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    Targeting of Inhaled Therapeutics to the Small Airways: Nanoleucine Carrier Formulations. Miller Danforth P,Tarara Thomas E,Weers Jeffry G Pharmaceutics Current dry powder formulations for inhalation deposit a large fraction of their emitted dose in the upper respiratory tract where they contribute to off-target adverse effects and variability in lung delivery. The purpose of the current study is to design a new formulation concept that more effectively targets inhaled dry powders to the large and small airways. The formulations are based on adhesive mixtures of drug nanoparticles and nanoleucine carrier particles prepared by spray drying of a co-suspension of leucine and drug particles from a nonsolvent. The physicochemical and aerosol properties of the resulting formulations are presented. The formulations achieve 93% lung delivery in the Alberta Idealized Throat model that is independent of inspiratory flow rate and relative humidity. Largely eliminating URT deposition with a particle size larger than solution pMDIs is expected to improve delivery to the large and small airways, while minimizing alveolar deposition and particle exhalation. 10.3390/pharmaceutics13111855
    Particle deposition in tracheobronchial airways of an infant, child and adult. Deng Qihong,Ou Cuiyun,Chen Jiao,Xiang Yuguang The Science of the total environment BACKGROUND:Particle deposition in human airways is important for assessing both health effects of inhaled particles and therapeutic efficacy of inhaled drug aerosols, but is not well understood for infants and children. OBJECTIVE:We investigate particle deposition in infants and children by using computational fluid dynamics (CFD), and compare this with particle deposition in adults. METHODS:We chose three population age groups: 7-month infant, 4-year old child, and 20-year old adult. Both airway structures and breathing conditions are considered to vary as a human grows from infancy to adulthood. We investigated deposition of micron-size particles (1-10μm) in both the upper (G3-G6) and lower (G9-G12) tracheobronchial (TB) airways under sedentary conditions. RESULTS:We found that particle deposition in both upper and lower airways is the highest in an infant, next in a child, and lowest in an adult. As age increases, particle deposition decreases in the upper airways but increases in the lower. For infants, inertial impaction is the dominant deposition mechanism, thus particles are deposited more in the upper airways than in the lower. However, particles are deposited more in the lower airways than in the upper in adults, as gravitational sedimentation is the dominant deposition mechanism. CONCLUSION:Given the differences in the airway structure and particle deposition mechanisms, particle deposition in infants and children differs from that in adults, not only in the efficiency of deposition but also in the site. Our findings provide evidence that "children are not small adults". 10.1016/j.scitotenv.2017.08.240
    Genetic variants of small airways and interstitial pulmonary disease in children. Alsamri Mohammed T,Alabdouli Amnah,Alkalbani Alia M,Iram Durdana,Tawil Mohamed I,Antony Priya,Vijayan Ranjit,Souid Abdul-Kader Scientific reports Genetic variants of small airways and interstitial pulmonary disease have not been comprehensively studied. This cluster of respiratory disorders usually manifests from early infancy ('lung disease in utero'). In this study, 24 variants linked to these entities are described. The variants involved two genes associated with surfactant metabolism dysfunction (ABCA3 and CSF2RB), two with pulmonary fibrosis (MUC5B and SFTP), one with bronchiectasis (SCNN1B), and one with alpha-1-antitrypsin deficiency (SERPINA1). A nonsense variant, MUC5B:c.16861G > T, p.Glu5621*, was found in homozygous state in two siblings with severe respiratory disease from birth. One of the siblings also had heterozygous SFTPA1:c.675C > G, p.Asn225Lys, which resulted in a more severe respiratory disease. The sibling with only the homozygous MUC5B variant had lung biopsy, which showed alveolar simplification, interstitial fibrosis, intra-alveolar lipid-laden macrophages, and foci of foreign body giant cell reaction in distal airspaces. Two missense variants, MUC5B:c.14936 T > C, p.Ile4979Thr (rs201287218) and MUC5B:c.16738G > A, p.Gly5580Arg (rs776709402), were also found in compound heterozygous state in two siblings with severe respiratory disease from birth. Overall, the results emphasize the need for genetic studies for patients with complex respiratory problems. Identifying pathogenic variants, such as those presented here, assists in effective family counseling aimed at genetic prevention. In addition, results of genetic studies improve the clinical care and provide opportunities for participating in clinical trials, such as those involving molecularly-targeted therapies. 10.1038/s41598-021-81280-x
    Ultrafine particle exposure and biomarkers of effect on small airways in children. Environmental research The small size and large surface area of ultrafine particles (UFP) enhance their ability to deposit in the lung periphery and their reactivity. The Ultrafine Particles from Traffic Emissions and Children's Health (UPTECH) cross-sectional study was conducted in 8-11-year-old schoolchildren attending 25 primary (elementary) schools, randomly selected from the Brisbane Metropolitan Area, Queensland, Australia. Main study findings outlined indirect evidence of distal airway deposition (raised C reactive protein) but as yet, there is no direct evidence in the literature of effects of UFP exposure on peripheral airway function. We present further UPTECH study data from two sensitive peripheral airway function tests, Oscillometry and Multiple Breath Nitrogen Washout (MBNW), performed in 577 and 627 children (88% and 96% of UPTECH study cohort) respectively: mean(SD) age 10.1(0.9) years, 46% male, with 50% atopy and 14% current asthma. Bayesian generalised linear mixed effects regression models were used to estimate the effect of UFP particle number count (PNC) exposure on key oscillometry (airway resistance, (Rrs), and reactance, (Xrs)) and MBNW (lung clearance index, (LCI) and functional residual capacity, (FRC)) indices. We adjusted for age, sex, and height, and potential confounders including socio-economic disadvantage, PM and NO exposure. All models contained an interaction term between UFP PNC exposure and atopy, allowing estimation of the effect of exposure on non-atopic and atopic students. Increasing UFP PNC was associated with greater lung stiffness as evidenced by a decrease in Xrs [mean (95% credible interval) -1.63 (-3.36 to -0.05)%] per 1000#.cm]. It was also associated with greater lung stiffness (decrease in Xrs) in atopic subjects across all models [mean change ranging from -2.06 to -2.40% per 1000#.cm]. A paradoxical positive effect was observed for Rrs across all models [mean change ranging from -1.55 to -1.70% per 1000#.cm] (decreases in Rrs indicating an increase in airway calibre), which was present for both atopic and non-atopic subjects. No effects on MBNW indices were observed. In conclusion, a modest detrimental effect of UFP on peripheral airway function among atopic subjects, as assessed by respiratory system reactance, was observed extending the main UPTECH study findings which reported a positive association with a biomarker for systemic inflammation, C-reactive protein (CRP). Further studies are warranted to explore the pathophysiological mechanisms underlying increased respiratory stiffness, and whether it persists through to adolescence and adulthood. 10.1016/j.envres.2022.113860
    [Silent lung zone - application of multi-breath nitrogen washout test (MBNW) in the diagnosis of small airways diseases in children - preliminary report based on literature and own experience]. Walicka-Serzysko Katarzyna,Postek Magdalena,Sands Dorota Developmental period medicine Small airways are the site of pathological changes often in an early stage in many diseases such as asthma or cystic fibrosis. However this part of the airways is overlooked in conventional respiratory function tests and it is therefore often referred to as "silent lung zone". This paper presents the theoretical background of MBNW multi-breath nitrogen washout in the diagnosis of minor respiratory diseases. The technical issues related to the preparation of pediatric patients for the test. Clinical applications of the MBNW test results are still subject to a number of studies. There is hope for filling the gaps in the small airway function tests. Due to the authors' involvement in the diagnosis and treatment of patients with cystic fibrosis, their own experience in the use of this study was also described. Currently, the method is in the phase of intensive analysis for the early diagnosis of lung disease in cystic fibrosis, when still other functional tests are in normal range or impossible to perform due to patient age. Correlation with medical imaging methods (chest computed tomography) and the severity of structural changes may in future limit the amount of radiology tests. In addition this can reduce the patient's exposure to ionizing radiation. Introduction of lung function tests such a MBW in infants and preschool children with cystic fibrosis and other minor respiratory diseases may modify clinical management and improve prognosis.
    Abnormal small airways function in children with mild asthma. Singer Florian,Abbas Chiara,Yammine Sophie,Casaulta Carmen,Frey Urs,Latzin Philipp Chest BACKGROUND:Small airways disease is a hallmark in adults with persistent asthma, but little is known about small airways function in children with mild asthma and normal spirometry. We assessed ventilation heterogeneity, a marker of small airways function, with an easy tidal breath single-breath washout (SBW) technique in school-aged children with mild asthma and normal FEV1 and healthy age-matched control subjects. METHODS:The primary outcome was the double-tracer gas phase III slope (SDTG), an index of ventilation heterogeneity in acinar airways derived from the tidal double-tracer gas SBW test. The second outcome was the nitrogen phase III slope (SN2), an index of global ventilation heterogeneity derived from the tidal nitrogen SBW test using pure oxygen. Triplicate SBW and spirometry tests were performed in healthy children (n=35) and children with asthma (n=31) at baseline and in children with asthma after bronchodilation. RESULTS:Acinar (SDTG) but not global (SN2) ventilation heterogeneity was significantly increased in asthma despite normal FEV1. Of the 31 children with asthma, abnormal results were found for SDTG (≤-2 z scores) in 11; forced expiratory flow, midexpiratory phase (FEF25%-75%) in three; and FEV1 in zero. After bronchodilation, SDTG, SN2, FEF25%-75%, and FEV1 significantly changed (mean [95% CI] change from baseline, 36% [15%-56%], 38% [18%-58%], 17% [9-25%], and 6% [3%-9%], respectively). CONCLUSIONS:Abnormal acinar ventilation heterogeneity in one-third of the children suggests that small airways disease may be present despite rare and mild asthma symptoms and normal spirometry. The easy tidal SBW technique has considerable potential as a clinical and research outcome in children with asthma. 10.1378/chest.13-0784
    Small airways targeted treatment with smart nebulizer technology could improve severe asthma in children: a retrospective analysis. The Journal of asthma : official journal of the Association for the Care of Asthma OBJECTIVE:Conventional inhaler devices have a low efficacy in targeting small airways. Smart nebulizers can be used to increase deposition to small airways by adjusting the flow and depth of each inhalation based on patients 'individual inspiratory capacity. We investigated whether targeting of high dose inhaled corticosteroids (ICS) to small airways with a smart nebulizer could reduce exacerbation rate in children with severe asthma (SA). METHODS:We conducted a retrospective study in children with SA using a smart nebulizer (Akita® Jet nebulizer) for the administration of high dose ICS in our outpatient clinic at the Erasmus MC - Sophia Children's Hospital. Clinical data before and after start of treatment were collected. The primary outcome was exacerbation rate, defined as: number of asthma exacerbations for which oral corticosteroid courses (OCS) were prescribed. The exacerbation rate 1 year before treatment was compared with the exacerbation rate 1 year after start of treatment. Secondary outcomes were changes in spirometry parameters, hospital admissions and medication use. RESULTS:Data on OCS use was available for 28/31 patients. Median number of asthma exacerbations requiring OCS courses 1 year before decreased from 2 (interquartile range(IQR) 2) to 0.5 (IQR 3) 1 year after treatment ( = 0.021). Hospital admission decreased from 1 (IQR 3) to 0 (IQR 1)( = 0.028). FEV1, FEF and FEF were not significantly improved after one year of treatment with the smart nebulizer ( = 0.191;  = 0.248;  = 0.572). CONCLUSION:Targeting small airways with high dose ICS using a smart nebulizer resulted in a significant reduction in exacerbations requiring OCS after one year of treatment. 10.1080/02770903.2021.1996597
    Computer-aided classification of small airways dysfunction using impulse oscillometric features: a children-focused review. Avila Nancy,Nazeran Homer,Gordillo Nelly,Meraz Erika,Gochicoa Laura Biomedizinische Technik. Biomedical engineering Background and objective Spirometry, which is the most commonly used technique for asthma diagnosis, is often unsuitable for small children as it requires them to follow exact instructions and perform extreme inspiration and expiration maneuvers. In contrast, impulse oscillometry (IOS) is a child-friendly technique that could serve as an alternative pulmonary function test (PFT) for asthma diagnosis and control in children as it offers several advantages over spirometry. However, the complex test results of IOS may be difficult to be understood by practitioners due to its reliance on mechanical and electrical models of the human pulmonary system. Recognizing this reality, computer-aided decision systems could help to improve the utility of IOS. The main objective of this paper is to understand the current computer-aided classification research works on this topic. Methods This paper presents a methodological review of research works related to the computer-aided classification of peripheral airway obstruction using the IOS technique, which is focused on, but not limited to, asthmatic children. Publications that focused on computer-aided classification of asthma, peripheral dysfunction and/or small airway impairment (SAI) based on impulse oscillometric features were selected for this review. Results Out of the 34 articles that were identified using the selected scientific web databases and topic-related parameters, only eight met the eligibility criteria. The most relevant results of the articles reviewed are related to the performance of the different classifiers using static features which are solely based on the first pulmonary function testing measurements (IOS and spirometry). These results included an overall classifiers' accuracy performance ranging from 42.24% to 98.61%. Conclusion There is still a great opportunity to improve the utility of IOS by developing more computer-aided robust classifiers, specifically for the asthmatic children population as the classification studies performed to date (1) are limited in number, (2) include features derived from tests that are not optimally suitable for children, (3) are solely bi-class (mostly asthma and non-asthma) and therefore fail to include different degrees of peripheral obstruction for disease prevention and control and (4) lack of validation in cases that focus on multi-class classification of the different degrees of peripheral airway obstruction. 10.1515/bmt-2018-0219
    Current and future approaches to large airways imaging in adults and children. Semple T,Calder A,Owens C M,Padley S Clinical radiology "Large airways disease" is a catch-all phrase encompassing a wide variety of pathology affecting the trachea, main, lobar, segmental, and proximal sub-segmental bronchi. Relevant pathologies can be divided into focal or diffuse processes and many conditions have classic appearances on computed tomography (CT). We provide a review of the imaging specifics of a wide range of large airway pathologies in adult, childhood, and fetal life with examples of common and rare pathologies ranging from well-known entities such as cystic fibrosis and allergic bronchopulmonary aspergillosis to rarities such as Williams-Campbell, primary ciliary dyskinesia, and congenital high-airway obstruction syndrome (CHAOS). Although the spatial and temporal resolution of modern multidetector CT lends itself well to the depiction of small structures such as the peripheral airways, concerns regarding radiation exposure and increasing interest in the role of functional and quantitative imaging have led to a surge in research into dose reduction in CT and both structural and functional airway imaging via magnetic resonance imaging. We discuss the current literature on these emerging techniques along with some exiting near future directions for large airways imaging. 10.1016/j.crad.2017.01.012
    Evaluation of small airway function and its application in patients with chronic obstructive pulmonary disease (Review). Li Yan,Li Xin-Yang,Yuan Li-Rong,Wang Hai-Long,Pang Min Experimental and therapeutic medicine Chronic obstructive pulmonary disease (COPD) is a chronic airway inflammatory disease characterized by incomplete reversible airflow limitation. The diagnosis of COPD is mainly based on pulmonary function examination. In recent years, it has been indicated that small airway dysfunction occurs in patients with all stages of COPD, even in high-risk smoking groups who have not yet met the diagnostic criteria for COPD. Early recognition of small airway dysfunction and early initiation of small airway targeted therapy have become foci of research. In the present review, the methods of evaluating small airway function were summarized and their merits and shortcomings were discussed. Furthermore, the potential of targeted treatment of small airways in patients with COPD was outlined. 10.3892/etm.2021.10822
    Computed tomography-identified phenotypes of small airway obstructions in chronic obstructive pulmonary disease. Li Tao,Zhou Hao-Peng,Zhou Zhi-Jun,Guo Li-Quan,Zhou Linfu Chinese medical journal ABSTRACT:Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characteristic of small airway inflammation, obstruction, and emphysema. It is well known that spirometry alone cannot differentiate each separate component. Computed tomography (CT) is widely used to determine the extent of emphysema and small airway involvement in COPD. Compared with the pulmonary function test, small airway CT phenotypes can accurately reflect disease severity in patients with COPD, which is conducive to improving the prognosis of this disease. CT measurement of central airway morphology has been applied in clinical, epidemiologic, and genetic investigations as an inference of the presence and severity of small airway disease. This review will focus on presenting the current knowledge and methodologies in chest CT that aid in identifying discrete COPD phenotypes. 10.1097/CM9.0000000000001724
    [Effect of family with sequence similarity 13 member A gene interference on apoptosis and proliferation of human airway epithelial cells and its relationship with small airway remodeling in patients with chronic obstructive pulmonary disease]. Zhu J Y,Ma L Q,Zhang J Zhonghua yi xue za zhi To explore the relationship between family with sequence similarity 13 member A (FAM13A) gene and small airway remodeling in chronic obstructive pulmonary disease (COPD), and the effect of interference with FAM13A gene expression on the apoptosis and proliferation phenotype of human airway epithelial cells (16HBE). From January 2018 to January 2020, 74 patients in the Department of Thoracic Surgery of General Hospital of Ningxia Medical University were treated by surgery for lung tumors or pulmonary bullae. According to the lung function and smoking history, the 74 patients were divided into four groups: non-smoking group with normal lung function (normal group, 23 patients), smoking group with normal lung function (smoking group, 24 patients), non-smoking group with COPD (11 patients) and smoking group with COPD (16 patients). The expression of FAM13A in small airway of each group was detected by immunohistochemistry, and the correlation between FAM13A and the airflow restriction indexes by pulmonary function was analyzed. The shRNA fragment of FAM13A gene was designed, and the shRNA lentivirus vector of FAM13A gene was constructed and packaged. The expression level of FAM13A gene was detected by real-time fluorescent quantitative PCR (qRT-PCR) and Western blot, and the best shRNA sequence was screened. Flow cytometry was used to detect apoptosis rate and the fluorescence intensity of proliferation marker Ki-67 in 16HBE cells. FAM13A was mainly expressed in the cytoplasm of small airway epithelial cells. The levels of FAM13A absorbance () of small airway epithelial cells in non-smoking group and smoking group with COPD were higher than those in normal group and smoking group (0.365±0.026, 0.412±0.053 to 0.113±0.018, 0.105±0.009, all 0.05), and they were negatively correlated with forced expiratory volume in 1s/forced vital capacity (FEV(1)/FVC) and FEV(1)% pre (-0.48 and -0.40, all 0.05). The FAM13A shRNA lentiviral vector was successfully constructed, and FAM13A interference was successfully achieved in the 16HBE cell line. After infection of 16HBE cells, the results of qRT-PCR and Western blot showed that the expression of FAM13A in shRNA-target-2 group decreased (all 0.01). Compared with the negative control group (shRNA-NC), the apoptosis rate of FAM13A shRNA group decreased (0.023), and the fluorescence intensity of Ki-67 also decreased (0.042). FAM13A gene expression is increased in COPD small airway epithelial cells, and it is related to COPD airflow limitation. FAM13A gene may participate in the process of COPD remodeling by affecting the apoptosis and proliferation of human airway epithelial cells. 10.3760/cma.j.cn112137-20200326-00945
    Development and Evaluation of a Small Airway Disease Index Derived From Modeling the Late-Expiratory Flattening of the Flow-Volume Loop. Frontiers in physiology Excessive decrease in the flow of the late expiratory portion of a flow volume loop (FVL) or "flattening", reflects small airway dysfunction. The assessment of the flattening is currently determined by visual inspection by the pulmonary function test (PFT) interpreters and is highly variable. In this study, we developed an objective measure to quantify the flattening. We downloaded 172 PFT reports in PDF format from the electronic medical records and digitized and extracted the expiratory portion of the FVL. We located point A (the point of the peak expiratory flow), point B (the point corresponding to 75% of the expiratory vital capacity), and point C (the end of the expiratory portion of the FVL intersecting with the -axis). We did a linear fitting to the A-B segment and the B-C segment. We calculated: 1) the AB-BC angle (∠ABC), 2) BC--axis angle (∠BCX), and 3) the log ratio of the BC slope over the vertical distance between point A and -axis [log (BC/A-x)]. We asked an expert pulmonologist to assess the FVLs and separated the 172 PFTs into the flattening and the non-flattening groups. We defined the cutoff value as the mean minus one standard deviation using data from the non-flattening group. ∠ABC had the best concordance rate of 80.2% with a cutoff value of 149.7°. We then asked eight pulmonologists to evaluate the flattening with and without ∠ABC in another 168 PFTs. The Fleiss' kappa was 0.320 (lower and upper confidence intervals [CIs]: 0.293 and 0.348 respectively) without ∠ABC and increased to 0.522 (lower and upper CIs: 0.494 and 0.550) with ∠ABC. There were 147 CT scans performed within 6 months of the 172 PFTs. Twenty-six of 55 PFTs (47.3%) with ∠ABC <149.7° had CT scans showing small airway disease patterns while 44 of 92 PFTs (47.8%) with ∠ABC ≥149.7° had no CT evidence of small airway disease. We concluded that ∠ABC improved the inter-rater agreement on the presence of the late expiratory flattening in FVL. It could be a useful addition to the assessment of small airway disease in the PFT interpretation algorithm and reporting. 10.3389/fphys.2022.914972
    Small Airway Disease Syndromes. Piercing the Quiet Zone. Berger Kenneth I Annals of the American Thoracic Society The role for direct assessment of small airway function in subjects with respiratory symptoms but normal airflow by spirometry is discussed. Small airway disease syndrome is described in numerous disease states using a multidisciplinary approach. Data demonstrate that small airway disease is related to presence of respiratory symptoms, exposure to inhaled toxins, presence of local and systemic inflammation, and presence of histologic abnormalities within the distal lung. Investigation of immunological derangements associated with distal airway dysfunction in the setting of normal spirometry may provide insight into pathophysiological mechanisms that are present at disease onset. For the purposes of this symposium, data were reviewed in selected clinical conditions (obesity, environmental inhalational injury, and cigarette smoking) that have been recently studied in the André Cournand Pulmonary Physiology Laboratory at Bellevue Hospital using the forced oscillation technique. 10.1513/AnnalsATS.201710-767KV
    The cullin4A is up-regulated in chronic obstructive pulmonary disease patient and contributes to epithelial-mesenchymal transition in small airway epithelium. Ren Yidan,Zhang Yi,Fan Lixia,Jiao Qinlian,Wang Yunshan,Wang Qin Respiratory research BACKGROUND:Chronic obstructive pulmonary disease (COPD) is a common respiratory disease with high morbidity and mortality. The most important pathophysiological change of COPD is airway obstruction. Airway obstruction can cause airflow restriction and obstructive ventilation dysfunction. Currently, many studies have shown that there is EMT phenomenon in the process of airway remodeling of COPD. Cullin4A (CUL4A) is an E3 ubiquitin ligase that interacts with other factors to form the E3 complex. Studies have shown that CLU4A is associated with EMT in non-small cell lung cancer and other cancers. However, its relationship with EMT in COPD has not been reported systematically. In this study, we detected the expression of CUL4A in lung epithelium of COPD patients. In addition, the regulatory effect and mechanism of CUL4A on EMT in COPD were clarified in small airway epithelial cells. METHODS:The expression of CUL4A was assessed by immunohistochemistry in lung epithelium specimens from smokers, non-smokers and patients with chronic obstructive pulmonary disease. The role of CUL4A on cigarette smoke extract (CSE)-induced epithelial-mesenchymal transition (EMT) in human small airway epithelial cells (HSAEpiCs) was assessed by silencing or overexpression CUL4A in vitro. Cigarette smoke is recognized as a high-risk factor in the induction of COPD, and its damage to the airway involves airway damage, airway inflammation and airway remodeling. RESULTS:The results shown that CUL4A expression in small airway epithelium was significantly increased in patients with COPD. We also observed a significant negative association between CUL4A and FEV%, a useful clinical marker for the diagnosis and evaluation of COPD severity, in small airway epithelial cells. In vitro, CSE-induced EMT is associated with high expression of CUL4A, and targeted silencing of CUL4A with shRNA inhibits CSE-induced EMT in human small airway epithelial cells. CONCLUSIONS:Our results showed that CUL4A was overexpressed in lung epithelium of COPD patients, and CUL4A could regulate EMT of human small airway epithelium, which revealed a new mechanism of remodeling of small airway epithelium of COPD patients. 10.1186/s12931-019-1048-4
    Longitudinal Impact of Sputum Inflammatory Phenotypes on Small Airway Dysfunction and Disease Outcomes in Asthma. The journal of allergy and clinical immunology. In practice BACKGROUND:Little is known about the relationship between airway inflammatory phenotypes and some important asthma features such as small airway dysfunction (SAD). OBJECTIVE:To describe the longitudinal impact of airway inflammatory phenotypes on SAD and asthma outcomes. METHODS:We measured eosinophil and neutrophil counts in induced sputum at baseline and 1 year later to stratify 197 adult patients with asthma into 4 inflammatory phenotypes. We conducted a comprehensive assessment of lung function using spirometry, body plethysmography, impulse oscillometry, and inert gas single and multiple breath washouts. We compared lung function, asthma severity, exacerbation frequency, and symptom control between the phenotypes. We studied the longitudinal impact of persistent sputum inflammatory phenotypes and the change of sputum cell counts on lung function. RESULTS:Patients were stratified into eosinophilic (23%, n = 45), neutrophilic (33%, n = 62), mixed granulocytic (22%, n = 43), and paucigranulocytic (24%, n = 47) phenotypes. Patients with eosinophilic and mixed granulocytic asthma had higher rates of airflow obstruction and severe exacerbation as well as poorer symptom control than patients with paucigranulocytic asthma. All SAD measures were worse in patients with eosinophilic and mixed asthma than in those with paucigranulocytic asthma (all P values <.05). Eosinophilic asthma also indicated worse distal airflow obstruction, increased ventilation inhomogeneity (all P values <.05), and higher tendency for severe exacerbation (P = .07) than neutrophilic asthma. Longitudinally, persistent mixed granulocytic asthma was associated with the worst follow-up measures of SAD compared with persistent neutrophilic, persistent paucigranulocytic, or nonpersistent asthma phenotypes. In patients with stable forced expiratory volume in 1 second (FEV1), the mean increase in small airway resistance (R5-20) was greater in patients with persistent mixed granulocytic asthma (+103%) than in patients with persistent neutrophilic (+26%), P = .040, or persistent paucigranulocytic asthma (-41%), P = .028. Multivariate models adjusted for confounders and treatment with inhaled or oral corticosteroids or antieosinophilic biologics indicated that the change of sputum eosinophil rather than neutrophil counts is an independent predictor for the longitudinal change in FEV1, forced expiratory flow at 25% to 75% of forced vital capacity, specific effective airway resistance, residual lung volume, and lung clearance index. CONCLUSIONS:In asthma, airway eosinophilic inflammation is the main driver of lung function impairment and poor disease outcomes, which might also be aggravated by the coexistence of airway neutrophilia to confer a severe mixed granulocytic asthma phenotype. Persistent airway eosinophilia might be associated with dynamic SAD even in patients with stable FEV1. 10.1016/j.jaip.2022.02.020
    Clinical and pulmonary function changes in cough variant asthma with small airway disease. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology BACKGROUND:It is known that small airway disease is present across all asthma severities; however, its prevalence and clinical characteristics in cough variant asthma (CVA) have not been fully illuminated. METHODS:A total of 77 CVA patients with preserved proximal airway function (FEV1/FVC > 70%) were enrolled in this study. The correlation between forced expiratory flow at 50% (FEF) and FEF in the CVA population was first evaluated. FEF was determined to be an easy and feasible parameter for identifying small airway disease. CVA with small airway disease is defined as FEF < 70%, whereas CVA with normal small airways is identified as FEF > 70%. Demographic features, clinical characteristics, lung function and induced sputum test results were determined at the initial visit and at the final visit 1 year later. RESULTS:FEF is a good marker for small airway disease. The cutoff value of 70% is more sensitive than the previously published 60% for identifying more patients with small airway problems early. Nearly half of the CVA population (45.4%) in our cohort had small airway disease. In both group, symptoms improved greatly after anti-asthmatic treatment. Interestingly, the changes in symptom scores [Asthma Control Test (ACT) and ACQ] were even greater in the CVA with small airway disease group than in the control group because of the higher medication usage in this subpopulation in real life. However anti-asthmatic therapy can not reverse small airway dysfunction. At last visit, FEF of CVA with small airway diseases was 57.2% ± 10.5%, still much lower than the control group (FEF = 92.6% ± 16.5%). CONCLUSIONS:In our cohort, nearly half of the CVA population had small airway disease. Their demographic features, clinical characteristics, airway eosinophils and drug responsiveness were quite similar between two groups, which means these indices can not be used as markers to identify small airway obstruction. We found FEF is an easy and feasible marker for early identification. Regular anti-asthmatic medication helped to improve clinical scores in patients with small airway disease, but the obstruction could not be reversed over 1-year period. 10.1186/s13223-019-0354-1
    Family with sequence similarity 13 member A mediates TGF-β1-induced EMT in small airway epithelium of patients with chronic obstructive pulmonary disease. Zhu Jinyuan,Wang Faxuan,Feng Xueyan,Li Beibei,Ma Liqiong,Zhang Jin Respiratory research BACKGROUND:To explore the role of family with sequence similarity 13 member A (FAM13A) in TGF-β1-induced EMT in the small airway epithelium of patients with chronic obstructive pulmonary disease (COPD). METHODS:Small airway wall thickness and protein levels of airway remodeling markers, EMT markers, TGF-β1, and FAM13A were measured in lung tissue samples from COPD and non-COPD patients. The correlations of FAM13A expression with COPD severity and EMT marker expression were evaluated. Gain- and loss-of-function assays were performed to explore the functions of FAM13A in cell proliferation, motility, and TGF-β1-induced EMT marker alterations in human bronchial epithelial cell line BEAS-2B. RESULTS:Independent of smoking status, lung tissue samples from COPD patients exhibited significantly increased small airway thickness and collagen fiber deposition, along with enhanced protein levels of remodeling markers (collagen I, fibronectin, and MMP-9), mesenchymal markers (α-SMA, vimentin, and N-cadherin), TGF-β1, and FAM13A, compared with those from non-COPD patients. FAM13A expression negatively correlated with FEV% and PO in COPD patients. In small airway epithelium, FAM13A expression negatively correlated with E-cadherin protein levels and positively correlated with vimentin protein levels. In BEAS-2B cells, TGF-β1 dose-dependently upregulated FAM13A protein levels. FAM13A overexpression significantly promoted cell proliferation and motility in BEAS-2B cells, whereas FAM13A silencing showed contrasting results. Furthermore, FAM13A knockdown partially reversed TGF-β1-induced EMT marker protein alterations in BEAS-2B cells. CONCLUSIONS:FAM13A upregulation is associated with TGF-β1-induced EMT in the small airway epithelium of COPD patients independent of smoking status, serving as a potential therapeutic target for anti-EMT therapy in COPD. 10.1186/s12931-021-01783-z
    Upper airway symptoms and Small Airways Disease in Chronic Obstructive Pulmonary Disease, COPD. Obling Nicolai,Rangelov Bojidar,Backer Vibeke,Hurst John R,Bodtger Uffe Respiratory medicine BACKGROUND:Small Airways Disease (SAD) is a recognised part of the pathology in Chronic Obstructive Pulmonary Disease (COPD) and contributes to the symptom burden in the disease. Upper airway symptoms in COPD is an emerging field of study, and in this study, we sought to examine the co-existence of SAD and upper airways symptoms in a cohort of COPD patients METHODS: We investigated a cohort of patients with COPD for the presence of SAD with three different modalities. We performed High-Resolution CT (HRCT) with Parametric Response Mapping (PRM) analysis and recorded distribution of emphysema (PRM) and functional Small Airways Disease (PRM). We measured central and peripheral lung resistance using Impulse Oscillometry (IOS) and recorded R5Hz, R20Hz, R5-R20Hz, X5, Fres and Ax. Static lung function parameters were obtained using Body Plethysmography. Data on upper and lower airway symptoms were evaluated using the Upper Airway subdomain of the 22 items Sino Nasal Outcome Test (SNOT22) and the COPD Assessment Test (CAT), respectively. FINDINGS:We recruited a total of 112 patients. (female sex: 58%, Age 68 (±8) years, FEV1%predicted: 53% (±16%), GOLD stage: A: 23%, B: 55%, C:1% D: 21%). Forty-five (40%) were classified as having high upper airway symptoms (UAS), defined as SNOT22 ≥6. Eighty-seven per cent showed signs of SAD using IOS (R5-R20Hz > 0.07 kPa/L/s). No significant differences were found between UAS groups in IOS, PRM or Body Plethysmography parameters. CONCLUSION:In patients with COPD, the prevalence of small airways disease was very high, but no association between upper airway symptoms and small airways disease was demonstrated. 10.1016/j.rmed.2021.106710
    Small Airway Disease in Pediatric Asthma: the Who, What, When, Where, Why, and How to Remediate. A Review and Commentary. Hopp Russell J,Wilson Mark C,Pasha M Asghar Clinical reviews in allergy & immunology Asthma affects all portions of the airways. Small airways, however, comprise a substantial component of the conducting lung air flow. In asthma, inflammatory processes can affect the whole respiratory tract, from central to peripheral/small airways. The emphasis in adult and pediatric respiratory disease clinics is to focus on large airway obstruction and reversibility. This information, although valuable, underemphasizes a large portion of the conduction airway of asthmatics. Standard descriptions of asthma management focus on a multiple medication approaches. We particularly focused on the management of asthma in the international guidelines for the Global Initiative for Asthma (GINA). Overall, however, minimal attention is placed on the small airway pool in asthma medical management. We took the opportunity to thoroughly review and present specific data from the adult asthma literature which supported the concept that small airway abnormalities may play a role in the pathogenesis and clinical expression of asthma. Based on the conclusions of the adult asthma literature, we here present a thorough review of the literature as it relates to small airway disease in children with asthma. We used, collectively, individual data sources of data to expand the information available from standard diagnostic techniques, especially spirometry, in the evaluation of small airway disease. As the pharmacological approaches to moderate to severe asthma are advancing rapidly into the realm of biologics, we sought to present potential pharmacological options for small airway dysfunction in pediatrics prior to biological modifier intervention. 10.1007/s12016-020-08818-1