Distal Airways Research Articles

Non-local impact of distal airway constrictions on patterns of inhaled particle deposition.

Airway constriction and blockage in obstructive lung diseases cause ventilation heterogeneity and create barriers to effective drug deposition. Established computational particle-deposition models have not accounted for these impacts of disease. We present a new particle-deposition model that calculates ventilation based on the resistance of each airway, such that ventilation responds to airway constriction. The model incorporates distal airway constrictions representative of cystic fibrosis, allowing us to investigate the resulting impact on patterns of deposition. Unlike previous models, our model predicts how constrictions affect deposition in airways throughout the lungs, not just in the constricted airways. Deposition is reduced in airways directly distal and proximal to constrictions. When constrictions are clustered together, central-airways deposition can increase significantly in regions away from constrictions, but distal-airways deposition in those regions remains largely unchanged. We use our model to calculate lung clearance index (LCI), a clinical measure of ventilation heterogeneity, after applying constrictions of varying severities in one lobe. We find an increase in LCI coinciding with significantly reduced deposition in the affected lobe. Our results show how the model provides a framework for development of computational tools that capture the impacts of airway disease, which could significantly affect predictions of regional dosing.

Airway epithelium damage in acute respiratory distress syndrome

BackgroundThe airway epithelium (AE) fulfils multiple functions to maintain pulmonary homeostasis, among which ensuring adequate barrier function, cell differentiation and polarization, and actively transporting immunoglobulin A (IgA), the predominant mucosal immunoglobulin in the airway lumen, via the polymeric immunoglobulin receptor (pIgR). Morphological changes of the airways have been reported in ARDS, while their detailed features, impact for mucosal immunity, and causative mechanisms remain unclear. Therefore, this study aimed to assess epithelial alterations in the distal airways of patients with ARDS.MethodsWe retrospectively analyzed lung tissue samples from ARDS patients and controls to investigate and quantify structural and functional changes in the small airways, using multiplex fluorescence immunostaining and computer-assisted quantification on whole tissue sections. Additionally, we measured markers of mucosal immunity, IgA and pIgR, alongside with other epithelial markers, in the serum and the broncho-alveolar lavage fluid (BALF) prospectively collected from ARDS patients and controls.ResultsCompared to controls, airways of ARDS were characterized by increased epithelial denudation (p = 0.0003) and diffuse epithelial infiltration by neutrophils (p = 0.0005). Quantitative evaluation of multiplex fluorescence immunostaining revealed a loss of ciliated cells (p = 0.0317) a trend towards decreased goblet cells (p = 0.056), and no change regarding cell progenitors (basal and club cells), indicating altered mucociliary differentiation. Increased epithelial permeability was also shown in ARDS with a significant decrease of tight (p < 0.0001) and adherens (p = 0.025) junctional proteins. Additionally, we observed a significant decrease of the expression of pIgR, (p < 0.0001), indicating impaired mucosal IgA immunity. Serum concentrations of secretory component (SC) and S-IgA were increased in ARDS (both p < 0.0001), along other lung-derived proteins (CC16, SP-D, sRAGE). However, their BALF concentrations remained unchanged, suggesting a spillover of airway and alveolar proteins through a damaged AE.ConclusionThe airway epithelium from patients with ARDS exhibits multifaceted alterations leading to altered mucociliary differentiation, compromised defense functions and increased permeability with pneumoproteinemia.

Defining VOC signatures of Airway Epithelial Cells with PM2.5 Exposure.

Volatile organic compounds (VOCs) produced by the lung in response to exposure to environmental pollutants can be utilized to study their impact on lung health and function. Previously, we developed a method to measure VOCs emitted from well-differentiated tracheobronchial epithelial cells in vitro. Using this method, we exposed well-differentiated proximal (PECs) and distal airway epithelial cells (DECs) to varying doses of traffic-related air pollutants (TRAP) and wildfire particulates to determine specific VOC signatures after exposure. We utilized PM2.5 TRAP collected from the Caldecott tunnel in Oakland, CA and the 2018 Camp Fire to model "real-life" exposures. The VOCs were collected and extracted from Twisters and analyzed using gas chromatography-mass spectrometry (GC-MS). Exposure to both types of particulate matter (PM) resulted in specific VOC responses grouped by individual subjects with little overlap. Interestingly the VOCs produced by the PECs and DECs were also differentiated from each other. Our studies suggest that PM exposure induces a specific compartmentalized cellular response that can be exploited for future studies. This response is cell-type specific and potentially related to a phenotype we have yet to uncover.

Chronic Hypoxia in an EXTrauterine Environment for Neonatal Development Impairs Lung Development.

Severe fetal hypoxia poses a significant risk to lung development resulting in severe postnatal complications. Existing chronic hypoxia animal models lack the ability to achieve pathologically reduced fetal oxygen without compromising animal development, placental blood flow, or maternal health. Using an established model of isolated chronic hypoxia involving the Extrauterine Environment for Neonatal Development (EXTEND), we are able to investigate the direct impact of fetal hypoxia on lung development. Oxygen delivery to preterm fetal lambs (105-110 days GA) delivered by cesarean section was reduced, and animals were supported on EXTEND through the canalicular or saccular stage of lung development. Fetal lambs in hypoxic conditions showed significant growth restriction compared to their normoxic counterparts. We also observed modest aberrant vascular remodeling in the saccular group after hypoxic conditions with decreased macrovessel numbers, microvascular endothelial cell numbers, and increased peripheral vessel muscularization. In addition, fetal hypoxia resulted in enlarged distal airspaces and decreased septal wall volume. Moreover, there was a reduction in mature SFTPB and processed SFTPC protein expression concomitant with a decrease in AT2 cell number. These findings demonstrate that maternally-independent fetal hypoxia predominantly impacts distal airway development, AT2 cell number, and surfactant production with mild effects on the vasculature.

Respiratory and physical health consequences in older adults in a high-risk volcanic area: Comparison of two rural villages

Introduction Volcanism is an important natural producer of pollution that impacts health and the quality of the environment. Lung changes caused by exposure to volcanoes have been previously studied. However, limited information exists regarding the effects of prolonged exposure to volcanic compounds. So, this study aimed to analyze the pulmonary effects and stress tolerance in older adults for chronic exposure to the volcanic ashes of the Galeras volcano. Methods A descriptive cross-sectional study of association included rural inhabitants aged over 60 years from Genoy, a village located in a high volcanic hazard zone of Galeras volcano, 2603 meters above sea level. Those in this group, called exposed, were contrasted with a sample of El Encano inhabitants with similar socioeconomic and cultural characteristics. Both villages belong to the rural area of San Juan de Pasto in Colombia. Results It was found that of 31 exposed participants, 18 had obstructive alteration, and in the control group, it was found that of 31 subjects, 6 presented this alteration. The difference between the two groups was significant (p&lt;0.001). A similar situation occurred with distal airway obstruction assessed with the forced expiratory flow of 25–75%. No significant differences were found in restrictive alteration between the exposed and unexposed groups. Conclusion Chronic exposure to volcanic compounds has generated obstructive changes in the population, and these changes were greater in number and severity than those in the control group of unexposed people.

Influence of mesenchymal and biophysical components on distal lung organoid differentiation

BackgroundChronic lung disease of prematurity, called bronchopulmonary dysplasia (BPD), lacks effective therapies, stressing the need for preclinical testing systems that reflect human pathology for identifying causal pathways and testing novel compounds. Alveolar organoids derived from human pluripotent stem cells (hPSC) are promising test platforms for studying distal airway diseases like BPD, but current protocols do not accurately replicate the distal niche environment of the native lung. Herein, we investigated the contributions of cellular constituents of the alveolus and fetal respiratory movements on hPSC-derived alveolar organoid formation.MethodsHuman PSCs were differentiated in 2D culture into lung progenitor cells (LPC) which were then further differentiated into alveolar organoids before and after removal of co-developing mesodermal cells. LPCs were also differentiated in Transwell® co-cultures with and without human fetal lung fibroblast. Forming organoids were subjected to phasic mechanical strain using a Flexcell® system. Differentiation within organoids and Transwell® cultures was assessed by flow cytometry, immunofluorescence, and qPCR for lung epithelial and alveolar markers of differentiation including GATA binding protein 6 (GATA 6), E-cadherin (CDH1), NK2 Homeobox 1 (NKX2-1), HT2-280, surfactant proteins B (SFTPB) and C (SFTPC).ResultsWe observed that co-developing mesenchymal progenitors promote alveolar epithelial type 2 cell (AEC2) differentiation within hPSC-derived lung organoids. This mesenchymal effect on AEC2 differentiation was corroborated by co-culturing hPSC-NKX2-1+ lung progenitors with human embryonic lung fibroblasts. The stimulatory effect did not require direct contact between fibroblasts and NKX2-1+ lung progenitors. Additionally, we demonstrate that episodic mechanical deformation of hPSC-derived lung organoids, mimicking in situ fetal respiratory movements, increased AEC2 differentiation without affecting proximal epithelial differentiation.ConclusionOur data suggest that biophysical and mesenchymal components promote AEC2 differentiation within hPSC-derived distal organoids in vitro.

Use and evaluation of the McMurray enhanced airway - Distal pharyngeal airway for improved airway management under deep sedation in the endoscopy clinic

BackgroundThe distal pharyngeal airway (DPA) is a novel airway management tool that relieves airway obstruction. Elongated tubing extends to distal pharyngeal tissues which traditional oral and nasal airways fail to reach. This Quality Improvement initiative aimed to develop and implement a DPA guideline for improving airway management and patient safety in patients undergoing deep sedation for endoscopic procedures. MethodsA quasi-experimental design was used to evaluate the use of a commercially available DPA, the McMurray Enhanced Airway (MEA), in comparison to another new solution, nasal positive airway pressure (nPAP) (SuperNO2VA). Adult patients (n = 47) receiving deep sedation for endoscopic procedures received either a DPA or nPAP based on the preference of the anesthesia provider. During the procedure, the number of airway obstructions and manual airway maneuvers was recorded, as were any adverse events. Anesthesia providers were surveyed regarding perceptions of how well the DPA worked to improve airway management in sedated patients. ResultsThere were no statistically significant differences between the DPA and nPAP groups. A desaturation event was reported for five (20 %) patients in the DPA group and five patients (22.7 %) in the nPAP group, p = 0.999. An airway maneuver was performed for seven (29.2 %) patients in the DPA group and nine (40.9 %) in the nPAP group (p = 0.538). No serious complications were seen in either group. In a subset of patients receiving a colonoscopy, 2 of 15 (13.3 %) in the DPA and 5 of 14 (35.7 %) in the nPAP group had a desaturation event (p = 0.215). In the anesthesia provider survey, 92 % agreed the DPA was successful in relieving an upper airway obstruction. ConclusionThis project shows that the DPA was useful in managing airway obstructions and most providers expressed overall satisfaction with its function. The rate of desaturations and airway maneuvers was equivalent in the two groups despite the DPA group having substantially higher BMIs. We found the DPA to be a useful multi-functional rescue device to restore adequate ventilation quickly and easily. As a result, a guideline and a flowchart based on this study were adopted at our institution.

Robotic-assisted Bronchoscopy Combined with Multimodal Imaging for Targeted Lung Cryobiopsies.

Robotic-assisted bronchoscopy (RAB) allows for targeted bronchoscopic biopsy in the lung. A robotic-assisted bronchoscope is navigated through the airways under direct vision after establishing a pathway to a target lesion based on mapping performed on a 3-dimensional (3D) lung and airway reconstruction obtained from a pre-procedure thin-slice computed tomography chest. RAB has maneuverability to distal airways throughout the lung, precise catheter tip articulation, and stability with the robotic arm. Adjunct imaging tools such as fluoroscopy, radial endobronchial ultrasound (r-EBUS), and cone beam computed tomography (CBCT) can be used with RAB. Studies using shape-sensing robotic-assisted bronchoscopy (ssRAB) have shown favorable diagnostic outcomes and safety profiles in both malignant and non-malignant processes for the biopsy of peripheral pulmonary lesions (PPLs). A 1.1 mm cryoprobe combined with ssRAB has been shown to be safe and effective for the diagnosis of PPLs compared to a traditional bronchoscopy with forceps biopsy. This technique can also be used for targeted lung sampling in benign processes. The aim of this article is to describe a stepwise approach to performing RAB combined with fluoroscopy, r-EBUS, and CBCT to obtain targeted transbronchial lung cryobiopsies (TBLC).

Endoscopic recannulation of long-segment, grade IV suprastomal tracheal stenosis: An operative technique

BackgroundLong-segment, grade IV suprastomal tracheal stenosis is rare and difficult to treat (Carpenter et al., 2022 [1]). Patients with grade IV stenosis have significant quality of life impairments since they are tracheostomy dependent and aphonic. Open airway surgery is often needed to improve tracheal patency, restore the patient's voice, and progress towards decannulation (Abouyared et al., 2017 [2]). However, not all patients are candidates for upfront open surgery (Abouyared et al., 2017; Shamji, 2018 [2,3]). Therefore, it is important to develop and refine endoscopic interventions to improve quality of life for these patients. MethodsWe describe a step-by-step endoscopic approach to the recannulation of long-segment, grade IV suprastomal tracheal stenosis. Briefly, our approach utilizes dual (proximal & distal) visualization of the stenosis prior to passing a 25 gauge needle through the stenosis to identify the proper trajectory for recannulation. Then a 16 gauge needle is passed in the same manner, and a wire is placed through the needle and into the distal airway. Once the airway is recannulated, the initial pinpoint opening is gradually widened in Seldinger fashion over the wire with Savary dilators followed by balloon dilation. Finally, a suprastomal L-stent (modified Montgomery T-Tube) is placed to reduce the risk of restenosis (Edwards et al., 2023 [4]). Case discussionA 39-year-old woman with a past medical history significant for poorly controlled type I diabetes mellitus and polysubstance abuse presented with tracheostomy dependence and aphonia. She was diagnosed with a long-segment, grade IV suprastomal tracheal stenosis and initially underwent endoscopic recannulation. This intervention restored her voice and allowed for optimization of her medical conditions before open airway surgery. ConclusionMost patients experience a significant improvement in their quality of life as their voice is typically restored following this procedure. Additionally, individuals who eventually require open airway surgery gain additional time for medical optimization. In our experience, this procedure represents a safe and effective means of extending the utility of traditional endoscopic airway interventions for the management of patients with grade IV stenosis.

Pulmonary Fibrosis Ferret Model Demonstrates Sustained Fibrosis, Restrictive Physiology, and Aberrant Repair.

The role of MUC5B mucin expression in IPF pathogenesis is unknown. Bleomycin-exposed rodent models do not exhibit sustained fibrosis or airway remodeling. Unlike mice, ferrets have human-like distribution of MUC5B expressing cell types and natively express the risk-conferring variant that induces high MUC5B expression in humans. We hypothesized that ferrets would consequently exhibit aberrant repair to propagate fibrosis similar to human IPF. Bleomycin (5U/kg) or saline-control was micro-sprayed intratracheally then wild-type ferrets were evaluated through 22 wks. Clinical phenotype was assessed with lung function. Fibrosis was assessed with µCT imaging and comparative histology with Ashcroft scoring. Airway remodeling was assessed with histology and quantitative immunofluorescence. Bleomycin ferrets exhibited sustained restrictive physiology including decreased inspiratory capacity, decreased compliance, and shifted Pressure-Volume loops through 22 wks. Volumetric µCT analysis revealed increased opacification of the lung bleomycin-ferrets. Histology showed extensive fibrotic injury that matured over time and MUC5B-positive cystic structures in the distal lung suggestive of honeycombing. Bleomycin ferrets had increased proportion of small airways that were double-positive for CCSP and alpha-tubulin compared to controls, indicating an aberrant 'proximalization' repair phenotype. Notably, this aberrant repair was associated with extent of fibrotic injury at the airway level. Bleomycin-exposed ferrets exhibit sustained fibrosis through 22 wks and have pathologic features of IPF not found in rodents. Ferrets exhibited proximalization of the distal airways and other pathologic features characteristic of human IPF. MUC5B expression through native cell types may play a key role in promoting airway remodeling and lung injury in IPF.

A case of asthmatic granulomatosis

Severe asthma (SA) is a pressing problem in respiratory diseases and accounts for 3–10% of all asthma cases. It is increasingly recognized that SA consists of multiple heterogeneous phenotypes and their histopathology, especially in the distal airways and interstitium, remains poorly understood. Transbronchial biopsy with video imaging and histologic examination allow the detection of various changes, including cases associated with granulomatous inflammation in addition to eosinophilic infiltrates. In the presented clinical case of a patient with severe eosinophilic bronchial asthma in the absence of autoimmune diseases, transbronchial biopsy with further histologic examination of the biopsy specimen revealed eosinophilic granuloma in the form of polyp-like masses in the lung tissue and walls of small bronchi. The cellular composition of the granuloma was represented by macrophage elements, a cluster of lymphocytes with an admixture of eosinophils, individual plasma cells, fibroblasts and capillary vessels with clusters of eosinophils. The treatment (baseline and anti-IL5 therapy), in addition to achieving complete control of asthma symptoms, reduction of nasal congestion, reduction of blood eosinophils, FENO, led to the disappearance of polyposis eosinophilic formation in the bronchial mucosa. Such pathology is described in the literature as “asthmatic granulomatosis” and is of interest for further studies.

Particles in Exhaled Air (PExA): Clinical Uses and Future Implications.

Access to distal airway samples to assess respiratory diseases is not straightforward and requires invasive procedures such as bronchoscopy and bronchoalveolar lavage. The particles in exhaled air (PExA) device provides a non-invasive means of assessing small airways; it captures distal airway particles (PEx) sized around 0.5-7 μm and contains particles of respiratory tract lining fluid (RTLF) that originate during airway closure and opening. The PExA device can count particles and measure particle mass according to their size. The PEx particles can be analysed for metabolites on various analytical platforms to quantitatively measure targeted and untargeted lung specific markers of inflammation. As such, the measurement of distal airway components may help to evaluate acute and chronic inflammatory conditions such as asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome, and more recently, acute viral infections such as COVID-19. PExA may provide an alternative to traditional methods of airway sampling, such as induced sputum, tracheal aspirate, or bronchoalveolar lavage. The measurement of specific biomarkers of airway inflammation obtained directly from the RTLF by PExA enables a more accurate and comprehensive understanding of pathophysiological changes at the molecular level in patients with acute and chronic lung diseases.

RSV infection of humanized lung-only mice induces pathological changes resembling severe bronchiolitis and bronchopneumonia.

Respiratory syncytial virus (RSV) is a substantial cause of severe lower respiratory tract infections in infants, young children, older adults, and immunocompromised individuals. There is a vital need for effective therapeutics to prevent and/or treat severe RSV infection in these high-risk individuals. The development and pre-clinical testing of candidate RSV therapeutics could be accelerated by their evaluation in animals models that recapitulate bronchiolitis and bronchopneumonia; both hallmark features of severe RSV infection of humans. Previously, we demonstrated that implanted human lung tissue in humanized lung-only mice (LoM) can be infected with RSV resulting in a sustained virus replication. Here, we analyzed RSV-associated human lung pathology in the human lung implants of RSV-infected LoM. RSV infected epithelial cells lining the airway and alveolar regions of human lung implants resulting in hallmark histological features of RSV bronchiolitis and bronchopneumonia including distal airway and alveolar lumens clogged with 1) sloughed and necrotic RSV-infected epithelial cells, 2) neutrophil-containing inflammatory infiltrates, and 3) MUC5B dominated mucus secretions. We also show that treatment of LoM with a small molecule antiviral (ribavirin) or a neutralizing antibody (palivizumab) significantly suppressed and/or prevented RSV infection in vivo. Together, our data show that RSV infection of human lung implants in vivo has appropriate cellular tropism and results in hallmark pathological characteristics of severe bronchiolitis and bronchopneumonia in humans. They also offer proof-of-principle of the utility of this model to evaluate novel approaches for the prevention/treatment of RSV infection.

Removal of airway foreign body using flexible bronchoscopy in children

BackgroundFlexible bronchoscopy is mainly used to diagnose airway foreign bodies (AFBs). Due to advances in pediatric anesthesia, many teams have considered the extraction of AFBs by flexible bronchoscopy. We aimed to assess the success of flexible bronchoscopy in AFB removal in children. Patients and methodsWe analyzed retrospectively the data of children admitted for AFB aspiration in the Pediatric Respiratory Diseases Department B of Abderrahmane Mami Hospital in Tunisia between January 2012 and December 2022. AFB removal was performed by flexible bronchoscopy through the use of a laryngeal mask airway (LMA) or intubation. ResultsOf the 105 children included, AFB was removed by flexible bronchoscopy in 99 children (94.3 %). The mean age of the children was 32 months (9–150 months) with a sex ratio of 2:3. The foreign body was organic in 67 % of cases. Overall, 37 children underwent rigid bronchoscopy first (35.2 %). Flexible bronchoscopy was performed through the LMA in 77 cases (73 %) and after intubation in the other cases. Thoracic surgery was needed in two cases (1.9 %). Four infants expectorated the AFB after the procedure (3.8 %). Only two children developed laryngeal edema with transient oxygen desaturation. ConclusionAFB removal using a flexible bronchoscope is an efficient and safe procedure when performed by an experienced team. The recent use of LMA has facilitated the use of a larger bronchofiberscope and the insertion of multiple tools that can reach distal airways.

Performance of the galactomannan test for the diagnosis of invasive pulmonary aspergillosis using non-invasive proximal airway samples

To diagnose invasive pulmonary aspergillosis (IPA), galactomannan (GM) detection in serum or bronchoalveolar lavage fluid (BALF) is widely used. However, the utility of proximal airway GM test (from induced sputum or tracheal aspirate) has not been well elucidated. In this retrospective cohort study, we evaluated the diagnostic performance of proximal airway GM in diagnosis of IPA including COVID-19 associated pulmonary aspergillosis (CAPA). Between January 2022 and January 2023, patients who had been tested for GM with clinical suspicion or for surveillance from any specimen (serum, induced sputum, tracheal aspirate, and BALF) were screened. IPA was diagnosed using EORTC/MSGERC criteria, and CAPA was diagnosed following the 2020 ECMM/ISHAM consensus criteria. Of 624 patients with GM results, 70 met the criteria for proven/probable IPA and 427 had no IPA. The others included possible IPA and chronic form of aspergillosis. The sensitivities and specificities of serum, proximal airway, and BALF GM for proven/probable IPA versus no IPA were 78.9% and 70.6%, 93.1% and 78.7%, and 78.6% and 91.0%, respectively. Areas under the receiver operating characteristic curve (AUCs) were 0.742 for serum GM, 0.935 for proximal airway GM, and 0.849 for BALF GM (serum GM vs proximal airway GM, p=0.014; proximal airway GM vs BALF GM, p=0.334; serum GM vs BALF GM, p=0.286). This study demonstrates that the performance of GM test from non-invasive proximal airway samples is comparable or even better than those from serum and distal airway sample (BALF).

Functional analysis of airway remodeling is related with fibrotic mediators in asthmatic children

Background Asthmatic children present variable degrees of airway inflammation, remodeling, and resistance, which correlate with disease control and severity. The chronic inflammatory process of the airway triggers airway remodeling, which reflects the degree of airway resistance. Pro-inflammatory and pro-fibrotic mediators are centrally involved in this process. Objective To investigate whether the levels of pulmonary and systemic pro-inflammatory and pro-fibrotic mediators present a correlation with the resistance of the respiratory system and of the proximal and distal airways. Methods 39 Asthmatic children (persistent mild and moderate) and 39 non-asthmatic children (both between 6 and 13 years old) were evaluated for anthropometric characteristics, lung function and mechanics, and pulmonary and systemic immune responses. Results Asthmatic children showed an increased number of blood eosinophils (p < 0.04), basophils (p < 0.04), monocytes (p < 0.002) and lymphocytes (p < 0.03). In addition, asthmatic children showed impaired lung function, as demonstrated by FEV1 (p < 0.0005) and FEV1/FVC (p < 0.004), decreased total resistance of the respiratory system (R5Hz; p < 0.009), increased resistance of the proximal airways (R20Hz; p < 0.02), increased elastance (Z5Hz; p < 0.02) and increased reactance (X5Hz; p < 0.002) compared to non-asthmatic children. Moreover, the following inflammatory factors were significantly higher in asthmatic than non-asthmatic children: GM-CSF in the breath condensate (BC) (p < 0.0001) and in the serum (p < 0.0001); TGF-beta in the BC (p < 0.0001) and in the serum (p < 0.004); IL-5 in the BC (p < 0.02) and in the serum (p < 0.01); IL-4 in the serum (p < 0.0002). Conclusions Impulse oscillometry is a sensitive method to detect airway resistance in persistent mild and moderate asthmatic children, an event followed by increased levels of pro-inflammatory and pro-fibrotic mediators.

Prevalence and Factors Affecting the Optimal and Non-optimal Peak Inspiratory Flow Rate in Stable and Exacerbation Phases of Chronic Obstructive Pulmonary Disease and Bronchial Asthma in India.

Chronic obstructive pulmonary disease (COPD) and bronchial asthma pose significant threats and challenges to global health care, emphasizing the need for precise inhaler therapies to overcome this burden. The optimal peak inspiratory flow rate (PIFR) is a crucial determinant for the right selection and effective use of an inhaler device. It also helps to improve the treatment effectiveness of obstructive airway diseases worldwide as it allows effective drug delivery to distal airways and lung parenchyma. It is used as a selection criterion by physicians around the worldfor selecting personalized inhaler devices. To find out the optimal and non-optimal PIFR prevalence and its influencing factors in stable and exacerbation phases of COPD and bronchial asthma in Tamil Nadu, India. It is a single-center, observational, cross-sectional study conducted from February 2022 to August 2023. The patients who meet the diagnostic criteria specified by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines for COPD and the Global Initiative for Asthma (GINA) guidelines for bronchial asthma are enrolled in our study. The PIFR was measured using a hand-held digital spirometry device, along with demographic data collection. Statistical analyses, including t-tests and chi-square tests, were performed using SPSS version 21 (IBM Corp., Armonk, NY). Gender, height, and disease severity significantly impacted the PIFR. Females, normal BMI individuals, and those with moderate disease severity exhibited higher optimal PIFR rates. Stable or exacerbation phases, disease, and smoking status do not influence either optimal or non-optimal PIFR. Notably, substantial differences in lung function parameters were observed between optimal (60-90 L/min) and non-optimal PIFR (insufficient: <30 L/min, suboptimal: 30-60 L/min, excessive: >90 L/min) groups, highlighting their impact on respiratory health. This study emphasizes the importance of personalized inhaler strategies, considering gender, height, and disease severity. Proper inhaler device selection, continuous monitoring of inhaler technique, and tailored inhaler education at every OPD visit are vital for optimizing effective COPD and bronchial asthma management and improving adherence to treatment.

Abstract 5657: The intricate relationship between genomic damage and epidemiological lung cancer risk in ever-smokers

Abstract Extensive epidemiological studies have illuminated the intricate relationship between tobacco smoking and lung cancer. Squamous cell carcinoma (LUSC), which is clinically tied to smoking, is formed in the proximal airway of the lung, whereas adenocarcinoma (LUAD), arising in the distal airway, has a weaker connection to tobacco and often occurs in never-smokers. The cessation of smoking promotes lung health and gradually lowers cancer risk. Dissecting the impact of smoking cessation on different lung cancer types in &amp;gt;650,000 individuals from UK Biobank and PLCO, we confirmed previous findings of LUSC risk diminishing more rapidly after quitting smoking, while LUAD risk endures over time. We previously found that normal bronchial epithelium in the proximal airway accumulates DNA damage proportionally to an individual’s smoking habits. However, our analysis identified a population of cells with near-normal mutation burden, evading tobacco-induced damage. We hypothesized that the reduction in LUSC risk with smoking cessation could be explained by the repopulation of the proximal airway by these cells. Here, we followed up on this finding by exploring the genomics of alveolar stem cells (ASCs), which are believed to be the origin of LUAD. Analyzing WGS data of &amp;gt;800 single-cell-derived organoids from 9 patients, we found that tobacco smoking is the major driver of increased mutation burden in ever- compared to never-smokers. More importantly, our results demonstrated no significant difference in the burden of tobacco-induced genomic damage between ex- and current-smokers, suggesting that DNA damage in the distal airway is both persistent and long-lasting. Using single-molecule sequencing in a cohort of 43 individuals with heterogeneous smoking histories confirmed this observation. Overall, contrasting this finding with the results from bronchial epithelium and the epidemiological lung cancer risk brings forth a genomic explanation for the differences in long-term cancer risk, ingrained in the abundance of near-normal mutation burden cells. By contextualizing our results within the carcinogenic process in the lung, we suggest that persistent genomic alterations are the major driver in the long-standing discussion about the reason for an epidemiological shift from LUSC to LUAD in the last 30 years. As the largest proportion of lung cancers occurs within ex-smokers, the persistent genomic damage in the distal airway will result in a relative increase in LUAD incidence compared to LUSC, likely explaining this clinical phenomenon. Citation Format: Moritz Jakob Przybilla, Amany Ammar, Hugh Selway-Clarke, Andrew R. Lawson, Hyunchul Jung, Adam Pennycuick, Kate Gowers, Ryan C. Khaw, Zoe Frazer, Kate Davies, Inigo Martincorena, Sam Janes, Peter J. Campbell. The intricate relationship between genomic damage and epidemiological lung cancer risk in ever-smokers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5657.

Robotic Bronchoscopy in Lung Cancer Diagnosis.

The widespread use of chest CT has increased the number of detected pulmonary nodules. Nodules with intermediate risk of malignancy warrant further evaluation with PET-CT or sampling. Although sampling with conventional bronchoscopy presents lower complication rates compared to transthoracic needle biopsy (TTNB), it is limited by the inability to reach distal airways. To overcome this shortcoming, a new bronchoscopic technique named robotic bronchoscopy (RB) has emerged. A literature review was used to clarify the rationale behind RB emergence, describe RB procedure, and summarize data regarding its efficacy and safety. The FDA has approved three RB platforms for clinical use. RB is safe, presenting a mortality and complication rate of 0% and 0-8.1%, respectively. Common complications include pneumothorax (0-5.7%) and minor bleeding (0-3.2%). However, its diagnostic yield remains lower than that of TTNB. RB is a promising bronchoscopic technique that aims to overcome the limitations of conventional bronchoscopy and improve upon the current techniques of guided bronchoscopy for the investigation of pulmonary nodules. Despite the lower complication rate, current evidence suggests a lower diagnostic yield compared to TTNB. Additional studies are required to adequately evaluate the role of RB in the diagnosis of pulmonary nodules.

Impact of biologics on lung hyperinflation in patients with severe asthma

BackgroundIn asthma, inflammation affects both the proximal and distal airways and can cause significant hyperinflation, which is thought to be a major cause of dyspnea. MethodsThis is a retrospective observational study evaluating the effect of three months of treatment with different biologic drugs (benralizumab, dupilumab and omalizumab) on pulmonary hyperinflation in a cohort of patients with severe asthma already receiving regular triple inhaled therapy. Changes in RV, RV/TLC ratio, FRC and FRC/TLC ratio were the primary efficacy measures. Secondary outcomes included FEV1, FVC, FEV1/FVC ratio, IC, IC/TLC ratio, asthma control test, the percentage of eosinophils in the blood and fractional FENO. ResultsBenralizumab led to significant changes (p < 0.001) in RV, RV/TLC, FRC, and FRC/TLC. Dupilumab demonstrated a notable reduction in RV (p = 0.017) and RV/TLC (p = 0.002), but the decreases in FRC and FRC/TLC were merely numerical and not as pronounced as those induced by benralizumab. Omalizumab's positive impact on RV (p = 0.057) and RV/TLC (p = 0.085), as well as FRC (p = 0.202) and FRC/TLC (p = 0.096), was also predominantly numerical, with a tendency towards efficacy, albeit excluding the effect on FRC. Treatment with biologics resulted in improvements in all other lung function parameters assessed and a decrease in FENO levels. ConclusionThis study, although limited by small sample size, lack of a placebo control, and unbalanced group sizes, suggests that biological agents are effective in reducing lung hyperinflation even after a relatively short treatment.