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

BACKGROUND: Chronic 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. METHODS: An 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. RESULTS: A 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. CONCLUSIONS: Severe 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.

Once-daily single-inhaler versus twice-daily multiple-inhaler triple therapy in patients with COPD: lung function and health status results from two replicate randomized controlled trials.

BACKGROUND: The comparative efficacy of inhaled corticosteroid/long-acting muscarinic antagonist/long-acting ß2-agonist (ICS/LAMA/LABA) triple therapy administered via single or multiple inhalers in patients with chronic obstructive pulmonary disease (COPD) has not been evaluated comprehensively. We conducted two replicate trials comparing single- with multiple-inhaler ICS/LAMA/LABA combination in COPD. METHODS: 207608 and 207609 were Phase IV, 12-week, randomized, double-blind, triple-dummy non-inferiority trials comparing once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 µg via Ellipta inhaler, with twice-daily budesonide/formoterol (BUD/FOR) 400/12 µg via metered-dose inhaler plus once-daily tiotropium (TIO) 18 µg via HandiHaler. Patients had symptomatic COPD and forced expiratory volume in 1 s (FEV1) < 50% predicted, or FEV1 < 80% predicted and ≥ 2 moderate or 1 severe exacerbations in the prior year. The primary endpoint in both trials was weighted mean change from baseline (wmCFB) in 0-24-h FEV1 at Week 12. Secondary endpoints included CFB in trough FEV1 at Day 84 and 85. Other endpoints included serial FEV1 and health status outcomes at Week 12. Safety was evaluated descriptively. RESULTS: The modified per-protocol population included 720 and 711 patients in studies 207608 and 207609 (intent-to-treat population: 728 and 732). FF/UMEC/VI was non-inferior to BUD/FOR+TIO for wmCFB in 0-24-h FEV1 at Week 12 (Study 207608 treatment difference [95% confidence interval]: 15 mL [- 13, 43]; Study 207609: 11 mL [- 20, 41]). FF/UMEC/VI improved trough FEV1 CFB versus BUD/FOR+TIO at Day 84 and 85 (Day 85 treatment difference: Study 207608: 38 mL [10, 66]; Study 207609: 51 mL [21, 82]) and FEV1 at 12 and 24 h post-morning dose at Week 12 in both studies. No treatment differences were seen in health status outcomes. Safety profiles were similar between treatments; pneumonia occurred in 7 (< 1%) patients with FF/UMEC/VI and 9 (1%) patients with BUD/FOR+TIO, across both studies. CONCLUSIONS: FF/UMEC/VI was non-inferior to BUD/FOR+TIO for wmCFB in 0-24-h FEV1 at Week 12 in patients with COPD. Greater improvements in trough and serial FEV1 measurements at Week 12 with FF/UMEC/VI versus BUD/FOR+TIO, together with similar health status improvements and safety outcomes including the incidence of pneumonia, suggest that once-daily single-inhaler FF/UMEC/VI triple therapy is a viable option for patients looking to simplify their treatment regimen. TRIAL REGISTRATION: GSK (207608/207609; NCT03478683/NCT03478696).

The effects of asthma medications on reactive oxygen species production in human monocytes.

OBJECTIVE: Asthma is a chronic inflammatory airway disease induced by many environmental factors. The inhalation of allergens and pollutants promotes the production of reactive oxygen species (ROS) leading to airway inflammation, hyper-responsiveness, and remodeling in allergic asthma. The effects of asthma medications on ROS production are unclear. The present study investigated the anti-ROS effects of current asthma medications including inhaled corticosteroid (ICS; budesonide and fluticasone), leukotriene receptor antagonist (LTRA; montelukast), long-acting ß2 agonists (LABAs; salmeterol and formoterol), and a new extra-LABA (indacaterol). METHODS: The human monocyte cell line THP-1 cells were pre-treated with different concentrations of the asthma medications at different time points after hydrogen peroxide (H2O2) stimulation. H2O2 production was measured with DCFH-DA by flow cytometry. RESULTS: Montelukast, fluticasone, and salmeterol suppressed H2O2-induced ROS production. Indacaterol enhanced H2O2-induced ROS production. Budesonide and formoterol alone had no anti-ROS effects, but the combination of these two drugs significantly suppressed H2O2-induced ROS production. CONCLUSIONS: Different asthma medications have different anti-ROS effects on monocytes. The combination therapy with LABA and ICS seemed not to be the only choice for asthma control. Montelukast may also be a good supplemental treatment for the poorly controlled asthma because of its powerful anti-ROS effects. Our findings provide a novel therapeutic view in asthma.

Effect of Long-term Inhaled Corticosteroids on the Hypothalamic-Pituitary-Adrenal Axis in Children with Asthma.

OBJECTIVES: To assess the effect of the long-term use of inhaled corticosteroids (ICS) on the hypothalamic-pituitary-adrenal (HPA) axis. METHODS: Children (5-18 y) diagnosed with asthma and on ICS therapy for ≥6 mo were included. In the first step, screening with fasting at 8 AM, cortisol level was measured; a value <15 mcg/dl was considered low. Children with low fasting cortisol levels were subjected to adreno-corticotropic hormone (ACTH) stimulation test in the second step. Post-ACTH stimulation, cortisol level <18 mcg/dl was considered to have HPA axis suppression. RESULTS: A total of 78 children (males 55, 70.5%) diagnosed with asthma, with a median age of 11.5 (8, 14) y, were enrolled. The median duration of ICS use was 12 (12-24) mo. The median value of post-ACTH stimulation cortisol level was 22.5 (20.6, 25.5) mcg/dl, and a value <18 mcg/dl was observed in 4 (5.1%; 95% CI 0.2-10%) children. There was statistically no significant correlation between low post-ACTH stimulation cortisol level with ICS dose (p = 0.23) and asthma control (p = 0.67). None of the children had clinical features of adrenal insufficiency. CONCLUSIONS: In this study, a few children had low post-ACTH stimulation cortisol values; however, none had clinical evidence of HPA axis suppression. Therefore, ICS is a safe drug in children for treating asthma, even for long-term use.

From Mild to Mayhem: A Life-Threatening Exacerbation of Mild Asthma.

This case illustrates an example of a patient with mild asthma who experiences a severe life-threatening exacerbation. This patient's experience is one of many that challenges the common misperception that mild, well-controlled asthma is not at risk for severe life-threatening exacerbations. The case exploration highlights the data fueling the new 2019/2020 Global Initiative for Asthma (GINA) guidelines, pharmaco-inequity, and barriers to healthcare access which can increase the risk for poor asthma outcomes. The graphic illustrates when patients with asthma, including those with mild asthma, may benefit from referral to an allergist-immunologist. Overall, this case underscores the importance of bridging the gap between generalists and allergist-immunologists to better serve an oft-overlooked patient population.

Racial Differences in Prevalence and Clinical Characteristics of Asthma-Chronic Obstructive Pulmonary Disease Overlap.

Background: This study examined the differences in the prevalence and clinical features of asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) with identical diagnostic criteria by race and ethnicity in two nationwide cohorts of COPD. Methods: We used data from the Korean COPD Subgroup Study (KOCOSS) and phase I of the US Genetic Epidemiology of COPD (COPDGene) study. We defined ACO by satisfying bronchodilator response (BDR) >15% and 400 ml and/or blood eosinophil count ≥300/µl. Results: The prevalences of ACO according to ethnicity were non-Hispanic white (NHW), 21.4%; African American (AA), 17.4%; and Asian, 23.8%. Asian patients with ACO were older, predominantly male, with fewer symptoms, more severe airflow limitation, and fewer comorbidities than NHW and AA patients. During 1-year follow-up, exacerbations occurred in 28.2, 22.0, and 48.4% of NHW, AA, and Asian patients with ACO, respectively. Compared to patients with non-ACO from the same racial group, the risk for exacerbation was significantly higher in NHW and Asian patients with ACO [adjusted incident rate ratio (aIRR), 1.17; 95% CI, 1.01-1.36, and aIRR, 1.37; 95% CI, 1.09-1.71 for NHW and Asian patients with ACO, respectively]. Inhaled corticosteroid (ICS) reduced the risk for future exacerbation in total patients with ACO but the effect was not significant in each racial group. Conclusions: The prevalence of ACO was similar in the two cohorts using the same diagnostic criteria. The risk for future exacerbation was significantly higher in ACO, and the use of ICS reduced the risk for exacerbation in total patients with ACO.

Effect of Adding Inhaled Corticosteroid to Long-Acting Muscarinic Antagonist/Long-Acting Beta-Agonist Therapy Among Patients With Chronic Obstructive Pulmonary Disease.

Background The role of inhaled corticosteroid (ICS) in chronic obstructive pulmonary disease (COPD) is unclear. Hence, this study aimed to evaluate the efficacy of ICS as an add-on to long-acting muscarinic antagonist (LAMA)/long-acting beta 2 agonist (LABA), which was assessed using the impulse oscillation system (IOS), in patients with COPD. Methodology We included patients with COPD whose treatment was changed from LAMA/LABA (≥four weeks) to ICS/LAMA/LABA between April 2019 and March 2021. To gain insight into the effect and safety of ICS-containing triple therapy for COPD, pulmonary function; Short-Form 36, St. George's Respiratory Questionnaire, COPD Assessment Test, and modified Medical Research Council scores; and airway resistance assessed using the IOS from one week before LAMA/LABA was switched to ICS/LAMA/LABA therapy until more than eight but less than twelve weeks after switching were evaluated. Results In total, 46 patients with COPD (mean age: 72.28 ± 7.81 years) were included in the study. None of the pulmonary function test parameters significantly changed from baseline values (mean difference in forced expiratory volume in one second [FEV1.0]: +0.032, P = 0.12; percentage FEV1.0 [FEV1.0%]/forced vital capacity [FVC]: -0.58, P = 0.42; and FVC: +0.087, P = 0.058). Meanwhile, the IOS showed that resonant frequency (mean difference from baseline: -2.12, P < 0.0001) and bodily pain scores in the St. George's Respiratory Questionnaire (mean difference: -7.03, P = 0.031) significantly decreased. Conclusions Switching from LAMA/LABA to ICS/LAMA/LABA therapy reduces airway elasticity-to-inertial resistance ratios, which may lead to structural airway improvements in patients with COPD.

Glucocorticoid-driven transcriptomes in human airway epithelial cells: commonalities, differences and functional insight from cell lines and primary cells.

BACKGROUND: Glucocorticoids act on the glucocorticoid receptor (GR; NR3C1) to resolve inflammation and, as inhaled corticosteroids (ICS), are the cornerstone of treatment for asthma. However, reduced efficacy in severe disease or exacerbations indicates a need to improve ICS actions. METHODS: Glucocorticoid-driven transcriptomes were compared using PrimeView microarrays between primary human bronchial epithelial (HBE) cells and the model cell lines, pulmonary type II A549 and bronchial epithelial BEAS-2B cells. RESULTS: In BEAS-2B cells, budesonide induced (≥2-fold, P ≤ 0.05) or, in a more delayed fashion, repressed (≤0.5-fold, P ≤ 0.05) the expression of 63, 133, 240, and 257 or 15, 56, 236, and 344 mRNAs at 1, 2, 6, and 18 h, respectively. Within the early-induced mRNAs were multiple transcriptional activators and repressors, thereby providing mechanisms for the subsequent modulation of gene expression. Using the above criteria, 17 (BCL6, BIRC3, CEBPD, ERRFI1, FBXL16, FKBP5, GADD45B, IRS2, KLF9, PDK4, PER1, RGCC, RGS2, SEC14L2, SLC16A12, TFCP2L1, TSC22D3) induced and 8 (ARL4C, FLRT2, IER3, IL11, PLAUR, SEMA3A, SLC4A7, SOX9) repressed mRNAs were common between A549, BEAS-2B and HBE cells at 6 h. As absolute gene expression change showed greater commonality, lowering the cut-off (≥1.25 or ≤ 0.8-fold) within these groups produced 93 induced and 82 repressed genes in common. Since large changes in few mRNAs and/or small changes in many mRNAs may drive function, gene ontology (GO)/pathway analyses were performed using both stringency criteria. Budesonide-induced genes showed GO term enrichment for positive and negative regulation of transcription, signaling, proliferation, apoptosis, and movement, as well as FOXO and PI3K-Akt signaling pathways. Repressed genes were enriched for inflammatory signaling pathways (TNF, NF-κB) and GO terms for cytokine activity, chemotaxis and cell signaling. Reduced growth factor expression and effects on proliferation and apoptosis were highlighted. CONCLUSIONS: While glucocorticoids repress mRNAs associated with inflammation, prior induction of transcriptional activators and repressors may explain longer-term responses to these agents. Furthermore, positive and negative effects on signaling, proliferation, migration and apoptosis were revealed. Since many such gene expression changes occurred in human airways post-ICS inhalation, the effects observed in cell lines and primary HBE cells in vitro may be relevant to ICS in vivo.

Nationwide use of inhaled corticosteroids by South Korean asthma patients: an examination of the Health Insurance Review and Service database.

BACKGROUND: Previous studies have found that the prescription rates of inhaled corticosteroid (ICS) were considerably low although it is recommended as the optimal asthma treatment. The aim of this study was to analyze the current status of ICS prescription for asthma patients in the South Korea. METHODS: We evaluated quality assessment data based on nationwide Health Insurance Review and Service (HIRA) database from July 2013 to June 2014. ICS prescription rates in asthma patients were analyzed by types and specialty of medical institutions. Also, we graded medical institutions by their ICS prescription rate. In addition, ICS prescription rates were calculated by patient gender, age, and insurance type. RESULTS: This study included 831,613 patients and 16,804 institutions in the analysis. The overall mean ICS prescription rate was 22.58%. Tertiary hospitals had the highest mean prescription rate (84.16%) whereas primary healthcare clinics had the lowest (20.71%). By specialty, internal medicine physicians prescribed ICS more frequently compared to other specialists. Of all, 47.17% of medical institutions prescribed ICS to <10% of asthma patients, while less than 6% of institutions prescribed ICS to >80% of asthma patients. Also, we found that female and patients with age >90 or <20 years exhibited lower ICS prescription rate. CONCLUSIONS: The ICS prescription rate was found to be inadequate, given the importance of ICS as an asthma treatment. The prescription rates were especially low in primary healthcare clinics, and by specialists in fields other than internal medicine.