Peripheral Airways Research Articles

Ventilation heterogeneity and oscillometry predict asthma control improvement following step-up inhaled therapy in uncontrolled asthma.

Abnormal peripheral airway function is an important feature of asthma and relates to asthma symptoms and poor asthma control. We aimed to determine whether peripheral airway function, as measured by forced oscillatory impedance and multiple-breath nitrogen washout (MBNW), relates to symptom improvement in asthmatic participants with uncontrolled asthma, after stepping up to high-dose ICS/LABA treatment. A total of 19 subjects (14 females, mean age: 29.9 ± 13.6 years) with uncontrolled asthma, as defined by an ACQ5 > 1.5, taking 500 μg/day fluticasone equivalent or less, underwent spirometry, plethysmography, fractional exhaled FeNO, forced oscillatory resistance (Rrs5Hz ) and reactance (Xrs5Hz ), and indices of MBNW ventilation heterogeneity (lung clearance index (LCI), diffusion-convection-dependent (Sacin) and convection-dependent (Scond)). Measurements were made before and after 8 weeks of treatment with fluticasone/formoterol combination inhaler 250/10 μg, 2 puffs twice daily. Treatment improved ACQ5 (P = 0.0002), FEV1 (P = 0.02), FVC (P = 0.04), FeNO (P = 0.0008), Xrs5Hz (P = 0.01), LCI (P = 0.0002), Sacin (P = 0.006) and Scond (P = 0.01). At baseline, ACQ5 correlated with Xrs5Hz (rs = 0.52, P = 0.03) and Rrs5Hz (rs = 0.55, P = 0.02). The improvement in ACQ5 was predicted by more abnormal baseline LCI (P = 0.03), Scond (P = 0.02) and Rrs5Hz (P = 0.006). Baseline Scond was the best predictor of a clinically meaningful improvement in asthma control (ΔACQ > 0.5, ROC-AUC = 0.91, P = 0.007). Step-up to high-dose combination treatment in uncontrolled asthma is associated with improved peripheral airway function as measured by Xrs5Hz and MBNW. Baseline MBNW and FOT parameters correlated with the improvement in symptoms and may predict a positive response to up-titration in uncontrolled asthmatic patients.

Cross-sectional phenotyping of small airway dysfunction in preschool asthma using the impulse oscillometry system

Objective. Asthma is a chronic inflammatory airway disorder known to induce small airways dysfunction (SAD). It is important to develop tools to assess the presence and extent of SAD in daily clinical practice. An Impulse Oscillometry System (IOS) might detect SAD, but the validity of the underlying model (serial Resistive airway and Compliant tissue model: RC model) in diseased lungs remains questionable.Methods. Our objective was to evaluate the usefulness of parameters obtained from six electrical circuit models that were fitted to the measurements of impedance obtained with IOS in asthmatic children characterized by an abnormal lung function defined by an increased baseline interrupter resistance (Rint, z-score > +1.645).Results. The six models were tested in 102 asthmatic children (median age: 5.5 years). Two models allowed the description of 92/102 (90%) children: 74 by the extended RIC model (central and peripheral Resistance, Inertance and peripheral airway Compliance) and 18 by the Mead1969 model (extended RIC plus lung compliance). Thus, peripheral airway compliance and resistance were essential to describe lung function abnormalities of these asthmatic children. Parenchyma impairment (increased lung compliance) which was responsive to salbutamol was present in 18% of asthmatic children. After salbutamol, peripheral airway resistance decreased while peripheral airway compliance increased, arguing for asthma-related SAD. R5-20Hz independently correlated with the two latter parameters but was increased in two thirds of children with increased Rint only.Conclusion. Additional modeling of IOS results can be a reliable tool to assess the presence and extent of SAD in young asthmatic children.

Dynamics of human monocytes and airway macrophages during healthy aging and after transplant.

The ontogeny of airway macrophages (AMs) in human lung and their contribution to disease are poorly mapped out. In mice, aging is associated with an increasing proportion of peripherally, as opposed to perinatally derived AMs. We sought to understand AM ontogeny in human lung during healthy aging and after transplant. We characterized monocyte/macrophage populations from the peripheral blood and airways of healthy volunteers across infancy/childhood (2-12 yr), maturity (20-50 yr), and older adulthood (>50 yr). Single-cell RNA sequencing (scRNA-seq) was performed on airway inflammatory cells isolated from sex-mismatched lung transplant recipients. During healthy aging, the proportions of blood bronchoalveolar lavage (BAL) classical monocytes peak in adulthood and decline in older adults. scRNA-seq of BAL cells from lung transplant recipients indicates that after transplant, the majority of AMs are recipient derived. These data show that during aging, the peripheral monocyte phenotype is consistent with that found in the airways and, furthermore, that the majority of human AMs after transplant are derived from circulating monocytes.

Fractional exhaled breath temperature in patients with asthma, chronic obstructive pulmonary disease, or systemic sclerosis compared to healthy controls

ABSTRACT Exhaled breath temperature has been suggested to reflect airway inflammation, and it would be plausible to measure the peripheral airway temperature as a correlate to peripheral airway inflammation. This study aims to explore the relative peripheral airway temperature in patients with asthma, chronic obstructive pulmonary disease (COPD) or systemic sclerosis (SSc) compared to healthy controls, and relate to lung function and exhaled nitric oxide. Sixty-five subjects (16 asthmatics, 18 COPD patients, 17 SSc patients and 14 healthy subjects) performed fractional exhaled breath temperature measurements using a novel device, fractional exhaled NO measurements, spirometry, impulse oscillometry, body plethysmography and CO-diffusion capacity test. A significant overall difference among all the patient groups was seen in both the Tmax (= peak values of the entire exhalation) and T3max (= peak value of the last fraction of the exhaled volume). A significant difference in T3/T1 ratio (= the ratio of peripheral versus central air temperature) was found between asthmatic subjects and those with COPD or SSc. In addition, T1max (= temperature in the central), T3max (= peripheral airways) and the T3/T1ratio related to several volumetric measurements (both in absolute values and as percent predicted), such as vital capacity, total lung capacity, forced expiratory volume in 1 s, and diffusion capacity. The temperature ratio of the peripheral versus central airways was lower in patients with COPD or SSc compared to asthmatics, who in turn presented similar levels as the controls. There was also a large overlap between the groups. Overall, the airway temperatures were related to absolute lung volumes, and specifically, the peripheral temperature was related to the gas diffusion capacity (% predicted), suggesting a link to the vascular component.

Effect of exposure to formalin on peripheral and smaller airways of 1st-year medical students

Context: One of the occupational hazards experienced by a doctor is the exposure to formaldehyde during gross anatomy dissection classes. As it vaporizes at room temperature, the respiratory system is easily affected. The present study was conducted to assess the effect of formaldehyde on the smaller and peripheral airways. Aims: The study aimed to evaluate the effect of formaldehyde exposure on the smaller and peripheral airways of 1st-year medical students. Settings and Design: A longitudinal, descriptive study was conducted in the Department of Physiology, Rohilkhand Medical College and Hospital, among 1st-year MBBS students in the academic year 2015–16. Materials and Methods: The spirometric parameter, forced expiratory flow at 25%–75% (FEF25%–75%)was recorded in eighty medical students using spirometer RMS Helios 401 available in the research laboratory of the department. Percent-predicated values were used for the analysis. The baseline values were recorded at the beginning of the academic calendar and followed up at the end of the 1st, 6th, and 10th months. Statistical Analysis Used: Data were analyzed using the SPSS software. Descriptive statistics and repeated measures ANOVA were used for the analysis.P

Identification of COPD From Multi-View Snapshots of 3D Lung Airway Tree via Deep CNN

Chronic obstructive pulmonary disease (COPD) is associated with morphologic abnormalities of airways with various patterns and severities. However, the way of effectively representing these abnormalities is lacking and whether these abnormalities enable to distinguish COPD from healthy controls is unknown. We propose to use deep convolutional neural network (CNN) to assess 3D lung airway tree from the perspective of computer vision, thereby constructing models of identifying COPD. After extracting airway trees from CT images, snapshots of their 3D visualizations are obtained from ventral, dorsal and isometric views. Using snapshots of each view, one deep CNN model is constructed and further optimized by Bayesian optimization algorithm to indentify COPD. The majority voting of three views presents the final prediction. Finally, the class-discriminative localization maps have been drawn to visually explain the CNNs’ decisions. The models trained with single view (ventral, dorsal and isometric) of colorful snapshots present the similar accuracy (ACC) (86.8%, 87.5% and 86.7%) and the model after voting achieves the ACC of 88.2%. The ACC of the final voting model using gray and binary snapshots achieves 88.6% and 86.4%, respectively. Our specially designed CNNs outperform the typical off-the-shelf CNNs and the pre-trained CNNs with fine tuning. The class-discriminative regions of COPD are mainly located at central airways; however, regions in HC are scattering and located at peripheral airways. It is feasible to identify COPD using snapshots of 3D lung airway tree extracted from CT images via deep CNN. The CNNs can represent the abnormalities of airway tree in COPD and make accurate CT-based diagnosis of COPD.

Bronchogenic Carcinoma: Endoscopy versus Histopathology

Introduction: Lung cancer is the malignancy with the highest mortality (1.76 million deaths per year, 18.4% of the total) worldwide, being the only one whose incidence of death has progressively increased despite improved and more aggressive therapy in recent years. Early diagnosis plays an important role in increasing survival in lung cancer patients. Fiber Optic Bronchoscopy (FOB) is currently considered the first method for evaluating the tracheobronchial tree in patients with suspected lung cancer. Even though histopathological examination of bronchial biopsy specimen remains the confirmatory or the gold standard test, morphological appearance along with side and site of the lesion is also important in the diagnosis. Aim: To compare the bronchoscopic presentations of bronchogenic carcinoma in relation to side, site and morphology with histopathology. Materials and Methods: This descriptive cross-sectional study was conducted prospectively in the Institute of Respiratory Diseases, SMS Medical College, Jaipur, Rajasthan, India. It included 122 patients suspected clinico-radiologically and bronchoscopically with lung cancer and admitted to the hospital during the period from March 2018 to May 2019. FOB findings were noted carefully with regard to side, site and type of the lesion. One hundred and two patients were pathologically diagnosed with primary lung cancer. The bronchoscopic findings were correlated with histopathology. Statistical analysis were done using the chi-square test using the software IBM Statistical Package for the Social Sciences (SPSS) Statistics, Version 25.0. Results: A total of 102 patients (90 males and 12 females) with primary lung cancer were included in the study; most of them were in the sixth decade of life. The main anatomical site of bronchogenic carcinoma were; main bronchi (n=36, 35.29%), followed by lobar bronchi (n=28, 27.45%). Most common morphologic presentation was endobronchial growth (n=86, 84.31%) and for all the endobronchial growths, Squamous Cell Carcinoma (SQCC) was the most common histopathological diagnosis i.e., 32 cases out of 86 (37.21%). For Adenocarcinoma (AC), non-specific morphological finding was the most common (7 out of 13, 53.85%) rather than endobronchial growth (6 out of 13, 46.15%). External compression was the most common among the non-specific findings of AC (n=3 out of 13, 23.08%). Conclusion: Bronchoscopic appearance was associated to histological type. Both SQCC and Small Cell Carcinoma (SCC) were more in the central airways and endoscopically had the presentation of intraluminal growth commonly. ACs were more in the peripheral airways and endoscopically had non-specific findings more than endoscopic growth.

Secondary Carina and Lobar Bronchi Stenting in Patients with Advanced Lung Cancer: Is It Worth the Effort? A Clinical Experience.

Background: The lobar airway stenting remains an endoscopic procedure not well standardized in patients with locally advanced lung cancer disease. The goal of this study was to evaluate technical feasibility, clinical outcome, and complications of different stents in patients with malignant lesions involving lobar bronchi, primary and secondary carina.Methods: Between November 2008 and October 2013, we retrospectively analyzed 146 patients with benign and malignant tracheobronchial stenosis who underwent airway stent insertion below main carina and main bronchi.Results: In all, 170 airway stenting procedures were performed on 146 patients. In all, 51 of them with malignant peripheral airway stenosis underwent stents placement below main carina. In all but one patient, the deployment of stents was successful with improvement of symptoms. The chest radiograph after the procedure detected the lung re-expansion in 29 of 51 patients. The mean follow-up duration was 123 days ± 157. Complications observed included stent migration, tumor overgrowth, infections, granulation tissue formation, and obstruction due to tenacious secretions. Longer survival was observed in patients who received additional treatment after airway stenting compared to those who did not (p <0.01).Conclusions: Stenting of lobar bronchi and primary or secondary carina is technically feasible, effective, and acceptably safe.

The Effect of Obesity on Asthma: Lung Function Analysis Using the Impulse Oscillometry in School-age Children

Objective: Studies investigating the lung function of school-age obese asthmatics are rare. The purpose of this study was to compare lung functions in school-age obese asthmatics with non-obese asthmatics. Methods: Ninety-two children were assigned to obese asthmatics (OA group, n=43) and non-obese asthmatics (A group, n=49) groups. A baseline impulse oscillometry test was performed to measure lung functions. Results: Baseline percent predicted value of R20 (p=0.025), R5-20 (p=0.040), and Fres (p=0.018) were significantly increased in obese asthmatics than non-obese asthmatics. AX was also higher in obese asthmatics compared to non-obese asthmatics, however, the difference was insignificant (p=0.787). Percent predicted value of R5 (p=0.007) and R10 (p=0.017) were higher in atopic than non-atopic obese asthmatics. Percent predicted value of R5 was higher in exercise-intolerant than exercise-tolerant non-obese asthmatics (p=0.045). Additionally, R10 was higher in non-obese asthmatics with household mold exposure than that without household mold exposure (p=0.045). The z scores of BMI or weight were correlated with none of the IOS parameters (p&gt;0.05). Conclusion: Main bronchial and peripheral airway resistance were higher in school-age obese asthmatics compared to non-obese asthmatics. Peripheral airway resistance was higher in atopic obese asthmatics as well as in exercise intolerant asthmatic children and those with household mold exposure.

Clinical and economic analysis of Reslizumab use in the treatment of patients with severe allergic eosinophilic asthma

Comparative clinical and economic analysis of reslizumab use in patients with allergic asthma and eosinophilia. Omalizumab was chosen as a reference drug, because until now it was the only MAb for the treatment of severe asthma in Russia. The study population included patients with allergic asthma with both high levels of IgE and high eosinophil counts in peripheral blood, i.e. individuals eligible for both omalizumab and reslizumab treatment. A decrease in the number of exacerbations requiring prescription of systemic corticosteroids and an increase in QALY index was used as efficacy criteria. An indirect comparative study was used, because no direct comparison has been conducted to date. As a result, reslizumab demonstrated a statistically significant reduction in the frequency of clinically significant asthma exacerbations compared with omalizumab. The utility of the both asthma treatment strategies was compared using Markov models, taking into account the frequency of exacerbations, their severity, as well as decrease in QALYs due to exacerbations. The time horizon was 12 months. Reslizumab treatment was 37.2% less expensive compared with omalizumab for the patients who are equally eligible for the both drugs. The calculated cost - effectiveness and cost - utility ratios were in favor of reslizumab. Budget impact analysis showed a significant effect of reslizumab on reducing budget costs. If reslizumab is used in 4250 patients (an estimated number of patients with severe allergic asthma and eosinophilia in Russia), this would reduce the costs for their treatment by up to 4896 million rubles per year. For patients with severe allergic eosinophilic asthma who are equally eligible for the both drugs, reslizumab can be considered a more reasonable medical technology in terms of pharmacoeconomics when compared with omalizumab.

Bile acids inhibit cholinergic constriction in proximal and peripheral airways from humans and rodents.

Duodenogastroesophageal reflux (DGER) is associated with chronic lung disease. Bile acids (BAs) are established markers of DGER aspiration and are important risk factors for reduced post-transplant lung allograft survival by disrupting the organ-specific innate immunity, facilitating airway infection and allograft failure. However, it is unknown whether BAs also affect airway reactivity. We investigated the acute effects of 13 BAs detected in post-lung-transplant surveillance bronchial washings (BW) on airway contraction. We exposed precision-cut slices from human and mouse lungs to BAs and monitored dynamic changes in the cross-sectional luminal area of peripheral airways using video phase-contrast microscopy. We also used guinea pig tracheal rings in organ baths to study BA effects in proximal airway contraction induced by electrical field stimulation. We found that most secondary BAs at low micromolar concentrations strongly and reversibly relaxed smooth muscle and inhibited peripheral airway constriction induced by acetylcholine but not by noncholinergic bronchoconstrictors. Similarly, secondary BAs strongly inhibited cholinergic constrictions in tracheal rings. In contrast, TC-G 1005, a specific agonist of the BA receptor Takeda G protein-coupled receptor 5 (TGR5), did not cause airway relaxation, and Tgr5 deletion in knockout mice did not affect BA-induced relaxation, suggesting that this receptor is not involved. BAs inhibited acetylcholine-induced inositol phosphate synthesis in human airway smooth muscle cells overexpressing the muscarinic M3 receptor. Our results demonstrate that select BAs found in BW of patients with lung transplantation can affect airway reactivity by inhibiting the cholinergic contractile responses of the proximal and peripheral airways, possibly by acting as antagonists of M3 muscarinic receptors.

Computer-aided classification of small airways dysfunction using impulse oscillometric features: a children-focused review.

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.

Prevalence of pneumoconiosis and spirometric findings in underground mining workers in Cundinamarca, Colombia

Introduction: Coal worker’s pneumoconiosis is caused by the inhalation of coal dust and its accumulation in the lungs after several years of exposure.Objective: To determine the prevalence of pneumoconiosis in underground mining workers exposed to coal dust in Cundinamarca, Colombia, and its association with their spirometry results and respiratory symptoms.Materials and methods: Cross-sectional study conducted on 215 workers who were administered a questionnaire on respiratory symptoms. For each worker a chest radiograph was taken according to the criteria of the International Labor Organization. Information on the workers’ socio-demographic characteristics, smoking habits, and spirometry results was included.Results: The average age was 45.5 ± 9.4 years and the average length of employment was 21.7±10.0 years. Expectoration was the symptom most frequently reported (73.5%). Regarding spirometry results, a normal pattern was observed in 89.8% of the sample, while obstructive and restrictive patterns were found in 5.1% and 3.7% of the subjects, and 0.5% had a peripheral airways dysfunction pattern. The prevalence of pneumoconiosis was 42.33%. FEV1/FVC ratio (81.75 vs. 83.74, p=0.045) and FF25-75% (84.96 vs. 91.95, p&lt;0.001) mean values were significantly lower in workers with pneumoconiosis.Conclusion: Pneumoconiosis was highly prevalent in the study population and its diagnosis was associated with spirometry results (FEV1/FVC and FEF25.75%); bearing in mind that currently there are not effective treatments for this disease, it is necessary to implement control and prevention strategies aimed at reducing occupational exposure to coal dust and, this way, prevent its occurrence.

S02.04 Dr. Gazdar as a Mentor

It was September in 1989 when I joined the NCI-Navy Medical Oncology Branch as a postdoctoral fellow. At that time, I was in my 10th year as a surgeon. The reason why I wanted to join the NCI-Navy was that I was greatly fascinated by the book entitled “The Biology of Lung Cancer” published by Marcel Dekker authored by many of the NCI-Navy MOB investigators. Especially, I was attracted by experimental works that used many lung cancer cell lines established by Adi’s group. When I first met Adi, my impression was that he was a calm and quiet person. My first project was to characterize peripheral airway cell phenotype in the adenocarcinoma cell lines by examining the expression of surfactant proteins as well as class II MHC. But I did not like this project and after 2 months or so, he agreed to change my theme to KRAS or TP53 mutations in lung cancer cell lines. He never pushed me to do or not to do something and never became emotional. I was deeply immersed in the research to look for the clinical and pathologic significance of those genetic abnormalities in lung cancer. This was what is called “translational research” today. I thought I could find what I should pursue throughout my life as a lung cancer doctor. It is obvious that without this experience and Adi, my life would have been so different. In addition, human network owing to Adi has been a precious treasure for me. One day in 1990, he gave me a paraffin block of bronchial biopsy sample and told me to search for TP53 mutation. It is currently a routine diagnostic workup to examine genetic alterations in the biopsy samples when you see lung cancer patients. It was as if he had known what would be the future diagnostic workup before 30 years. During this fruitful time of my life, I am so proud that I was able to co-authored 18 papers with Adi. After coming back to Japan, I saw Adi occasionally but periodically at various meetings such as the AACR, ASCO, ELCC and especially WCLC. Every time, he encouraged me to pursue my goal and gave some suggestions on my experiments. When Adi was to edit a special issue on Lung Cancer in Never Smokers in Translational Lung Cancer Research in 2018, he invited me to write about GGO lesions in never smokers. It was the last homework that he assigned to me. I am going to organize the Annual meeting of the Japanese Lung Cancer Society in December 2019. When I talked to him and his wife Celia at the Toronto WCLC meeting in 2018, Adi promised me to come to Japan to give a lecture. That was our last conversation. The promise has been broken and I really miss him. Adi. Please rest in peace. There are many of your children all over the world who have inherited your spirit as a lung cancer researcher. Translational research, mentor

Transcription Factor T-bet Attenuates the Development of Elastase-induced Emphysema in Mice.

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by peripheral airways inflammation and emphysema. Emerging evidence indicates a contribution of both innate and adaptive immune cells to the development of COPD. Transcription factor T-bet modulates the function of immune cells and therefore might be involved in the pathogenesis of COPD. To elucidate the role for T-bet in elastase-induced emphysema, pathological phenotypes were compared between wild-type and T-bet-/- mice. T-bet-/- mice demonstrated enhanced emphysema development on histological analyses, with higher values of mean linear intercept and dynamic compliance relative to wild-type mice. The number of neutrophils in BAL fluids, lung IL-6 and IL-17 expression, and the proportion of CD4+ T cells positive for IL-17 or retinoic acid receptor-related orphan receptor-γt were higher in T-bet-/- mice than in wild-type mice. Although T-bet downregulates cytokine expression in bone marrow-derived macrophages and MH-S cells, a murine alveolar cell line, depending on the surrounding environment, IL-6 expression in alveolar macrophages isolated from elastase-treated mice was not dependent on T-bet. Coculture of bone marrow-derived macrophages and CD4+ T cells revealed that T-bet regulation of IL-17 expression was dependent on CD4+ T cells. Neutralizing antibodies against IL-6R or IL-17 ameliorated the development of emphysema in T-bet-/- mice. In conclusion, we demonstrate that T-bet ameliorates elastase-induced emphysema formation by modulating the host immune response in the lungs.

Direct evaluation of peripheral airways using ultra-high-resolution CT in chronic obstructive pulmonary disease

PurposeDisease in small airways <2 mm in diameter is a major pathology of chronic obstructive pulmonary disease (COPD). However, compared to airways <1 mm in diameter, the pathophysiological role of airways 1–2 mm in diameter remains unclear. This study analysed phantom and human COPD data to test the hypothesis that ultra-high-resolution computed tomography (U-HRCT) can accurately measure peripheral airways that are difficult to measure with conventional CT. MethodThe lower limit of lumen sizes measurable on U-HRCT was determined using phantom tubes. In the cross-sectional data of 110 males with COPD who underwent U-HRCT (1024 × 1024 matrix, 0.25 mm slice thickness) and spirometry, all 3rd (segmental) to 6th generation airways of the right apical and basal posterior bronchus (RB1 and RB10) were analysed. ResultsThe errors in measuring the lumen area (LA) of phantom tubes ≥1.3 and 1.0 mm in diameter were within ±10 and -24%, respectively. The internal diameters for 70 and 62% of the 6th generation RB1 and RB10 airways were <2 mm. The numbers of 6th generation RB1 and RB10 airways decreased as the airflow limitation severity increased. Among the mean LA and sum of LA(sum-LA) of the 3rd to 6th generation airways, the sum-LA of the 6th generation had the largest impact on airflow limitation. ConclusionsU-HRCT enables accurate and direct evaluation of peripheral airways 1–2 mm in diameter. The 6th generation airways are commonly <2 mm in diameter, and the sum-LA can be a useful CT biomarker that reflects airflow limitation in COPD.

The Effect of Flavored E-cigarettes on Murine Allergic Airways Disease

Flavored e-cigarettes are preferred by the majority of users yet their potential toxicity is unknown. Therefore our aim was to determine the effect of selected flavored e-cigarettes, with or without nicotine, on allergic airways disease in mice. Balb/c mice were challenged with PBS or house dust mite (HDM) (Days 0, 7, 14–18) and exposed to room air or e-cigarette aerosol for 30 min twice daily, 6 days/week from Days 0–18 (n = 8–12/group). Mice were exposed to Room Air, vehicle control (50%VG/%50PG), Black Licorice, Kola, Banana Pudding or Cinnacide without or with 12 mg/mL nicotine. Mice were assessed at 72 hours after the final HDM challenge. Compared to mice challenged with HDM and exposed to Room Air, nicotine-free Cinnacide reduced airway inflammation (p = 0.045) and increased peripheral airway hyperresponsiveness (p = 0.02), nicotine-free Banana Pudding increased soluble lung collagen (p = 0.049), with a trend towards increased airway inflammation with nicotine-free Black Licorice exposure (p = 0.089). In contrast, all e-cigarettes containing nicotine suppressed airway inflammation (p < 0.001 for all) but did not alter airway hyperresponsiveness or airway remodeling. Flavored e-cigarettes without nicotine had significant but heterogeneous effects on features of allergic airways disease. This suggests that some flavored e-cigarettes may alter asthma pathophysiology even when used without nicotine.

Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases.

Cellular senescence is now considered an important driving mechanism for chronic lung diseases, particularly chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis. Cellular senescence is due to replicative and stress-related senescence with activation of p53 and p16INK4a, respectively, leading to activation of p21CIP1 and cell cycle arrest. Senescent cells secrete multiple inflammatory proteins known as the senescence-associated secretory phenotype, leading to low-grade chronic inflammation, which further drives senescence. Loss of key antiaging molecules sirtuin-1 and sirtuin-6 may be important in acceleration of aging and arises from oxidative stress reducing phosphatase PTEN (phosphatase tensin homolog), thereby activating PI3K (phosphoinositide-3-kinase) and mTOR (mammalian target of rapamycin). MicroRNA-34a (miR-34a), which is regulated by PI3K-mTOR signaling, plays a pivotal role in reducing sirtuin-1/6, and its inhibition with an antagomir results in their restoration, reducing markers of senescence, reducing senescence-associated secretory phenotype, and reversing cell cycle arrest in epithelial cells from peripheral airways of patients with COPD. miR-570 is also involved in reduction of sirtuin-1 and cellular senescence and is activated by p38 mitogen-activated protein kinase. These miRNAs may be released from cells in extracellular vesicles that are taken up by other cells, thereby spreading senescence locally within the lung but also outside the lung through the circulation; this may account for comorbidities of COPD and other lung diseases. Understanding the mechanisms of cellular senescence may result in new treatments for chronic lung disease, either by inhibiting PI3K-mTOR signaling, by inhibiting specific miRNAs, or by deletion of senescent cells with senolytic therapies, already shown to be effective in experimental lung fibrosis.

Short-term pulmonary infiltrate with eosinophilia caused by asthma: a phenotype of severe, eosinophilic asthma? Five cases and a review of the literature

BackgroundAsthma is often accompanied by peripheral eosinophilia and eosinophilic airway inflammation. This article explores the relationship between asthma and short-term pulmonary infiltrate with eosinophilia, which results from irregular asthma treatment.Case presentationWe report five unique cases of asthma-induced short-term eosinophilic pneumonia encountered at our pulmonary and critical care centre in Hunan, China, from January 1, 2014, to August 31, 2018. The 5 asthma patients were women with persistent dyspnoea symptoms, an increased peripheral eosinophil count and a high level of exhaled nitric oxide (FeNO). Chest CT revealed multiple infiltrates and ground-glass opacities in both lung fields in all 5 patients. Four of the 5 patients had increased eosinophils in bronchoalveolar lavage (BAL). Three were positive for reversibility in lung function testing, and two had eosinophil infiltration as revealed by lung biopsy. No antibiotic treatment was given, and after a short period of glucocorticoid therapy and inhaled corticosteroid plus long-acting β2-agonist (ICS + LABA) treatment, the symptoms of all of the patients disappeared. In addition, their blood eosinophils returned to normal, and their lung lesions were quickly absorbed and improved.ConclusionThese cases show a unique association between short-term eosinophilic pneumonia and asthma. The occurrence of eosinophilic pneumonia can prove fatal during a serious asthma attack. Additionally, the presence of peripheral eosinophilia with lung infiltrates poses a diagnostic challenge for clinicians by creating suspicion of pulmonary infiltrate with eosinophilia when present in asthmatic patients.

Airway reversibility and inflammation in stable pre- to late-adolescent asthmatics without long-term control medications

Objective: Pulmonary function and airway inflammation were investigated in stable pre- to late-adolescent asthmatics without long-term control medications and compared with those in currently medicated asthmatics.Methods: Subjects comprised 34 well-controlled asthmatic children (aged 8.1–18.0 years; group without medication). Flow volume curves before and after inhaling a β2 agonist, a bronchodilator (BD), were compared and fractional exhaled nitric oxide (FENO) concentrations were measured. All patients were attack-free for at least 12 months prior to testing without the use of asthma medications for at least three months. Fifty-one age-matched stable asthmatics with medications at the time of the present study (group with current medication) underwent the same examinations.Results: The rate of children whose respiratory function after BD improved by 20% or more in both the central and peripheral airways (High responder at total airways subtype: HTA) was significantly higher in the group without medication than in that with current medication (17.6 and 2.0%, respectively; p < 0.01). Furthermore, FEV1.0% pred after BD was significantly lower for HTA than for the low responder subtype in the same group (94.8 ± 3.5 and 104.1 ± 1.5% respectively, p < 0.05). FENO concentrations in the group without medication were high, but not significantly different from those in the group with current medication.Conclusions: Stable asthmatic children without medication include a certain percentage of those with irreversible airflow limitation possibly due to airway remodeling. The control of daily asthma symptoms with long-term control medications may effectively prevent airway remodeling.