Use of Mitomycin-C in Laryngotracheal Stenosis: A Focused Clinical Review.

BACKGROUND: Therapeutic options for managing laryngotracheal stenosis (LTS) are limited. Endoscopy is a minimally invasive approach to treating LTS, but carries a high risk of stenosis recurrence. Mitomycin C (MMC) is often used as an adjunct therapy to delay the time to symptomatic recurrence of LTS. This review synthesizes the current literature on the topic of MMC as an adjunct treatment strategy for LTS. METHODS: A focused literature search was carried out from PubMed on June 12, 2022 using the terms "mitomycin c AND stenosis" in all fields with no date limitations. Evidence-based recommendations relevant to the clinical application of MMC as an adjunct therapy for LTS were formulated. Three questions were addressed: 1) efficacy of MMC, 2) single versus multiple application(s) of MMC, and 3) safety of MMC. The evidence rating and recommendation strength were guided by the GRADE system. RESULTS: Twenty-nine studies were reviewed. The efficacy of MMC as an adjunct therapy for LTS varied across studies. Randomized controlled trials have not shown an outcome difference with MMC use, although methodologic flaws including underpowering were noted. A meta-analysis of observational studies with a comparator arm found the unadjusted probability of remaining symptom-free for > 1 year is greater with versus without MMC application (73% vs. 35%). Single versus multiple application(s) of MMC resulted in similar restenosis rates at long-term follow-up. Complications related to MMC use are rarely reported using conventional doses (0.4 mg/mL). Overall, the quality of evidence was low and the recommendation for intervention was weak. CONCLUSION: The role for MMC as an adjunct therapy in LTS is uncertain. While safe in its application, the efficacy of MMC in reducing stenosis recurrence remains a matter of debate. Large, prospective studies are needed to inform future recommendations.

Sirolimus-eluting airway stent reduces profibrotic Th17 cells and inhibits laryngotracheal stenosis.

Laryngotracheal stenosis (LTS) is pathologic fibrotic narrowing of the larynx and trachea characterized by hypermetabolic fibroblasts and CD4+ T cell-mediated inflammation. However, the role of CD4+ T cells in promoting LTS fibrosis is unknown. The mTOR signaling pathways have been shown to regulate the T cell phenotype. Here we investigated the influence of mTOR signaling in CD4+ T cells on LTS pathogenesis. In this study, human LTS specimens revealed a higher population of CD4+ T cells expressing the activated isoform of mTOR. In a murine LTS model, targeting mTOR with systemic sirolimus and a sirolimus-eluting airway stent reduced fibrosis and Th17 cells. Selective deletion of mTOR in CD4+ cells reduced Th17 cells and attenuated fibrosis, demonstrating CD4+ T cells' pathologic role in LTS. Multispectral immunofluorescence of human LTS revealed increased Th17 cells. In vitro, Th17 cells increased collagen-1 production by LTS fibroblasts, which was prevented with sirolimus pretreatment of Th17 cells. Collectively, mTOR signaling drove pathologic CD4+ T cell phenotypes in LTS, and targeting mTOR with sirolimus was effective at treating LTS through inhibition of profibrotic Th17 cells. Finally, sirolimus may be delivered locally with a drug-eluting stent, transforming clinical therapy for LTS.

Role of systemic immunosuppression on subglottic stenosis in granulomatosis with polyangiitis: Analysis of a single-centre cohort.

PURPOSE: Subglottic stenosis (SGS) is a potentially life-threatening manifestation of granulomatosis with polyangiitis (GPA). Endoscopic dilation is effective, but relapses are frequent and the benefit of systemic immunosuppression in this setting is still controversial. We aimed to investigate the role of immunosuppressive treatment on SGS relapse risk. METHODS: This is a retrospective observational study based on review of medical charts among our cohort of patients with GPA. RESULTS: Twenty-one patients with SGS-GPA were identified, with a prevalence of 20% among our entire GPA cohort (n = 105). Compared to patients without SGS, patients with SGS-GPA had an earlier disease onset (mean age 30.2 vs. 47.3 years, p<0.001), and lower BVAS (mean 10.5 vs 13.5; p = 0.018). Five patients didn't receive systemic immunosuppression for SGS and they all (100%) relapsed after the first procedure, while among medical treatment group relapse rate was 44% (p = 0.045). When single treatment regimens are considered, rituximab (RTX) and cyclophosphamide (CYC) yielded a protective role towards the need of subsequent dilation procedure after the first if compared with absence of medical treatment. Patients with SGS and generalized disease, who initially received either a RTX- or a CYC-based induction treatment, and higher cumulative doses of glucocorticoids, showed a delayed median time to SGS relapse (36 vs. 12 months, p = 0.024). CONCLUSIONS: Subglottic stenosis is highly prevalent in patients with GPA and may define a milder systemic disease subset occurring more frequently in younger patients. Systemic immunosuppression provides benefit in preventing recurrence of SGS in GPA patients and regimens based on cyclophosphamide or rituximab might have a non-redundant role in this setting.

Comparison of Inhaled Drug Delivery in Patients With One- and Two-level Laryngotracheal Stenosis.

OBJECTIVES/HYPOTHESIS: Laryngotracheal stenosis (LTS) is a functionally devastating condition with high respiratory morbidity and mortality. This preliminary study investigates airflow dynamics and stenotic drug delivery in patients with one- and two-level LTS. STUDY DESIGN: A Computational Modeling Restropective Cohort Study. METHODS: Computed tomography scans from seven LTS patients, five with one-level (three subglottic, two tracheal), and two with two-level (glottis + trachea, glottis + subglottis) were used to reconstruct patient-specific three-dimensional upper airway models. Airflow and orally inhaled drug particle transport were simulated using computational fluid dynamics modeling. Drug particle transport was simulated for 1-20 µm particles released into the mouth at velocities of 0 m/s, 1 m/s, 3 m/s, and 10 m/s for metered dose inhaler (MDI) and 0 m/s for dry powder inhaler (DPI) simulations. Airflow resistance and stenotic drug deposition in the patients' airway models were compared. RESULTS: Overall, there was increased airflow resistance at stenotic sites in subjects with two-level versus one-level stenosis (0.136 Pa s/ml vs. 0.069 Pa s/ml averages). Subjects with two-level stenosis had greater particle deposition at sites of stenosis compared to subjects with one-level stenosis (average deposition 2.31% vs. 0.96%). One-level stenosis subjects, as well as one two-level stenosis subject, had the greatest deposition using MDI with a spacer (0 m/s): 2.59% and 4.34%, respectively. The second two-level stenosis subject had the greatest deposition using DPI (3.45%). Maximum deposition across all stenotic subtypes except one-level tracheal stenosis was achieved with particle sizes of 6-10 µm. CONCLUSIONS: Our results suggest that patients with two-level LTS may experience a more constricted laryngotracheal airflow profile compared to patients with one-level LTS, which may enhance overall stenotic drug deposition. LEVEL OF EVIDENCE: NA Laryngoscope, 133:366-374, 2023.

Efficacy of Office-Based Intralesional Steroid Injections in the Management of Subglottic Stenosis: A Systematic Review.

OBJECTIVE: To determine the efficacy of office-based intralesional steroid injections (ILSI) as a management therapy for adult subglottic stenosis (SGS). DATA SOURCES: A systematic review was completed using PubMed and Science Direct for office-based management of SGS due to various etiologies. REVIEW METHODS: The primary end point measured was a change in surgery free interval (SFI) between endoscopic procedures due to office-based serial ILSI. The secondary end point was to determine what percentage of patients did not require further operative intervention for SGS maintenance therapy after changing management to office-based serial ILSI. RESULTS: We identified 187 abstracts, 4 of which were included in the analysis. The total number of participants was 55. The mean age was 50.4, and 78.1% were women. The etiologies were as follows: idiopathic (58.2%), postintubation/tracheotomy (29.1%), and autoimmune (12.7%). The SFI was reported in 3 of the 4 studies. The reported mean pre-ILSI SFI was 362.9 days and the post-ILSI SFI was 582.2 days. The secondary outcome was reported in 3 of the 4 studies. Forty-one of the 55 patients (74.5%) did not require further operative intervention during the duration of the study. CONCLUSION: This review explored office-based ILSI as a potential treatment option for patients with SGS. The limited data presented found ILSI significantly lengthened SFI, potentially reducing surgical burden. In addition, ILSI was found to be safe with few reported side effects.

The Effect of Subglottic Steroid injection on Blood Glucose in a Cohort of Patients With Subglottic Stenosis.

OBJECTIVE: The objective of this work was to assess the effect of a single intralesional subglottic steroid injection on fasting blood glucose over 7 days in a cohort of patients with subglottic stenosis. METHODS: A prospective cohort study of patients undergoing intralesional steroid injections at a tertiary academic center. Patients had baseline bloodwork performed, including fasting blood glucose (FBG), and hemoglobin A1C levels. Demographic data and risk factors were collected. Fasting capillary glucose (FCG) was measured using a capillary glucometer and performed by patients daily from days 0 to 7 after a single injection of Triamcinolone into the subglottic airway. Data were analyzed using descriptive and comparative statistics. RESULTS: Eleven patients were enrolled, and 10 completed data collection over 7 days. All were female, with a mean age of 52.6 years (SD 17.5). Two patients were diabetic (non-insulin dependent). There was a statistically significant increase in FCG on day 1 post-injection (mean = 122.4 mg/dl compared to 100.7 mg/dl) that normalized for all patients within 24-72 h. The mean increase in FCG was 21.5% (SD 22.5%) of the initial value for the cohort. The diabetic group had statistically significant higher glucose values on day 1 compared to the non-diabetic group (146.5 mg/dl compared to 117.0 mg/dl). CONCLUSION: A single subglottic steroid injection appears to cause a transient increase in FCG 1 day post injection, which resolves after 24-72 h and can be more pronounced in diabetic patients. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:1590-1594, 2023.

A survey of patients with laryngotracheal stenosis on future clinical trial design.

BACKGROUND/AIMS: 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.

Development of Cushing Syndrome After Serial In-office Subglottic Steroid Injections.

In-office subglottic intralesional steroid injections (SILSI) have gained popularity as an adjunct to operating room dilation in the treatment of subglottic stenosis. They are generally thought to have a low risk profile for development of systemic side effects. Here, we present a case of a 55 year old woman who developed symptoms of Cushing syndrome after receiving SILSI, including weight gain, striae, dorsal hump and alopecia. This case illustrates that despite the localized nature of SILSI, there is still a risk of developing systemic effects as a result of the treatment. Laryngoscope, 132:942-943, 2022.

Down-Regulation of a Profibrotic Transforming Growth Factor-ß1/Cellular Communication Network Factor 2/Matrix Metalloprotease 9 Axis by Triamcinolone Improves Idiopathic Subglottic Stenosis.

Idiopathic subglottic stenosis (iSGS) is a progressive fibrotic disease characterized by life-threatening airway narrowing. Although the molecular underpinnings are unknown, previous reports showing that subglottic serial intralesional steroid injections (SILSIs) improve clinical outcomes suggest a steroid-sensitive pathway in iSGS. Herein, a prospective study was conducted to determine the changes in profibrotic markers during SILSI to identify steroid-sensitive profibrotic drivers. Seven newly diagnosed patients with iSGS were recruited for SILSI. Subglottic biopsies before and after SILSI treatments were evaluated for histologic and molecular markers by confocal microscopy and RT-qPCR. At baseline, iSGS subglottises contained abundant vimentin-positive/α-smooth muscle actin-negative fibroblasts, intermingled with a matrix of fibronectin and types I and VI collagen. Transforming growth factor (TGF)-ß1 was up-regulated primarily in glandular epithelium. Cellular communication network factor 2 (CCN2) was mainly up-regulated in stromal fibroblasts surrounding TGF-ß1-positive glandular structures. SILSI improved iSGS by reducing fibroblast infiltration and increasing matrix remodeling. Mechanistically, SILSI counteracted the effects of TGF-ß1 by inducing matrix metalloprotease 9 (MMP9) expression while repressing CCN2 expression, without affecting TGFß1 levels. Treatment of primary iSGS-derived fibroblasts with TGF-ß1 recapitulated aspects of the disease in vivo, demonstrating that the induction in CCN2 and repression of MMP9 are caused by changes in histone acetylation induced by TGF-ß1. Triamcinolone counteracted the coregulation of these genes by impairing SMAD2/3 binding to promoter regions, and not through histone acetylation. In conclusion, this study shows that SILSI counteracts a dysregulated TGF-ß1/CCN2/MMP9 axis involved in iSGS development.

Glutamine Inhibition Reduces Iatrogenic Laryngotracheal Stenosis.

OBJECTIVE/HYPOTHESIS: Glutamine inhibition has been demonstrated an antifibrotic effect in iatrogenic laryngotracheal stenosis (iLTS) scar fibroblasts in vitro. We hypothesize that broadly active glutamine antagonist, DON will reduce collagen formation and fibrosis-associated gene expression in iLTS mice. STUDY DESIGN: Prospective controlled animal study. METHODS: iLTS in mice were induced by chemomechanical injury of the trachea using a bleomycin-coated wire brush. PBS or DON (1.3 mg/kg) were administered by intraperitoneal injection (i.p.) every other day. Laryngotracheal complexes were harvested at days 7 and 14 after the initiation of DON treatment for the measurement of lamina propria thickness, trichrome stain, immunofluorescence staining of collagen 1, and fibrosis-associated gene expression. RESULTS: The study demonstrated that DON treatment reduced lamina propria thickness (P = .025) and collagen formation in trichrome stain and immunofluorescence staining of collagen 1. In addition, DON decreased fibrosis-associated gene expression in iLTS mice. At day 7, DON inhibited Col1a1 (P < .0001), Col3a1 (P = .0046), Col5a1 (P < .0001), and Tgfß (P = .023) expression. At day 14, DON reduced Co1a1 (P = .0076) and Tgfß (P = .023) expression. CONCLUSIONS: Broadly active glutamine antagonist, DON, significantly reduces fibrosis in iLTS mice. These results suggest that the concept of glutamine inhibition may be a therapeutic option to reduce fibrosis in the laryngotracheal stenosis. LEVEL OF EVIDENCE: N/A Laryngoscope, 131:E2125-E2130, 2021.

Voice-Related Quality of Life in Idiopathic Subglottic Stenosis: Effect of Serial Intralesional Steroid Injections.

OBJECTIVES: Serial intralesional steroid injection (SILSI) is an emerging treatment for idiopathic subglottic stenosis (ISGS), providing improvement in both subjective symptoms and objective airflow parameters. Little is known about how this airway remodeling affects the voice. This project analyzes subjective voice changes after SILSI and correlates these with airflow parameters. METHODS: An ISGS database containing voice-related quality of life (V-RQOL) and spirometry (peak expiratory flow percentage [%PEF]) was retrospectively queried. Included were ISGS patients from 2009 to 2019 who had at least one SILSI treatment. Encounters without complete data were excluded. Differences between preprocedure and postprocedure metrics were calculated. Correlations and nonparametric bivariate analysis were performed. RESULTS: Six hundred and seventeen steroid injections were performed in 55 patients, with an average of 3.5 years of follow-up. The average V-RQOL for all patient encounters, both pre- and postprocedure, showed little subjective dysphonia (83.5 of 100, 95% confidence interval [CI] 81.6 to 85.4). Considering SILSI-only treatments, there were 143 encounters with full data; of these, V-RQOL improved in 70 (49.0%), did not change in 40 (28.0%), and worsened in 33 (23.0%). Average V-RQOL improvement for the entire cohort was 1.9 points (95% CI: 0.7 to 3.2), which was small but significant (P = .0003). Across all data, there was a weak but significant correlation between PEF% and V-RQOL (ρ = 0.22, P = .0043). CONCLUSION: SILSI was associated with improvement in subjective voice ratings in about half of patients, and the improvement correlated with improved airflow measurements. This research adds to the growing body of data regarding SILSI and suggests that further work on functional changes to the larynx with airway remodeling is imperative. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:366-369, 2021.

Sirolimus use in patients with subglottic stenosis in the context of granulomatosis with polyangiitis (GPA), suspected GPA, and immunoglobulin G4-related disease.

Objective: Subglottic stenosis (SGS) is a severe, life-threatening disease found in immune-mediated diseases such as granulomatosis with polyangiitis (GPA) and in rare cases of immunoglobulin G4 (IgG4)-related disease. It can result in persistent airway compromise due to the fibrotic response following inflammation. Standard management involves repeated endoscopic interventions to dilate the airway, and tracheostomy is occasionally required. In addition, immunosuppression remains a cornerstone of therapy aimed at controlling the underlying inflammatory disease; however, cumulative dosing leads to significant adverse effects. We present five cases of predominantly anti-neutrophil cytoplasmic antibody-negative GPA and a case of IgG4-related disease with SGS, in whom we evaluated the long-term utility of sirolimus, which has beneficial anti-proliferative and fibrotic effects, in the management of their disease. Method: We conducted a retrospective review of a cohort of patients with SGS at a tertiary vasculitis unit. These patients were treated with sirolimus, in addition to conventional medical and endoscopic treatment. Clinical symptoms, frequency and time to endoscopic intervention pre- and post-treatment, additional rescue therapy, and any adverse effects were recorded and analysed. Results: Six patients were treated with sirolimus and followed for up to 9 years; two discontinued the drug owing to adverse effects, early on. In the remaining four patients, glucocorticoids were withdrawn, and the frequency of endoscopic intervention was reduced. One patient on sirolimus required rituximab therapy for disease flare. Conclusion: Sirolimus may be a therapeutic option for some patients with severe SGS, allowing steroid withdrawal and resulting in a positive adverse effect profile.

Orally Inhaled Drug Particle Transport in Computerized Models of Laryngotracheal Stenosis.

OBJECTIVE: Adjuvant management for laryngotracheal stenosis (LTS) may involve inhaled corticosteroids, but metered dose inhalers are designed for pulmonary drug delivery. Comprehensive analyses of drug particle deposition efficiency for orally inhaled corticosteroids in the stenosis of LTS subjects are lacking. STUDY DESIGN: Descriptive research. SETTING: Academic medical center. METHODS: Anatomically realistic 3-dimensional reconstructions of the upper airway were created from computed tomography images of 4 LTS subjects-2 subglottic stenosis and 2 tracheal stenosis subjects. Computational fluid dynamics modeling was used to simulate airflow and drug particle transport in each airway. Three inhalation pressures were simulated, 10 Pa, 25 Pa, and 40 Pa. Drug particle transport was simulated for 100 to 950 nanoparticles and 1 to 50 micron-particles. Particles were released into the airway to mimic varying inhaler conditions with and without a spacer chamber. RESULTS: Based on smallest to largest cross-sectional area ratio, the laryngotracheal stenotic segment shrunk by 57% and 47%, respectively, for subglottic stenosis models and by 53% for both tracheal stenosis models. Airflow resistance at the stenotic segment was lower in subglottic stenosis models than in tracheal stenosis models: 0.001 to 0.011 Pa.s/mL vs 0.024 to 0.082 Pa.s/mL. Drug depositions for micron-particles and nanoparticles at stenosis were 0.06% to 2.48% and 0.10% to 2.60% for subglottic stenosis and tracheal stenosis models, respectively. Particle sizes with highest stenotic deposition were 6 to 20 µm for subglottic stenosis models and 1 to 10 µm for tracheal stenosis models. CONCLUSION: This study suggests that at most, 2.60% of inhaled drug particles deposit at the stenosis. Particle size ranges with highest stenotic deposition may not represent typical sizes emitted by inhalers.

Assessment of side effects after serial intralesional steroid injections for idiopathic subglottic stenosis.

PURPOSE: To assess the incidence and severity of 12 systemic side effects of serial intralesional steroid injections (SILSI) in patients with idiopathic subglottic stenosis (iSGS). METHODS: This retrospective study included patients with iSGS who underwent SILSI with Triamcinolone 40 mg/dL. After SILSI, the patients were asked to answer 12 questions regarding frequently encountered systemic side effects of steroids. Each answer was rated as mild, moderate, or severe. Descriptive statistics were used to analyze and present the findings. RESULTS: The study included 49 patients (42 female and 7 male) with a mean age of 59.1 years (range 21-83 years). Post-SILSI treatment, 27 (55%) reported experiencing side effects while 22 (45%) patients reported no side effects. The most frequent side effect reported in women of reproductive age (n: 8) was menstrual irregularities (3/8, 37%). Other frequently reported side effects were feeling joyful and sleeping difficulties, each reported by 30% of the patients. All side effects resolved after the completion of SILSI. CONCLUSIONS: SILSI can be administered with minimal tolerable side effects. Clinicians should make their patients aware of the most frequent side effects. Special attention should be given to women of reproductive age to inform them of the possibility of menstrual irregularities during SILSI.

Inyección intralesional de corticoide como tratamiento para la estenosis subglótica idiopática / Intralesional corticosteroid injection for treatment of idiopathic subglottic stenosis

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An Adolescent With Progressive Shortness of Breath.

Shortness of breath and wheezing are common presenting signs for children in the emergency department. In adolescence, it is often due to asthma or lower respiratory tract infections. We present a rare pediatric case of an adolescent with biphasic stridor and progressive exercise-induced shortness of breath who was found to have severe idiopathic subglottic stenosis.

Inhibition of glutaminase to reverse fibrosis in iatrogenic laryngotracheal stenosis.

OBJECTIVES/HYPOTHESIS: Glutamine metabolism is a critical energy source for iatrogenic laryngotracheal stenosis (iLTS) scar fibroblasts, and glutaminase (GLS) is an essential enzyme converting glutamine to glutamate. We hypothesize that the GLS-specific inhibitor BPTES will block glutaminolysis and reduce iLTS scar fibroblast proliferation, collagen deposition, and fibroblast metabolism in vitro. STUDY DESIGN: Test-tube Lab Research. METHODS: Immunohistochemistry of a cricotracheal resection (n = 1) and a normal airway specimen (n = 1) were assessed for GLS expression. GLS expression was assessed in brush biopsies of subglottic/tracheal fibrosis and normal airway from patients with iLTS (n = 6). Fibroblasts were isolated and cultured from biopsies of subglottic/tracheal fibrosis (n = 6). Fibroblast were treated with BPTES and BPTES + dimethyl α-ketoglutarate (DMK), an analogue of the downstream product of GLS. Fibroblast proliferation, gene expression, protein production, and metabolism were assessed in all treatment conditions and compared to control. RESULTS: GLS was overexpressed in brush biopsies of iLTS scar specimens (P = .029) compared to normal controls. In vitro, BPTES inhibited iLTS scar fibroblast proliferation (P = .007), collagen I (Col I) (P < .0001), collagen III (P = .004), and α-smooth muscle actin (P = .0025) gene expression and protein production (P = .031). Metabolic analysis demonstrated that BPTES reduced glycolytic reserve (P = .007) but had no effects on mitochondrial oxidative phosphorylation. DMK rescued BPTES inhibition of Col I gene expression (P = .0018) and protein production (P = .021). CONCLUSIONS: GLS is overexpressed in iLTS scar. Blockage of GLS with BPTES significantly inhibits iLTS scar fibroblasts proliferation and function, demonstrating a critical role for GLS in iLTS. Targeting GLS to inhibit glutaminolysis may be a successful strategy to reverse scar formation in the airway. LEVEL OF EVIDENCE: NA Laryngoscope, 2020.