Airway Pathology Research Articles

Defining a phenotype of severe COPD patients who develop chronic hypercapnia

IntroductionChronic hypercapnia, defined by elevated blood CO2 levels, is a serious complication most prevalent in severe COPD. It negatively impacts quality of life, increases hospitalization rates, and elevates mortality risks. However, not all severe COPD patients develop chronic hypercapnia, and its underlying mechanisms remain unclear. Identifying clinical and pathophysiological predictors of hypercapnia is essential for tailored treatment strategies. This study investigates the relationship between hypercapnia and patient characteristics, lung function, and CT scan features to identify potential therapeutic targets. MethodsThis cross-sectional study included 1,526 COPD patients from three cohorts: a standard care cohort and two research cohorts (NCT04023409; NCT03053973). Data collected included demographic and clinical information, blood gases, lung function (FEV1, FVC, TLC, RV, DLCOc), and high-resolution CT scans (lung volumes, air trapping, emphysema scores, airway wall thickness (Pi10), and diaphragm indices). ResultsHypercapnia prevalence increased with COPD severity. Hypercapnic patients were older, more likely to smoke, and had more comorbidities. They exhibited lower FEV1 and FVC, and higher RV/TLC ratios, with CT scans showing lower emphysema scores and greater Pi10. Multivariate analysis identified lower PaO2, FEV1% predicted, and emphysema scores, along with higher RV/TLC ratios and NT-proBNP levels, as independent predictors of PaCO2, collectively explaining 46.3% of the variance. ConclusionCOPD patients with chronic hypercapnia are characterized by higher smoking rates, lower PaO2 levels, poorer lung function, less emphysema, and increased airway pathology. These findings underscore the multifactorial nature of hypercapnia in COPD, highlighting the need for personalized therapeutic strategies targeting these factors to improve outcomes.

Evidence for Cytotoxicity and Mitochondrial Dysfunction in Human Lung Cells Exposed to Biomass Burning Aerosol Constituents: Levoglucosan and 4-Nitrocatechol

Biomass burning (BB) emissions are one of the largest sources of carbonaceous aerosol, posing a significant risk as an airway irritant. Important BB markers include wood pyrolysis emissions, such as levoglucosan (LG) that is an anhydrous sugar bearing a six-carbon ring structure (i.e., 1,6-anhydro-β-D-glucopyranose). Atmospheric chemical aging of BB-derived aerosol (BBA) in the presence of nitrogen oxides (NOx) can yield nitro-aromatic compounds, including 4-nitrocatechol (4NC). There is building evidence that NOx-mediated chemical aging of BBA poses a more serious exposure effect than primary pyrolysis emissions. This study provides a comparative toxicological assessment following the exposure to important BBA marker compounds in human lung cells (i.e., A549 and BEAS-2B) to determine whether aromatic 4NC is more toxic than BBA-bound anhydrous carbohydrate (i.e., LG). We determined inhibitory concentration-50 (IC50) and examined reactive oxygen species (ROS) changes, mitochondrial dysfunction, and apoptosis induction in the two cell lines following exposure to LG and 4NC in a dose-response manner. In the BEAS-2B cells, estimated IC50 values for 4NC were 33 and 8.8 μg mL-1, and for LG were 2546 and ∼ 3 × 107 μg mL-1 at 24 h and 48 h of exposure, respectively. A549 cells exhibited a much higher IC50 value than BEAS-2B cells. LG exposures resulted in mitochondrial stress with viability inhibition, but cells recovered with increasing exposure time. 4NC exposures at 200 μg mL-1 resulted in the induction of apoptosis at 6 h. Mitochondrial dysfunction and ROS imbalance induced the intrinsic apoptotic pathway induction following 4NC exposures. While increased ROS is caused by LG exposure in lung cells, 4NC is a marker of concern during BB emissions, as we observed apoptosis and high mitochondrial ROS in both lung cells at atmospherically-relevant aerosol concentrations. It may be associated with higher airway or inhalation pathologies in higher BBA emissions, such as wildfires or during wood combustion.

Outcomes of heliox use in children with respiratory compromise: A 10-year single institution experience.

Heliox, a mixture of helium and oxygen, has been shown to improve laminar airflow and decrease airway resistance in children. This study aims to describe the outcomes of heliox use in children with respiratory compromise and to identify variables associated with a need for airway surgical intervention. A retrospective cohort study of patients who received heliox between 2012 and 2022 at a tertiary care children's hospital. A hundred and thirty-eight heliox treatments were recorded in 119 children. Twelve patients were excluded. Most (n = 100, 84%) patients had significant comorbidities. On average, patients spent a cumulative mean of 94 ± 187 h on heliox therapy per hospital admission. Patients with croup or asthma without known airway pathology presented at an older age than patients with other indications for heliox therapy (4.0 ± 4.7 vs. 2.2 ± 3.6 years, p = 0.04) and were significantly less likely to have background diseases (n = 14, 52% vs. n = 74, 93%, p < 0.0001). Overall, 51 (47.7%) patients were recommended tracheostomy placement, airway reconstruction, or palliative care. Cumulative use of heliox for more than 47 h was associated with an increased risk of needing tracheostomy or airway reconstruction (odds ratio 6.2, 95% confidence intervals 2.56-14.13, p < 0.0001). In multivariable regression analysis, neuromuscular disease, intracranial neuropathology, and cumulative time of heliox were associated with a need for definitive airway intervention. Heliox may be used as a temporizing agent in children with upper airway obstruction. The effectiveness of heliox use for more than 47 h in children, especially in the presence of neuromuscular disease and intracranial neuropathology should be reconsidered.Level of evidence: 4.

Awake flexible bronchoscopy in children: A case series, feasibility and precautions

IntroductionFlexible bronchoscopy under anesthesia is a mainstay diagnostic tool for evaluating respiratory disorders in pediatric patients. While flexible bronchoscopy is generally regarded as a safe procedure with low risk for major complications, it does entail additional risks associated with the use of general anesthesia. The use of diagnostic awake flexible bronchoscopy in children is not well documented in current literature. ObjectivesThe objective of this case series is to investigate the feasibility and potential utility of awake flexible bronchoscopy in pediatric patients and to highlight important precautions and complications. MethodsThis was a consecutive case series of patients who underwent an awake flexible bronchoscopy over a two year period at a tertiary children's hospital. Data collection included demographics, indications, number of attempts, scope findings, and complications. Successful attempts of flexible bronchoscopy were defined by visualization of the trachea and mainstem bronchi while failed attempts include if the scope entered the esophagus or if cough, vocal fold adduction, or movement prevented the scope from entering the trachea. Results11 patients were involved in this study (mean age 20 months, age range 0d to 5y 1m, 72 % male). Common indications for bronchoscopy were suspicion of foreign body (5, 45.4 %), chronic cough (4, 36.4 %), and stridor (4, 36.4 %). The mean number of attempts until successful was 1.72 (range 1–3). One patient experienced a 30-s episode of gagging with mucinous emesis. There were no other complications. One patient ultimately underwent another flexible bronchoscopy under general anesthesia to confirm the findings and to evaluate the tertiary bronchioles and another patient underwent a surgical resection of an oral mass under general anesthesia after awake flexible bronchoscopy. DiscussionAwake flexible bronchoscopy was well tolerated in this study and could serve as a useful diagnostic tool without necessitating anesthetic. However, further study is needed to compare awake flexible bronchoscopy with flexible bronchoscopy under general anesthesia. Additionally, the patients selected for this study were limited to those with minimal risk, such as patients without cardiac disease. Limitations of this technique include suboptimal visualization of subglottic region and limited diagnostic utility for sleep related airway pathologies and cases where therapeutic intervention is needed.

European Respiratory Society statement on preschool wheezing disorders: updated definitions, knowledge gaps and proposed future research directions.

Since the publication of the European Respiratory Society (ERS) task force reports on the management of preschool wheezing in 2008 and 2014, a large body of evidence has accumulated suggesting that the clinical phenotypes that were proposed (episodic (viral) wheezing and multiple-trigger wheezing) do not relate to underlying airway pathology and may not help determine response to treatment. Specifically, using clinical phenotypes alone may no longer be appropriate, and new approaches that can be used to inform clinical care are needed for future research. This ERS task force reviewed the literature published after 2008 related to preschool wheezing and has suggested that the criteria used to define wheezing disorders in preschool children should include age of diagnosis (0 to <6 years), confirmation of wheezing on at least one occasion, and more than one episode of wheezing ever. Furthermore, diagnosis and management may be improved by identifying treatable traits, including inflammatory biomarkers (blood eosinophils, aeroallergen sensitisation) associated with type-2 immunity and differential response to inhaled corticosteroids, lung function parameters and airway infection. However, more comprehensive use of biomarkers/treatable traits in predicting the response to treatment requires prospective validation. There is evidence that specific genetic traits may help guide management, but these must be adequately tested. In addition, the task force identified an absence of caregiver-reported outcomes, caregiver/self-management options and features that should prompt specialist referral for this age group. Priorities for future research include a focus on identifying 1) mechanisms driving preschool wheezing; 2) biomarkers of treatable traits and efficacy of interventions in those without allergic sensitisation/eosinophilia; 3) the need to include both objective outcomes and caregiver-reported outcomes in clinical trials; 4) the need for a suitable action plan for children with preschool wheezing; and 5) a definition of severe/difficult-to-treat preschool wheezing.

S. mansoni -derived omega-1 prevents OVA-specific allergic airway inflammation via hampering of cDC2 migration.

Chronic infection with Schistosoma mansoni parasites is associated with reduced allergic sensitization in humans, while schistosome eggs protects against allergic airway inflammation (AAI) in mice. One of the main secretory/excretory molecules from schistosome eggs is the glycosylated T2-RNAse Omega-1 (ω1). We hypothesized that ω1 induces protection against AAI during infection. Peritoneal administration of ω1 prior to sensitization with Ovalbumin (OVA) reduced airway eosinophilia and pathology, and OVA-specific Th2 responses upon challenge, independent from changes in regulatory T cells. ω1 was taken up by monocyte-derived dendritic cells, mannose receptor (CD206)-positive conventional type 2 dendritic cells (CD206+ cDC2), and by recruited peritoneal macrophages. Additionally, ω1 impaired CCR7, F-actin, and costimulatory molecule expression on myeloid cells and cDC2 migration in and ex vivo, as evidenced by reduced OVA+ CD206+ cDC2 in the draining mediastinal lymph nodes (medLn) and retainment in the peritoneal cavity, while antigen processing and presentation in cDC2 were not affected by ω1 treatment. Importantly, RNAse mutant ω1 was unable to reduce AAI or affect DC migration, indicating that ω1 effects are dependent on its RNAse activity. Altogether, ω1 hampers migration of OVA+ cDC2 to the draining medLn in mice, elucidating how ω1 prevents allergic airway inflammation in the OVA/alum mouse model.

Transoral robotic surgery for pediatric upper airway pathology: An institutional update

ObjectiveProvide an update on our institution's experience with utilizing transoral robotic surgery (TORS) in pediatric airway surgery and compare these results to surgery by traditional methods. MethodsPediatric patients who underwent TORS for treatment of upper airway pathology between 2010 and 2021 at our institution were retrospectively identified and compared to patients with the same or similar pathology who underwent a traditional (open or endoscopic) surgical approach over the same time period. Outcomes of interest included patient demographics, operative times, adverse events, hospital length of stay (LOS), and modified barium swallow (MBSS) results. ResultsForty children (19M, 21F) underwent 46 TORS procedures. Mean age was 6.4 years (range: 6 days-17 years). Most commonly treated pathology included: laryngeal clefts (LC) (n = 18), lymphatic malformations (n = 9), and base of tongue masses (n = 7). Surgical time was decreased in traditional type I LC repairs (mean: 111 vs 149 min, P = 0.04) and lymphatic malformation excisions (59 vs 120 min, p = 0.005). Hospital LOS was increased in TORS type I LC repairs (2.6 vs 1.2 days, P = 0.04). Adverse event rate was similar between TORS and traditional cohorts (17 % vs 16 % cases, P = 0.9). Postoperative MBSS results were improved for TORS type I LC repairs at 6 months (70 % vs 33 %, P = 0.09) and 12 months (82 % vs 43 %, P = 0.05). ConclusionsPediatric TORS is practical and safe and has comparable outcomes to traditional surgery. Robotic-assisted LC repair displayed improved postoperative swallow results versus traditional approaches and may be particularly useful in recurrent cases. Level of evidence3.

Rare presence and function of neuroendocrine cells in the nasal mucosa.

There is growing evidence that neurogenic inflammation contributes to the pathophysiology of upper airway diseases, with nasal hyperreactivity (NHR) being a key symptom. The rare neuroendocrine cells (NECs) in the epithelium have been linked to the pathophysiology of bronchial and intestinal hyperreactivity, however their presence in the nasal mucosa and their potential role in NHR remains unclear. Therefore, we studied the presence of NECs in the nasal epithelium of controls, allergic rhinitis patients and chronic rhinosinusitis with nasal polyps patients, and their link to NHR. The expression of typical NECs markers, CHGA, ASCL1 and CGRP, were evaluated on gene and protein level in human samples using real-time quantitative PCR (RT-qPCR), western blot, immunohistochemistry fluorescence staining, RNA scope assay, flow cytometry and single cell RNA-sequencing. Furthermore, the change in peak nasal inspiratory flow after cold dry air provocation and visual analogue scale scores were used to evaluate NHR or disease severity, respectively. Limited gene expression of the NECs markers CHGA and ASCL1 was measured in patients with upper airway diseases and controls. Gene expression of these markers did not correlate with NHR severity nor disease severity. In vitro, CHGA and ASCL1 expression was also evaluated in primary nasal epithelial cell cultures from patients with upper airway disease and controls using RT-qPCR and western blot. Both on gene and protein level only limited CHGA and ASCL1 expression was found. Additionally, NECs were studied in nasal biopsies of patients with upper airway diseases and controls using immunohistochemistry fluorescence staining, RNA scope and flow cytometry. Unlike in ileum samples, CHGA could not be detected in nasal biopsies of patients with upper airway diseases and control subjects. Lastly, single cell RNA-sequencing of upper airway tissue could not identify a NEC cluster. In summary, in contrast to the bronchi and gut, there is only limited evidence for the presence of NECs in the nasal mucosa, and without correlation with NHR, thereby questioning the relevance of NECs in upper airway pathology.

Novel approach for tracheal resection in Morquio a syndrome with end-stage critical airway obstruction: a UK case series

BackgroundMucopolysaccharidosis (MPS) type IVA is a rare lysosomal storage disorder caused by aberrations of the N-acetyl-galactosamine-6-sulfatase (GALNS) enzyme. MPS IVA is associated with a wide gamut of respiratory and airway disorders that manifest in a continuum of severity. In individuals exhibiting severe phenotypic expression, terminal stages of the disease frequently culminate in life-threatening, critical airway obstruction. These manifestations of end-stage disease are engendered by an insidious progression of multi-level airway pathologies, comprising of tracheomalacia, stenosis, tortuosity and 'buckling'. Historically, the management of end-stage airway disease has predominantly leaned towards palliative modalities. However, contemporary literature has posited that the potential benefits of tracheal resection with aortopexy, performed under cardiopulmonary bypass (CPB), may offer a promising therapeutic option. In this context, we report on outcomes from patients undergoing a novel approach to tracheal resection that is combined with manubrial resection, leading to improved airway calibre, obviating the requisition for CPB.ResultsIn this study, seven patients with severe MPS IVA exhibited clinical symptoms and radiological evidence indicative of advanced airway obstruction. All patients had a tracheal resection with a partial upper manubriectomy via transcervical approach, which did not require CPB. The surgical cohort consisted of 5 females and 2 males, the median age was 16 years (range 11-19) and the median height was 105.6cm (range 96.4-113.4). Postoperatively, significant improvements were seen in forced expiratory volume in 1 second (FEV1), with a mean increase of 0.68 litres (95% CI: 0.45-0.91; SD: 0.20). Notably, other spirometry variables also showed meaningful improvements, providing evidence of positive treatment effects. Furthermore, there were no major long-term complications, and the procedure resulted in a significant enhancement in patient-reported domains using PedsQL (version 4.0).ConclusionsThis study represents the largest case series to date, on tracheal resection in patients with severe MPS IVA. Our findings demonstrate the effectiveness of the transcervical approach with partial manubriectomy for improving respiratory function and quality of life for individuals with advanced airway obstruction. Tracheal resection presents a promising treatment modality for severe cases of MPS IVA. Successful outcomes rely on meticulous multidisciplinary assessment, judicious decision-making, and appropriate timing of tracheal surgery. Further research and long-term follow-up studies are warranted to validate the long-term efficacy and safety of this approach.

Endotyping Chronic Respiratory Diseases: T2 Inflammation in the United Airways Model.

Over the past 15 years, the paradigm of viewing the upper and lower airways as a unified system has progressively shifted the approach to chronic respiratory diseases (CRDs). As the global prevalence of CRDs continues to increase, it becomes evident that acknowledging the presence of airway pathology as an integrated entity could profoundly impact healthcare resource allocation and guide the implementation of pharmacological and rehabilitation strategies. In the era of precision medicine, endotyping has emerged as another novel approach to CRDs, whereby pathologies are categorized into distinct subtypes based on specific molecular mechanisms. This has contributed to the growing acknowledgment of a group of conditions that, in both the upper and lower airways, share a common type 2 (T2) inflammatory signature. These diverse pathologies, ranging from allergic rhinitis to severe asthma, frequently coexist and share diagnostic and prognostic biomarkers, as well as therapeutic strategies targeting common molecular pathways. Thus, T2 inflammation may serve as a unifying endotypic trait for the upper and lower airways, reinforcing the practical significance of the united airways model. This review aims to summarize the literature on the role of T2 inflammation in major CRDs, emphasizing the value of common biomarkers and integrated treatment strategies targeting shared molecular mechanisms.

Development and characterization of an immortalized nasopharyngeal epithelial cell line to explore airway physiology and pathology in yak (Bos grunniens).

Airway epithelial cells play a crucial role in investigating the physiological and pathological mechanisms of the respiratory tract in yaks, a species whose unique respiratory system has garnered extensive interest. Despite this growing interest, there currently are no available airway epithelial cell lines from yaks, underscoring the crucial need to establish a yak respiratory epithelial cell line. Therefore, our objective was to isolate a population of primary yak nasopharyngeal epithelial cells (pYNE) and transform them into immortalized yak nasopharyngeal epithelial cells (iYNE), assessing their suitability as an in vitro model. Employing a combined method of physical elimination and differential adhesion, we successfully isolated a population of high-purity pYNE, and developed an iYNE line through pCI-neo-hTERT plasmid transfection. Karyotype and transmission electron microscopy analyses confirmed that pYNE and iYNE share identical morphologies and structures. Gel electrophoresis and real-time PCR analyses demonstrated that pYNE and iYNE expressed similar levels of KRT18 and CDH1 genes (p ≥ 0.541). Notably, iYNE expressed a significantly high level of TERT gene expression (p < 0.001). Immunofluorescence analysis demonstrated that both cell types expressed Pan-Cytokeratin, ZO-1, and E-cadherin proteins. Furthermore, immunoblotting analysis indicated significantly higher levels of hTERT and Ki67 proteins in iYNE (p < 0.001), and similar levels of Cluadin-3 and Occludin proteins (p ≥ 0.103). Proliferation curve analysis highlighted iYNE's serum-dependency and significantly enhanced proliferation capacities (p < 0.001). Additionally, pYNE and iYNE cells demonstrated comparable susceptibilities to infectious bovine rhinotracheitis virus (IBRV). These findings collectively suggest that the developed iYNE retains the evaluated physiological characteristics of pYNE, making it an appropriate in vitro model. This advancement will facilitate further investigation into the respiratory physiological and pathological mechanisms in yaks.

The anesthetic management of a child with ohtahara syndrome and severe stridor: a case report

BackgroundOhtahara syndrome is a progressive developmental and epileptic encephalopathy that manifests in the early infantile period. This rare condition is characterized by intractable seizures, psychomotor retardation, and poor prognosis. To date, there are a handful of case reports regarding the anesthetic management of children with Ohtahara syndrome. However, limited reports exist of patients with Ohtahara syndrome who present with difficult airways. This report describes our airway findings and general anesthetic management of a pediatric patient with Ohtahara syndrome undergoing diagnostic bronchoscopy for severe inspiratory stridor.Case presentationA 14-month-old, 9 kg, male patient with Ohtahara syndrome presented with a year-long history of severe inspiratory stridor and was scheduled for bronchoscopy with lavage. On exam, the patient had noisy breathing, was non-verbal with developmental delay, and had poor head control with significant central hypotonia. The patient was induced with ketamine and general anesthesia was maintained with propofol. Bronchoscopic evaluation was completed uneventfully and revealed a diagnosis of laryngotracheomalacia. The patient’s breathing was maintained spontaneously throughout the procedure and no seizures were noted. In the post anesthesia care unit, the patient’s respiratory and cardiovascular function were stable.ConclusionsThis report documents the unusual finding of severe inspiratory stridor in a 14-month-old child diagnosed with Ohtahara syndrome and our anesthetic management during their diagnostic bronchoscopy. Currently, documentation of complex airway pathology present in patients with Ohtahara syndrome is limited and should be further evaluated. This will assist pediatric anesthesiologists as these patients may require careful preoperative assessment, thoughtful airway management, and surgical alternatives on standby.

Lung microbiota participated in fibrous microplastics (MPs) aggravating OVA-induced asthma disease in mice

Environmental pollution is one of the risk factors for asthma. Currently, whether micro-plastics could aggravate asthma, is still unclear. In the air, fibrous MPs are the predominant shape. Since fibrous micro-plastics are reported to be detected in the lower respiratory tract and other body parts, the relationship of fibrous MP and asthma, as well as the potential mechanism is not well investigated. In this study, we produced fibrous MPs, whose lengths and widths were in accordance with the natural environment, and further, investigated the potential adverse effect of which on the asthma in a OVA (ovalbumin)-induced mice model, aiming at exploring the true life hazard of MP to the respiratory system. Following nasal exposure to fibrous MPs, the airway inflammation, mucus hypersecretion and fibrosis were aggravated in asthmatic mice. Fibrous MPs exposure also significantly increased the levels of total IgE, and, cardinal Th2 and Th1 pro-inflammatory cytokines participated in the etiopathogenesis of allergic airway inflammation. In addition, MP fibers exposure induced lung epithelial cells apoptosis, disruption of epithelial barrier integrity and activation of NLRP3 related signaling pathways. Moreover, fibrous MPs significantly altered the bacterial composition at the genus level. Compared to the control group, the relative abundance of Escherichia-Shigella and Uncultured were decreased to 4.47% and 0.15% in OVA group, while Blautia and Prevotella were elevated to 4.96% and 2.94%. For the OVA + MPs group, the relative abundance of Blautia and Uncultured were decreased to 2.27% and 0.006%, while Prevotella was increased to 3.05%. Our study highlights the detrimental effect of fibrous MPs on asthmatic population and facilitates an indication of the latent mechanisms of fibrous MPs induced airway pathology.

Assessing the Influence of Vehicular Traffic-Associated Atmospheric Pollutants on Pulmonary Function Using Spirometry and Impulse Oscillometry in Healthy Participants: Insights from Bogotá, 2020–2021

Air pollution, particularly from particulate matter (PM2.5) and black carbon (eBC), has been implicated in airway pathologies. This study aims to assess the relationship between exposure to these pollutants and respiratory function in various populations, including healthy individuals, while seeking an accurate assessment method. A cross-sectional study was conducted in Bogotá, evaluating respiratory function in the users of bicycles, minivans, and buses through spirometry and impulse oscillometry. Measurements were taken along two main avenues, assessing the PM2.5 and eBC concentrations. The results reveal higher pollutant levels on AVE KR 9, correlating with changes in oscillometry values post-travel. Cyclists exhibited differing pre- and post-travel values compared to bus and minivan users, suggesting aerobic exercise mitigates pollutant impacts. However, no statistically significant spirometry or impulse oscillometry variations were observed among routes or modes. Public transport and minivan users showed greater PM2.5 and eBC exposure, yet no significant changes associated with environmental contaminants were found in respiratory function values. These findings underscore the importance of further research on pollutant effects and respiratory health in urban environments, particularly concerning different transport modes.

Obstructive sleep apnea in children with cystic fibrosis on highly effective modulator therapy.

Obstructive sleep apnea (OSA) is common in children with cystic fibrosis (CF). Highly effective modulator therapies (HEMT) have led to improved sinopulmonary disease, but whether this translates to a lower frequency of OSA is unknown. We conducted a single center retrospective review of polysomnographic (PSG) data from 2012 to 2023 in patients aged 0-18 years with CF to assess frequency of OSA. Participants were classified based on HEMT status. Logistic regression was used to quantify the association between HEMT and OSA with p < .05 considered significant. Forty-nine children underwent PSG during the study period. Ten percent were of non-White race and 24% were of Hispanic ethnicity. Twenty-one children (43%) were on HEMT. These children were older than those not on modulators (11.6 vs. 6.4 years; p = .0001) but no different with respect to gender, race, nutritional status, or lung function. Twenty-eight (57%) children had OSA. Odds of having OSA were higher in the HEMT group (odds ratio [OR] = 4.3; 95% confidence interval [CI]: 1.2-14.9; p = .02). Tonsillar hypertrophy was associated with an increased odds of having OSA independent of modulator status (OR: 6.6; 95% CI: 1.2-37.9; p = .03). OSA is frequently diagnosed in the post-HEMT era in this large, racially diverse group of children with CF. Children on HEMT were older and more likely to have OSA as compared to those not on modulators but similar in nutritional status, lung function, and presence of upper airway pathology. Prospective studies are needed to further clarify the relationship between HEMT and OSA in children with CF.

A common polymorphism in the Intelectin-1 gene influences mucus plugging in severe asthma

By incompletely understood mechanisms, type 2 (T2) inflammation present in the airways of severe asthmatics drives the formation of pathologic mucus which leads to airway mucus plugging. Here we investigate the molecular role and clinical significance of intelectin-1 (ITLN-1) in the development of pathologic airway mucus in asthma. Through analyses of human airway epithelial cells we find that ITLN1 gene expression is highly induced by interleukin-13 (IL-13) in a subset of metaplastic MUC5AC+ mucus secretory cells, and that ITLN-1 protein is a secreted component of IL-13-induced mucus. Additionally, we find ITLN-1 protein binds the C-terminus of the MUC5AC mucin and that its deletion in airway epithelial cells partially reverses IL-13-induced mucostasis. Through analysis of nasal airway epithelial brushings, we find that ITLN1 is highly expressed in T2-high asthmatics, when compared to T2-low children. Furthermore, we demonstrate that both ITLN-1 gene expression and protein levels are significantly reduced by a common genetic variant that is associated with protection from the formation of mucus plugs in T2-high asthma. This work identifies an important biomarker and targetable pathways for the treatment of mucus obstruction in asthma.

Progesterone amplifies allergic inflammation and airway pathology in association with higher lung ILC2 responses.

Perimenstrual worsening of asthma occurs in up to 40% of women with asthma, leading to increased acute exacerbations requiring clinical care. The role of sex hormones during these times remains unclear. In the current study, we used a translational approach to determine whether progesterone exacerbates allergic inflammation in the traditional chicken egg ovalbumin (OVA) model in BALB/c mice. Simultaneously, we used peripheral blood mononuclear cells (PBMC) from healthy human donors to assess the effects of progesterone on circulating group 2 innate lymphoid cells (ILC2). Briefly, lungs of ovariectomized (OVX) or sham-operated female (F-Sham) controls were implanted with a progesterone (P4, 25 mg) (OVX-P4) or placebo pellet (OVX-Placebo), followed by sensitization and challenge with ovalbumin (OVA). Progesterone increased total inflammatory histologic scores, increased hyper-responsiveness to methacholine (MCh), increased select chemokines in the bronchoalveolar lavage (BAL) and serum, and increased ILC2 and neutrophil numbers, along the airways compared with F-Sham-OVA and OVX-Placebo-OVA animals. Lung ILC2 were sorted from F-Sham-OVA, OVX-Placebo-OVA and OVX-P4-OVA treated animals and stimulated with IL-33. OVX-P4-OVA lung ILC2 were more responsive to interleukin 33 (IL-33) compared with F-Sham-OVA treated, producing more IL-13 and chemokines following IL-33 stimulation. We confirmed the expression of the progesterone receptor (PR) on human ILC2, and showed that P4 + IL-33 stimulation also increased IL-13 and chemokine production from human ILC2. We establish that murine ILC2 are capable of responding to P4 and thereby contribute to allergic inflammation in the lung. We confirmed that human ILC2 are also hyper-responsive to P4 and IL-33 and likely contribute to airway exacerbations following allergen exposures in asthmatic women with increased symptoms around the time of menstruation.NEW & NOTEWORTHY There is a strong association between female biological sex and severe asthma. We investigated the allergic immune response, lung pathology, and airway mechanics in the well-described chicken egg ovalbumin (OVA) model with steady levels of progesterone delivered throughout the treatment period. We found that progesterone enhances the activation of mouse group 2 innate lymphoid cells (ILC2). Human ILC2 are also hyper-responsive to progesterone and interleukin 33 (IL-33), and likely contribute to airway exacerbations following allergen exposures in women with asthma.

A Comprehensive Flow Cytometry Panel for Analysis of Idiopathic Subglottic Stenosis.

To present a comprehensive flow cytometry panel for idiopathic subglottic stenosis (iSGS). Controlled ex vivo cohort study. Tertiary care academic hospital in a metropolitan area. Flow cytometry and single-cell RNA sequencing were performed on 9 paired normal and scar tissue samples from iSGS patients. Flow cytometry was used to assess the presence of myeloid (CD11b, CD14, CD15, Siglec8), lymphoid (CD3, CD4, CD8, gamma delta [γδ], FOXP3), endothelial (CD31), fibroblast (CD90, SMA), and epithelial (CD326, CK5) markers. On flow cytometry, iSGS scar is characterized by an increased presence of myeloid, lymphoid, endothelial, and fibroblast cell types, but a decreased presence of epithelial cells. In the myeloid lineage, iSGS scar samples demonstrated increased CD11b+ monocytes (P < .001), Siglec8+ eosinophils (P = .03), and CD14+ monocytes (P = .02). In the lymphoid lineage, iSGS scar demonstrated increased CD3+ T-cells (P < .001), CD4+ helper T-cells (P < .001), γδ+ T-cells (P < .001), and FOXP3+ regulatory T-cells (P = .002). iSGS scar exhibited specific increases in CD90+ (P = .04) and SMA+ (P < .001) fibroblasts but decreased CD326+ (E-cadherin) epithelial cells (P = .01) relative to normal samples. We present a comprehensive flow cytometry panel for iSGS. This flow panel may serve as a common platform among airway scientists to elucidate the cellular mechanisms underpinning iSGS and other upper airway pathologies. Scar iSGS samples demonstrate a distinct cellular profile relative to normal iSGS specimens, exhibiting increased fibroblast, endothelial, and inflammatory cell types but decreased epithelium.

Chronic stridor in a toddler after ingestion of a discharged button battery: a case report

BackgroundButton battery (BB) ingestions (BBI) are increasingly prevalent in children and constitute a significant, potentially life-threatening health hazard, and thus a pediatric emergency. Ingested BBs are usually charged and can cause severe symptom within 2 h. Discharged BBs ingestion is very rare and protracted symptom trajectories complicate diagnosis. Timely imaging is all the more important. Discharged BBs pose specific hazards, such as impaction, and necessitate additional interventions.Case presentationWe present the case of a previously healthy 19-month-old girl who was admitted to our pediatric university clinic in Germany for assessment of a three-month history of intermittent, mainly inspiratory stridor, snoring and feeding problems (swallowing, crying at the sight of food). The child’s physical examination and vital signs were normal. Common infectious causes, such as bronchitis, were ruled out by normal lab results including normal infection parameters, negative serology for common respiratory viruses, and normal blood gas analysis, the absence of fever or pathological auscultation findings. The patient’s history contained no evidence of an ingestion or aspiration event, no other red flags (e.g., traveling, contact to TBC). Considering this and with bronchoscopy being the gold standard for foreign body (FB) detection, an x-ray was initially deferred. A diagnostic bronchoscopy, performed to check for airway pathologies, revealed normal mucosal and anatomic findings, but a non-pulsatile bulge in the trachea. Subsequent esophagoscopy showed an undefined FB, lodged in the upper third of the otherwise intact esophagus. The FB was identified as a BB by a chest X-ray. Retrieval of the battery proved extremely difficult due to its wedged position and prolonged ingestion and required a two-stage procedure with consultation of Ear Nose Throat colleagues. Recurring stenosis and regurgitation required one-time esophageal bougienage during follow-up examinations. Since then, the child has been asymptomatic in the biannual endoscopic controls and is thriving satisfactorily.ConclusionThis case describes the rare and unusual case of a long-term ingested, discharged BB. It underscores the need for heightened vigilance among healthcare providers regarding the potential hazards posed by discharged BBIs in otherwise healthy children with newly, unexplained stridor and feeding problems. This case emphasizes the critical role of early diagnostic imaging and interdisciplinary interventions in ensuring timely management and preventing long-term complications associated even to discharged BBs.

Respiratory function after 30+ years following sulfur mustard exposure in survivors in Sweden.

Sulfur mustard (SM) exposure causes acute and chronic respiratory diseases. The extent of small airway dysfunction (SAD) in individuals exposed to SM is unclear. This study evaluated and compared SAD in SM-exposed and SM-unexposed participants using noninvasive lung function tests assessing small airway function. This retrospective cohort study involved SM-exposed (n = 15, mean age: 53 ± 8 years) and SM-unexposed (n = 15, mean age: 53 ± 7 years) Kurdish-Swedish individuals in Sweden. Small airway resistance and reactance were assessed using impulse oscillometry (IOS). Nitrogen (N2) multiple breath washout (MBW) was employed to assess lung ventilation heterogeneity. The gas-exchanging capacity of the lungs was assessed using the diffusing capacity of the lungs for the carbon monoxide (DLCO) test. Lung function outcomes were reported as absolute values and z-scores. Group comparisons were performed using the Mann-Whitney U test. No statistically significant differences in age, height, or body mass index were observed between the two groups. IOS showed significantly increased small airway resistance, while N2MBW exhibited significantly increased global and acinar ventilation heterogeneity in SM-exposed individuals compared to that in unexposed individuals. SAD was identified in 14 of 15 SM-exposed individuals, defined as at least one abnormal IOS difference between resistance at 5 and 20 Hz (R5-R20) and/or area of reactance (AX) or N2MBW lung's acinar zone (Sacin), and DLCO adjusted to the alveolar volume (DLCO/VA) outcome. Of these 14 individuals, only 5 demonstrated concordant findings across the IOS and N2MBW tests. Exposure to SM was positively associated with long-term impairment of respiratory tract function in the small airways in the majority of the previously SM-exposed individuals in the present study. Furthermore, both IOS and N2MBW should be employed to detect SAD in SM-exposed survivors as they provide complementary information. Identifying and characterizing the remaining pathology of the small airways in survivors of SM exposure is a first step toward improved treatment and follow-up.