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  • 1
    Online Resource
    Online Resource
    Association of Social Determinants of Health with Time to Diagnosis and Treatment Outcomes in Idiopathic Subglottic Stenosis
    SAGE Publications ; 2021
    In:  Annals of Otology, Rhinology & Laryngology Vol. 130, No. 10 ( 2021-10), p. 1116-1124
    Details
    In: Annals of Otology, Rhinology & Laryngology, SAGE Publications, Vol. 130, No. 10 ( 2021-10), p. 1116-1124
    Abstract: To examine whether social determinants of health (SDH) factors are associated with time to diagnosis, treatment selection, and time to recurrent surgical intervention in idiopathic subglottic stenosis (iSGS) patients. Methods: Adult patients with diagnosed iSGS were recruited prospectively (2015-2017) via clinical providers as part of the North American Airway Collaborative (NoAAC) and via an online iSGS support community on Facebook. Patient-specific SDH factors included highest educational attainment (self-reported), median household income (matched from home zip code via U.S. Census data), and number of close friends (self-reported) as a measure of social support. Main outcomes of interest were time to disease diagnosis (years from symptom onset), treatment selection (endoscopic dilation [ED] vs cricotracheal resection [CTR] vs endoscopic resection with adjuvant medical therapy [ERMT]), and time to recurrent surgical intervention (number of days from initial surgical procedure) as a surrogate for disease recurrence. Results: The total 810 participants were 98.5% female, 97.2% Caucasian, and had a median age of 50 years (IQR, 43-58). The cohort had a median household income of $62 307 (IQR, $50 345-$79 773), a median of 7 close friends (IQR, 4-10), and 64.7% of patients completed college or graduate school. Education, income, and number of friends were not associated with time to diagnosis via multivariable linear regression modeling. Univariable multinominal logistic regression demonstrated an association between education and income for selecting ED versus ERMT, but no associations were noted for CTR. No associations were noted for time to recurrent surgical procedure via Kaplan Meier modeling and Cox proportional hazards regression. Conclusions: Patient education, income, and social support were not associated with time to diagnosis or time to disease recurrence. This suggests additional patient, procedure, or disease-specific factors contribute to the observed variations in iSGS surgical outcomes.
    Type of Medium: Online Resource
    ISSN: 0003-4894 , 1943-572X
    URL: Article
    DOI: 10.1177/0003489421995283
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2021
    detail.hit.zdb_id: 2033055-8
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  • 2
    Online Resource
    Online Resource
    Comparative Treatment Outcomes for Idiopathic Subglottic Stenosis: 5‐Year Update
    Wiley ; 2023
    In:  Otolaryngology–Head and Neck Surgery Vol. 168, No. 6 ( 2023-06), p. 1570-1575
    Details
    In: Otolaryngology–Head and Neck Surgery, Wiley, Vol. 168, No. 6 ( 2023-06), p. 1570-1575
    Abstract: The North American Airway Collaborative (NoAAC) previously published a 3‐year multi‐institutional prospective cohort study showing variation in treatment effectiveness between 3 primary surgical techniques for idiopathic subglottic stenosis (iSGS). In this report, we update these findings to include 5 years of data evaluating treatment effectiveness. Patients in the NoAAC cohort were re‐enrolled for 2 additional years and followed using the prespecified published protocol. Consistent with prior data, prospective observation of 487 iSGS patients for 5 years showed treatment effectiveness differed by modality. Cricotracheal resection maintained the lowest rate of recurrent operation (5%), followed by endoscopic resection with adjuvant medical therapy (30%) and endoscopic dilation (50%). These data support the initial observations and continue to provide value to providers and patients navigating longitudinal decision‐making. Level of evidence: 2—prospective cohort study.
    Type of Medium: Online Resource
    ISSN: 0194-5998 , 1097-6817
    URL: Issue
    URL: Article
    DOI: 10.1002/ohn.v168.6
    DOI: 10.1002/ohn.190
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2008453-5
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  • 3
    Online Resource
    Online Resource
    Comparative Treatment Outcomes for Patients With Idiopathic Subglottic Stenosis
    American Medical Association (AMA) ; 2020
    In:  JAMA Otolaryngology–Head & Neck Surgery Vol. 146, No. 1 ( 2020-01-01), p. 20-
    Details
    In: JAMA Otolaryngology–Head & Neck Surgery, American Medical Association (AMA), Vol. 146, No. 1 ( 2020-01-01), p. 20-
    Type of Medium: Online Resource
    ISSN: 2168-6181
    URL: Article
    DOI: 10.1001/jamaoto.2019.3022
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2020
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  • 4
    Online Resource
    Online Resource
    Disease homogeneity and treatment heterogeneity in idiopathic subglottic stenosis
    Wiley ; 2016
    In:  The Laryngoscope Vol. 126, No. 6 ( 2016-06), p. 1390-1396
    Details
    In: The Laryngoscope, Wiley, Vol. 126, No. 6 ( 2016-06), p. 1390-1396
    Abstract: Idiopathic subglottic stenosis (iSGS) is a rare and potentially life‐threatening disease marked by recurrent and progressive airway obstruction frequently requiring repeated surgery to stabilize the airway. Unknown etiology and low disease prevalence have limited the ability to characterize the natural history of iSGS and resulted in variability in surgical management. It is uncertain how this variation relates to clinical outcomes. Study Design Medical record abstraction. Methods Utilizing an international, multi‐institutional collaborative, we collected retrospective data on patient characteristics, treatment, and clinical outcomes. We investigated variation between and within open and endoscopic treatment approaches and assessed therapeutic outcomes; specifically, disease recurrence and need for tracheostomy at last follow‐up. Results Strikingly, 479 iSGS patients across 10 participating centers were nearly exclusively female (98%, 95% confidence interval [CI], 96.1–99.6), Caucasian (95%, 95% CI, 92.2–98.8), and otherwise healthy (mean age‐adjusted Charlson Comorbidity Index 1.5; 95% CI, 1.44–1.69). The patients presented at a mean age of 50 years (95% CI, 48.8–51.1). A total of 80.2% were managed endoscopically, whereas 19.8% underwent open reconstruction. Endoscopic surgery had a significantly higher rate of disease recurrence than the open approach (chi 2 = 4.09, P = 0.043). Tracheostomy was avoided in 97% of patients irrespective of surgical approach (95% CI, 94.5–99.8). Interestingly, there were outliers in rates of disease recurrence between centers using similar treatment approaches. Conclusion Idiopathic subglottic stenosis patients are surprisingly homogeneous. The heterogeneity of treatment approaches and the observed outliers in disease recurrence rates between centers raises the potential for improved clinical outcomes through a detailed understanding of the processes of care. Level of Evidence 4. Laryngoscope , 126:1390–1396, 2016
    Type of Medium: Online Resource
    ISSN: 0023-852X , 1531-4995
    URL: Issue
    URL: Article
    DOI: 10.1002/lary.v126.6
    DOI: 10.1002/lary.25708
    Language: English
    Publisher: Wiley
    Publication Date: 2016
    detail.hit.zdb_id: 2026089-1
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  • 5
    Online Resource
    Online Resource
    Increased Expression of PD ‐1 and PD‐L1 in Patients With Laryngotracheal Stenosis
    Wiley ; 2021
    In:  The Laryngoscope Vol. 131, No. 5 ( 2021-05), p. 967-974
    Details
    In: The Laryngoscope, Wiley, Vol. 131, No. 5 ( 2021-05), p. 967-974
    Abstract: Laryngotracheal stenosis (LTS) is a fibrotic condition of the upper airway. Recent evidence suggests dysregulated host immunity plays a role in LTS development and progression. The programmed death‐1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) axis, targeted by paradigm‐shifting immunotherapies for cancer treatment, has also recently been implicated in the pathogenesis of fibrotic pulmonary disease. However, a role for the PD‐1/PD‐L1 axis in the proximal airway fibrosis seen in LTS patients has not been explored. Study Design Controlled ex vivo study. Methods Expression of PD‐1, PD‐L1, CD4, and CD8 were evaluated using immunohistochemical staining of cricotracheal resection specimens from postintubation iatrogenic laryngotracheal stenosis (iLTS), idiopathic subglottic stenosis (iSGS) patients, and normal controls derived from rapid autopsy (n = 8 per group). Fibroblasts derived from iLTS scar were also treated with transforming growth factor beta 1 (TGFβ1) and analyzed for PD‐L1 expression by quantitative real‐time polymerase chain reaction (n = 6). Results iLTS specimens exhibited increased expression of PD‐1, PD‐L1, and CD4 (all P 〈  .0167) compared to controls, whereas iSGS specimens exhibited increased expression of PD‐1 and CD4 ( P 〈  .0167) compared to controls. PD‐1, PD‐L1, and CD4 showed periepithelial patterns of expression in both disease cohorts. TGFβ1 treatment of iLTS fibroblasts increased expression of PD‐L1 (the cognate ligand for PD‐1). Conclusion Expression of both PD‐1 and its ligand PD‐L1 are significantly greater in patients with iLTS compared to controls, and PD‐1 expression is also elevated in patients with iSGS. Given published evidence implicating the PD‐1/PD‐L1 axis in pulmonary fibrosis, this suggests a possible role for checkpoint inhibitors targeting the PD‐1/PD‐L1 axis for the treatment of LTS. Level of Evidence N/A Laryngoscope , 131:967–974, 2021
    Type of Medium: Online Resource
    ISSN: 0023-852X , 1531-4995
    URL: Issue
    URL: Article
    DOI: 10.1002/lary.v131.5
    DOI: 10.1002/lary.28790
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2026089-1
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  • 6
    Online Resource
    Online Resource
    Familial Aggregation in Idiopathic Subglottic Stenosis
    Wiley ; 2020
    In:  Otolaryngology–Head and Neck Surgery Vol. 163, No. 5 ( 2020-11), p. 1011-1017
    Details
    In: Otolaryngology–Head and Neck Surgery, Wiley, Vol. 163, No. 5 ( 2020-11), p. 1011-1017
    Abstract: To evaluate inheritance patterns and define the familial clustering rate of idiopathic subglottic stenosis (iSGS). Study Design Retrospective observational study. Setting International multicenter collaborative of 〉 30 tertiary care centers. Methods Patients with a clinically confirmed iSGS diagnosis within the North American Airway Collaborative’s iSGS 1000 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. Results A 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). Conclusion This 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.
    Type of Medium: Online Resource
    ISSN: 0194-5998 , 1097-6817
    URL: Article
    DOI: 10.1177/0194599820935402
    Language: English
    Publisher: Wiley
    Publication Date: 2020
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  • 7
    Online Resource
    Online Resource
    Quantitative Assessment of the Immune Microenvironment in Patients With Iatrogenic Laryngotracheal Stenosis
    Wiley ; 2021
    In:  Otolaryngology–Head and Neck Surgery Vol. 164, No. 6 ( 2021-06), p. 1257-1264
    Details
    In: Otolaryngology–Head and Neck Surgery, Wiley, Vol. 164, No. 6 ( 2021-06), p. 1257-1264
    Abstract: Iatrogenic laryngotracheal stenosis (iLTS) is characterized by fibroinflammatory narrowing of the upper airway and is most commonly caused by intubation injury. Evidence suggests a key role for CD4 T cells in its pathogenesis. The objective of this study is to validate emerging multiplex immunofluorescence (mIF) technology for use in the larynx and trachea while quantitatively characterizing the immune cell infiltrate in iLTS. In addition to analyzing previously unstudied immune cell subsets, this study aims to validate previously observed elevations in the immune checkpoint PD‐1 and its ligand PD‐L1 while exploring their spatial and cellular distributions in the iLTS microenvironment. Study Design Controlled ex vivo cohort study. Setting Tertiary care center. Methods mIF staining was performed with formalin‐fixed, paraffin‐embedded slides from 10 patients with iLTS who underwent cricotracheal resection and 10 control specimens derived from rapid autopsy for CD4, CD8, CD20, FoxP3, PD‐1, PD‐L1, and cytokeratin. Results There was greater infiltration of CD4 + T cells, CD8 + T cells, CD20 + B cells, FoxP3 + CD4 + Tregs, and FoxP3 + CD8 + early effector T cells in the submucosa of iLTS specimens as compared with controls ( P 〈 . 05 for all). PD‐1 was primarily expressed on T cells and PD‐L1 predominantly on CD4 + cells and “other” cells. Conclusion This study leverages the power of mIF to quantify the iLTS immune infiltrate in greater detail. It confirms the highly inflammatory nature of iLTS, with CD4 + cells dominating the immune cell infiltrate; it further characterizes the cellular and spatial distribution of PD‐1 and PD‐L1; and it identifies novel immunologic targets in iLTS.
    Type of Medium: Online Resource
    ISSN: 0194-5998 , 1097-6817
    URL: Article
    DOI: 10.1177/0194599820978271
    Language: English
    Publisher: Wiley
    Publication Date: 2021
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  • 8
    Online Resource
    Online Resource
    A survey of patients with laryngotracheal stenosis on future clinical trial design
    SAGE Publications ; 2022
    In:  Clinical Trials Vol. 19, No. 2 ( 2022-04), p. 194-200
    Details
    In: Clinical Trials, SAGE Publications, Vol. 19, No. 2 ( 2022-04), p. 194-200
    Abstract: Laryngotracheal stenosis is a rare but devastating proximal airway fibrosis that restricts a patient’s ability to breathe. Treatment is primarily surgical and to date, there has never been a multi-institutional, randomized, prospective, and interventional clinical trial for a medical therapy to treat laryngotracheal stenosis. Therefore, we aimed to obtain patient feedback to guide successful trial design, recruitment, retention, and for identifying potential barriers to study participation. Methods Over 1000 members of an international laryngotracheal stenosis online support community (the Living with Idiopathic Subglottic Stenosis Facebook group) were sent two questionnaires for a proposed interventional double-blinded, randomized, placebo-controlled clinical trial. Results A total of 317 and 558 participants responded to the first and second surveys, respectively. The majority of participants (77%) were willing to consider enrollment, regardless of having a 50% chance of receiving placebo versus treatment (78%). The majority (84%) of participants were willing to travel 200 miles to participate for up to six in-person visits over 50 days. Specific side effects, including anemia/thrombocytopenia (72%) or risk of infection (69.3%) had the greatest impact on clinical trial participation with other side effects (peripheral edema (53%), oral ulcers (51%), and gastrointestinal side effects (41%)) having less impact. Conclusion Patients with laryngotracheal stenosis possess nuanced insight into their disease and treatment options. As a group, they are extremely motivated for better therapies. Future laryngotracheal stenosis clinical trials should focus on providing excellent side effect -related education and utilizing feedback from online advocacy groups to optimize recruitment and retention.
    Type of Medium: Online Resource
    ISSN: 1740-7745 , 1740-7753
    URL: Article
    DOI: 10.1177/17407745211065744
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2022
    detail.hit.zdb_id: 2159773-X
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  • 9
    Online Resource
    Online Resource
    Mapping Genetic Susceptibility to Stenosis in the Proximal Airway
    Wiley ; 2023
    In:  The Laryngoscope
    Details
    In: The Laryngoscope, Wiley
    Abstract: Recent translational scientific efforts in subglottic stenosis (SGS) support a disease model where epithelial alterations facilitate microbiome displacement, dysregulated immune activation, and localized fibrosis. Yet despite recent advances, the genetic basis of SGS remains poorly understood. We sought to identify candidate risk genes associated with an SGS phenotype, investigate their biological function, and identify the cell types enriched for their expression. Methods The Online Mendelian Inheritance in Man (OMIM) database was queried for single gene variants associated with an SGS phenotype. The functional intersections and molecular roles of the identified genes were explored using pathway enrichment analysis (PEA) computational methods. Cellular localization of the candidate risk genes was measured via transcriptional quantification in an established single cell RNA sequencing (scRNA‐seq) atlas of the proximal airway. Results Twenty genes associated with SGS phenotype were identified. PEA resulted in 24 significantly enriched terms including “cellular response to TGF‐β,” “epithelial‐to‐mesenchymal transition,” and “adherens junctions.” Mapping the 20 candidate risk genes to the scRNA‐seq atlas found 3 (15%) genes were enriched in epithelial cells, 3 (15%) in fibroblasts, and 3 (15%) in endothelial cells. 11 (55%) genes were expressed ubiquitously among tissue types. Interestingly, immune cells were not significantly enriched for candidate risk genes. Conclusion We identify and provide biologic context for 20 genes associated with fibrotic disease of the proximal airway and form the foundation for future detailed genetic study. Level of evidence N/A Laryngoscope , 2023
    Type of Medium: Online Resource
    ISSN: 0023-852X , 1531-4995
    URL: Article
    DOI: 10.1002/lary.30718
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2026089-1
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  • 10
    Online Resource
    Online Resource
    Laryngotracheal Mucosal Surface Expression of Candidate Biomarkers in Idiopathic Subglottic Stenosis
    Wiley ; 2021
    In:  The Laryngoscope Vol. 131, No. 2 ( 2021-02), p. 342-349
    Details
    In: The Laryngoscope, Wiley, Vol. 131, No. 2 ( 2021-02), p. 342-349
    Abstract: Idiopathic 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 Design In vitro comparative study of human cells. Methods Levels 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. Results Pulmonary 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. Conclusion Pro‐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 Evidence 4 Laryngoscope , 131:342–349, 2021
    Type of Medium: Online Resource
    ISSN: 0023-852X , 1531-4995
    URL: Issue
    URL: Article
    DOI: 10.1002/lary.v131.2
    DOI: 10.1002/lary.28712
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2026089-1
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