Molecular analysis of idiopathic subglottic stenosis for Mycobacterium species.
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ABSTRACT: Objectives/hypothesis
Idiopathic subglottic stenosis (iSGS) is an unexplained obstruction involving the lower laryngeal and upper tracheal airway. Persistent mucosal inflammation is a hallmark of the disease. Epithelial microbiota dysbiosis is found in other chronic inflammatory mucosal diseases; however, the relationship between tracheal microbiota composition and iSGS is unknown. Given the critical role for host defense at mucosal barriers, we analyzed tissue specimens from iSGS patients for the presence of microbial pathogens.Methods
Utilizing 30 human iSGS, 20 intubation-related tracheal stenosis (iLTS), and 20 healthy control specimens, we applied molecular, immunohistochemical, electron microscopic, immunologic, and Sanger-sequencing techniques.Results
With unbiased culture-independent nucleic acid, protein, and immunologic approaches, we demonstrate that Mycobacterium species are uniquely associated with iSGS. Phylogenetic analysis of the mycobacterial virulence factor rpoB suggests that, rather than Mycobacterium tuberculosis, a variant member of the Mycobacterium tuberculosis complex or a closely related novel mycobacterium is present in iSGS specimens.Conclusion
These studies identify a novel pathogenic role for established large airway bacteria and provide new targets for future therapeutic intervention.Level of evidence
NA Laryngoscope, 127:179-185, 2017.
SUBMITTER: Gelbard A
PROVIDER: S-EPMC5156582 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveTo evaluate inheritance patterns and define the familial clustering rate of idiopathic subglottic stenosis (iSGS).Study designRetrospective observational study.SettingInternational multicenter collaborative of >30 tertiary care centers.MethodsPatients with a clinically confirmed iSGS diagnosis within the North American Airway Collaborative's iSGS1000 cohort consented between 2014 and 2018 were eligible for enrollment. Patient demographics and disease severity were abstracted from the collaborative's iSGS longitudinal registry. Pedigrees of affected families were created.ResultsA total of 810 patients with iSGS were identified. Positive family history for iSGS was reported in 44 patients in 20 families. The rate of familial clustering in iSGS is 2.5%. Mean age of disease onset is 42.6 years. Of the 44 patients with familial aggregation of iSGS, 42 were female and 2 were male; 13 were mother-daughter pairs and 2 were father-daughter pairs. There were 3 sister-sister pairs. There was 1 niece-aunt pair and 2 groups of 3 family members. One pedigree demonstrated 2 affected mother-daughter pairs, with the mothers being first-degree paternal cousins. Inheritance is non-Mendelian, and anticipation is present in 11 of 13 (84%) parent-offspring pairs. The mean age of onset between parents (48.4 years) and offspring (36.1 years) was significantly different (P = .016).ConclusionThis study quantifies the rate of familial clustering of iSGS at 2.5%. Inheritance is non-Mendelian, and disease demonstrates anticipation. These data suggest that there may be a genetic contribution in iSGS.
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Project description:ObjectiveTo characterize presentation, disease course, and treatment of idiopathic subglottic stenosis (iSGS) in non-Caucasian women and compare this cohort to the predominantly female, Caucasian patient cohorts identified in the literature.Study designRetrospective review. Results are compared to systematic review of demographics.SettingMultiple California institutions from 2008 to 2021.MethodsPatients with intubation within 2 years of disease or who met exclusion criteria listed in prior publications were excluded. A systematic review of iSGS patient demographics was also completed for comparison.ResultsOf 421 patients with iSGS, 58 self-identified as non-Caucasian women, with 50 ultimately included. Mean age of onset was 45.1 years old (95% confidence interval [CI], 41.5-48.8), and mean age at diagnosis was 47.2 years (95% CI, 43.6-50.7). Mean Charlson comorbidity index was 1.06 (n = 49, 95% CI, 0.69-1.44). At diagnosis, Cotton-Meyer severity scores (documented in n = 45) were Cotton-Myer (CM) I (28.9%), CM II (40%), and CM III (31.1%). Mean age at first endoscopic surgery was 47.7 (95% CI, 44.2-51.3) years. 64% experienced disease recurrence with a median of 11 months between their first and second surgery. Our systematic review identified 60 studies that reported demographic features in patients with iSGS. 95% of pooled patients were Caucasian, while other demographic features were similar to the current cohort.ConclusionThe non-Caucasian population, almost 14% of this Californian cohort, does not differ from the majority Caucasian population detailed in contemporary literature. This cohort supports the presence of some racial and ethnic heterogeneity in this disease population.
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Project description:iSGS exhibits distinct genomic methylation signatures. These signatures expand current understanding of the iSGS phenotype and may inform the direction of future experimental studies.
2021-03-12 | GSE168614 | GEO
Project description:ImportanceSurgical treatment comparisons in rare diseases are difficult secondary to the geographic distribution of patients. Fortunately, emerging technologies offer promise to reduce these barriers for research.ObjectiveTo prospectively compare the outcomes of the 3 most common surgical approaches for idiopathic subglottic stenosis (iSGS), a rare airway disease.Design, setting, and participantsIn this international, prospective, 3-year multicenter cohort study, 810 patients with untreated, newly diagnosed, or previously treated iSGS were enrolled after undergoing a surgical procedure (endoscopic dilation [ED], endoscopic resection with adjuvant medical therapy [ERMT], or cricotracheal resection [CTR]). Patients were recruited from clinician practices in the North American Airway Collaborative and an online iSGS community on Facebook.Main outcomes and measuresThe primary end point was days from initial surgical procedure to recurrent surgical procedure. Secondary end points included quality of life using the Clinical COPD (chronic obstructive pulmonary disease) Questionnaire (CCQ), Voice Handicap Index-10 (VHI-10), Eating Assessment Test-10 (EAT-10), the 12-Item Short-Form Version 2 (SF-12v2), and postoperative complications.ResultsOf 810 patients in this cohort, 798 (98.5%) were female and 787 (97.2%) were white, with a median age of 50 years (interquartile range, 43-58 years). Index surgical procedures were ED (n?=?603; 74.4%), ERMT (n?=?121; 14.9%), and CTR (n?=?86; 10.6%). Overall, 185 patients (22.8%) had a recurrent surgical procedure during the 3-year study, but recurrence differed by modality (CTR, 1 patient [1.2%]; ERMT, 15 [12.4%]; and ED, 169 [28.0%]). Weighted, propensity score-matched, Cox proportional hazards regression models showed ED was inferior to ERMT (hazard ratio [HR], 3.16; 95% CI, 1.8-5.5). Among successfully treated patients without recurrence, those treated with CTR had the best CCQ (0.75 points) and SF-12v2 (54 points) scores and worst VHI-10 score (13 points) 360 days after enrollment as well as the greatest perioperative risk.Conclusions and relevanceIn this cohort study of 810 patients with iSGS, endoscopic dilation, the most popular surgical approach for iSGS, was associated with a higher recurrence rate compared with other procedures. Cricotracheal resection offered the most durable results but showed the greatest perioperative risk and the worst long-term voice outcomes. Endoscopic resection with medical therapy was associated with better disease control compared with ED and had minimal association with vocal function. These results may be used to inform individual patient treatment decision-making.
| S-EPMC6824232 | biostudies-literature
Project description:ObjectiveIdiopathic subglottic stenosis (iSGS) is a chronic inflammatory condition that causes dyspnea and affects middle-aged women of White race and non-Latino or Hispanic ethnicity. To better characterize its phenotype and pathogenesis, we assessed the proteomic and genomic methylation signatures of subglottic tissue collected from iSGS patients compared to controls.Study designMolecular analysis of clinical biospecimens.MethodsWe collected subglottic tissue biopsies from 12 patients during direct laryngoscopy, immediately prior to surgical treatment of iSGS; as well as from 4 age-, sex-, and race/ethnicity-matched control patients undergoing other direct laryngoscopic procedures. We isolated protein and genomic DNA, acquired proteomic data using label-free quantitative mass spectrometry techniques, and acquired genome-wide methylation data using bisulfite conversion and a microarray platform. We compared molecular profiles across the iSGS and control groups, and with respect to clinical course in the iSGS group. Eight of the 12 iSGS patients underwent subsequent blood collection and plasma isolation for further assessment.ResultsProteomic analysis revealed 42 differentially abundant proteins in the iSGS biopsies compared to controls, inferring enrichment of biological pathways associated with early wound healing, innate immunity, matrix remodeling, and metabolism. Proteome-based hierarchical clustering organized patients into two iSGS and one control subgroups. Methylation analysis revealed five hypermethylated genes in the iSGS biopsies compared to controls, including the biotin recycling enzyme biotinidase (BTD). Follow-up analysis showed elevated plasma BTD activity in iSGS patients compared to both controls and published normative data.ConclusioniSGS exhibits distinct proteomic and genomic methylation signatures. These signatures expand current understanding of the iSGS phenotype, support the possibility of disease subgroups, and should inform the direction of future experimental studies.Level of evidenceNot applicable Laryngoscope, 131:E540-E546, 2021.
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Project description:OBJECTIVE:To characterize the phenotype and function of fibroblasts derived from airway scar in idiopathic subglottic stenosis (iSGS) and to explore scar fibroblast response to interleukin 17A (IL-17A). STUDY DESIGN:Basic science. SETTING:Laboratory. SUBJECTS AND METHODS:Primary fibroblast cell lines from iSGS subjects, idiopathic pulmonary fibrosis subjects, and normal control airways were utilized for analysis. Protein, molecular, and flow cytometric techniques were applied in vitro to assess the phenotype and functional response of disease fibroblasts to IL-17A. RESULTS:Mechanistically, IL-17A drives iSGS scar fibroblast proliferation ( P < .01), synergizes with transforming growth factor ß1 to promote extracellular matrix production (collagen and fibronectin; P = .04), and directly stimulates scar fibroblasts to produce chemokines (chemokine ligand 2) and cytokines (IL-6 and granulocyte-macrophage colony-stimulating factor) critical to the recruitment and differentiation of myeloid cells ( P < .01). Glucocorticoids abrogated IL-17A-dependent iSGS scar fibroblast production of granulocyte-macrophage colony-stimulating factor ( P = .02). CONCLUSION:IL-17A directly drives iSGS scar fibroblast proliferation, synergizes with transforming growth factor ß1 to promote extracellular matrix production, and amplifies local inflammatory signaling. Glucocorticoids appear to partially abrogate fibroblast-dependent inflammatory signaling. These results offer mechanistic support for future translational study of clinical reagents for manipulation of the IL-17A pathway in iSGS patients.
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Project description:Cellular characterization of proximal airway scar in idiopathic subglottic stenosis
2023-08-07 | GSE191128 | GEO
Project description:ObjectivesIdiopathic subglottic stenosis (iSGS) is an inflammatory process leading to fibrosis and narrowing of the laryngotracheal airway. There is variability in patient response to surgical intervention, but the mechanisms underlying this variability are unknown. In this pilot study, we measure expression of candidate targets at the mucosal surface of the subglottis in iSGS patients. We aim to identify putative biomarkers for iSGS that provide insights into the molecular basis of disease progression, yield a gene signature for the disease, and/or predict a response to therapy.Study designIn vitro comparative study of human cells.MethodsLevels of candidate transcripts and proteins were measured in healthy and stenotic laryngotracheal tissue specimens taken from the mucosal surface in 16 iSGS patients undergoing endoscopic balloon dilation. Pre- and post-operative pulmonary function test and patient reported voice and breathing outcomes were also assessed. Unsupervised clustering was used to define patient subgroups based on expression profile.ResultsPulmonary function and voice and breathing outcome metrics demonstrated significant post-operative improvement. Transcript levels of αSMA, CCL2, COL1A1, COL3A1, FN1, IFNG, and TGFB1 and protein levels of CCL2, IFNG, and IL-6 were significantly upregulated in stenotic as compared to healthy tissues. Marked heterogeneity was observed in the patterns of expression of candidate markers across individuals and tissue types. Patient subgroups defined by expression profile did not show a statistically significant difference in dilation interval.ConclusionPro-inflammatory and pro-fibrotic pathways are significantly upregulated along the mucosal surface of stenotic laryngotracheal tissues, and CCL2 and IFNG merit further investigation as potential iSGS biomarkers.Level of evidence4 Laryngoscope, 131:342-349, 2021.
| S-EPMC7641987 | biostudies-literature
Project description:Genomic methylation signatures of idiopathic subglottic stenosis (iSGS)
| PRJNA713017 | ENA
Project description:IntroductionIdiopathic subglottic stenosis (iSGS) is an unexplained progressive obstruction of the upper airway that occurs almost exclusively in adult, Caucasian women. The disease is characterised by mucosal inflammation and localised fibrosis resulting in life-threatening blockage of the upper airway. Because of high recurrence rates, patients with iSGS will frequently require multiple procedures following their initial diagnosis. Both the disease and its therapies profoundly affect patients' ability to breathe, communicate and swallow. A variety of treatments have been advanced to manage this condition. However, comparative data on effectiveness and side effects of the unique approaches have never been systematically evaluated. This study will create an international, multi-institutional prospective cohort of patients with iSGS. It will compare three surgical approaches to determine how well the most commonly used treatments in iSGS 'work' and what quality of life (QOL) trade-offs are associated with each approach.Methods and analysisA prospective pragmatic trial comparing the 'Standard of Care' for iSGS at multiple international institutions. Patients with a diagnosis of iSGS without clinical or laboratory evidence of vasculitis or a history of endotracheal intubation 2 years prior to symptom onset will be included in the study. Prospective evaluation of disease recurrence requiring operative intervention, validated patient-reported outcome (PRO) measures as well as patient-generated health data (mobile peak flow recordings and daily steps taken) will be longitudinally tracked for 36 months. The primary endpoint is treatment effectiveness defined as time to recurrent operative procedure. Secondary endpoints relate to treatment side effects and include PRO measures in voice, swallowing, breathing and global QOL as well as patient-generated health data.Ethics and disseminationThis protocol was approved by the local IRB Committee of the Vanderbilt University Medical Center in July 2015. The findings of the trial will be disseminated through peer-reviewed journals, national and international conference presentations and directly to patient with iSGS via social media-based support groups.Trial registration numberNCT02481817.
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