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Mucus hypersecretion and mucus obstruction are pathogenic features in many chronic lung diseases directly linked to disease severity, exacerbation, progression, and mortality. The Jagged-1/Notch pathway is a promising therapeutic target that regulates secretory and ciliated cell trans-differentiation in the lung. However, the Notch pathway is also required in various other organs. Hence, pulmonary delivery of therapeutic agents is a promising approach to target this pathway while minimizing systemic exposure. Using Anticalin technology, Jagged-1 Anticalin binding proteins were generated and engineered to potent and selective inhalable Jagged-1 antagonists. Their therapeutic potential to reduce airway mucus hyperproduction and obstruction was investigated ex vivo and in vivo. In primary airway cell cultures grown at an air-liquid interface and stimulated with inflammatory cytokines, Jagged-1 Anticalin binding proteins reduced both mucin gene expression and mucous cell metaplasia. In vivo, prophylactic and therapeutic treatment with a pulmonary-delivered Jagged-1 Anticalin binding protein reduced mucous cell metaplasia, epithelial thickening, and airway mucus hyperproduction in IL-13 and house dust mite allergen-challenged mice, respectively. Furthermore, in a transgenic mouse model with pathophysiologic features of cystic fibrosis and chronic obstructive pulmonary disease (COPD), pulmonary-delivered Jagged-1 Anticalin binding protein reduced hallmarks of airway mucus obstruction. In all in vivo models, a reduction of mucous cells with a concomitant increase of ciliated cells was observed. Collectively, these findings support Jagged-1 antagonists' therapeutic potential for patients with muco-obstructive lung diseases and the feasibility of targeting the Jagged-1/Notch pathway by inhalation. NEW & NOTEWORTHY Airway mucus drives severity and mortality in diverse chronic lung diseases. The Jagged-1/Notch pathway controls the balance of ciliated versus mucous cells, but targeting the pathway systemically carries the risk of side effects. Here we developed novel, Anticalin-derived, pulmonary-delivered Jagged-1 antagonists, to inhibit airway mucus hyperproduction and obstruction in chronic lung diseases. Our preclinical data demonstrate the effectiveness of these antagonists in diminishing secretory cell and mucus levels and alleviating hallmarks of mucus obstruction.

Introduction: The adenoids and palatine tonsils, part of the lymphoid tissue, act as a first line of defense protecting the lower airways and gastrointestinal tract. Adenotonsillar hypertrophy in children may lead to airway obstruction. This study aims to demonstrate the association between adenotonsillar hypertrophy and decreased blood oxygen saturation., Methods: A retrospective cohort study was conducted among children aged 7-12 years with adenotonsillar hypertrophy and obstructive symptoms, admitted to King Fahad Hospital and Prince Mishari Hospital, Saudi Arabia, for tonsillectomy between July 2023 and January 2024. Exclusion criteria included respiratory diseases, cardiac disease, nasal polyps, nasal septum deviation, chest wall abnormality, and lower airway diseases. The control group included 56 healthy children. An otolaryngologist determined the severity of airway obstruction using the tonsil size. Oxygen saturation was measured using pulse oximetry. The determinants of oxygen saturation were assessed using multiple linear regression, with significance set at p<0.05., Results: The study included 357 participants, with an even age distribution between 7-9 years (49.6%) and 10-12 years (50.4%), and 52% males. Diagnoses included adenoid hypertrophy (30%), tonsil hypertrophy (35%), both conditions (19%), and the control group (16%). Tonsil sizes ranged from Grade 1 (48%) to Grade 4 (8.4%), with 17% normal. The median oxygen saturation was 96.0% for the adenotonsillar hypertrophy group and 99.0% for the control. Oxygen saturation levels differed significantly across groups (p<0.0001), with lower median saturation in hypertrophy groups than controls. Males had a lower oxygen than females (estimate: -0.338, 95% CI [--0.640, -0.036], p=0.028). Adenoid hypertrophy (estimate: -3.863, 95% CI [-5.241, -2.484], p<0.001), tonsil hypertrophy (estimate: -3.631, 95% CI [-5.053, -2.208], p<0.001) and having both conditions (estimate: -3.777, 95% CI [-5.3.7, -2.247], p<0.001) was associated with lower oxygen saturation. Grade 1 tonsil size was associated with an increase in oxygen saturation (estimate = 2.905, 95% CI [1.616, 4.194], p<0.001). In contrast, Grade 4 tonsil size was linked to lower oxygen saturation (estimate=-4.848, 95% CI [-6.367, -3.329], p<0.001). Grades 2 and 3 were not significantly associated with changes in oxygen saturation., Conclusion: Adenotonsillar hypertrophy is significantly associated with decreased blood oxygen saturation and related cardiopulmonary complications in children. Early adenotonsillectomy may be of benefit in preventing these complications and improving oxygen saturation levels.

Benign airway stenosis (BAS) means airway stenosis or obstruction that results from a variety of non-malignant factors, including tuberculosis, trauma, benign tumors, etc. In consideration of the currently limited research on microRNAs in BAS, this study aimed to explore the role and mechanism of miR-34c-5p in BAS. The expression of miR-34c-5p in BAS granulation tissues showed a significant down-regulation compared with the normal control group. Moreover, miR-34c-5p mimics suppressed the proliferation and differentiation of human bronchial fibroblasts (HBFs) and the epithelial-mesenchymal transition (EMT) of human bronchial epithelial cells (HBE). Conversely, miR-34c-5p inhibitors aggravated those effects. A dual-luciferase reporter assay confirmed that miR-34c-5p can target MDMX rather than Notch1. The over-expression of MDMX can reverse the inhibiting effect of miR-34c-5p on HBFs proliferation, differentiation and EMT. Furthermore, the expressions of tumor protein (p53) and PTEN were down-regulated following the over-expression of MDMX. In addition, the expressions of PI3K and AKT showed an up-regulation. In conclusion, miR-34c-5p was down-regulated in BAS and may inhibit fibroblast proliferation differentiation and EMT in BAS via the MDMX/p53 signaling axis. These findings expand the understanding of the role of miR-34c-5p and will help develop new treatment strategies for BAS., (© 2024. The Author(s).)

Introduction: Being choked/strangled during partnered sex is an emerging sexual behavior, particularly prevalent among young adult women. Using a multiparameter morphometric imaging approach, we aimed to characterize neuroanatomical differences between young adult women (18-30 years old) who were exposed to frequent sexual choking and their choking naïve controls., Methods: This cross-sectional study consisted of two groups (choking [≥4 times in the past 30 days] vs. choking-naïve group). Participants who reported being choked four or more times during sex in the past 30 days were enrolled in the choking group, whereas those without were assigned to the choking naïve group. High-resolution anatomical magnetic resonance imaging (MRI) data were analyzed using both volumetric features (cortical thickness) and geometric features (fractal dimensionality, gyrification, sulcal depth)., Results: Forty-one participants (choking n = 20; choking-naïve n = 21) contributed to the final analysis. The choking group showed significantly increased cortical thickness across multiple regions (e.g., fusiform, lateral occipital, lingual gyri) compared to the choking-naïve group. Widespread reductions of the gyrification were observed in the choking group as opposed to the choking-naïve group. However, there was no group difference in sulcal depth. The fractal dimensionality showed bi-directional results, where the choking group exhibited increased dimensionality in areas including the postcentral gyrus, insula, and fusiform, whereas decreased dimensionality was observed in the bilateral superior frontal gyrus and pericalcarine cortex., Conclusion: These data in cortical morphology suggest that sexual choking events may be associated with neuroanatomical alteration. A longitudinal study with multimodal assessment is needed to better understand the temporal ordering of sexual choking and neurological outcomes., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Congenital laryngeal cysts are rare lesions that may occur in newborns, characterized by symptoms of respiratory obstruction and severe dyspnea. The aim of this study was to indicate optimal surgical treatment of congenital laryngeal cysts in newborns. We present a case series of five neonates treated for congenital laryngeal cysts during the 2011-2017 period at our pediatric tertiary care hospital. Patient age ranged from one day to 14 days. All patients had unilateral cysts. After surgical excision, burning of the walls of the cysts was performed by a CO2 laser. In one case, after four months, a recurrent cyst appeared, and re-operation was performed. Our relatively small case series indicates that symptoms such as stridor and labored breathing can occur already during the first days of life and potentially endanger the patient's life. Complete excision of the cyst and burning of its walls with CO2 laser leads to complete cure and prevent recurrence of the lesion., (Sestre Milosrdnice University Hospital.)

Brachycephalic obstructive airway syndrome (BOAS) is a chronic, lifelong, debilitating, primarily obstructive airway disease which adversely affects the quality of life of many popular dog breeds. Respiratory restriction in bulldog breeds, pugs and Boston terriers frequently co-exist with pathologies of the gastrointestinal tract. In addition, many brachycephalic dogs that appear clinically normal are, in fact suffering from chronic hypoxia and its systemic consequences. Concurrent gastroesophageal reflux-associated conditions, sleep disorders and systemic hypertension further impact the welfare of affected dogs. Acceptance of BOAS and associated clinical signs as being 'normal for the breed' is common amongst owners. While surgical correction of the upper airway is the mainstay of treatment, the provision of subsequent, frequently lifelong medical management is equally important for the maintenance of an acceptable quality of life, at least for some affected patients. Here we review the current knowledge concerning brachycephaly, combine it with shared clinical experience in the management of this debilitating condition, and discuss ethical considerations and the responsibility of veterinarians to contribute public education and to support appropriate breed standards for animals under our care.

Objective: The aim of the study was to investigate the awareness for the breed-related brachycephalic obstructive airway syndrome (BOAS) and the occurrence of other breed-typical diseases within the framework of an online survey for pug owners., Material and Methods: A digital questionnaire for owners was created, distributed via social media and subsequently evaluated., Results: The questionnaire was completed by 1220 pug owners. According to the owners, 32 % (344/1073) of the animals that did not undergo airway dilatation surgery show slight and 3 % (34/1073) show distinct breathing sounds when at rest. 86 % (326/378) of the owners perceive these breathing sounds as "normal, breed-specific" and 14 % (51/378) consider them as sign of "disease". 20 % (210/1073) of the animals are considered "somewhat" and 5 % (57/1073) "frequently tired and quickly short of breath" after a small amount of time. 24 % (245/1220) of all animals suffer from ocular diseases, 10 % (122/1220) from skin diseases and 11 % (134/1220) from spinal diseases, among others., Conclusion: The survey shows that with 67 % (814/1220) more than half of the pug owners perceive clinical signs of BOAS and/or other breed-specific diseases in their animals, however, a large proportion consider these as being non-problematic., Clinical Relevance: The present study reveals that the animals' clinical limitations associated with brachycephaly are oftentimes not perceived as being pathologic and are hence underestimated by the owners., Competing Interests: Die Autoren bestätigen, dass kein Interessenskonflikt besteht., (Thieme. All rights reserved.)

Background: IL-5-dependent residential and IL-18-transformed pathogenic eosinophils have been reported; however, the role of IL-18-transformed CD274-expressing pathogenic eosinophils compared to IL-5-generated eosinophils in promoting airway obstruction in asthma has not yet been examined., Methods: Eosinophils are detected by tissue anti-MBP and anti-EPX immunostaining, CD274 expression by flow cytometry, and airway resistance using the Buxco FinePointe RC system., Results: We show that A. fumigatus-challenged wild-type mice, and different gene-deficient mice including naïve CC10-IL-18-transgenic mice, accumulate mostly peribronchial and perivascular CD274-expressing eosinophils except naïve CD2-IL-5-transgenic mice. Additionally, we show that CD2-IL-5 transgenic mice following rIL-18 treatment accumulate high number of CD274-expressing perivascular and peribronchial eosinophils with induced collagen, goblet cell hyperplasia and airway resistance compared to saline-challenged CD2-IL5 transgenic mice. Furthermore, we also show that even A. fumigatus-challenged IL-5 -/- mice and rIL-18 given ΔdblGATA mice accumulate CD274-expressing eosinophil-associated asthma pathogenesis including airway obstruction. Most importantly, we provide evidence that neutralization of CD274 and IL-18 in A. fumigatus-challenged mice ameliorate experimental asthma. Taken together, the data presented are clinically significant in establishing that anti-IL-18 neutralization is a novel immunotherapy to restrict asthma pathogenesis., Conclusions: We demonstrate that IL-18 is critical for inducing asthma pathogenesis, and neutralization of CD274 is a potential immunotherapeutic strategy for asthma., (© European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Traditionally, staphylectomy has been performed using scissors cutting and suturing. Alternative surgical techniques such as staphylectomy with monopolar electrocoagulation, CO 2 or diode laser, bipolar vessel sealing device and harmonic shears have also been described. The purpose of this prospective study was to compare the difference in surgical time, intraoperative haemorrhage and histological damage between staphylectomy performed with harmonic shears (HSS), diode laser (DLS) and traditional scissor 'cutting and suturing' technique with Metzenbaum scissors (SIS). Group HSS included 17 dogs, whereas Group DLS and Group SIS included 10 dogs each. Double masked histological evaluation was performed on the excised specimens. The harmonic shears resulted in the shortest surgical times (HSS 46 s, DLS 300 s, SIS 360 s; P < 0.001). There was a difference in the intraoperative haemorrhage among the three techniques; intraoperative haemorrhage did not occur in HSS and DLS groups. HSS was associated with more frequent damage involving the connective tissue (P = 0.001), muscle (P = 0.038), salivary gland tissue (P < 0.001), but less oedema was observed (P < 0.001). HSS was the fastest of the techniques evaluated for caudal elongated soft palate resection, resulting in less tissue oedema, and no intra-operative haemorrhage. These characteristics might result in reduced postoperative swelling and airway obstruction compared to other techniques., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: This study aimed to investigate and compare the anatomical features of the nasolacrimal drainage system (NDS) in three brachycephalic dog breeds with those of normocephalic dogs, taking into account how the NDS was related to the malformed brachycephalic head., Animals: Fifty-one brachycephalic dogs were examined, comprising 23 Pugs, 18 French Bulldogs, and 10 English Bulldogs. Six normocephalic dogs of different breeds served as a comparison., Methods: Computed tomographic dacryocystography was performed. Parameters such as length, angulation, and gradient were determined. Crossing of the nasolacrimal duct (NLD) beneath the maxillary canine root, as well as the incidence of an accessory opening, were also analyzed., Results and Conclusions: In all three brachycephalic breeds, the NDS was grossly malformed. We regard this as a further consequence of exaggerated breeding for a short head conformation. While the length of the NLD was substantially reduced by 41 to 57 percent in brachycephalic dogs, their lacrimal canaliculi were two to three times as long as those of normocephalic dogs. Varying parts of the nasolacrimal drainage system followed an inverse direction in short-headed dogs, giving the entire nasolacrimal apparatus an anomalous U- or V-shaped appearance. The NLD exhibited a three to five times steeper alignment in brachycephalic dogs than in normocephalic ones. Obviously, this strong slope did not cause clinical symptoms only because there was an aberrant outflow pathway. The brachycephalic dogs consistently exhibited an accessory opening, through which most of fluid escaped into the posterior nasal cavity instead of through the common route into the nasal vestibule via the nasolacrimal ostia., Competing Interests: The authors have declared that no competing interests exist.

Background: The aim of this study was to integrate the physical findings of drug-induced sleep endoscopy with snoring sound analysis in patients with obstructive sleep apnea/hypopnea syndrome (OSAS) and to compare the findings with previously published data., Methods: This was a prospective, non-randomized study. Participants were all candidates for surgical treatment of OSAS and formed three groups, retropalatal (RP) obstructions, retrolingual (RL) obstructions, and multilevel (ML) obstructions. At the time of DISE, recordings of concurrent snoring sounds were made. Mean pitch frequency, peak sound frequency, and fundamental frequency (Fo) components were determined., Results: A total of 55 participants had mean age 46.2 ± 7.3 years, mean BMI 30.0 ± 3.7 kg/m 2 , and included 11 women (20%). Differences in mean pitch frequency, Fo, and peak sound frequency were all statistically significant between the RP and RL (p = 0.001), between ML and RL (p = 0.025) but were not significantly different between RP and ML. Mean pitch frequency of RP was lower than RL, and ML frequency was between RL and RP. The sound analysis graphics revealed RP waves with sharp peaks and lower frequencies and RL with smooth curves and higher frequencies. ML showed irregular patterns. Mean pitch frequency of RL was always above 400 Hz, whereas RP was below this value., Conclusions: It is feasible to apply sound analysis to determine the site of obstruction during DISE. Combining the data may help surgeons make more accurate assessments of the pattern of the disease., (© 2020. Springer Nature Switzerland AG.)

Tornwaldt cyst is a relatively rare lesion that is found in the posterior wall of the nasopharynx. It occurs in the midline bursa of the nasopharynx and represents a persistent communication between the roof of the nasopharynx and the notochordal remnants. Smaller cysts are usually asymptomatic; cysts exceeding a diameter of 1 to 2 cm may be symptomatic. Magnetic resonance imaging is the best imaging modality for diagnosing Tornwaldt cyst. We present a rare case of a huge Tornwaldt cyst completely obstructing the nasopharyngeal airway.

Mucus-secreting goblet cells are the dominant cell type in pulmonary diseases, e.g., asthma and cystic fibrosis (CF), leading to pathologic mucus metaplasia and airway obstruction. Cytokines including IL-13 are the major players in the transdifferentiation of club cells into goblet cells. Unexpectedly, we have uncovered a previously undescribed pathway promoting mucous metaplasia that involves VEGFa and its receptor KDR. Single-cell RNA sequencing analysis coupled with genetic mouse modeling demonstrates that loss of epithelial VEGFa, KDR, or MEK/ERK kinase promotes excessive club-to-goblet transdifferentiation during development and regeneration. Sox9 is required for goblet cell differentiation following Kdr inhibition in both mouse and human club cells. Significantly, airway mucous metaplasia in asthmatic and CF patients is also associated with reduced KDR signaling and increased SOX9 expression. Together, these findings reveal an unexpected role for VEGFa/KDR signaling in the defense against mucous metaplasia, offering a potential therapeutic target for this common airway pathology., Competing Interests: Declaration of interests A patent application (CU21016, “SUPPRESSION OF KDR, VEGF OR THE DOWNSTREAM MEK/ERK KINASE PATHWAY”) related to this work has been filed by Columbia Technology Ventures. M.J. and J.Q. are listed as co-inventors on this application., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Patients with COVID-19 and ARDS on prolonged mechanical ventilation are at risk for developing endotracheal tube (ETT) obstruction that has not been previously described in patients with ARDS due to other causes. The purpose of this report is to describe a case series of patients with COVID-19 and ARDS in which ETT occlusion resulted in significant clinical consequences and to define the pathology of the obstructing material., Methods: Incidents of ETT occlusion during mechanical ventilation of COVID-19 patients were reported by clinicians and retrospective chart review was conducted. Statistical analysis was performed comparing event rates between COVID-19 and non-COVID 19 patients on mechanical ventilation over the predefined period. Specimens were collected and submitted for pathological examination., Findings: Eleven COVID-19 patients experienced endotracheal tube occlusion over a period of 2 months. Average age was 69 (14.3, range 33-85) years. Mean APACHE III score was 73.6 (17.3). All patients had AKI and cytokine storm. Nine exhibited biomarkers for hypercoagulability. Average days on mechanical ventilation before intervention for ETT occlusion was 14 (5.18) days (range of 9 to 23 days). Five patients were discharged from the ICU, and 4 expired. Average documented airway resistance on admission was 14.2 (3.0) cm H 2 O/L/sec. Airway resistance before tube exchange was 28.1 (8.0) cm H 2 O /L/sec. No similar events of endotracheal tube occlusion were identified in non-COVID patients on mechanical ventilation during the same time period. Microscopically, the material consisted of mucin admixed with necrotic cell debris, variable numbers of degenerated inflammatory cells, oral contaminants and red blood cells., Interpretation: Patients with COVID-19 and ARDS on prolonged mechanical ventilation are at risk for developing ETT obstruction due to deposition of a thick, tenacious material within the tube that consists primarily of mucin and cellular debris. Clinicians should be aware of this dangerous but treatable complication.

The present study aimed to examine the effects of 2.5 µm particulate matter (PM2.5) on airway inflammation and to investigate the possible underlying mechanism. Specifically, the focus was on the imbalance of T helper (Th)1/Th2 cells and the dysregulated expression of transcription factors, including trans ‑acting T cell‑specific transcription factor 3 (GATA3), runt‑related transcription factor 3 (Runx3) and T‑box transcription factor TBX21 (T‑bet). In this study, ambient PM2.5 was collected and analyzed, male BALB/c mice were sensitized and treated with PBS, ovalbumin (OVA), PM2.5 or OVA + PM2.5. The effects of PM2.5 alone or PM2.5 + OVA on immunopathological changes, the expression of transcription factors GATA3, Runx3 and T‑bet, and the imbalance of Th1/Th2 were investigated. It was found that PM2.5 + OVA co‑exposure significantly enhanced inflammatory cell infiltration, increased higher tracheal secretions in lung tissue and upregulated respiratory resistance response to acetylcholine compared with PM2.5 or OVA single exposure and control groups. In addition, higher protein and mRNA expression levels of Th2 inflammatory mediators interleukin (IL)‑4, IL‑5 and IL‑13 in bronchoalveolar lavage fluid were observed in PM2.5 + OVA treated mice, whereas the expression levels of GATA3 and STAT6 were exhibited in mice exposed to OVA + PM2.5 compared with the OVA and PM2.5 groups. By contrast, PM2.5 exposure decreased the protein and mRNA expression levels of Th1 cytokine interferon‑γ and transcription factors Runx3 and T‑bet, especially among asthmatic mice, different from OVA group, PM2.5 exposure only failed to influence the expression of T‑bet. To conclude, PM2.5 exposure evoked the allergic airway inflammation response, especially in the asthmatic mouse model and led to Th1/Th2 imbalance. These effects worked mainly by upregulating GATA3 and downregulating Runx3. These data suggested that Runx3 may play an important role in PM2.5‑aggravated asthma in BALB/c mice.

OSA pediatric subjects suffer from episodes of upper airway obstruction that can be partial or complete, with atypical sleep patterns and blood-gas level alteration. If poor treated and/or diagnosed, it can cause cardiovascular disease, learning difficulties, behavioural issues, and retardation of growth. In the literature, there are conflicting evidence about OSA assessment and treatment in pediatric age, so the aim of this paper is to highlight the multidisciplinary approach in the management of sleep disorders, stressing the role of the pediatric dentist in both diagnosing and treating the OSAS in children, according to the current evidence of the treatment options effectiveness of the syndrome itself. Conclusions . Scientific evidence shows that OSAS management requires a multidisciplinary approach in order to make an early diagnosis and a correct treatment plan. The orthodontic treatment approach includes orthopedic maxillary expansion and mandibular advancement using intraoral appliances. Hence, the orthodontist and the pediatric dentist play an important role not only in early diagnosis but also in the treatment of pediatric OSAS., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Maria Rita Giuca et al.)

Cystic fibrosis (CF) is characterized by an airway obstruction caused by a thick mucus due to a malfunctioning Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. The sticky mucus restricts drugs in reaching target cells limiting the efficiency of treatments. The development of new approaches to enhance drug delivery to the lungs represents CF treatment's main challenge. In this work, we report the production and characterization of hybrid core-shell nanoparticles (hNPs) comprising a PLGA core and a dipalmitoylphosphatidylcholine (DPPC) shell engineered for inhalation. We loaded hNPs with a 7-mer peptide nucleic acid (PNA) previously considered for its ability to modulate the post-transcriptional regulation of the CFTR gene. We also investigated the in vitro release kinetics of hNPs and their efficacy in PNA delivery across the human epithelial airway barrier using an ex vivo model based on human primary nasal epithelial cells (HNEC) from CF patients. Confocal analyses and hNPs transport assay demonstrated the ability of hNPs to overcome the mucus barrier and release their PNA cargo within the cytoplasm, where it can exert its biological function.

Abstract: Two cases of clinically undiagnosed laryngeal squamous cell carcinomas in men aged 57 and 66 years, respectively, are reported that resulted in sudden death from upper airway occlusion. The cause of the terminal event differed between the 2 cases with acute airway narrowing being precipitated by tenacious mucopurulent secretions in case 1 and hemorrhage from surface ulceration with glottic occlusion by blood clot in case 2. At autopsy, the immediate cause of acute airway compromise in cases of space-occupying laryngeal lesions may, therefore, be due to the synergistic effects of different factors., Competing Interests: The authors report no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Respiratory outcomes in Mucopolysaccharidosis Type I (MPS I), have mainly focused on upper airway obstruction, with the evolution of the restrictive lung disease being poorly documented. We report the long-term pulmonary function outcomes and examine the potential factors affecting these in 2 cohorts of MPS I patients, those who have undergone Haematopoietic Stem Cell Transplantation (HSCT) and those treated with Enzyme Replacement Therapy (ERT). The results were stratified using the American Thoracic Society (ATS) guidelines. 66 patients, capable of adequately performing testing, were identified by a retrospective case note review, 46 transplanted (45 Hurler, 1 Non-Hurler) and 20 having ERT (17 Non-Hurler and 3 Hurler diagnosed too late for HSCT). 5 patients died; 4 in the ERT group including the 3 Hurler patients. Overall 14% of patients required respiratory support (non-invasive ventilation (NIV) or supplemental oxygen)) at the end of follow up. Median length of follow-up was 12.2 (range = 4.9-32) years post HSCT and 14.34 (range = 3.89-20.4) years on ERT. All patients had restrictive lung disease. Cobb angle and male sex were significantly associated with more severe outcomes in the HSCT cohort, with 49% having severe to very severe disease. In the 17 Non-Hurler ERT treated patients there was no variable predictive of severity of disease with 59% having severe to very severe disease. During the course of follow up 67% of the HSCT cohort had no change or improved pulmonary function as did 52% of the ERT patients. However, direct comparison between therapeutic modalities was not possible. This initial evidence would suggest that a degree of restrictive lung disease is present in all treated paediatrically diagnosed MPS I and is still a significant cause of morbidity, though further stratification incorporating diffusing capacity for carbon monoxide (DLCO) is needed., Competing Interests: Declaration of Competing Interest Dr. A Broomfield declares travel assistance from Takeda Pharmaceutical, Sanofi and Biomarin Pharmaceutical and consulting fees from Sanofi, unrelated to this work. Dr. A Ghosh declares travel assistance from Biomarin Pharmaceutical and honoraria from Alexion Pharmaceuticals, unrelated to this work. Dr. KM Stepien has received travel grants from BioMarin, Genzyme, Alexion, Takeda Pharmaceutical and honoraria from Biomarin Pharmaceutical Chiesi, Sanofi, Orchard Therapeutics and Takeda unrelated to this work. K Tylee declares prior travel assistance from Biomarin Pharmaceutical, unrelated to this work. Dr. S Jones declares consultancy for Genzyme, Shire, Alexion Pharmaceuticals, Orchard Therapeutics, Denali Therapeutics, and Ultragenyx Pharmaceutical, unrelated to this work. All other authors declare no conflict of interest., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Acute, major pulmonary haemorrhage in children, is rare, may be life-threatening and at times presents atypically. Dieulafoy's disease of the bronchus presenting with recurrent or massive hemoptysis was first described in adults. Prior to reviewing the literature, we report an illustrative case of bronchial Dieulafoy's disease (BDD) in a child presenting unusually with massive apparent hematemesis. The source of bleeding is a bronchial artery that fails to taper as it terminates within the bronchial submucosa. A high index of suspicion is required to identify such lesions via radiological imaging and the role of bronchial artery embolisation is highlighted with video images of angiography included., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Brachycephalic airway syndrome (BAS) is a well-established cause of respiratory distress in dogs. BAS without surgical correction results in eventual laryngeal collapse. Arytenoid lateralization has been used to treat severe laryngeal collapse with some highly variable results. Chondromalacia and decreased stiffness of the arytenoid cartilage has been postulated a source of failure after arytenoid lateralization but no report of the histological characteristics and mechanical strength of arytenoid cartilage in brachycephalic dogs has been reported. Here we report histological and mechanical features in arytenoid cartilage of brachycephalic dogs. We identified the arytenoid cartilage in brachycephalic dogs presented degenerative histological characteristics and decreased load to failure and stiffness compared to that in non-brachycephalic dogs. Together, these observations suggest that degenerative condition of arytenoid cartilage in brachycephalic dogs could contribute to chondromalacia and mechanical weakness of arytenoid cartilage and result in cause of failure after arytenoid lateralization., Competing Interests: E.J. Ehrhart is an employee of Ethos Diagnostic Science. The other authors have declared that no competing interest exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: A significant proportion of lung cancer patients suffer from malignant airway obstruction (MAO). Palliative external beam radiotherapy (EBRT) is often used to control the symptoms caused by MAO. In this study, we report the effect of palliative EBRT on lung cancer with MAO and analyze the factors that influence it., Methods: This study included 75 patients with MAO in lung cancer who underwent palliative EBRT, between 2009 and 2018 and were analyzed retrospectively. Change of dyspnea, tumor response, and overall survival (OS) were recorded. Univariate and multivariate analyses were performed to determine the prognostic factors for treatment outcomes., Results: The median follow-up duration was 2.5 months, and median OS was 2.3 months. Out of 75 patients, dyspnea was improved in 46 patients (61.3%), and tumor was partially decreased in 39 patients (52%). Symptoms improved in all tumor responding patients. The symptom improvement was significantly affected by radiation dose and time to EBRT. The tumor response was significantly affected by pathology, radiation dose, and time to EBRT., Conclusions: Palliative EBRT is an effective and safe treatment option for patients with MAO in lung cancer. In particular, high-dose irradiation and prompt treatment can improve treatment results., Key Points: SIGNIFICANT FINDINGS OF THE STUDY: In MAO patients, tumor response is an important factor for resolving dyspnea and improving survival rate. In order to increase the tumor response, high-dose irradiation and prompt treatment after symptoms occur are necessary., What This Study Adds: Our study reported the effects of EBRT and prognostic factors in MAO patients. We emphasize that palliative EBRT is a relatively safe and effective treatment in MAO patients, which is a complement to previous studies., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Endobronchial hamartochondroma is a rare benign tumor which differs from the parenchymal form in its symptomatology and also by its treatment which should be as conservative as possible. The endobronchial location is exceptional. Here we present the cases of two patients with endobronchial hamartochondroma associated with clinical manifestation, chest pain and repeated pulmonary infections, respectively. The diagnosis was made after performing a CT-scan, a PET-SCAN and histological analysis. After discussion in a multidisciplinary staff meeting, conservative treatment was chosen in both cases., (Copyright © 2020 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Tenacious mucus produced by tracheal and bronchial submucosal glands is a defining feature of several airway diseases, including cystic fibrosis (CF). Airway acidification as a driving force of CF airway pathology has been controversial. Here we tested the hypothesis that transient airway acidification produces pathologic mucus and impairs mucociliary transport. We studied pigs challenged with intra-airway acid. Acid had a minimal effect on mucus properties under basal conditions. However, cholinergic stimulation in acid-challenged pigs revealed retention of mucin 5B (MUC5B) in the submucosal glands, decreased concentrations of MUC5B in the lung lavage fluid, and airway obstruction. To more closely mimic a CF-like environment, we also examined mucus secretion and transport following cholinergic stimulation under diminished bicarbonate and chloride transport conditions ex vivo. Under these conditions, airways from acid-challenged pigs displayed extensive mucus films and decreased mucociliary transport. Pretreatment with diminazene aceturate, a small molecule with ability to inhibit acid detection through blockade of the acid-sensing ion channel (ASIC) at the doses provided, did not prevent acid-induced pathologic mucus or transport defects but did mitigate airway obstruction. These findings suggest that transient airway acidification early in life has significant impacts on mucus secretion and transport properties. Furthermore, they highlight diminazene aceturate as an agent that might be beneficial in alleviating airway obstruction.

Objective: To correlate the clinical severity of laryngomalacia (LM) with endoscopic findings, swallowing evaluations and polysomnography in a cohort of patients. Method: We conducted a retrospective analysis between 2017-2018 on a cohort of patients diagnosed with upper airway obstruction (UAO), stridor, noisy breathing or laryngomalacia. This study took place at the Pediatric Pulmonology Department, Riley Children's Hospital, Indianapolis, United States of America., Results:   There were 157 patients with laryngomalacia included in the study. Patients with severe LM were significantly younger than those with mild LM (p=0.0214) and moderate LM (p=0.0220). Subjects with type I of LM were significantly older than type III (p=0.0051). When associations were tested between polysomnogram (PSG) variables and clinical severity, there were significant associations with age at PSG. The overall apnea-hypopnea index (AHI) in mild (p=0.0103) and moderate (p=0.0242) were significantly lower than the severe group. The rapid eye movement (REM) AHI was significantly lower in moderate cases than severe (p=0.0134). The end-tidal carbon dioxide (EtCO2) peak was significantly lower in mild cases than severe (p=0.0141). The total sleep time (TST) peripheral capillary oxygen saturation (SpO2) 90% occurs in both mild (p=0.0197) and moderate (p=0.0498) were significantly lower than the severe group., Conclusions: The severity of the clinical manifestations of LM did not correlate with the different endoscopic types in our study. The presence of cyanosis was associated with type III LM. Rapid eye movement AHI and EtCO2 in polysomnogram were remained significantly associated with clinical severity.

Background: Congenital High Airway Obstruction Syndrome (CHAOS) is an uncommon anomaly. Prenatal ultrasonography allows a prenatal diagnosis to prepare for immediate surgical correction at birth. If the obstruction is severe and a correct therapeutic approach is not planned, CHAOS can cause neonatal death shortly after delivery from a potentially surgically correctable lesion. Case report: This neonate died unexpectedly shortly after delivery due to CHAOS. Ultrasonographic findings of enlarged echogenic lungs, dilated airways distal to the obstruction, flattened or inverted diaphragms, or ascites were absent. This was due to a type-II laryngeal-atresia and a type-C esophageal-atresia, with a resultant distal fistula that allowed intrauterine decompression of the fluid in the lungs. Conclusions: The absence of prenatal ultrasonographic findings of CHAOS may be due to a lower fistula between respiratory and gastrointestinal tracts. This set of associations may not be a surgically correctable cause of CHAOS.

Introduction and Objective: Silicon and metallic are two types of stents in use. In this study, we compared complications and long-term survival among patients who received silicon or fully covered, bifurcated self-expandable metallic stents (SEMS) for a malignant tracheobronchial obstruction and/or tracheo/bronchial oesophageal fistulas., Methods: Patients in whom Y-shaped stents were used from January 2013 to June 2017 in our interventional pulmonology unit were evaluated retrospectively from patient files., Results: Of the 47 patients, 30 (23 males, 76.7%) were in the silicon stent group and 17 (14 males, 82.4%) were in the covered SEMS group. No differences between the groups were detected in ECOG status, pathological properties of the disease, radiotherapy or chemotherapy history before the procedure, symptoms at presentation, or comorbidities. The most common symptom was dyspnoea (96.7% and 100%), and the most common comorbidity was chronic obstructive pulmonary disease (26.7% and 23.5%). A total of 20 complications (42.6%) were seen, with no significant difference between the groups (silicon, 40%; SEMS, 47.1%; P = . 62). Mean survival was 164.51 ± 38.83 days for the silicon stent group and 254.45 ± 103.32 days for the SEMS group (P = .588). No differences were observed in 30-, 90- or 180-day mortality between the two groups (P = .966, .846 and .534, respectively)., Conclusions: No significant differences in symptom palliation, insertion safety, complication rate or survival were detected between the two types of stent., (© 2019 John Wiley & Sons Ltd.)

Background: Airway obstruction due to decreased airway diameter and increased incidence of mucus plugs has not been directly observed in asthma exacerbation. We studied the changes in the inner diameter of the airway (Din) and the frequency of mucus plugs by airway generation in patients with asthma exacerbation. We compared these patients to those in a stable phase using high-resolution computed tomography (HRCT)., Methods and Findings: Thirteen patients with asthma were studied by HRCT during asthma exacerbation and in a stable period. The HRCT study was performed on patients who could safely hold their breath for a short while in a supine position 1 hour after initial treatment for asthma exacerbation. Using a curved multiplanar reconstruction (MPR) software, we reconstructed the longitudinal airway images and the images exactly perpendicular to the airway axis to measure the Din and mucus plugs from the second- (segmental) to sixth-generation bronchi in all segments of the lungs.The ratios of Din (exacerbation/stable) were 0.91(P = 0.016), 0.88 (P = 0.002), 0.83 (P = 0.001), 0.80 (P = 0.001), and 0.87 (NS) in the second-, third-, fourth-, fifth-, and sixth-generation bronchi, respectively. The percentages of airway obstruction due to mucus plugs were notably higher in the fourth- and fifth-generation bronchi (17.9%/18.1% in stable phase and 43.2%/45.9% in the exacerbation phase, respectively) than in the other generations of bronchi., Conclusions: Among the bronchi examined, the fourth- and fifth-generation bronchi were significantly obstructed during asthma exacerbation compared with the stable phase in terms of a decreased airway diameter and mucus plugs., Competing Interests: The authors have declared that no competing interests exist.

Osteopontin (OPN) plays a role in inflammation via recruitment of neutrophils and tissue remodeling. In this study, we investigated the distribution of OPN-expressing cells in the airway epithelium of normal lung tissue and that from patients with chronic obstructive pulmonary disease (COPD). OPN was detected on the epithelial cell surface of small airways and in scattered cells within the epithelial cell layer. Staining revealed higher OPN concentrations in tissue showing moderate to severe COPD compared to that in controls. In addition, OPN expression was confined to goblet and club cells, and was absent from ciliated and basal cells as detected via immunohistochemistry. However, OPN expression was up-regulated in submerged basal cells cultures exposed to cigarette smoke (CS) extract. Cell fractioning of air-liquid interface cultures revealed increased OPN production from basal compartment cells compared to that in luminal fraction cells. Furthermore, both constitutive and CS-induced expression of OPN decreased during differentiation. In contrast, cultures stimulated with interleukin (IL)-13 to promote goblet cell hyperplasia showed increased OPN production in response to CS exposure. These results indicate that the cellular composition of the airway epithelium plays an important role in OPN expression and that these levels may reflect disease endotypes in COPD.

Hairy polyps are benign lesions found in the oropharynx or nasopharynx that are thought to be present at birth and can lead to upper airway obstruction in infants. Also known as naso-oropharyngeal choristoma, they are increasingly viewed as aggregates of bigeminal tissue, likely from the first or second branchial arches, found in aberrant locations. They are benign lesions that are usually successfully treated by surgical excision. Here we present a rare case of a hairy polyp originating in the eustachian tube of a 7-week-old male, discuss our management of the patient, and put forth a new hypothesis as to the origin of these lesions. Laryngoscope, 129:2398-2402, 2019., (© 2018 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: Posterior glottic stenosis (PGS) often requires a destructive surgical treatment. Early PGS treatment involves glottic dilation to reduce airway constriction associated with chronic PGS. Round laryngeal dilation may not optimize posterior glottic dilation due to the teardrop shape of the glottis and may injure vocal fold tissue. We compared pressure applied to the glottis during traditional single balloon dilation and a novel, anatomically appropriate dilation technique (teardrop-shaped glottic dilation [TSGD])., Methods: Pressure sensors were affixed at various points on a three-dimensional printed glottic model. The anterior glottis was stented with a triangular stent (18-32F) in combination with balloon dilator (10-20 mm) placed in the posterior glottis (TSGD) in 30 unique combinations. Force applied to the vocal folds (VF) and posterior commissure (PC) during round balloon dilation and TSGD was measured., Results: Dilatory force in the PC ranged from 0.0-3.8 newtons (N) using balloon dilators and 0.0-17.5 N using TSGD. The TSGD technique yielded a superior ratio of force applied to the PC versus VF (P = 0.0296) compared to round balloon dilation alone. Optimal targeting of the PC occurred when the sum of the anteroposterior (AP) dimensions of the stent and balloon dilator approached the AP length of the glottis., Conclusion: Use of an anatomically appropriate glottic dilation maximizes expansive force applied to the posterior commissure and decreased force to the vocal folds. This study demonstrates that TSGD minimizes force to the anterior glottis and maximizes dilation of the posterior glottis. This technique may play a role in preventing laryngeal stenosis associated with chronic PGS., Level of Evidence: NA Laryngoscope, 129:2239-2243, 2019., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: To develop and validate a preoperative brachycephalic risk (BRisk) score that objectively and accurately predicts the risk of major complications or death in dogs undergoing corrective surgery for brachycephalic obstructive airway syndrome (BOAS)., Study Design: Retrospective multicenter cohort study., Sample Population: Score development n = 233 dogs, validation n = 50 dogs., Methods: Data were collected on signalment, medical history, reason for presentation, physical examination, and preoperative diagnostic findings. The primary outcome measures included risk of major complications (requirement for postoperative oxygen support for >48 hours or postoperative temporary/permanent tracheostomy) or death within the hospitalization period. The score was developed by using data from two centers and was validated in a third center. The 10-point BRisk score was modeled on breed, history of previous surgery, concurrent procedures, body condition score, airway status, and admission rectal temperature., Results: The score was associated with negative outcome (P < .0001) and discriminated well in both the construction (area under the receiver operator characteristic [AUROC] = 0.83) and validation groups (AUROC = 0.84). Dogs with scores >3 were 9.1 times more likely to have a negative outcome (95% CI = 3.9-21.2) compared with dogs with scores ≤3., Conclusion: The BRisk score developed from admission data in this study accurately rated the risk of negative outcome of dogs undergoing corrective surgery for BOAS., Clinical Significance: Preoperative determination of the BRisk score may assist triage, management of owner expectations, decision making regarding intervention selection, and characterization of populations in clinical research., (© 2019 The American College of Veterinary Surgeons.)

Background: An open-label, single-arm study was conducted to assess the safety of a cryosurgery unit named CRYO2 for debulking at the site of obstruction or stenosis., Patients and Methods: In order to treat central airway tumor-related stenosis, debulking at the stenotic site of the airway was performed using CRYO2 under general or local anesthesia. The primary endpoint was the incidence of moderate to massive hemorrhage., Results: Incidence of moderate to massive hemorrhage during surgery was 3.8% (1/26) (95% confidence interval(CI)=0.1-19.6%). Technical success was 96.2% (25/26), with a 95% confidence interval of 80.4-99.9%., Conclusion: CRYO2 for debulking at the site of obstruction or stenosis can be performed safely., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Understanding inconsistent clinical outcomes in infants with severe congenital diaphragmatic hernia (CDH) after tracheal occlusion (TO) is a crucial step for advancing neonatal care. The objective of this study is to explore the heterogeneous airspace morphometry and the metabolic landscape changes in fetal lungs after TO., Methods: Fetal lungs on days 1 and 4 after TO were examined using mass spectrometry-based metabolomics, fluorescence lifetime imaging microscopy (FLIM), the number of airspaces, and tissue-to-airspace ratio (TAR)., Results: Two morphometric areas were identified in TO lungs compared with controls (more small airspaces at day 1 and a higher number of enlarged airspaces at day 4). Global metabolomics analysis revealed a significant upregulation of glycolysis and a suppression of the tricarboxylic acid cycle in day 4 TO lungs compared with day 1 TO lungs. In addition, there was a significant increase in polyamines involved in cell growth and proliferation. Locally, FLIM analysis on day 1 TO lungs demonstrated two types of heterogeneous zones-similar to control and with increased oxidative phosphorylation. FLIM on day 4 TO lungs demonstrated appearance of zones with enlarged airspaces and a metabolic shift toward glycolysis, accompanied by a decrease in the FLIM "lipid-surfactant" signal., Conclusions: In normal fetal lungs, we report a novel temporal pattern of varied morphometric and metabolic changes. Initially, there is formation of zones with small airspaces, followed by airspace enlargement over time. Metabolically day 1 TO lungs have zones with increased oxidative phosphorylation, whereas day 4 TO lungs have a shift toward glycolysis in the enlarged airspaces. Based on our observations, we speculate that the "best responders" to tracheal occlusion should have bigger lungs with small airspaces and normal surfactant production., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Intraluminal contributor(s) to airflow obstruction in severe asthma are patient-specific and must be evaluated to personalize treatment. The occurrence and functional consequence of airway mucus in the presence or absence of airway eosinophils remain undetermined., Objective: The objective of this study was to understand the functional consequence of airway mucus in the presence or absence of eosinophils and to identify biomarkers of mucus-related airflow obstruction., Methods: Mucus plugs were quantified on CT scans, and their contribution to ventilation heterogeneity (using MRI ventilation defect percent [VDP]) was evaluated in 27 patients with severe asthma. Patients were dichotomized based on sputum eosinophilia such that the relationship between mucus, eosinophilia, and ventilation heterogeneity could be investigated. Fractional exhaled nitric oxide (Feno) and related cytokines in sputum were measured., Results: Mucus plugging was present in 100% of asthma patients with sputum eosinophils and 36% of those without sputum eosinophils (P = .0006) and was correlated with MRI VDP prebronchodilator (r = 0.68; P = .0001) and postbronchodilator (r = 0.72; P < .0001). In a multivariable regression, both mucus and eosinophils contributed to the prediction of postbronchodilator MRI VDP (R 2  = 0.75; P < .0001). Patients with asthma in whom the mucus score was high had raised Feno (P = .03) and IL-4 (P = .02) values. Mucus plugging correlated with Feno (r = 0.63; P = .005)., Conclusions: Both airway eosinophils and mucus can contribute to ventilation heterogeneity in patients with severe asthma. Patients in whom mucus is the dominant cause of airway obstruction have evidence of an upregulated IL-4/IL-13 pathway that could be identified according to increased Feno level., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Objective: To determine whether the sensitivity of clinical examination for assessing upper airway disease severity in 3 breeds of brachycephalic dogs can be improved by incorporating an exercise test (ET) or by auscultation of a laryngeal stridor to predict laryngeal collapse., Study Design: Prospective clinical study., Animals: Client-owned brachycephalic dogs (n = 44 ET; n = 57 laryngeal stridor assessment)., Methods: In the first part of the study, clinical examinations were performed at rest and after 5-minute walk and 3-minute trot tests, and a grade reflective of brachycephalic obstructive airway syndrome (BOAS) severity was assigned. Whole-body barometric plethysmography was used as a comparative, objective measure of disease severity. In the second part of the study, the degree of laryngeal collapse present in dogs undergoing BOAS surgery was compared to pre-exercise and postexercise laryngeal stridor detected during functional testing., Results: The sensitivity of clinical examination for BOAS diagnosis was 56.7% pre-ET, 70% after a 5-minute walk test, and 93.3% after a 3-minute trot test. The sensitivity of laryngeal stridor as a predictor of laryngeal collapse was improved after exercise (70%) compared with before exercise (60%). Specificity of laryngeal stridor for laryngeal collapse was 100% (pre-exercise and postexercise)., Conclusion: The sensitivity of clinical examination for BOAS diagnosis was improved by inclusion of an ET, particularly the 3-minute trot test. Audible laryngeal stridor was highly specific but only moderately sensitive for laryngeal collapse., Clinical Significance: Inclusion of a 3-minute trot test and careful auscultation for laryngeal stridor are recommended during BOAS assessment of brachycephalic dogs., (© 2019 The American College of Veterinary Surgeons.)

Benign multinodular goitre is a common illness. When accompanied by obstructive symptoms, such as dyspnoea, it carries an indication for surgery. Benign multinodular goitres rarely cause acute airway obstruction. We report the case of a 88-year-old woman who presented with acute shortness of breath and stridor. A chest CT revealed marked enlargement of the thyroid gland, with an extensive intrathoracic component. She was proposed for total thyroidectomy. Her intraoperative course was unremarkable, but the patient passed away in postoperative period from ventricular fibrillation. Recognition of these cases is important, as they constitute a preventable cause of mortality if timely diagnosed and treated., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: Besides its role as an inflammatory marker in asthma, fractional exhaled nitric oxide (F E NO) provides information on the extent of the airway obstruction process through evaluating its change after bronchodilation., Objective: To investigate whether F E NO change after bronchodilation can identify different sites of airway obstruction in COPD patients., Methods: F E NO, FEV 1 and the slopes (S) of the alveolar plateau of the single breath washout test (SBWT) were measured in 61 stable COPD patients (FEV 1 34.5% predicted) before and after the inhalation of 400 μg salbutamol. SBWT used Helium (He), and sulfur-hexafluoride (SF 6 ). Obstruction relief occurring in pre-acinar and intra-acinar small airways is expected to decrease S He and S SF6 , respectively. Indices changes (Δ) after bronchodilation were expressed as a percentage of pre-bronchodilation values., Results: F E NO stability (∣ΔF E NO∣ ≤ 11%) was observed in 19 patients [-2.7(6.7)%] [mean (SD)] (NO = group); ΔF E NO > 11% [+37.4(27.7)%] in 20 patients (NO+ group) and ΔF E NO < -11% in 22 patients [-31.2(9.8)%] (NO- group). A similar ΔFEV 1 (p = 0.583; [+9.4(9.6)%]) was found in the three groups. In NO = and NO+ groups, neither S He nor S SF6 changed; in NO- both S He [-12.4(27.5)%, p = 0.007] and S SF6 [-20.2(20.4)%, p < 0.001] significantly decreased., Conclusion: Different patterns of F E NO response to β 2 -agonists were observed in COPD most likely depending on the extent of the dilation process. A profile of airway obstruction with an extensive β 2 -agonist response down to lung periphery is identified by F E NO reduction after acute bronchodilation in 30% of COPD patients. The clinical relevance of this profile requires further investigation.