The Incidence, Mortality and Medical Expenditure in Patients with Asthma in Taiwan: Ten-year Nationwide Study.

BACKGROUND: This study examines incidence, mortality, medical expenditure and prescription patterns for asthma on a national scale, particularly in Asian countries for asthma is limited. Our aim is to investigate incidence, mortality, prescription patterns and provide a comprehensive overview of healthcare utilization trends for asthma from 2009 to 2018. METHODS: We included patients diagnosed with asthma between 2009 and 2018. We excluded patients with missing demographic data. Our analysis covered comorbidities, including diabetes mellitus, hypertension, allergic rhinitis, eczema, atopic dermatitis, coronary artery disease, congestive heart failure, chronic kidney disease, chronic hepatitis, stroke, and cancer. Investigated medications comprised oral and intravenous steroids, short-acting beta-agonists, inhaled corticosteroids (ICS), combinations of ICS and long-acting beta-agonists, long-acting muscarinic antagonists, and leukotriene receptor antagonists montelukast. We also assessed the number of outpatient visits, emergency visits, and hospitalizations per year, as well as the average length of hospitalization and average medical costs. RESULTS: The study included a final count of 88,244 subjects from 1,998,311 randomly selected samples between 2000 and 2019. Over the past decade, there was a gradual decline in newly diagnosed asthma patients per year, from 10,140 to 6,487. The mean age annually increased from 47.59 in 2009 to 53.41 in 2018. Over 55% of the patients were female. Eczema was diagnosed in over 55% of the patients. Around 90% of the patients used oral steroids, with a peak of 97.29% in 2018, while the usage of ICS varied between 86.20% and 91.75%. Intravenous steroids use rose from 40.94% in 2009 to 54.14% in 2018. The average annual hospital stay ranged from 9 to 12 days, with a maximum of 12.26 days in 2013. Lastly, the average medical expenses per year ranged from New Taiwan dollars 5558 to 7921. CONCLUSIONS: In summary, both asthma incidence and all-cause mortality rates decreased in Taiwan from 2009 to 2018. Further analysis of medical expenses in patients with asthma who required multiple hospitalizations annually revealed an increase in outpatient and emergency visits and hospitalizations, along with longer hospital stays and higher medical costs.

Vitamin D constrains inflammation by modulating the expression of key genes on Chr17q12-21.1.

Vitamin D possesses immunomodulatory functions and vitamin D deficiency has been associated with the rise in chronic inflammatory diseases, including asthma (Litonjua and Weiss, 2007). Vitamin D supplementation studies do not provide insight into the molecular genetic mechanisms of vitamin D-mediated immunoregulation. Here, we provide evidence for vitamin D regulation of two human chromosomal loci, Chr17q12-21.1 and Chr17q21.2, reliably associated with autoimmune and chronic inflammatory diseases. We demonstrate increased vitamin D receptor (Vdr) expression in mouse lung CD4+ Th2 cells, differential expression of Chr17q12-21.1 and Chr17q21.2 genes in Th2 cells based on vitamin D status and identify the IL-2/Stat5 pathway as a target of vitamin D signaling. Vitamin D deficiency caused severe lung inflammation after allergen challenge in mice that was prevented by long-term prenatal vitamin D supplementation. Mechanistically, vitamin D induced the expression of the Ikzf3-encoded protein Aiolos to suppress IL-2 signaling and ameliorate cytokine production in Th2 cells. These translational findings demonstrate mechanisms for the immune protective effect of vitamin D in allergic lung inflammation with a strong molecular genetic link to the regulation of both Chr17q12-21.1 and Chr17q21.2 genes and suggest further functional studies and interventional strategies for long-term prevention of asthma and other autoimmune disorders.

MicroRNA-mediated Krüppel-like factor 4 upregulation induces alternatively activated macrophage-associated marker and chemokine transcription in 4,4'-methylene diphenyl diisocyanate exposed macrophages.

1. Occupational exposure to 4,4'-methylene diphenyl diisocyanate (MDI) is associated with occupational asthma (OA) development. Alveolar macrophage-induced recruitment of immune cells to the lung microenvironment plays an important role during asthma pathogenesis. Previous studies identified that MDI/MDI-glutathione (GSH)-exposure downregulates endogenous hsa-miR-206-3p/hsa-miR-381-3p. Our prior report shows that alternatively activated (M2) macrophage-associated markers/chemokines are induced by MDI/MDI-GSH-mediated Krüppel-Like Factor 4 (KLF4) upregulation in macrophages and stimulates immune cell chemotaxis. However, the underlying molecular mechanism(s) by which MDI/MDI-GSH upregulates KLF4 remain unclear.2. Following MDI-GSH exposure, microRNA(miR)-inhibitors/mimics or plasmid transfection, endogenous hsa-miR-206-3p/hsa-miR-381-3p, KLF4, or M2 macrophage-associated markers (CD206, TGM2), and chemokines (CCL17, CCL22, CCL24) were measured by either RT-qPCR, western blot, or luciferase assay.3. MDI-GSH exposure downregulates hsa-miR-206-3p/hsa-miR-381-3p by 1.46- to 9.75-fold whereas upregulates KLF4 by 1.68- to 1.99-fold, respectively. In silico analysis predicts binding between hsa-miR-206-3p/hsa-miR-381-3p and KLF4. Gain- and loss-of-function, luciferase reporter assays and RNA-induced silencing complex-immunoprecipitation (RISC-IP) studies confirm the posttranscriptional regulatory roles of hsa-miR-206-3p/hsa-miR-381-3p and KLF4 in macrophages. Furthermore, hsa-miR-206-3p/hsa-miR-381-3p regulate the expression of M2 macrophage-associated markers and chemokines via KLF4.4. In conclusion, hsa-miR-206-3p/hsa-miR-381-3p play a major role in regulation of MDI/MDI-GSH-induced M2 macrophage-associated markers and chemokines by targeting the KLF4 transcript, and KLF4-mediated regulation in macrophages.

Multivariate Cluster Analyses to Characterize Asthma Heterogeneity and Benralizumab Responsiveness.

BACKGROUND: An improved understanding of how severe asthma heterogeneity affects response could inform treatment decisions. OBJECTIVES: Characterize heterogeneity and benralizumab responsiveness in patients grouped by predefined Severe Asthma Research Program clusters using a multivariate approach. METHODS: In post-hoc analyses of the randomized, double-blind, placebo-controlled phase III SIROCCO (NCT01928771) and CALIMA (NCT01914757) studies, patients with severe asthma who received benralizumab or placebo were assigned to clusters using an established discriminant function to simultaneously analyze 11 clinical characteristics. Annualized asthma exacerbation rate, exacerbation incidence, and lung function were analyzed across clusters. RESULTS: Patients (N = 2,281) met criteria for 4 of 5 clusters: Cluster 2 (early-onset moderate asthma, n = 393), Cluster 4 (early-onset severe, n = 386), Cluster 3 (late-onset severe, n = 641), and Cluster 5 (late-onset severe, obstructed, n = 861); no patients met Cluster 1 criteria. Exacerbation rate reductions were significant in late-onset severe (-48% [95% CI: -61%, -31%], P<.0001) and late-onset severe, obstructed asthma (-50% [95% CI: -59%, -38%], P<.0001), with non-significant reductions in early-onset clusters. These differences could not be fully explained by blood eosinophil count differences. Forced expiratory volume in 1 second improvements were significant in late-onset severe (+133 mL [95% CI: 66 mL, 200 mL], P=.0001) and late-onset severe, obstructed asthma (+160 mL [95% CI: 85 mL, 235 mL], P<.0001) while maintaining acute bronchodilator responsiveness. CONCLUSIONS: Benralizumab reduced exacerbations and improved lung function, primarily in late-onset asthma clusters. This multivariate approach to identify subphenotypes, potentially reflecting pathobiological mechanisms, can guide therapy beyond univariate approaches.

Eosinophil peroxidase promotes bronchial epithelial cells to secrete asthma-related factors and induces the early stage of airway remodeling.

Asthma is a heterogeneous disease characterized by chronic airway inflammation, reversible airflow limitation, and airway remodeling. Eosinophil peroxidase (EPX) is the most abundant secondary granule protein unique to activated eosinophils. In this study, we aimed to illustrate the effect of EPX on the epithelial-mesenchymal transition (EMT) in BEAS-2B cells. Our research found that both EPX and ADAM33 were negatively correlated with FEV1/FVC and FEV1%pred, and positively correlated with IL-5 levels. Asthma patients had relatively higher levels of ADAM33 and EPX compared to the healthy control group. The expression of TSLP, TGF-ß1 and ADAM33 in the EPX intervention group was significantly higher. Moreover, EPX could promote the proliferation, migration and EMT of BEAS-2B cells, and the effect of EPX on various factors was significantly improved by the PI3K inhibitor LY294002. The findings from this study could potentially offer a novel therapeutic target for addressing airway remodeling in bronchial asthma, particularly focusing on EMT.

Utility of eosinophil peroxidase as a biomarker of eosinophilic inflammation in asthma.

BACKGROUND: The relative utility of eosinophil peroxidase (EPX) and blood and sputum eosinophil counts as disease biomarkers in asthma is uncertain. OBJECTIVE: To determine the utility of EPX as a biomarker of systemic and airway eosinophilic inflammation in asthma. METHODS: EPX protein was measured by immunoassay in serum and sputum in 110 healthy controls to establish a normal reference range and in repeated samples of serum and sputum collected during three years of observation in 480 participants in the Severe Asthma Research Program (SARP)-3. RESULTS: Over three years, EPX levels in asthma patients were higher than normal in 27-31% of serum samples and 36-53% of sputum samples. Eosinophils and EPX correlated better in blood than in sputum (rs values of 0.74 and 0.43, respectively), and high sputum EPX levels occurred in 27% of participants with blood eosinophil counts < 150 cells/uL and 42% of participants with blood eosinophil counts 150-299 cells/uL. Patients with persistently high sputum EPX values for three years were characterized by severe airflow obstruction, frequent exacerbations, and high mucus plug scores. In 59 asthma patients who started mepolizumab during observation, serum EPX levels normalized in 96% but sputum EPX normalized in only 49%. Lung function remained abnormal even when sputum EPX normalized. CONCLUSION: Serum EPX is a valid protein biomarker of systemic eosinophilic inflammation in asthma, and sputum EPX levels are a more sensitive biomarker of airway eosinophilic inflammation than sputum eosinophil counts. Eosinophil measures in blood frequently miss airway eosinophilic inflammation, and mepolizumab frequently fails to normalize airway eosinophilic inflammation even though it invariably normalizes systemic eosinophilic inflammation.

The association between waist circumference and adult asthma attack using nationally representative samples.

AIMS: This study aims to explore the relationship between waist circumference and asthma attack in adults. METHODS: In this cross-sectional study, we analysed data from 5,530 U.S. adults diagnosed with asthma. Participants were categorized into two groups based on their experience of asthma attacks: with or without asthma attacks. We employed adjusted weighted logistic regression models, weighted restricted cubic splines, subgroup and sensitivity analyses to assess the association between waist circumference and asthma attack. RESULTS: The median age of all participants was 43 years, and the median waist circumference was 98.9 cm, with a median BMI was 28.50 kg/m2. Participants in the asthma attack group had significantly higher waist circumferences than those in the non-attack group (P < 0.001). After full adjustment for body mass index-defined obesity, age, gender, race, education levels, poverty income ratio levels, smoking status, and metabolic syndrome, every 5 cm increase in waist circumference exhibited a 1.06 times higher likelihood of asthma attack probability. The weighted restricted cubic spline analysis demonstrated an increased risk of asthma attacks with rising waist circumference. Subgroup analyses confirmed this relationship across various groups differentiated by gender, age, and smoking status. When applying a stricter definition of asthma attack, the weighted logistic regression models showed robust association between waist circumference and asthma attack. CONCLUSION: Waist circumference is an independent predictor of asthma attacks. Our findings underscore the importance of waist circumference measurement in evaluating the risk of asthma attacks.

TFEB regulates dendritic cell antigen presentation to modulate immune balance in asthma.

OBJECTIVE: Asthma stands as one of the most prevalent chronic respiratory conditions in children, with its pathogenesis tied to the actived antigen presentation by dendritic cells (DCs) and the imbalance within T cell subgroups. This study seeks to investigate the role of the transcription factor EB (TFEB) in modulating the antigen presentation process of DCs and its impact on the differentiation of T cell subgroups. METHODS: Bone marrow dendritic cells (BMDCs) were activated using house dust mites (HDM) and underwent RNA sequencing (RNA-seq) to pinpoint differentially expressed genes. TFEB mRNA expression levels were assessed in the peripheral blood mononuclear cells (PBMCs) of both healthy children and those diagnosed with asthma. In an asthma mouse model induced by HDM, the TFEB expression in lung tissue DCs was evaluated. Further experiments involved LV-shTFEB BMDCs co-cultured with T cells to explore the influence of TFEB on DCs' antigen presentation, T cell subset differentiation, and cytokine production. RESULTS: Transcriptomic sequencing identified TFEB as a significantly differentially expressed gene associated with immune system pathways and antigen presentation. Notably, TFEB expression showed a significant increase in the PBMCs of children diagnosed with asthma compared to healthy counterparts. Moreover, TFEB exhibited heightened expression in lung tissue DCs of HDM-induced asthmatic mice and HDM-stimulated BMDCs. Silencing TFEB resulted in the downregulation of MHC II, CD80, CD86, and CD40 on DCs. This action reinstated the equilibrium among Th1/Th2 and Th17/Treg cell subgroups, suppressed the expression of pro-inflammatory cytokines like IL-4, IL-5, IL-13, and IL-17, while augmenting the expression of the anti-inflammatory cytokine IL-10. CONCLUSION: TFEB might have a vital role in asthma's development by impacting the antigen presentation of DCs, regulating T cell subgroup differentiation, and influencing cytokine secretion. Its involvement could be pivotal in rebalancing the immune system in asthma. These research findings could potentially unveil novel therapeutic avenues for treating asthma.

Recommendations for asthma monitoring in children: A PeARL document endorsed by APAPARI, EAACI, INTERASMA, REG, and WAO.

Monitoring is a major component of asthma management in children. Regular monitoring allows for diagnosis confirmation, treatment optimization, and natural history review. Numerous factors that may affect disease activity and patient well-being need to be monitored: response and adherence to treatment, disease control, disease progression, comorbidities, quality of life, medication side-effects, allergen and irritant exposures, diet and more. However, the prioritization of such factors and the selection of relevant assessment tools is an unmet need. Furthermore, rapidly developing technologies promise new opportunities for closer, or even "real-time," monitoring between visits. Following an approach that included needs assessment, evidence appraisal, and Delphi consensus, the PeARL Think Tank, in collaboration with major international professional and patient organizations, has developed a set of 24 recommendations on pediatric asthma monitoring, to support healthcare professionals in decision-making and care pathway design.

Seasonal extreme temperatures and short-term fine particulate matter increases pediatric respiratory healthcare encounters in a sparsely populated region of the intermountain western United States.

BACKGROUND: Western Montana, USA, experiences complex air pollution patterns with predominant exposure sources from summer wildfire smoke and winter wood smoke. In addition, climate change related temperatures events are becoming more extreme and expected to contribute to increases in hospital admissions for a range of health outcomes. Evaluating while accounting for these exposures (air pollution and temperature) that often occur simultaneously and may act synergistically on health is becoming more important. METHODS: We explored short-term exposure to air pollution on children's respiratory health outcomes and how extreme temperature or seasonal period modify the risk of air pollution-associated healthcare events. The main outcome measure included individual-based address located respiratory-related healthcare visits for three categories: asthma, lower respiratory tract infections (LRTI), and upper respiratory tract infections (URTI) across western Montana for ages 0-17 from 2017-2020. We used a time-stratified, case-crossover analysis with distributed lag models to identify sensitive exposure windows of fine particulate matter (PM2.5) lagged from 0 (same-day) to 14 prior-days modified by temperature or season. RESULTS: For asthma, increases of 1 µg/m3 in PM2.5 exposure 7-13 days prior a healthcare visit date was associated with increased odds that were magnified during median to colder temperatures and winter periods. For LRTIs, 1 µg/m3 increases during 12 days of cumulative PM2.5 with peak exposure periods between 6-12 days before healthcare visit date was associated with elevated LRTI events, also heightened in median to colder temperatures but no seasonal effect was observed. For URTIs, 1 unit increases during 13 days of cumulative PM2.5 with peak exposure periods between 4-10 days prior event date was associated with greater risk for URTIs visits that were intensified during median to hotter temperatures and spring to summer periods. CONCLUSIONS: Delayed, short-term exposure increases of PM2.5 were associated with elevated odds of all three pediatric respiratory healthcare visit categories in a sparsely population area of the inter-Rocky Mountains, USA. PM2.5 in colder temperatures tended to increase instances of asthma and LRTIs, while PM2.5 during hotter periods increased URTIs.

Respiratory allergic diseases and allergen immunotherapy: A French patient survey before and during the COVID-19 pandemic.

Background: The COVID-19 pandemic brought unprecedented global disruption to both healthcare providers and patients with respiratory allergies. There are limited real-life data on the impact of the COVID-19 pandemic on the risk perception of patients with allergy treated with allergen immunotherapy (AIT). Objective: To understand the risk perception of allergic patients treated with sublingual immunotherapy (SLIT) before and during the pandemic, and their attitudes towards COVID-19 infection and vaccination. Methods: This was a non-interventional, cross-sectional survey conducted from October to November 2021 in France. Adult patients, who had been prescribed and had received a Stallergenes SLIT (liquid or liquid and tablets) before the pandemic (from August 1, 2018 to March 10, 2020) and during the pandemic (from March 11, 2020 to August 31, 2021), were identified from the Stallergenes named-patient products (NPP) database. Patients completed an online questionnaire. Data were analyzed descriptively. Results: A total of 5258 patients from all over France completed the questionnaire. Mean (±SD) age of the respondents was 39.3 (±13.0) years and 66.9% were female. Some of them (11.8%) were obese (BMI >30 kg/m2). Main allergic diseases were rhinitis (80.0% of patients) with or without conjunctivitis, and asthma (39.0%). More than half of the patients experienced moderate to severe (58.0%) and persistent allergic rhinitis profile (70.4%). Most patients were poly-allergic (72.7%), mostly to house dust mites (61.9%), grass pollens (61.5%), tree pollens (57.8%), and cat dander (37.2%). Only 14.1% of patients experienced an aggravation of their allergy symptoms during lockdown and 14.8% were infected with COVID-19, with hospitalization required for 1.8%. Only 3.1% of patients reported their SLIT initiation as being postponed due to the pandemic. SLIT was changed, temporarily interrupted or permanently discontinued during the pandemic in 21.9% of patients. Changes mainly concerned the maintenance dose for SLIT-liquid (63.2%). SLIT modification was due to COVID-19 infection in only 4.2%. Most patients did not feel vulnerable (53.1%), anxious (55.2%), at risk to present severe symptoms of COVID-19 (77.1%), or at risk to transmit coronavirus (80.4%). However, greater anxiety was reported in patients with allergic asthma (33.6%) or other respiratory disorders (50.4%). Patients who felt vulnerable partly assigned their vulnerability to their allergic disease (59.3%). Suffering from an allergic disease did not make patients feel more vulnerable to side effects of COVID-19 vaccine for 79.6% of them. Conclusion: Overall, most patients with allergy and under SLIT were not strongly concerned by the COVID-19 infection. SLIT did not have a negative impact on the COVID-19 symptoms.

Short-Term Nitrogen Dioxide Exposure and Emergency Hospital Admissions for Asthma in Children: A Case-Crossover Analysis in England.

Background: There is an increasing body of evidence associating short-term ambient nitrogen dioxide (NO2) exposure with asthma-related hospital admissions in children. However, most studies have relied on temporally resolved exposure information, potentially ignoring the spatial variability of NO2. We aimed to investigate how daily NO2 estimates from a highly resolved spatio-temporal model are associated with the risk of emergency hospital admission for asthma in children in England. Methods: We conducted a time-stratified case-crossover study including 111,766 emergency hospital admissions for asthma in children (aged 0-14 years) between 1st January 2011 and 31st December 2015 in England. Daily NO2 levels were predicted at the patients' place of residence using spatio-temporal models by combining land use data and chemical transport model estimates. Conditional logistic regression models were used to obtain the odds ratios (OR) and confidence intervals (CI) after adjusting for temperature, relative humidity, bank holidays, and influenza rates. The effect modifications by age, sex, season, area-level income deprivation, and region were explored in stratified analyses. Results: For each 10 µg/m³ increase in NO2 exposure, we observed an 8% increase in asthma-related emergency admissions using a five-day moving NO2 average (mean lag 0-4) (OR 1.08, 95% CI 1.06-1.10). In the stratified analysis, we found larger effect sizes for male (OR 1.10, 95% CI 1.07-1.12) and during the cold season (OR 1.10, 95% CI 1.08-1.12). The effect estimates varied slightly by age group, area-level income deprivation, and region. Significance: Short-term exposure to NO2 was significantly associated with an increased risk of asthma emergency admissions among children in England. Future guidance and policies need to consider reflecting certain proven modifications, such as using season-specific countermeasures for air pollution control, to protect the at-risk population.

Mitochondria protective and anti-apoptotic effects of peripheral benzodiazepine receptor and its ligands on the treatment of asthma in vitro and vivo.

BACKGROUND: Asthma is a prevalent respiratory inflammatory disease. Abnormal apoptosis of bronchial epithelial cells is one of the major factors in the progression of asthma. Peripheral benzodiazepine receptors are highly expressed in bronchial epithelial cells, which act as a component of the mitochondrial permeability transition pore to regulate its opening and closing and apoptosis of bronchial epithelial cells. We aimed to investigate the mechanisms by which peripheral benzodiazepine receptor and its ligands, agonist 4'-Chlorodiazepam (Ro5-4864) and antagonist 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK 11,195), modulate the mitochondrial function and cell apoptosis in the treatment of asthma. METHODS: In vitro study, Ro5-4864 and PK 11,195 were utilized to pretreat cells prior to the inflammatory injury induced by Lipopolysaccharide. The reactive oxygen species, the apoptosis of cell, the mitochondrial membrane potentials, the ultrastructures of the mitochondria and the expression levels of peripheral benzodiazepine receptors and apoptosis-related proteins and genes were detected. In vivo study, mice were administrated intraperitoneally with Ro5-4864 and PK 11,195 before sensitized and challenged by ovalbumin. Serum IgE and bronchoalveolar lavage fluid cytokines were detected, and lung tissues were underwent the histopathological examination. RESULTS: The ligands of peripheral benzodiazepine receptor counteracted the effects of the increase of reactive oxygen species, the elevated extent of apoptosis, the decrease of mitochondrial membrane potentials and the disruption of mitochondrial ultrastructures induced by Lipopolysaccharide. The ligands also promoted the expression of anti-apoptosis-related proteins and genes and inhibited the expression of pro-apoptosis-related proteins and genes. Besides, the ligands reduced the levels of serum IgE and bronchoalveolar lavage fluid cytokines in asthmatic mice and attenuated the histopathological damage of lungs. CONCLUSION: Peripheral benzodiazepine receptor serves as a potential therapeutic target for the treatment of asthma, with its ligands exerting mitochondrial protective and anti-apoptotic effects on bronchial epithelial cells.

Long-term exposure to ambient ozone and adult-onset asthma: A prospective cohort study.

BACKGROUND: The association between long-term exposure to ozone (O3) and adult-onset asthma (AOA) remains inconclusive, and analysis of causality is lacking. OBJECTIVES: To examine the causal association between long-term O3 exposure and AOA. METHODS: A prospective cohort study of 362,098 participants was conducted using the UK Biobank study. Incident cases of AOA were identified using health administrative data of the National Health Services. O3 exposure at participants' residential addresses was estimated by a spatio-temporal model. Instrumental variable (IV) modelling was used to analyze the causal association between O3 exposure and AOA, by incorporating wind speed and planetary boundary layer height as IVs into time-dependent Cox model. Negative control outcome (accidental injury) was also used to additionally evaluate unmeasured confounding. RESULTS: During a mean follow-up of 11.38 years, a total of 10,973 incident AOA cases were identified. A U-shaped concentration-response relationship was observed between O3 exposure and AOA in the traditional Cox models with HR of 0.916 (95% CI: 0.888, 0.945) for O3 at low levels (<38.17 ppb), and 1.204 (95% CI: 1.168, 1.242) for O3 at high levels (≥38.17 ppb). However, in the IV analysis we only found a statistically significant association between high-level O3 exposure and AOA risk, but not for low-level O3 exposure. No significant associations between O3 exposure and accidental injury were observed. CONCLUSION: Our findings suggest a potential causal relationship between long-term exposure to high-level ambient O3 and increased risks of AOA.

Suboptimal peak inspiratory flow rate: a noticeable risk factor for inhaler concordance in patients with chronic airway diseases.

BACKGROUND: Inhaler concordance and the peak inspiratory flow rate (PIFR) are important determinants of treatment effects in patients with chronic airway diseases. Adequate PIFR is required for driving aerosol medication into the lower respiratory tract. However, the relationship between them has not been discussed previously. This study aimed to describe the characteristics of inhaler concordance and PIFR in Chinese patients with chronic airway diseases and discuss the associated variables and the relationship between them. METHODS: In this single-centre, observational study, a total of 680 patients with chronic airway diseases were enrolled from July 2021 to April 2023. We collected data on the socio-demographic and clinical variables of inhaler concordance using the test of adherence to inhalers (TAI) and PIFR. Multivariate logistic regression was conducted to examine variables related to inhaler concordance and PIFR. RESULTS: A total of 49.4% of patients had low concordance. Patients with chronic obstructive pulmonary disease (COPD) were more concordant than patients with asthma (mean TAI score: 43.60 vs 41.20; p<0.01), while there was no difference in concordance between the asthma-COPD overlap group and the asthma or COPD group. Suboptimal PIFR (adjusted OR, 1.61; 95% CI 1.04 to 2.51) increased the risk of poor concordance among all patients, while triple therapy (adjusted OR, 0.60; 95% CI 0.35 to 0.86) reduced the risk. A total of 54.9% of patients had suboptimal PIFR. Older age, lower educational level, use of dry powder inhalers and lower forced expiratory volume in 1 s % predicted were significantly correlated with insufficient PIFR. Subgroup analysis revealed a greater proportion of patients with insufficient PIFR during exacerbation than during the stable phase (61.7% vs 43.5%, p<0.001). CONCLUSION: Inhaler concordance was low, and suboptimal PIFR was a risk factor for poor concordance among Chinese patients with chronic airway diseases. In addition, current inhalation devices may not be suitable, and PIFR reassessment should be considered for patients with COPD during exacerbation. TRIAL REGISTRATION NUMBER: The study was registered in chictr.org.cn (ChiCTR2100052527) on 31 October 2021.

PPARγ attenuates cellular senescence of alveolar macrophages in asthma-COPD overlap.

BACKGROUND: Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) represents a complex condition characterized by shared clinical and pathophysiological features of asthma and COPD in older individuals. However, the pathophysiology of ACO remains unexplored. We aimed to identify the major inflammatory cells in ACO, examine senescence within these cells, and elucidate the genes responsible for regulating senescence. METHODS: Bioinformatic analyses were performed to investigate major cell types and cellular senescence signatures in a public single-cell RNA sequencing (scRNA-Seq) dataset derived from the lung tissues of patients with ACO. Similar analyses were carried out in an independent cohort study Immune Mechanisms Severe Asthma (IMSA), which included bulk RNA-Seq and CyTOF data from bronchoalveolar lavage fluid (BALF) samples. RESULTS: The analysis of the scRNA-Seq data revealed that monocytes/ macrophages were the predominant cell type in the lung tissues of ACO patients, constituting more than 50% of the cells analyzed. Lung monocytes/macrophages from patients with ACO exhibited a lower prevalence of senescence as defined by lower enrichment scores of SenMayo and expression levels of cellular senescence markers. Intriguingly, analysis of the IMSA dataset showed similar results in patients with severe asthma. They also exhibited a lower prevalence of senescence, particularly in airway CD206 + macrophages, along with increased cytokine expression (e.g., IL-4, IL-13, and IL-22). Further exploration identified alveolar macrophages as a major subtype of monocytes/macrophages driving cellular senescence in ACO. Differentially expressed genes related to oxidation-reduction, cytokines, and growth factors were implicated in regulating senescence in alveolar macrophages. PPARγ (Peroxisome Proliferator-Activated Receptor Gamma) emerged as one of the predominant regulators modulating the senescent signature of alveolar macrophages in ACO. CONCLUSION: The findings suggest that senescence in macrophages, particularly alveolar macrophages, plays a crucial role in the pathophysiology of ACO. Furthermore, PPARγ may represent a potential therapeutic target for interventions aimed at modulating senescence-associated processes in ACO.Key words ACO, Asthma, COPD, Macrophages, Senescence, PPARγ.

Stigmasterol alleviates airway inflammation in OVA-induced asthmatic mice via inhibiting the TGF-ß1/Smad2 and IL-17A signaling pathways.

Stigmasterol is a common dietary phytosterol with high nutritional value and physiological activity. In this study, we evaluated the effects of stigmasterol on inflammatory cytokines and the TGF-ß1/Smad2 and IL-17A signaling pathway in an ovalbumin (OVA)-induced asthma mouse model. Stigmasterol treatment improved airway remodeling. In addition, it significantly attenuated the symptoms of asthma attacks, reduced the number of macrophages, lymphocytes, neutrophils, and eosinophils in BALF and inflammatory cytokines, including IL-1ß, IL-5, IL-6, and IL-13. It further decreased the level of IL-17A in BALF, serum and spleen. Spleen single-cell suspension analysis via flow cytometry showed that IL-17A level was consistent with the results obtained in BALF, serum and spleen. Stigmasterol decreased the protein expression levels of TGF-ß, p-Smad2 and IL-17A in the spleen, by increasing the protein expression level of IL-10. After 24 h of co-culture of TGF-ß, IL-6 and stigmasterol, the level of IL-17 in CD4+ T cell supernatant was lower relative to levels in the group without stigmasterol. Meanwhile, stigmasterol treatment attenuated the expression level of TGF- ß, p-Smad2 and IL-17A proteins in CD4+ T cells and enhanced the expression levels of IL-10 protein. These data suggested that stigmasterol inhibited the TGF-ß1/Smad2 and IL-17A signaling pathway to achieve anti-asthmatic effects in the OVA-induced asthma mouse model. Collectively, the results of this study are that stigmasterol has achieved preliminary efficacy in the non-clinical laboratory, further studies are needed to consider the clinical application of stigmasterol.

Childhood asthma biomarkers including zinc: An exploratory cross-sectional study.

BACKGROUND: Childhood bronchial asthma (BA) is a chronic inflammatory respiratory disease. Nutritional conditions, including zinc deficiency, can affect such allergic disorders. AIM: To outline the difference in serum zinc levels between asthmatic children and healthy controls. METHODS: A cross-sectional study was carried out at Children's Hospital, Cairo University, investigating serum zinc levels in children with BA (n = 40) and healthy children (n = 21). Other markers included serum ferritin, iron, hemoglobin (Hb), and immunoglobulin E (IgE) levels. Independent t-tests and Mann-Whinny tests were used for comparisons. The Kruskal-Wallis test was applied to compare serum ferritin and IgE levels with regard to asthma severity. Spearman's rank correlation was performed to explore the relationship between serum ferritin levels and both iron and Hb levels in asthmatic children. RESULTS: Children with BA had higher levels of zinc, yet the difference was not significant (P = 0.115). Serum ferritin and IgE levels were significantly higher in asthmatic children (P = 0.006 and 0.001, respectively), yet their levels did not differ significantly by severity (P = 0.623 and 0.126, respectively). There was a nonsignificant weak correlation between serum ferritin levels and both serum iron and Hb levels. CONCLUSION: Serum zinc levels do not seem to differ between asthmatic children and healthy children. Serum ferritin levels may be a marker of asthma control. Serum IgE levels are not markers of asthma severity.

Respiratory-related deaths and associated factors in Alicho-Weriro district, southern Ethiopia: verbal autopsy data analysis.

BACKGROUND: Respiratory diseases disproportionately affect people living in resource-limited settings. However, obtaining information that explains respiratory-related deaths has been difficult, mainly due to a lack of medical certification of death and the fact that most deaths occur outside of health institutions. This study aimed to determine the proportion of respiratory-related deaths and identify associated factors in Alicho-Weriro district, southern Ethiopia, using the verbal autopsy method. METHODS: A community-based cross-sectional study was conducted from April to June 2022. All deceased people in the study area from January 2020 to December 2021 were included in the study. Trained physicians ascertained the cause of death from verbal autopsy data that were collected using a pre-tested and modified WHO-designed questionnaire. The binary logistic regression models were used to identify factors associated with respiratory-related deaths. RESULTS: Respiratory-related deaths accounted for 25% of the deaths from all causes, with 20.8% of male and 29.5% of female deaths. Of which, 9.7% were from tuberculosis, 8.3% were from asthma and 6.2% were from acute lower-respiratory tract infections. Moreover, being female (adjusted OR, AOR: 3.3; 95% CI: (1.75 to 6.22)), age 50-64 years (AOR: 9.3; 95% CI: (1.16 to 73.90)), age above 64 years (AOR: 8.9; 95% CI: (1.130 to 70.79)), family size of five persons or more (AOR: 1.9; 95% CI: (1.15 to 3.29)), smoking (AOR: 3.9; 95% CI: (1.86 to 8.35)), using wood and/or animal dung for household cooking (AOR: 6.6; 95% CI: (1.92 to 22.59)) and poor house ventilation (AOR: 3.1; 95% CI: (1.75 to 5.38)) were significantly associated with increased odds of dying from respiratory-related diseases. CONCLUSION: This study has determined that about a quarter of deaths from all causes were due to respiratory diseases, mainly tuberculosis, asthma and acute lower respiratory tract infections. Therefore, interventions to reduce this burden should focus on supporting early case detection and treatment, promoting healthy lifestyles, exercising women's equality at the household level and improving housing conditions.