Heterogeneous Airway Disease Research Articles

Upper Airway Comorbidities of Asthma.

Asthma, characterized as a chronic heterogeneous airway disease, often presents with common comorbid conditions. The concept of 'one-airway-one-disease' was coined, emphasizing the connection between asthma and upper airway comorbidities (UACs) such as allergic or non-allergic rhinitis, chronic rhinosinusitis with or without nasal polyps, and aspirin/nonsteroidal anti-inflammatory drug-exacerbated respiratory disease more than 20 years ago. Since then, numerous studies demonstrate that UACs are closely related and affect asthma phenotypes. Recognizing and managing these UACs are crucial aspects of comprehensive asthma care. Addressing these conditions as part of asthma treatment can lead to better control of symptoms, improved lung function and the quality of life. Moreover, it is important to explore the field of respiratory biologics that represent the latest advancements in medical treatment options for asthma patients with UACs.

Chinese expert consensus on the etiological diagnosis of adult bronchiectasis

Bronchiectasis is a highly heterogeneous chronic airway disease for which accurate etiological diagnosis is crucial for effective management. A group of experts from the China Bronchiectasis Alliance and the Infection Assembly of the Chinese Thoracic Society conducted a comprehensive review of recent research into the etiology of bronchiectasis. Using the widely accepted Delphi methodology, the experts reached a consensus on the etiological diagnosis of bronchiectasis through multiple rounds of discussion and revision. The consensus is divided into four sections: the definition and classification of the etiology of bronchiectasis, the etiological diagnostic procedures for bronchiectasis, the treatable causes of bronchiectasis, and other causes of bronchiectasis. The ultimate goal of this consensus is to improve the diagnostic accuracy and optimize the management of bronchiectasis in China. The main recommendations of Section 1 focused on chest thin-section computed tomography (CT) for the diagnosis of bronchiectasis and the etiological classification. The main recommendations of Section 2 focused on the medical history collection for bronchiectasis and the etiological diagnostic protocol for bronchiectasis. The main recommendations of Section 3 focused on the recommendations of the diagnosis of bronchiectasis secondary to COPD, the diagnosis of bronchiectasis due to asthma, diffuse pan-bronchiolitis, allergic bronchopulmonary aspergillosis, connective tissue disease (CTD)-related bronchiectasis or gastroesophageal reflux disease (GERD)-related bronchiectasis. The main recommendations of Section 4 focused on suspected primary ciliary dyskinesia (PCD)-associated bronchiectasis, cystic fibrosis and the diagnosis of congenital airway malformations.

Combination of androgen and estrogen improves asthma by mediating Runx3 expression.

Objective: Asthma is a chronic heterogeneous airway disease, and imbalanced T-helper type 1 (Th1) and Th2 cell-mediated inflammation contribute to its pathogenesis. Although it has been suggested that androgen and estrogen were involved in development of asthma, the underlying mechanisms remained largely unclear. Studies have demonstrated that Runx3 could promote naive CD4+ T cells to differentiate into Th1 cells. Hence, our study aimed to explore the potential regulatory mechanism of androgen and estrogen on asthma via modulating Runx3. Methods: First, clinical assessments and pulmonary function tests were conducted on 35 asthma patients and 24 healthy controls. The concentrations of androgen, estrogen, and androgen estrogen ratios were assessed in peripheral blood samples of asthma patients and healthy controls. Then, a murine asthma model was established to explore the effects of estrogen and androgen (alone or in combination) on asthma. Third, an in vitro assay was used to explore the mechanism of combination of androgen and estrogen in asthma. Results: We observed decreased androgen and increased estrogen levels in asthma patients compared with healthy controls. In mice with experimental asthma, there were increased serum concentrations of estrogen and decreased serum concentrations of androgen, intervention with combination of androgen and estrogen alleviated airway inflammations, increased Runx3 expressions and elevated Th1 differentiation. In CD4+ T cells co-cultured with bronchial epithelial cells (BECs), treatment with androgen plus estrogen combination promoted Th1 differentiation, which was mitigated by Runx3 knockdown in BECs and enhanced by Runx3 overexpression. Conclusion: These findings suggest that androgen estrogen combination modulate the Th1/Th2 balance via regulating the expression of Runx3 in BECs, thereby providing experimental evidence supporting androgen and estrogen combination as a novel therapy for asthma.

The SMYD3-dependent H3K4me3 status of IGF2 intensifies local Th2 differentiation in CRSwNP via positive feedback

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous and common upper airway disease divided into various inflammatory endotypes. Recent epidemiological findings showed a T helper 2 (Th2)-skewed dominance in CRSwNP patients. Histone modification alterations can regulate transcriptional and translational expression, resulting in abnormal pathogenic changes and the occurrence of diseases. Trimethylation of histone H3 lysine 4 (H3K4me3) is considered an activator of gene expression through modulation of accessibility for transcription, which is closely related to CRSwNP. H3K4me3 levels in the human nasal epithelium may change under Th2-biased inflammatory conditions, resulting in exaggerated local nasal Th2 responses via the regulation of naïve CD4+ T-cell differentiation. Here, we revealed that the level of SET and MYND domain-containing protein 3 (SMYD3)-mediated H3K4me3 was increased in NPs from Th2 CRSwNP patients compared with those from healthy controls. We demonstrated that SMYD3-mediated H3K4me3 is increased in human nasal epithelial cells under Th2-biased inflammatory conditions via S-adenosyl-L-methionine (SAM) production and further found that the H3K4me3high status of insulin-like growth factor 2 (IGF2) produced in primary human nasal epithelial cells could promote naïve CD4+ T-cell differentiation into Th2 cells. Moreover, we found that SAM production was dependent on the c-Myc/methionine adenosyltransferase 2A (MAT2A) axis in the nasal epithelium. Understanding histone modifications in the nasal epithelium has immense potential utility in the development of novel classes of therapeutics targeting Th2 polarization in Th2 CRSwNP.Et9-hJKHbB2Mg3CRtXWvn_Video

Prospective Real-World Analysis of Asthma Patients With Preserved and Reduced Physical Activity.

Asthma is a highly heterogeneous airway disease, and the clinical characteristics of patients with asthma with preserved and reduced physical activity are poorly understood. We aimed to investigate the risk factors and clinical phenotypes associated with reduced physical activity in a wide range of patients with asthma. We conducted a prospective observational study of 138 patients with asthma, including patients with asthma without chronic obstructive pulmonary disease (COPD) (n= 104) and asthma-COPD overlap (n= 34), and 42 healthy controls. Physical activity levels were measured for 2 weeks using a triaxial accelerometer at baseline and 1 year later. Higher eosinophils and body mass index (BMI) were associated with reduced physical activity in patients with asthma without COPD. Cluster analysis of asthma without COPD revealed 4 asthma phenotypes. We identified a cluster with preserved physical activity (n= 43) that was characterized by good symptom control and lung function and included a high proportion of biologics users (34.9%). Multivariate regression analysis revealed that patients with late-onset eosinophilic (n= 21), high-BMI noneosinophilic (n= 14), and symptom-predominant asthma phenotypes (n= 26) had lower levels of physical activity than controls. Patients with asthma-COPD overlap also had significantly lower physical activity levels than controls. Similar trends in physical activity levels were observed in each asthma group at 1-year follow-up. This study showed the clinical features of patients with asthma with preserved and reduced physical activity. Reduced physical activity was observed in various asthma phenotypes and in asthma-COPD overlap.

Dosimetry Sensitivity in a Lower Dimensional Model of Patient-Specific Asthma Subjects.

Experimental uncertainty will impact in silico model calculations of aerosol delivery and deposition. Patient-specific dosimetry models are often parameterized based on medical imaging data, which contain inherent experimental variability. Here, we created and parameterized 1D models of three subject-specific asthmatic subjects and randomly assigned perturbations of up to 15 % on airway diameter, segmental volume, and defected volume. Sensitivity of imaging data experimental variability on dosimetry metrics were quantified. Lobar particle delivery primarily depended on the distal segmental volumes; 15 % range of noise resulted in delivery to the upper right lobe to vary at most from 15.2 and 18.2 % for one of the severe subjects. Particle deposition was most sensitive to airway diameter; 95 % confidence intervals spanned from 8 to 10.6 % in the mild/moderate subject for 15 % variation on input metrics for 5 [Formula: see text] diameter particles. While these results provide possible ranges of dosimetry calculations for a specific subject, the perturbations were not sufficient to model the large observed inter-subject variability (8.9, 19, and 14.5 % deposition, subjects 1--3, respectively, 5 [Formula: see text] diameter particles). This study highlights that in silico model predictions are robust in the presence of experimental uncertainty and that it continues to be necessary to perform subject-specific simulations, especially within the presence of heterogeneous airway disease. Sensitivity analysis provides confidence in calculating deposition in the airways of asthmatic subjects within the presence of experimental uncertainty.

Mepolizumab in chronic rhinosinusitis with nasal polyposis.

Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a heterogeneous upper airway disease that is prevalent globally. Recent research into the molecular basis of the disease has led to the development of biologics as a new therapeutic option for severe and recalcitrant forms of CRSwNP. Mepolizumab is a monoclonal antibody targeting IL-5, one of the signature cytokines of the type 2 immune response and which plays an important role in the pathogenesis of CRSwNP. Here we present the latest evidence behind mepolizumab, examining disease pathophysiology and pharmacology, as well as data from clinical trials, real-life studies and meta-analyses. As we welcome this promising step forward into precision medicine, we discuss practical issues and future perspectives on mepolizumab and biologics for CRSwNP.

Programmed Cell Death in Asthma: Apoptosis, Autophagy, Pyroptosis, Ferroptosis, and Necroptosis.

Bronchial asthma is a complex heterogeneous airway disease, which has emerged as a global health issue. A comprehensive understanding of the different molecular mechanisms of bronchial asthma may be an efficient means to improve its clinical efficacy in the future. Increasing research evidence indicates that some types of programmed cell death (PCD), including apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis, contributed to asthma pathogenesis, and may become new targets for future asthma treatment. This review briefly discusses the molecular mechanism and signaling pathway of these forms of PCD focuses on summarizing their roles in the pathogenesis and treatment strategies of asthma and offers some efficient means to improve clinical efficacy of therapeutics for asthma in the near future.

Calcium-Sensing Receptor Negative Allosteric Modulators Oppose Contraction of Mouse Airways.

Asthma is a heterogeneous chronic airways disease with an unmet need for improved therapeutics in uncontrolled severe disease. The calcium-sensing receptor (CaSR) is a G protein-coupled receptor upregulated in asthma. The CaSR agonist, spermine, is also increased in asthmatic airways and contributes to bronchoconstriction. CaSR negative allosteric modulators (NAMs) oppose chronic airway inflammation, remodelling and hyperresponsiveness in murine and guinea pig asthma models, but whether CaSR NAMs are effective acute bronchodilators compared to standard-of-care has not yet been established. Further, the ability of different classes of NAMs to inhibit spermine-induced CaSR signaling or MCh-induced airway contraction has not been quantified. Here, we show CaSR NAMs differentially inhibit spermine-induced intracellular calcium mobilisation and inositol monophosphate accumulation in HEK293 cells stably expressing the CaSR. NAMs reverse methacholine (MCh)-mediated airway contraction in mouse precision cut lung slices with similar maximal relaxation compared to the standard treatment, salbutamol. Of note, the bronchodilator effects of CaSR NAMs are maintained under conditions of β2 adrenergic receptor desensitization when salbutamol efficacy is abolished. Furthermore, overnight treatment with some, but not all, CaSR NAMs prevents MCh-mediated bronchoconstriction. These findings further support the CaSR as a putative drug target, and NAMs as alternative or adjunct bronchodilators, in asthma.

Noncoding RNAs in asthmatic airway smooth muscle cells.

Asthma is a complex and heterogeneous airway disease caused by genetic, environmental and epigenetic factors treated with hormones and biologics. Irreversible pathological changes to airway smooth muscle cells (ASMCs) such as hyperplasia and hypertrophy can occur in asthmatic patients. Determining the mechanisms responsible is vital for preventing such changes. In recent years, noncoding RNAs (ncRNAs), especially microRNAs, long noncoding RNAs and circular RNAs, have been found to be associated with abnormalities of the ASMCs. This review highlights recent ncRNA research into ASMC pathologies. We present a schematic that illustrates the role of ncRNAs in pathophysiological changes to ASMCs that may be useful in future research in diagnostic and treatment strategies for patients with asthma.

New insights into autophagy in inflammatory subtypes of asthma.

Asthma is a heterogeneous airway disease characterized by airway inflammation and hyperresponsiveness. Autophagy is a self-degrading process that helps maintain cellular homeostasis. Dysregulation of autophagy is involved in the pathogenesis of many diseases. In the context of asthma, autophagy has been shown to be associated with inflammation, airway remodeling, and responsiveness to drug therapy. In-depth characterization of the role of autophagy in asthma can enhance the understanding of the pathogenesis, and provide a theoretical basis for the development of new biomarkers and targeted therapy for asthma. In this article, we focus on the relationship of autophagy and asthma, and discuss its implications for asthma pathogenesis and treatment.

Organization of biological therapy for patients with severe eosinophilic bronchial asthma in the Krasnoyarsk region

Patients with severe bronchial asthma, which remains uncontrolled despite the optimal basic therapy, carry a significant healthcare burden and require substantial financial investments. Severe asthma is a heterogeneous airway disease with complex pathophysiological mechanisms that can be broadly divided into inflammatory pathways with eosinophilic and non-eosinophilic inflammation.Aim. This study aimed to analyze the literature data on the use of targeted genetic engineering therapy in patients with severe bronchial asthma, as well as to analyze the organization of immunobiological therapy in the Krasnoyarsk Territory. The addition of targeted drugs for severe eosinophilic bronchial asthma based on phenotyping has proven to be effective and is recommended by all current guidelines. Today, several biologics targeting specific endotypes and phenotypes has been approved for the treatment of severe eosinophilic asthma worldwide. These are antibodies binding immunoglobulin E (omalizumab), antagonists of interleukin-5 (mepolizumab, reslizumab) and its receptor (benralizumab), as well as antibodies selectively binding to the IL-4 and IL-13 receptors (dupilumab). Eosinophilic inflammation therapy is a relatively new direction of asthma treatment, and understanding its long-term efficacy and safety is important.Conclusion. It is essential to differentiate patients with severe eosinophilic asthma from the general cohort of asthma patients, timely refer them to specialists who can prescribe this therapy and have experience with it, select the drug correctly, and monitor the patients during the treatment. This article describes organization of biological therapy for patients with severe eosinophilic bronchial asthma in the Krasnoyarsk Territory.

Life Course of Asthma.

Asthma is a heterogeneous chronic airway disease that can vary over a lifetime. Although broad categories of asthma by severity and type have been constructed, there remains a tremendous opportunity to discover an approach to managing asthma with additional factors in mind. Many in the field have suggested and are pursuing a novel paradigm shift in how asthma might be better managed, considering the life course of exposures, management priorities, and predicted trajectory of lung function growth. This approach will require a more holistic view of prenatal, postnatal, adolescence, hormonal and gender aspects, and the aging process. In addition, the environment, externally and internally, including in one's genetic code and epigenetic changes, are factors that affect how asthma progresses or becomes more stable in individuals. This chapter focuses on the various influences that may, to differing degrees, affect people with asthma, which can develop at any time in their lives. Shifting the paradigm of thought and strategies for care and advocating for public policies and health delivery that focus on this philosophy is paramount to advance asthma care for all.

The Establishment of China Bronchiectasis Registry and Research Collaboration (BE-China): Protocol of a prospective multicenter observational study

BackgroundBronchiectasis is a highly heterogeneous chronic airway disease with marked geographic and ethnic variations. Most influential cohort studies to date have been performed in Europe and USA, which serve as the examples for developing a cohort study in China where there is a high burden of bronchiectasis. The Establishment of China Bronchiectasis Registry and Research Collaboration (BE-China) is designed to: (1) describe the clinical characteristics and natural history of bronchiectasis in China and identify the differences of bronchiectasis between the western countries and China; (2) identify the risk factors associated with disease progression in Chinese population; (3) elucidate the phenotype and endotype of bronchiectasis by integrating the genome, microbiome, proteome, and transcriptome with detailed clinical data; (4) facilitate large randomized controlled trials in China.MethodsThe BE-China is an ongoing prospective, longitudinal, multi-center, observational cohort study aiming to recruit a minimum of 10,000 patients, which was initiated in January 2020 in China. Comprehensive data, including medical history, aetiological testing, lung function, microbiological profiles, radiological scores, comorbidities, mental status, and quality of life (QoL), will be collected at baseline. Patients will be followed up annually for up to 10 years to record longitudinal data on outcomes, treatment patterns and QoL. Biospecimens, if possible, will be collected and stored at − 80 °C for further research. Up to October 2021, the BE-China has enrolled 3758 patients, and collected 666 blood samples and 196 sputum samples from 91 medical centers. The study protocol has been approved by the Shanghai Pulmonary Hospital ethics committee, and all collaborating centers have received approvals from their local ethics committee. All patients will be required to provide written informed consent to their participation.ConclusionsFindings of the BE-China will be crucial to reveal the clinical characteristics and natural history of bronchiectasis and facilitate evidence-based clinical practice in China.Trial registration Registration Number in ClinicalTrials.gov: NCT03643653

Zeaxanthin attenuates OVA-induced allergic asthma in mice by regulating the p38 MAPK/β-catenin signaling pathway

Background: Asthma is a heterogeneous and complex chronic airway disease with a high incidence rate, characterized by chronic airway inflammation. Although the anti-inflammatory effect of zeaxanthin has been demonstrated in various disease models, its explicit role in allergic asthma remains elusive. Methods: An allergic asthma model was established by ovalbumin (OVA) stimulation in BALB/c nude mice. The pathological examination, collagen deposition and expression of α-smooth muscle actin (α-SMA) in lung tissues were determined by hematoxylin and eosin (H&E), MASSON and immunofluorescence staining, respectively. Besides, the effect of zeaxanthin on inflammation and oxidative stress was assessed by the enzyme-linked immunosorbent assay (ELISA) and spectrophotometry measure. Moreover, the underlying mechanism was analyzed by detecting the expression of phosphorylated p38 (p-p38), p38, β-catenin, p-c-Jun N-terminal kinase (p-JNK) and JNK with western blot assays. Results: The distinct infiltration of inflammatory cells was observed in the OVA-induced asthma mice model with significantly increased concentrations of immunoglobulin E (IgE), interleukin-4 (IL-4), IL-5, IL-13 and eotaxin (p˂0.001), which were prominently reversed by zeaxanthin treatment (p˂0.001). In addition, zeaxanthin treatment decreased the OVA-induced collagen deposition and α-SMA expression. A similar inhibitory effect of zeaxanthin on the oxidative stress was also observed in the OVA-induced asthma mice model, as evidenced by the prominent decrease of malondialdehyde (MDA) concentration and the remarkable increase of superoxide dismutase (SOD), glutathione S transferase (GST) and Glutathione (GSH) concentrations (p˂0.001). Moreover, zeaxanthin introduction markedly reduced the relative expressions of p-p38/p38, β-catenin and p-JNK/JNK in the OVA-induced asthma mice model (p˂0.001), indicating that zeaxanthin suppressed the p38 mitogen-activated protein kinase (p38 MAPK)/β-catenin signaling pathway in the OVA-induced asthma mice model. Conclusions: Zeaxanthin attenuated OVA-induced allergic asthma in mice via modulating the p38 MAPK/β-catenin signaling pathway.

Aerosol Biologics for the Treatment of Eosinophilic Asthma

Asthma is a heterogeneous chronic airway disease comprising of distinct phenotypes characterized by different immunopathophysiologic pathways, clinical features, disease severity, and response to treatment. The phenotypes of asthma include eosinophilic, neutrophilic, mixed cellularity, and paucigranulocytic asthma. Eosinophilic asthma is principally a T helper type 2 (Th2)-mediated airway disease. However, several other immune and structural cells secrete the cytokines implicated in the pathogenesis of eosinophilic asthma. Innate type 2 lymphoid cells, mast cells, basophils, and eosinophils secrete Th2 cytokines, such as interleukin-4 (IL-4), IL-13, and IL-5. Additionally, airway epithelial cells produce alarmin cytokines, including IL-25, IL-33, and thymic stromal lymphopoietin (TSLP). Alarmins are the key initiators of allergic inflammation at the sentinel mucosal surfaces. Innovative biotherapeutic research has led to the discovery of monoclonal antibodies which target and inhibit the immunopathological effects of the cytokines involved in the pathogenesis of eosinophilic asthma. Parenteral biologics targeting the inciting interleukins, include mepolizumab and reslizumab (anti-IL-5), benralizumab (anti-IL-5Rα), dupilumab (anti-4Rα), and tezelizumab (anti-TSLP). They have been shown to significantly reduce annualized exacerbation rates, improve asthma control, lung function, and quality of life. Currently, there are no pulmonary delivered aerosol biologics for topical treatment of asthma. CSJ117 is a potent neutralizing antibody Fab fragment against TSLP, formulated as a PulmoSol TM engineered powder, and is delivered to the lungs by a dry powder inhaler. Phase 2 placebo-controlled clinical trial evaluated the efficacy and safety of CSJ117. CSJ117 delivered as an inhaler attenuated the late asthmatic response (LAR), and the early asthmatic response (EAR) after allergen inhalation challenge (AIC) at day 84 of treatment. The maximum decrease in FVE1 from pre-AIC were significantly lower in the CSJ117 group compared to placebo (P = 029), during LAR. CSJ117 also significantly reduced fractional exhaled nitric oxide before AIC at day 83; and significantly reduced the allergen-induced increase in % sputum eosinophil count. Pulmonary delivery of biologics directly to the airway mucosal surface has several advantages over parenteral routes, particularly in treating airway diseases such as asthma. Inhaler delivered biologics, such as CSJ117 are innovative and attractive methods of future precision treatment of asthma, and other respiratory diseases.

Nonrespiratory Comorbidities in Asthma

Asthma is a chronic heterogeneous airway disease. Common comorbid conditions are often disproportionately present in severe asthma. Optimal care of patients with asthma requires the recognition and treatment of these comorbid conditions. This review outlines the pathophysiological mechanisms between nonrespiratory comorbid conditions and asthma and their effect on asthma outcomes. They include: type 2 diabetes mellitus, hypertension, atherosclerotic cardiovascular disease, adrenal and thyroid gland diseases, pregnancy, osteoporosis, adverse effects from medications, and mental health disorders. Studies indicate how poor glycemic control of type 2 diabetes mellitus is associated with not only greater health care utilization but poorer asthma outcomes. Also, a large health care claims database indicates that a substantial proportion of pregnant women have uncontrolled asthma and are prescribed suboptimal controller therapy. Additional data about these nonrespiratory comorbidities and medications known to benefit both nonrespiratory comorbidities and asthma are necessary.

Pediatric asthma

Introduction Asthma is a heterogeneous chronic airway disease that is common in childhood. Childhood asthma is commonly related to other atopic diseases. The potential correlation of allergic sensitization and asthma in children has been contributed to the allergic model of the March. Aim The study aims to estimate the age of onset of asthma in children in Minia governorate, in middle Egypt, and also to see the presenting features of bronchial asthma in our locality and compare this with what is present in different parts of the world. Patients and methods This study was carried out in the Pediatric and Chest Departments of Minia University hospitals. The study included 100 children with a clear diagnosis of bronchial asthma. Detailed medical history concerned mainly with the respiratory events were recorded between birth and the time of study enrollment. This also included some asthma family history or other allergic disorders (allergic rhinitis, eczema, and allergic conjunctivitis). Results In most cases, asthma symptoms started less than 1 year of age (64% of the studied group). Asthma symptoms started between the age of 1.1 and 2 years in 16% of patients and above 6 years of age in only 12% of cases. Overall, 40% of the studied group had a positive family history of bronchial asthma in their mothers and 44% of them had a positive family history of bronchial asthma in their fathers. Only 10% of the studied group had a positive family history of bronchial asthma of both parents. Conclusion A great portion of asthmatic children fulfill the criteria of bronchial asthma diagnosis in the first year of their life. Only a small portion of asthmatic children start their asthma after the age of 6 years.

Heterogeneity of Childhood Asthma in Korea: Cluster Analysis of the Korean Childhood Asthma Study Cohort.

PurposeAsthma is a heterogeneous airway disease occurring in children, and it has various clinical phenotypes. A clear differentiation of the clinical phenotypes can provide better asthma management and prediction of asthma prognosis. Little is currently known about asthma phenotypes in Korean children. This study was designed to identify asthma phenotypes in school-aged Korean children.MethodsThis study enrolled 674 children with physician-diagnosed asthma from the Korean childhood Asthma Study (KAS) cohort. The physicians verified the relevant histories of asthma and comorbid diseases, as well as airway lability and hyper-responsiveness from the results of pulmonary function tests and bronchial provocation tests. Questionnaires regarding the participants' baseline characteristics, their environment and self-rating of asthma control were collected at the time of enrollment. Laboratory tests were performed to assess allergy and airway inflammation. Children with asthma were classified by hierarchical cluster analysis.ResultsOf the 674 patients enrolled from the KAS cohort, 447 were included in the cluster analysis. Cluster analysis of these 447 children revealed 4 asthma phenotypes: cluster 1 (n = 216, 48.3%) which was characterized by male-dominant atopic asthma; cluster 2 (n = 79, 17.7%) which was characterized by early-onset atopic asthma with atopic dermatitis; cluster 3 (n = 47, 10.5%) which was characterized by puberty-onset, female-dominant atopic asthma with the low lung function; and cluster 4 (n = 105, 23.5%) which was characterized by early-onset, non-atopic dominant asthma.ConclusionsThe asthma phenotypes among Korean children can be classified into 4 distinct clusters. Long-term follow-up with these phenotypes will be needed to define their prognosis and response to treatment.

Breath Hold Facilitates Targeted Deposition of Aerosolized Droplets in a 3D Printed Bifurcating Airway Tree.

The lungs have long been considered a desired route for drug delivery but, there is still a lack of strategies to rationally target delivery sites especially in the presence of heterogeneous airway disease. Furthermore, no standardized system has been proposed to rapidly test different ventilation strategies and how they alter the overall and regional deposition pattern in the airways. In this study, a 3D printed symmetric bifurcating tree model mimicking part of the human airway tree was developed that can be used to quantify the regional deposition patterns of different delivery methodologies. The model is constructed in a novel way that allows for repeated measurements of regional deposition using reusable parts. During ventilation, nebulized ~3-micron-sized fluid droplets were delivered into the model. Regional delivery, quantified by precision weighing individual airways, was highly reproducible. A successful strategy to control regional deposition was achieved by combining an inspiratory wave form with a "breath hold" pause after each inspiration. Specifically, the second generation of the tree was successfully targeted, and deposition was increased by up to four times in generation 2 when compared to a ventilation without the breath hold (p < 0.0001). Breath hold was also demonstrated to facilitate deposition into blocked regions of the model, which mimic airway closure during an asthma that receive no flow during inhalation. Additionally, visualization experiments demonstrated that in the absence of fluid flow, the deposition of 3-micron water droplets is dominated by gravity, which, to our knowledge, has not been confirmed under standard laboratory conditions.