it did not show a significant association with AE either on its own or with changes in treatment.

Impact of Asthma Medications During Pregnancy on Asthma Exacerbation, Maternal, and Neonatal Outcomes

Asthma affects 5% to 13% of pregnant women, and many require daily pharmacotherapy to achieve asthma control; however, adherence to medication during pregnancy often decreases. To understand the association between the use of or adherence to asthma medication with asthma exacerbation and maternal/neonatal outcomes. Using linked population-based administrative databases from Alberta, Canada (2012-2018), pregnant women with asthma were categorized based on asthma medication use 1 year before pregnancy: short-acting β-agonists (SABA), inhaled corticosteroids (ICS), and ICS with long-acting β-agonists (ICS+LABA). Women on ICS+LABA were grouped by trajectory of adherence during pregnancy using group-based trajectory modeling. Logistic regressions were used to estimate the associations between the use of or trajectories of adherence to asthma medication during pregnancy with asthma exacerbation and maternal/neonatal outcomes. Overall, 13,509 of 238,751 (5.7%) pregnant women had asthma before pregnancy (SABA: 24.7%; ICS: 12.5%; ICS+LABA: 25.1%; none: 36.1%). The use of SABA (adjusted odds ratio [aOR]: 1.79, 95% confidence interval [CI]: 1.21, 2.64), ICS (aOR: 3.37, 95% CI: 2.10, 5.39), and ICS+LABA (aOR: 3.64, 95% CI: 2.57, 5.17) had greater odds of disease exacerbation than no asthma medication during pregnancy. ICS+LABA adherence groups during pregnancy included low (79.8%), moderate-to-decreasing (14.0%), and moderate-to-increasing (6.2%). The moderate-to-decreasing (aOR: 1.45, 95% CI: 1.14, 1.84) and moderate-to-increasing (aOR: 2.06, 95% CI: 1.50, 2.83) adherence groups had greater odds of disease exacerbation than the low adherence group. ICS use during pregnancy decreased odds of preterm birth (aOR: 0.62; 95% CI: 0.39, 0.99) and neonatal intensive care unit admission (aOR: 0.66; 95% CI: 0.45, 0.97). Other group comparisons were not statistically significant. Our study shows the importance of continuing asthma maintenance medication during pregnancy to improve outcomes. Future research should study the postpartum and long-term outcomes with asthma medication during pregnancy.

Assessing Inhaled Corticosteroid Adherence and Responsiveness in Severe Asthma Using Beclometasone Dipropionate/Formoterol NEXThaler Dose-Counting and Nitric Oxide Monitoring

65% of people with severe asthma and a FeNO ≥45 ppb are non-adherent to inhaled corticosteroids (ICS). Digital devices recording both time-of-use and inhaler technique identify non-adherence and ICS responsiveness but are not widely available. As the NEXThaler™ dose counter only activates at an inspiratory flow of 35 L/min, this may provide an alternative to identifying ICS responsiveness. To assess ICS adherence and responsiveness in severe asthma using beclometasone/formoterol (200/6 mcg) NEXThaler™ (BFN) dose-counting. Severe asthmatics with a FeNO ≥45 ppb were invited to use BFN in place of their usual ICS/long-acting β2-agonist (LABA). FeNO, ACQ6, lung function and blood eosinophil count were monitored for 3 months. A log10ΔFeNO ≥0.24 was used to define FeNO suppression as the primary marker of ICS responsiveness at day 28. 27/48 (56%) patients demonstrated significant FeNO suppression at month 1 (median pre-114, post-48 ppb, p<0.001). A small but significant reduction occurred in FeNO non-suppressors. ACQ6 fell a median 1.2 units in FeNO suppressors (p<0.001) and 0.5 units in non-suppressors (p=0.025). These effects were sustained until month 3 in FeNO suppressors with a significant improvement in FEV1 and blood eosinophils. 67% (18/27) of those with baseline ICS/LABA prescription refills of ≥80% were FeNO suppressors suggesting prior non-adherence despite adequate prescription collection. 79% of FeNO suppressors did not require biologics within mean 11.4 months from initial dose counting. BFN dose counting identifies ICS responsiveness in severe asthma with the implication that these patients may not need to progress to biological therapies.

START CARE: a protocol for a randomised controlled trial of step-wise budesonide-formoterol reliever-based treatment in children.

Asthma is the most common chronic childhood respiratory condition globally. Inhaled corticosteroid (ICS)-formoterol reliever-based regimens reduce the risk of asthma exacerbations compared with conventional short-acting β2-agonist (SABA) reliever-based regimens in adults and adolescents. The current limited evidence for anti-inflammatory reliever therapy in children means it is unknown whether these findings are also applicable to children. High-quality randomised controlled trials (RCTs) are needed. The study aim is to determine the efficacy and safety of budesonide-formoterol reliever alone or maintenance and reliever therapy (MART) compared with standard therapy: budesonide or budesonide-formoterol maintenance, both with terbutaline reliever, in children aged 5 to 11 years with mild, moderate and severe asthma. A 52-week, multicentre, open-label, parallel group, phase III, two-sided superiority RCT will recruit 400 children aged 5 to 11 years with asthma. Participants will be randomised 1:1 to either budesonide-formoterol 100/6 µg Turbuhaler reliever alone or MART; or budesonide or budesonide-formoterol Turbuhaler maintenance, with terbutaline Turbuhaler reliever. The primary outcome is moderate and severe asthma exacerbations as rate per participant per year. Secondary outcomes are asthma control, lung function, exhaled nitric oxide and treatment step change. Assessment of Turbuhaler technique and cost-effectiveness analysis are also planned. This will be the first RCT to compare the efficacy and safety of a step-wise budesonide-formoterol reliever alone or MART regimen with conventional inhaled ICS or ICS-long-acting β-agonist maintenance plus SABA reliever in children. The results will provide a much-needed evidence base for the treatment of asthma in children.

Machine Learning Prediction of Treatment Response to Inhaled Corticosteroids in Asthma.

Although inhaled corticosteroids (ICS) are the first-line therapy for patients with persistent asthma, many patients continue to have exacerbations. We developed machine learning models to predict the ICS response in patients with asthma. The subjects included asthma patients of European ancestry (n = 1371; 448 children; 916 adults). A genome-wide association study was performed to identify the SNPs associated with ICS response. Using the SNPs identified, two machine learning models were developed to predict ICS response: (1) least absolute shrinkage and selection operator (LASSO) regression and (2) random forest. The LASSO regression model achieved an AUC of 0.71 (95% CI 0.67-0.76; sensitivity: 0.57; specificity: 0.75) in an independent test cohort, and the random forest model achieved an AUC of 0.74 (95% CI 0.70-0.78; sensitivity: 0.70; specificity: 0.68). The genes contributing to the prediction of ICS response included those associated with ICS responses in asthma (TPSAB1, FBXL16), asthma symptoms and severity (ABCA7, CNN2, PTRN3, and BSG/CD147), airway remodeling (ELANE, FSTL3), mucin production (GAL3ST), leukotriene synthesis (GPX4), allergic asthma (ZFPM1, SBNO2), and others. An accurate risk prediction of ICS response can be obtained using machine learning methods, with the potential to inform personalized treatment decisions. Further studies are needed to examine if the integration of richer phenotype data could improve risk prediction.

Identification and treatment of persistent small airway dysfunction in paediatric patients with asthma: a retrospective cohort study

BackgroundAsthma is a common respiratory disease. In asthma, the small airways have more intensive inflammation and prominent airway remodelling, compared to the central airways. We aimed to investigate the predictive value of risk factors and the fractional concentration of exhaled nitric oxide (FeNO) for persistent small airway dysfunction (p-SAD), and compare the effects of different treatment modalities.MethodsThis retrospective cohort study included 248 children with asthma (aged 4–11 years). Binary logistic regression was used to analyse the risk factors for p-SAD. Correlations among FEV1/FVC, small airway function parameters, and FeNO levels in patients with asthma were analysed using Spearman’s rank correlation. The receiver operating characteristic curve and the Delong test were used to analyse the predictive value of FeNO for p-SAD. Differences in the treatment effects of inhaled corticosteroids (ICS) and ICS with a long-acting beta-agonist (ICS/LABA) on p-SAD were analysed using Fisher’s exact test.ResultsAsthmatic children with older age of receiving the regular treatment (OR 1.782, 95% CI 1.082–2.935), with younger age at the time of onset of suspected asthma symptoms (OR 0.602, 95% CI 0.365–0.993), with longer duration of using ICS or ICS/LABA (OR 1.642, 95% CI 1.170–2.305) and with worse asthma control (OR 3.893, 95% CI 1.699–8.922) had increased risk for p-SAD. Significant negative correlations of small airway function parameters with FeNO at a 200 mL/s flow rate (FeNO200), and the concentration of nitric oxide in the alveolar or acinar region (CaNO) were observed. The areas under the curve of FeNO200 (cut-off:10.5ppb), CaNO (cut-off:5.1ppb), and FeNO200 combined with CaNO were 0.743, 0.697, and 0.750, respectively, for asthma with p-SAD. After using ICS or ICS/LABA, switching to ICS/LABA was easier than continuing with ICS to improve small airway dysfunction (SAD) in the 8th month.ConclusionsPaediatric asthma with p-SAD is associated with older age at receiving regular treatment, younger age at the time of onset of suspected asthma symptoms, longer duration of using ICS or ICS/LABA, worse asthma control, and higher FeNO200 and CaNO levels, all of which can be combined with small airway function indicators to distinguish p-SAD from asthma. ICS/LABA improves SAD better than ICS alone.

Inhaled Corticosteroids May Not Affect the Clinical Outcomes of Pneumonia in Patients with Chronic Obstructive Pulmonary Disease.

Although inhaled corticosteroids (ICS) is reportedly associated with a higher risk of pneumonia in chronic obstructive pulmonary disease (COPD), the clinical implications of ICS have not been sufficiently verified to determine their effect on the prognosis of pneumonia. The electronic health records of patients hospitalized for pneumonia with underlying COPD were retrospectively reviewed. Pneumonia was confirmed using chest radiography or computed tomography. The clinical outcomes of pneumonia in patients with COPD who received ICS and those who received long-acting bronchodilators other than ICS were compared. Among the 255 hospitalized patients, 89 met the inclusion criteria. The numbers of ICS and non-ICS users were 46 and 43, respectively. The CURB-65 (confusion, uremia, respiratory rate, blood pressure, age ≥65 years) scores at the initial presentation of pneumonia were comparable between the two groups. The proportions of patients with multilobar infiltration, pleural effusion, and complicated pneumonia in the radiological studies did not vary between the two groups. Additionally, the defervescence time, proportion of mechanical ventilation, intensive care unit admission, length of hospital stays, and mortality rate at 30 and 90 days were not significantly different between the two groups. ICS use and blood eosinophils count were not associated with all pneumonia outcomes and mortality in multivariate analyses. The clinical outcomes of pneumonia following ICS use in patients with COPD did not differ from those in patients treated without ICS. Thus, ICS may not contribute to the severity and outcomes of pneumonia in patients with COPD.

Budesonide/Formoterol or Budesonide/Albuterol as Anti-Inflammatory Reliever Therapy for Asthma

Over use of reliever as short acting beta-agonist (SABA) and associated underuse of controller as inhaled corticosteroid (ICS) administered via separate inhalers results in worse asthma outcomes . Such discordance can be obviated by combining both controller and reliever in the same inhaler. So called anti-inflammatory reliever (AIR) therapy comprises the use of a single inhaler containing an ICS such as budesonide (BUD) in conjunction with a reliever as either albuterol (ALB) or formoterol (FORM) ,to be used on demand with variable dosing driven by asthma symptoms in a flexible patient centred regimen. Global guidelines now support the use of BUD-ALB as AIR therapy to reduce exacerbations , either on its own in mild asthma or in conjunction with fixed dose maintenance ICS-long acting beta-agonist (LABA) in moderate to severe asthma . Using BUD-FORM on its own allows patients to seamlessly move in an intuitive flexible fashion between AIR or maintenance and reliever therapy (MART) , by stepping up and down the dosing escalator across a spectrum of asthma severities . Head to head clinical studies are indicated to compare BUD-FORM versus BUD-ALB as AIR in mild asthma ,and also BUD-FORM as MART versus BUD-ALB as AIR plus maintenance ICS-LABA in moderate to severe asthma. Patients should be encouraged to make an informed decision in conjunction with their health care professional regarding the best therapeutic option tailored to their individual needs , which in turn is likely to result in long term compliance and associated optimal asthma control.

Lower airway microbiota in COPD and healthy controls

BackgroundThe lower airway microbiota in patients with chronic obstructive pulmonary disease (COPD) are likely altered compared with the microbiota in healthy individuals. Information on how the microbiota is affected by...