Idiopathic Subglottic Stenosis Research Articles

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.

Impact of Procedural Variation in Endoscopic Dilation for Idiopathic Subglottic Stenosis.

A small number of Idiopathic subglottic stenosis (iSGS) patients are treated at institutions across the country. Divergence in operative techniques for endoscopic dilation (ED) of iSGS has been anecdotally recognized but not formally characterized. Additionally, the relationship between procedural variation and clinical outcome has not been studied. Secondary analysis of the NoAAC iSGS1000 cohort investigated variation in procedural techniques and treatment outcomes in patients treated with ED across high-enrolling treatment centers (enrolled >10 patients in PR-02 trial). Thirteen NoAAC centers each enrolled >10 patients treated with ED for a total of 281 subjects. There was significant variation in procedural details and rate of recurrence among institutions. Hierarchal cluster analysis revealed significant heterogeneity among institutions and clusters in all procedural variables. However, analysis demonstrated a transient delay in disease recurrence in cluster 2 which disappeared with longer longitudinal follow-up. Patient-reported outcome and peak expiratory flow data supported the potential benefit of the technical variation in Cluster 2. Distinct to cluster 2, however, was routine use of adjuvant triple medical therapy (proton pump inhibitor (PPI), antibacterial agent, and steroid inhaler). Both outcome and procedural technique vary among centers employing ED to treat iSGS. A transient delay in recurrence was observed among centers that routinely prescribed adjuvant medical therapy (antibiotic, inhaled corticosteroid, and PPI) to iSGS patients after endoscopic dilation, which was further supported by patient-reported data and peak expiratory flow data. Prospective studies are needed to understand the effects of adjuvant medical therapy on recurrence after endoscopic dilation. 4 Laryngoscope, 2024.

The ESTS-AIR database-initial results of a multi-institutional database on airway surgery.

Compared to lung resections, airway procedures are relatively rare in thoracic surgery. Despite this, a growing number of dedicated airway centers has formed throughout Europe. These centers are characterized by a close interdisciplinary collaboration and they often act as supra-regional referring centers. To date, most evidence of airway surgery comes from retrospective, single-center analysis as there is a lack of large-scale, multi-institutional databases. In 2018, an initiative was formed, which aimed to create an airway database within the framework of the ESTS database (AIR-ESTS). Five dedicated airway centers were asked to test the database in a pilot phase. A first descriptive analysis of AIR-ESTS was performed. A total of 415 cases were included in the analysis. For adults, the most common indication for airway surgery was post-tracheostomy stenosis and idiopathic subglottic stenosis; in children, most resections/reconstructions had to be performed for post-intubation stenosis. Malignant indications required significantly longer resections (36.0 (21.4-50.6) mm) when compared to benign indications (26.6 (9.4-43.8) mm). Length of hospital stay was 11.0 (4.1-17.3) days (adults) and 13.4 (7.6-19.6) days (children). Overall, the rates of complications were low with wound infections being reported as the most common morbidity. This evaluation of the first cases in the AIR-ESTS database allowed a large-scale analysis of the practice of airway surgery in dedicated European airway centers. It provides proof for the functionality of AIR-ESTS and sets the basis for rolling out the AIR subsection to all centers participating in the ESTS database.

Similarity Network Analysis of the Adaptive Immune Response in the Proximal Airway.

Recent immunologic study of the adaptive immune repertoire in the subglottic airway demonstrated high-frequency T cell clones that do not overlap between individuals. However, the anatomic distribution and antigenic target of the T cell repertoire in the proximal airway mucosa remain unresolved. Single-cell RNA sequencing of matched scar and unaffected mucosa from idiopathic subglottic stenosis patients (iSGS, n = 32) was performed and compared with airway mucosa from healthy controls (n = 10). T cell receptor (TCR) sequences were interrogated via similarity network analysis to explore antigenic targets using the published algorithm: Grouping of Lymphocyte Interactions by Paratope Hotspots (GLIPH2). The mucosal T cell repertoire in healthy control airways consisted of highly expressed T cell clones conserved across anatomic subsites (trachea, bronchi, bronchioles, and lung). In iSGS, high-frequency clones were equally represented in both scar and adjacent non-scar tissue. Significant differences in repertoire structure between iSGS scar and unaffected mucosa was observed, driven by unique low-frequency clones. GLIPH2 results suggest low-frequency clones share targets between multiple iSGS patients. Healthy airway mucosa has a highly conserved T cell repertoire across multiple anatomic subsites. Similarly, iSGS patients have highly expressed T cell clones present in both scar and unaffected mucosa. iSGS airway scar possesses an abundance of less highly expanded clones with predicted antigen targets shared between patients. Interrogation of these shared motifs suggests abundant adaptive immunity to viral targets in iSGS airway scar. These results provide insight into disease pathogenesis and illuminate new treatment strategies in iSGS. Level NA Laryngoscope, 2024.

Lipoaspirate Injection in Relapsing Idiopathic Subglottic Stenosis: Preliminary Results.

The management of idiopathic subglottic stenosis (iSGS) poses a clinical challenge due to high recurrence rates following both endoscopic and open approaches, often leading to tracheostomy. The activation of abnormal T-cells and cytokine pathways has been linked to iSGS pathogenesis. Autologous adipose tissue centrifugation yields lipoaspirate, offering optimal anti-inflammatory effects and biocompatibility widely utilized in various medical settings. This report presents the first 3 cases employing endoscopic dilation (ED) in combination with local lipoaspirate injection to address recurrent iSGS. A prospective observational study was conducted, involving multidisciplinary evaluation by the Tracheal Team at the University of Modena. Patients meeting specific criteria were directed to undergo ED + lipoaspirate injection. Three patients fulfilled the inclusion criteria. The mean number of prior endoscopic procedures performed was 8. Endoscopic examination revealed 90% stenosis in patient A, 60% stenosis in patient B, and 60% stenosis in patient C. All patients presented inflammatory tissue or incipient granulations at the stenotic site, with an average time of 6 months between previous procedures. After 15 months, none of the patients required further procedures, and endoscopic examination revealed a significant reduction or disappearance of inflammatory tissue with a stable airway lumen. The observed results are encouraging in terms of reducing local inflammation and halting stenosis progression, especially in cases of short-term relapsing iSGS.

[Idiopathic Subglottic Tracheal Stenosis].

Idiopathic subglottic stenosis is a circular scarred narrowing of the airway at the transition from the cricoid cartilage to the trachea. The stenosis is found radiologically and endoscopically at the level of the cricoid cartilage without involvement of the cricoid or tracheal cartilage itself. The disease practically only affects women between the ages of 20 and 60. The same clinical picture occurs in granulomatosis with polyangiitis and less frequently in other autoimmune diseases, where it requires systemic treatment. The clinical picture usually begins insidiously with coughing and sputum production and leads to dyspnoea and a restricted cough. As the course is insidious and the patients are otherwise healthy, the symptoms are often misinterpreted and the diagnosis is delayed. Treatment consists of local measures, ranging from dilatation and laser surgical resection, sometimes with local application of medication to inhibit the proliferation of new scar tissue, to laryngotracheal resection of varying degrees. The disease is located in the border area between the trachea and larynx and the patients are therefore treated by ENT medicine, pneumology and thoracic surgery.

A novel technique of voice-sparing cricotracheal resection

BackgroundCricotracheal resection (CTR) is considered the standard of care for patients suffering from idiopathic subglottic stenosis (iSGS). Although CTR results in permanent restoration of airway patency, it has a mild to moderate impact on voice quality. Here we propose modifications of the standard CTR technique to make it a voice-preserving procedure. MethodsFive women with iSGS underwent voice-sparing CTR between January 2022 and January 2023. In this procedure, through several technical adaptations, the function of the cricothyroid joint was preserved. Outcomes of these voice-sparing CTRs were compared to outcomes in patients who underwent standard CTR in our institution. All patients underwent full functional preoperative and postoperative workups, including spirometry, voice measurements, patient self-assessment, and fiberoptic endoscopic evaluation of swallowing. ResultsAll 5 patients in the study group suffered from iSGS with high-grade Myer-Cotton III° stenosis (100%); 1 patient had previously undergone endoscopic laser resection. Voice evaluation demonstrated a nearly unchanged fundamental pitch (mean preoperative, 191 ± 73.1 Hz; postoperative, 182 ± 64.2 Hz) and dynamic voice range (preoperative, 24.4 semitones; postoperative, 20.4 semitones). This was in contrast to the control group, in which significantly reduced voice quality was observed. ConclusionsIn selected patients suffering from iSGS, excellent functional results can be obtained with voice-sparing CTR.

Mucosal Microbiome Disruption in Acute Laryngeal Injury Following Intubation.

The objective of this study was to characterize mucosal microbial shifts in patients with acute laryngeal injury (ALgI) after intubation. This cross-sectional study included 20 patients with ALgI who underwent early endoscopic intervention with tissue culture, 20 patients with idiopathic subglottic stenosis (iSGS) who underwent tissue culture during the routine endoscopic intervention, and 3 control patients who underwent mucosal swab culture. 70% of the ALgI patients had a positive culture compared to 5% of the iSGS patients and none of the controls. The most identified microbes isolated from ALgI patients included Staphylococcus species in 30% and Streptococcus species in 25%. The high rate of pathologic bacterial infiltration into postintubation laryngeal wounds supports efforts to reduce bacterial colonization of endotracheal tubes and highlights the role of culture-directed antibiotic therapy as a part of early intervention to improve outcomes for patients with ALgI.

Does Idiopathic Subglottic Stenosis Length and Location Change with Serial Endoscopic Interventions?

The aim was to assess changes in physical parameters of subglottic stenosis (SGS) following serial endoscopic surgical intervention. This was a retrospective chart review. A retrospective review of 52 idiopathic subglottic stenosis (iSGS) patients undergoing multiple endoscopic (excision/dilation) procedures between 2014 and 2022 was completed. Parameters including proximal stenosis distance from the vocal process and total stenosis length collected intraoperatively were compared over serial treatments. Differences between patient variables affecting distances from the vocal process and mean stenosis length were statistically analyzed utilizing nonparametric estimators including the Mann Whitney U, Fisher exact, and linear regression models. For the cohort of iSGS patients (N = 52), the mean age was 55.1 (±15.1). The patients were predominantly female (96.2%) and Caucasian (84.6%). Patients underwent an average of 3.4 (±1.3) endoscopic procedures for long-term treatment of iSGS (range: 1 to 5 procedures). Patients undergoing a total of two (2) total procedures within the data collection window demonstrated a statistically significant decrease in mean stenosis length between the first and second procedures (p = 0.014). Changes in distance of the stenosis from the glottis was not found to be statistically significant (p = 0.833). There was a statistically significant decrease in mean length of stenosis from the 1st to the 2nd procedure by approximately 0.11 cm (p = 0.0003). No additional statistically significant differences in stenosis length or location were detected. Serial endoscopic excision/dilation procedures (the mainstay of iSGS surgical management) do not appear to significantly lengthen intraluminal stenosis nor change the distance of the stenosis from the glottis. 4 Laryngoscope, 134:1769-1772, 2024.

Idiopathic Subglottic Stenosis Is Associated With More Frequent and Abnormal Squamous Metaplasia.

Gain insights into the pathophysiology of idiopathic subglottic stenosis (iSGS) by investigating differences in transcriptome of subglottic mucosal tissue between patients with iSGS and controls, and between tracheal and subglottic tissue within patients. RNA sequencing was conducted on biopsied mucosal samples collected from subglottic and tracheal (in-patient control) regions in iSGS patients, and from subglottis in controls. The gene expression differences were validated on a protein level by (1) staining the tissue samples obtained from a second cohort of patients and controls; and (2) in vitro functional assays using primary subglottic epithelial cells from both iSGS patients and healthy donors. We found 7 upregulated genes in the subglottic region of iSGS patients relative to both the tracheal mucosa and subglottic region of controls. A gene ontology enrichment analysis found that the epithelial cell differentiation and cornification pathways are significant, involving specifically 3 of the genes: involucrin (IVL), small proline rich protein 1B (SPRR1B), and keratin 16 (KRT16). Involvement of these pathways suggests squamous metaplasia of the epithelium. Histological analyses of epithelium in subglottic mucosal biopsies revealed squamous metaplasia in 41% of the samples from iSGS patients and in 25% from controls. Immunohistochemical evaluation of the samples presented with squamous epithelium revealed increased expression of the protein encoded by SPRR1B, hyperproliferative basal cells, shedding of apical layers, and accompanying lesions in iSGS compared to CTRL. Cultured primary subglottic epithelial cells from iSGS patients had higher proliferation rates compared to healthy donors and squamous metaplastic differentiation formed thinner epithelia with increased expression proteins encoded by INV, SPRR1B, and KRT16, suggesting intrinsic dysfunction of basal cells in iSGS. Abnormal squamous differentiation of epithelial cells may contribute to the pathogenesis of iSGS. Patients having metaplastic epithelial phenotype may be sensitive to drugs that reverse it to a normal phenotype.

Predictors of response to endoscopic management of subglottic/tracheal stenosis in patients without tracheostomy

IntroductionSubglottic and tracheal stenosis (SGTS) in adults is an acquired or idiopathic condition that can lead to dyspnea, and even life-threatening airway obstruction. Endoscopic techniques have advanced and largely eclipsed open surgery, with open surgery now reserved for refractory cases (Hseu et al., 2013; Feinstein et al., 2017). Currently, there is no accepted guideline for the endoscopic treatment of SGTS. Thus, the aim of the present study is to examine the impact of various clinical and pathological characteristics on outcomes to endoscopic treatment in a cohort of SGTS patients. DisclosureNone of the authors have any financial or personal relationship that could cause a conflict of interest regarding this article. MethodsRetrospective chart review was performed for 41 patients presenting with SGS without a tracheostomy over a 4-year-period (2018–2022), within a single tertiary care center. Quantitative outcomes including number of dilation procedures undergone and need for open procedures were examined. The qualitative variables included a history of pulmonary disease, prior tracheostomy/tracheal resection, presence of tracheomalacia, granulation tissue, excessive dynamic airway collapse (EDAC), and etiology of idiopathic subglottic stenosis. ResultsThe presence of granulation tissue seen on tracheoscopy was associated with a higher number (4+) of dilation procedures (p = 0.01). A history of pulmonary disease (p = 0.037), the presence of tracheomalacia (p = 0.039), and the presence of granulation tissue (0.003) were all associated with a need for open procedures. ConclusionPatients with the presence of granulation tissue, tracheomalacia, and a history of pulmonary disease were more associated with more severe disease requiring either a higher number of endoscopic procedures or need for open procedures.

Association between Estrogen Exposure and Idiopathic Subglottic Stenosis.

Idiopathic subglottic stenosis (iSGS) is a rare, recurrent, fibroinflammatory disease affecting the larynx and proximal trachea. Given it occurs primarily in adult females, estrogen is speculated to play a central pathophysiological role. This study aimed to evaluate relationships between estrogen exposure, disease progression, and recurrence. North American Airway Collaborative (NoAAC) data of adults with iSGS obstructive airway lesions, who underwent index endoscopic airway dilation, were used to identify associations between estrogen exposure, disease characteristics, and time to recurrence (TTR), and interventions were analyzed using Kruskal-Wallis test and Pearson coefficient. Cox proportional hazards regression models compared hazard ratios by estrogen exposure. Kaplan-Meier curves were plotted for TTR based on menopausal status. In all, 533 females had complete estrogen data (33% premenopausal, 17% perimenopausal, 50% postmenopausal). Median estrogen exposure was 28 years. Overall, there was no dose-response relationship between estrogen exposure and disease recurrence. Premenopausal patients had significantly shorter time from symptom manifestation to diagnosis (1.17 vs. 1.42 years perimenopausal vs. 2.08 years postmenopausal, p < 0.001), shorter time from diagnosis to index endoscopic airway dilation (1.90 vs. 2.50 vs. 3.76 years, p = 0.005), and higher number of procedures (1.73 vs. 1.20 vs. 1.08 procedures, p < 0.001). We demonstrate premenopausal patients may have a more aggressive disease variant than their peri- and postmenopausal counterparts. However, it is unclear as to whether this is related to reduced estrogen in the peri- and postmenopausal states or the age-related physiology of wound healing and inflammation, regardless of estrogen. 3 Laryngoscope, 134:825-830, 2024.

Decision-Making in the Treatment of Idiopathic Subglottic Stenosis: A Survey of Laryngologists.

Idiopathic subglottic stenosis (iSGS) is a rare condition involving the subglottic larynx and upper trachea, commonly affecting Caucasian females between 30 and 50 years of age. Despite its homogeneous presentation, clinical management for iSGS is yet to be standardized, leading to variability in outcomes between predominant interventions. In recognition of the heterogenicity in iSGS treatment and the need to improve patient outcomes, this study aimed to survey laryngologists to understand the factors influencing clinical decision-making and the incorporation of new treatment modalities for iSGS. An online survey was sent to 145 academic laryngologists. The survey assessed respondents' professional backgrounds, experience treating iSGS, treatment algorithms, and how various patient factors affect management. Of the 87 (60%) laryngologists who responded to the survey, the most common clinical assessments were tracheoscopy/bronchoscopy (96.8%) and pulmonary function tests (43.6%). Endoscopic dilation (ED) was the most common primary treatment offered (97.5%): 28.7% of surveyed laryngologists offer SISI as a primary treatment, and 74.7% perform SISI as a planned postoperative treatment. The most common SISI protocol was repeated injections every 4-6 weeks for a series of 1-3 total injections. Notably, 9.2% perform the Maddern procedure. Routine algorithms of care involving surgery were most often based on prior experience and prior patient outcomes (75.9%) and conversations with colleagues (64.4%). Only 31% report using the same protocol learned during their fellowship training. This survey highlights significant variation in the management of patients with iSGS. Understanding the factors that influence decision-making may lead to potential standardization in heterogeneous treatment approaches and may improve clinical outcomes. 5 Laryngoscope, 134:865-872, 2024.

Murine Model of Airway Fibrosis has Anatomic, Physiologic, and Molecular Congruency to Human iSGS.

To narrow knowledge gaps in the pathophysiology of idiopathic subglottic stenosis (iSGS) through comparison of a murine subglottic stenosis model with iSGS. In vivo animal study. Academic institution. Murine samples/measurements were obtained from mice that underwent chemomechanical injury with a wire brush and bleomycin. Human samples/measurements were obtained from iSGS patients. Anatomic, physiologic, and epithelial molecular data were collected using histology, human peak expiratory flow (PEF) and murine airway conductance, gene expression analysis with quantitative polymerase chain reaction, and protein analysis with quantitative immunohistochemistry. Anatomic patterns of scars at the subglottis and proximal trachea seen in the murine model are similar to iSGS patients. Subglottic stenosis (SGS) mice had a decrease (P = .0194) in airway conductance compared to healthy controls, similar to a decrease (P = .0001) in predilation PEF versus postdilation in iSGS patients. There was decreased epithelial gene expression of E-cadherin (ECAD) (P < 0.01), occludin (OCLN) (P < .01), and cytokeratin-5 (CK5) (P < .05) and protein expression of ECAD(H/M: P < .001), OCLN (H: P < 0.05, M: P < .001), and CK5 (H: P < .001, M: P < .01) in murine SGS and iSGS versus controls. The murine SGS model shows anatomic, physiologic, and molecular congruency with human iSGS, making it a reasonable model to investigate iSGS. The molecular similarities in epithelial barrier dysfunction suggest it may best be suited to explore epithelial mechanisms of iSGS and therapies directed at epithelial reconstitution. This model provides a foundation to collect data that will improve understanding of iSGS, and, ultimately, translate into more accurate animal models for future use.

Dysfunctional Epithelial Barrier Is Characterized by Reduced E-Cadherin in Idiopathic Subglottic Stenosis.

To aim of the study was to characterize the molecular profile and functional phenotype of idiopathic subglottic stenosis (iSGS)-scar epithelium. Human tracheal biopsies from iSGS scar (n = 6) and matched non-scar (n = 6) regions were analyzed using single-cell RNA sequencing (scRNA-seq). Separate specimens were used for epithelial cell expansion in vitro to assess average growth rate and functional capabilities using transepithelial-electrical resistance (TEER), fluorescein isothiocyanate-dextran flux permeability assay, ciliary coverage, and cilia beating frequency (CBF). Finally, epithelial tight junction protein expression of cultured cells was quantified using immunoblot assay (n = 4) and immunofluorescence (n = 6). scRNA-seq analysis revealed a decrease in goblet, ciliated, and basal epithelial cells in the scar iSGS cohort. Furthermore, mRNA expression of proteins E-cadherin, claudin-3, claudin-10, occludin, TJP1, and TJP2 was also reduced (p < 0.001) in scar epithelium. Functional assays demonstrated a decrease in TEER (paired 95% confidence interval [CI], 195.68-890.83 Ω × cm2 , p < 0.05), an increase in permeability (paired 95% CI, -6116.00 to -1401.99 RFU, p < 0.05), and reduced epithelial coverage (paired 95% CI, 0.1814-1.766, fold change p < 0.05) in iSGS-scar epithelium relative to normal controls. No difference in growth rate (p < 0.05) or CBF was found (paired 95% CI, -2.118 to 3.820 Hz, p > 0.05). Immunoblot assay (paired 95% CI, 0.0367-0.605, p < 0.05) and immunofluorescence (paired 95% CI, 13.748-59.191 mean grey value, p < 0.05) revealed E-cadherin reduction in iSGS-scar epithelium. iSGS-scar epithelium has a dysfunctional barrier and reduced structural protein expression. These results are consistent with dysfunctional epithelium seen in other airway pathology. Further studies are warranted to delineate the causality of epithelial dysfunction on the downstream fibroinflammatory cascade in iSGS. NA Laryngoscope, 134:374-381, 2024.

The Subglottic Stenosis 6 Questionnaire: A Novel Quality-of-Life Survey Validated to Predict Need for Intervention in Patients With Idiopathic Subglottic Stenosis

Idiopathic subglottic stenosis (iSGS) is a recurrent, chronic disease defined by fibroinflammatory narrowing of the subglottic airway. A key challenge in treatment is monitoring disease progression, which may be debilitating and unpredictable in its timing. Can the Subglottic Stenosis 6 (SGS-6) questionnaire be validated as a novel quality-of-life (QOL) instrument to monitor breathing, disease progression, and disease severity proactively in patients with iSGS? Panel data from 51 patients with iSGS were collected from January 2012 through June 2022, representing 1,684 patient encounters including routine office visits and treatment encounters. Subjective QOL scores (including the novel SGS-6 and established RAND-36 and EuroQol Five Dimensions [EQ-5D] Visual Analog Scale) and objective pulmonary function test (PFT) results were collected at each visit. Subjective SGS-6 QOL scores were repeated within 1week of initial reporting. Panel regression analyses were performed to assess the relationship between SGS-6 scores, PFT results, and a patient's need for intervention. Minimal clinically important differences (MCIDs) for SGS-6 and peak expiratory flow percentage (PEF%) were assessed using receiver operating characteristic (ROC) curve analysis and a patient's need for intervention as the external anchor. Each one-point increase in SGS-6 score (of a maximum of 27) was associated with a 3.26%decrease in PEF%, a 1.93-point decrease in RAND-36 Physical Health composite score, a 1.27-point decrease in RAND-36 Mental Health composite score, and a 0.88-point decrease in EQ-5D Visual Analog Scale score. The intracorrelation coefficient for the SGS-6 composite score is 0.838 (95%CI, 0.770-0.888). Compared with patient baselines, SGS-6 scores were 4.66 points greater at the time of intervention with an MCID of 2.25 from a patient's baseline. The area under the ROC curve for SGS-6 and a patient's intervention point was 0.81. iSGS disease severity can be modeled using the SGS-6 questionnaire, offering physicians and patients a potentially new method of tracking disease progression and need for intervention remotely.

Localizing Hormone Receptor Expression to Cellular Compartments in Idiopathic Subglottic Stenosis.

Idiopathic subglottic stenosis (iSGS) is an unexplained progressive fibrosis of the upper airway. iSGS almost exclusively affects women; as a result, female hormones (estrogen and progesterone) have been proposed to participate in the pathogenesis of iSGS. Our aim was to localize cell-specific gene expression of estrogen receptors (ESR1 and ESR2) and progesterone receptor (PGR) using an established iSGS single-cell RNA sequencing (scRNAseq) cell atlas. Ex vivo molecular study of airway scar and healthy mucosa from iSGS patients. An established scRNAseq atlas consisting of 25,974 individually sequenced cells from subglottic scar (n = 7) or matched unaffected mucosa (n = 3) in iSGS patients was interrogated for RNA expression of ESR1, ESR2, and PGR. Results were quantified and compared across cell subsets, then visualized using Uniform Manifold Approximation and Projection (UMAP). Confirmatory protein assessment of endocrine receptors in fibroblasts from iSGS patients (n = 5) was performed via flow cytometry. The proximal airway mucosa in iSGS patients demonstrates differential expression of endocrine receptors (ESR1, ESR2, PGR). Within airway scar, endocrine receptors are primarily expressed by fibroblasts, immune cells, and endothelial cells. Fibroblasts show strong ESR1 and PGR expression, while immune cells possess RNA for both ESR1 and ESR2. Endothelial cells predominantly express ESR2. Epithelial cells in unaffected mucosa express all three receptors, which are all reduced in airway scar. scRNAseq data localized endocrine receptor expression to specific cell subsets. These results provide the foundation for future work interrogating how hormone-dependent mechanisms promote, sustain, or participate in iSGS disease pathogenesis. NA; Basic science Laryngoscope, 133:3506-3511, 2023.

Characteristics of Idiopathic Subglottic Stenosis in the Elderly.

To compare characteristics of patients ≥65 years presenting with idiopathic subglottic stenosis (iSGS) to patients diagnosed at <65 years. We hypothesize that the groups have similar comorbidities and disease courses. Medical records of patients treated for iSGS at a tertiary care institution from January 2005-September 2022. Patient demographics, time from symptom onset to diagnosis, medical history and comorbidities, and treatment modalities/intervals were recorded and analyzed. Characteristics of patients ≥65 and <65 years at presentation were compared using Chi-square analysis for non-numeric values and the Mann-Whitney U-test for numeric values. One hundred seven patients with iSGS were identified and 16 (15%) were aged ≥65 years (mean age 72.6, 15 female) at presentation. These patients were compared to 91 patients aged <65 years (mean age = 47.6, 90 female). Patients ≥65 years had higher rates of type 2 diabetes mellitus (T2DM) (p = 0.004) and tobacco use (p = 0.004). There were no significant differences in body mass index, gastroesophageal reflux disease, hormone replacement therapy, time from symptom onset to presentation, or length of operative treatment intervals. Patients ≥65 years with iSGS have higher rates of tobacco use, suggesting that alterations in wound healing may play a role in the development of iSGS in this age group. Although rates of T2DM were higher in the elderly group, clinical significance may be limited given the overall higher rate of diabetes mellitus in the elderly population. 4 Laryngoscope, 133:3075-3079, 2023.

Long-Term Follow-up of 64 Patients With Idiopathic Subglottic Stenosis: Treatment Pathways, Outcomes, and Impact of Serial Intralesional Steroid Injections.

To describe treatment pathways and long-term outcomes in 64 patients with idiopathic subglottic stenosis (iSGS), including the impact of serial intralesional steroid injection (SILSI) on degree of stenosis, need for subsequent operation, and patient-reported outcome measures. Retrospective review of 64 female patients with iSGS undergoing varied management approaches, 57 of whom underwent SILSI as at least part of their care. Treatment pathways included SILSI only, endoscopic intervention followed by SILSI only, endoscopic interventions only, endoscopic intervention followed by SILSI followed by need for repeat endoscopic intervention, open surgery, and tracheotomy. Outcomes assessed included subjectively estimated percent airway stenosis, dyspnea index (DI), modified medical research council (MMRC) dyspnea scale, voice handicap index-10 (VHI-10), number of operative and office-based procedures performed, need for subsequent operative intervention, and inter-operative interval. Treatment pathways included SILSI alone (n = 6), endoscopic intervention(s) followed by SILSI only (n = 31), SILSI followed by additional endoscopic or office-based procedures (n = 16), open surgery (n = 3), and tracheostomy (n = 4). 57 of 64 patients underwent SILSI as at least part of their treatment. Inter-operative interval was increased after starting SILSI. Of patients undergoing SILSI, those with more procedures or shorter inter-operative interval prior to SILSI were more likely to return to the operating room. Estimated stenosis, DI, MMRC, and VHI-10 decreased with SILSI. Stenosis was not correlated with DI, MMRC, or VHI-10, though DI was correlated with both MMRC and VHI-10 score. Of 57 patients undergoing SILSI, 37 did not require further operative intervention. Improvements in inter-operative interval, dyspnea, and voice were observed across patients. Randomized trials to identify which patients may benefit most from SILSI are warranted.

Human Leukocyte Antigen Genotyping of Idiopathic Subglottic Stenosis.

Despite recent scientific inquiry, idiopathic subglottic stenosis (iSGS) remains an enigmatic disease. The consistent demographics of the affected population suggest genetic factors may contribute to disease susceptibility. Given the inflammation observed in the affected proximal airway mucosa, we interrogated disease association with human leukocyte antigen (HLA) polymorphisms. Polymorphisms in the HLA locus have previously been shown to influence individuals' susceptibility to distinct inflammatory diseases. High-resolution HLA typing of 37 iSGS patients was compared with 1,242,890 healthy Caucasian controls of European ancestry from the USA National Marrow Donor Program and 281 patients with granulomatosis with polyangiitis (GPA). Complete HLA genotyping of an iSGS population showed no significant associations when compared to a North American Caucasian control population. Unlike GPA patients, iSGS was not associated with allele DPB1*04:01 nor did allele homozygosity correlate with disease severity. There was not a detectable HLA association observed in iSGS. These results support the concept that iSGS possesses a distinct genetic architecture from GPA. If genetic susceptibility exists in iSGS, it likely lies outside the HLA locus. NA, basic science Laryngoscope, 133:2533-2539, 2023.