Objectives
Retrograde cricopharyngeal dysfunction (RCPD) is a newly described condition resulting from failure of cricopharyngeal sphincter relaxation during periods of esophageal distension that ...results in the inability to burp. Patients' perspectives on symptom experiences, barriers to care, and treatment benefits were investigated.
Study Design
Qualitative semi‐structured interviews were conducted with patients diagnosed with RCPD who had been treated with botulinum toxin injection into the cricopharyngeus muscle. Interview questions centered on their experience living with RCPD. Conventional content analysis was performed on interview transcripts.
Results
Thematic saturation was reached with 13 participants. All participants were diagnosed with RCPD by an otolaryngologist and underwent botulinum toxin injection into the cricopharyngeus muscle with or without dilation of the upper esophageal sphincter in the operating room. Participants described having no memories of ever being able to burp, and all started experiencing RCPD symptoms during adolescence. Patients with RCPD experienced increased social isolation, lost productivity, and worsened mental health. Unanimously, participants first learned about RCPD on social media. All patients were seen by physicians in non‐otolaryngology specialties regarding their symptoms prior to learning about their RCPD diagnosis and undergoing treatment by an otolaryngologist. Dilation and chemodenervation resulted in complete resolution of RCPD symptoms for 84.6% of participants. Participants emphasized a desire for more health providers to learn about RCPD and the impact it has on quality‐of‐life.
Conclusion(s)
The lived experience of patients with RCPD significantly impacts quality of life and is often met with diagnostic barriers in the medical community. Although social media plays a significant role in increasing awareness of RCPD, physician education about the impact of RCPD is essential to improve diagnosis and treatment.
Level of Evidence
4 Laryngoscope, 134:2136–2143, 2024
Qualitative semi‐structured interviews were conducted with patients diagnosed with retrograde cricopharyngeal dysfunction (RCPD) who had been treated with botulinum toxin injection into the cricopharyngeus muscle. The lived experience of patients with RCPD significantly impacts quality of life and is often met with diagnostic barriers in the medical community. Although social media plays a significant role in increasing awareness of RCPD, physician education about the impact of RCPD is essential to improve diagnosis and treatment.
Abstract Background context A persistent challenge in spine surgery is improving screw fixation in patients with poor bone quality. Augmenting pedicle screw fixation with cement appears to be a ...promising approach. Purpose The purpose of this study was to survey the literature and assess the previous biomechanical studies on pedicle screw augmentation with cement to provide in-depth discussions of the biomechanical benefits of multiple parameters in screw augmentation. Study design/Setting This is a systematic literature review. Methods A search of Medline was performed, combining search terms of pedicle screw, augmentation, vertebroplasty, kyphoplasty, polymethylmethacrylate, calcium phosphate, or calcium sulfate. The retrieved articles and their references were reviewed, and articles dealing with biomechanical testing were included in this article. Results Polymethylmethacrylate is an effective material for enhancing pedicle screw fixation in both osteoporosis and revision spine surgery models. Several other calcium ceramics also appear promising, although further work is needed in material development. Although fenestrated screw delivery appears to have some benefits, it results in similar screw fixation to prefilling the cement with a solid screw. Some differences in screw biomechanics were noted with varying cement volume and curing time, and some benefits from a kyphoplasty approach over a vertebroplasty approach have been noted. Additionally, in cadaveric models, cemented-augmented screws were able to be removed, albeit at higher extraction torques, without catastrophic damage to the vertebral body. However, there is a risk of cement extravasation leading to potentially neurological or cardiovascular complications with cement use. A major limitation of these reviewed studies is that biomechanical tests were generally performed at screw implantation or after a limited cyclic loading cycle; thus, the results may not be entirely clinically applicable. This is particularly true in the case of the bioactive calcium ceramics, as these biomechanical studies would not have measured the effects of osseointegration. Conclusions Polymethylmethacrylate and various calcium ceramics appear promising for the augmentation of pedicle screw fixation biomechanically in both osteoporosis and revision spine surgery models. Further translational studies should be performed, and the results summarized in this review will need to be correlated with the clinical outcomes.
Objectives
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
Objective
Idiopathic subglottic stenosis (iSGS) is a rare disease, causing life‐threatening dyspnea secondary to scarring. Perhaps because it is rarely encountered, there is often a delay in ...diagnosing iSGS. The objective of this study is to characterize diagnostic delay of iSGS, factors that prolong delay, and its impact on iSGS patients.
Study Design
Retrospective chart review.
Methods
A retrospective chart review of 124 iSGS patients was performed. Times of symptom onset, presentation to otolaryngologist, diagnosis, imaging, pulmonary function testing (PFTs), surgeries, emergency department (ED) visits, and hospitalizations were recorded and univariate analyses were used to identify risk factors for delay.
Results
The median total time to diagnosis from symptom onset was 24.5 months, with time to first presentation of 6.3 months and healthcare delay of 17.8 months. 54.8% of patients were diagnosed with asthma. Earlier presentation to otolaryngologist was associated with shorter healthcare delay and total time to diagnosis (rho = 0.75, rho = 0.99, P < .0001). Earlier CT imaging was correlated to shorter healthcare delay (rho = 0.84, P < .0001) and total time to diagnosis (rho = 0.74, P < .001), while earlier PFTs were correlated to shorter total time to diagnosis alone (rho = 0.71, P = .01). During evaluation, 10.5% (n = 17/124) of patients had ED visits and 13.7% (n = 13/124) patients were hospitalized. Before diagnosis, 7% (9/124) of patients underwent surgeries (including 3% (n = 4) undergoing tracheostomy) and 8% (n = 10) of patients required unplanned urgent endoscopic surgery that may have been avoided with earlier diagnosis.
Conclusion
iSGS diagnosis is frequently delayed, resulting in additional surgeries (including tracheostomy), ED visits, and hospitalizations. Further, patients' symptoms are commonly attributed to asthma. Earlier otolaryngologist evaluation, PFTs, and CT imaging may expedite iSGS diagnosis.
Level of Evidence
4 Laryngoscope, 132:413–418, 2022
Objective(s)
Tracheostomy‐associated granulation tissue is a common, recurrent problem occurring secondary to chronic mucosal irritation. Although granulation tissue is composed of predominantly ...innate immune cells, the phenotype of monocytes and macrophages in tracheostomy‐associated granulation tissue is unknown. This study aims to define the myeloid cell population in granulation tissue secondary to tracheostomy.
Methods
Granulation tissue biopsies were obtained from 8 patients with tracheostomy secondary to laryngotracheal stenosis. Cell type analysis was performed by flow cytometry and gene expression was measured by quantitative real‐time polymerase chain reaction. These methods and immunohistochemistry were used to define the monocyte/macrophage population in granulation tissue and were compared to tracheal autopsy control specimens.
Results
Flow cytometry demonstrated macrophages (CD45+CD11b+) and monocytes (CD45+FSClowSSClow) represent 23.2 ± 6% of the granulation tissue cell population. The M2 phenotype (CD206) is present in 77 ± 11% of the macrophage population and increased compared to the M1 phenotype (p = 0.012). Classical monocytes (CD45+CD14highCD16low) were increased in granulation tissue compared to controls (61.2 ± 7% and 30 ± 8.5%, p = 0.038). Eighty‐five percent of macrophages expressed pro‐inflammatory S100A8/A9 and 36 ± 4% of macrophages co‐localized CD169, associated with tissue‐resident macrophages. M2 gene expression (Arg1/CD206) was increased in granulation tissue (3.7 ± 0.4, p = 0.035 and 3.5 ± 0.5, p = 0.047) whereas M1 gene expression (CD80/CD86) was similar to controls (p = 0.64, p = 0.3). Immunohistochemistry of granulation tissue demonstrated increased cells co‐localizing CD11b and CD206.
Conclusions
M2 macrophages are the dominant macrophage phenotype in tracheostomy‐associated granulation tissue. The role of this cell type in promoting ongoing inflammation warrants future investigation to identify potential treatments for granulation tissue secondary to tracheostomy.
Level of Evidence
3 Laryngoscope, 133:2346–2356, 2023
In patients with indwelling tracheostomy, granulation tissue is a common, recurrent problem that may lead to multiple surgeries, difficulties with decannulation, and even wound contracture leading to stenosis at the site of prosthesis. This study demonstrates that alternatively activated M2 macrophages are increased in airway granulation tissue as determined by gene expression analysis of canonical biomarkers and cell surface antigens assessed by flow cytometry and immunohistochemistry. The monocyte cell populations associated with granulation tissue are predominantly classical subtype and the majority of macrophages were positive for pro‐inflammatory marker S100A8/A9 with 36% of macrophages co‐localizing the biomarker CD169+, highlighting these cell population as potential therapeutic targets for airway granulation tissue.
Objectives
To aim of the study was to characterize the molecular profile and functional phenotype of idiopathic subglottic stenosis (iSGS)‐scar epithelium.
Methods
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).
Results
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.
Conclusion
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.
Level of Evidence
NA Laryngoscope, 134:374–381, 2024
This study explored the molecular and functional phenotype of idiopathic subglottic stenosis epithelium via transcriptomics and functional assays that assessed the resistance, paracellular permeability, and ciliary function of epithelium, demonstrating a dysfunctional barrier.
Objectives
Idiopathic subglottic stenosis (iSGS) is characterized by progressive fibrosis and subglottic luminal narrowing. Currently, immune characterization has focused on T‐cells; however, ...macrophages remain largely unexplored. The goals of this study are to characterize the transcriptome of iSGS macrophages and the fibrogenic nature of identifed biomarkers.
Study Design
Bioinformatics and in vitro.
Methods
Human tracheal biopsies from iSGS scar (n = 4), and matched non‐scar (n = 4) regions were analyzed using single‐cell RNA‐seq (scRNA‐seq). Immunofluorescence (IF) was performed on rapidly processed autopsies (RPA) and iSGS tracheal resections (n = 4) to co‐localize S100A8/9 and CD11b. Collagen gene/protein expression was assessed in iSGS fibroblasts (n = 4) treated with protein S100A8/9 (1000 ng/ml). Macrophages were subclustered to identify distinct subpopulations.
Results
scRNA‐seq analysis revealed S100A8/S100A9 (fold change (FC) = 4.1/1.88, p < 0.001) as top differentially expressed genes in iSGS macrophages. IF exhibited increased CD11b+/S100A8/9+ cells in tracheal samples of iSGS versus RPA (26.75% ± 7.08 vs. 0.594% ± 0.974, n = 4, p = 0.029). iSGS fibroblasts treated with S100A8/9 demonstrated increased gene expression of COL1A1 (FC = 2.30 ± 0.45, p = 0.03, n = 4) and COL3A1 (FC = 2.44 ± 0.40, p = 0.03, n = 4). COL1A1 protein assays revealed an increase in the experimental group, albeit not significant, (p = 0.12, n = 4). Finally, macrophage sub clustering revealed one subpopulation as a predominant source of S100A8/S100A9 expression (FC = 7.94/5.47, p < 0.001).
Conclusions
S100A8/9 is a key biomarker in iSGS macrophages. Although S100A8/9 demonstrates profibrotic nature in vitro, the role of S100A8/9+ macrophages in vivo warrants further investigation.
Level of Evidence
NA Laryngoscope, 133:2308–2316, 2023
This study describes the transcriptional profile of macrophages in iSGS tissue using single‐cell RNA sequencing. In addition, it explores the in vitro effects of top‐identified markers.
During respiratory disease outbreaks such as the COVID-19 pandemic, aerosol-generating procedures, including tracheostomy, are associated with the risk of viral transmission to health care workers.
...To quantify particle aerosolization during tracheostomy surgery and tracheostomy care and to evaluate interventions that minimize the risk of viral particle exposure.
This comparative effectiveness study was conducted from August 2020 to January 2021 at a tertiary care academic institution. Aerosol generation was measured in real time with an optical particle counter during simulated (manikin) tracheostomy surgical and clinical conditions, including cough, airway nebulization, open suctioning, and electrocautery. Aerosol sampling was also performed during in vivo swine tracheostomy procedures (n = 4), with or without electrocautery. Fluorescent dye was used to visualize cough spread onto the surgical field during swine tracheostomy. Finally, 6 tracheostomy coverings were compared with no tracheostomy covering to quantify reduction in particle aerosolization.
Respirable aerosolized particle concentration.
Cough, airway humidification, open suctioning, and electrocautery produced aerosol particles substantially above baseline. Compared with uncovered tracheostomy, decreased aerosolization was found with the use of tracheostomy coverings, including a cotton mask (73.8% (95% CI, 63.0%-84.5%; d = 3.8), polyester gaiter 79.5% 95% CI, 68.7%-90.3%; d = 7.2), humidification mask (82.8% 95% CI, 72.0%-93.7%; d = 8.6), heat moisture exchanger (HME) (91.0% 95% CI, 80.2%-101.7%; d = 19.0), and surgical mask (89.9% 95% CI, 79.3%-100.6%; d = 12.8). Simultaneous use of a surgical mask and HME decreased the particle concentration compared with either the HME (95% CI, 1.6%-12.3%; Cohen d = 1.2) or surgical mask (95% CI, 2.7%-13.2%; d = 1.9) used independently. Procedures performed with electrocautery increased total aerosolized particles by 1500 particles/m3 per 5-second interval (95% CI, 1380-1610 particles/m3 per 5-second interval; d = 1.8).
The findings of this laboratory and animal comparative effectiveness study indicate that tracheostomy surgery and tracheostomy care are associated with significant aerosol generation, putting health care workers at risk for viral transmission of airborne diseases. Combined HME and surgical mask coverage of the tracheostomy was associated with decreased aerosolization, thereby reducing the risk of viral transmission to health care workers.
Objective
Characterize and quantify epithelium in multiple etiologies of laryngotracheal stenosis (LTS) to better understand its role in pathogenesis.
Study Design
Controlled in vitro cohort study.
...Methods
Endoscopic brush biopsy samples of both normal (non‐scar) and scar were obtained in four patients with idiopathic subglottic stenosis (iSGS) and four patients with iatrogenic LTS (iLTS). mRNA expression of basal, ciliary, and secretory cell markers were evaluated using quantitative PCR. Cricotracheal resection tissue samples (n = 5 per group) were also collected, analyzed using quantitative immunohistochemistry, and compared with rapid autopsy tracheal samples.
Results
Both iSGS and iLTS‐scar epithelium had reduced epithelial thickness compared with non‐scar control epithelium (P = .0009 and P = .0011, respectively). Basal cell gene and protein expression for cytokeratin 14 was increased in iSGS‐scar epithelium compared with iLTS or controls. Immunohistochemical expression of ciliary tubulin alpha 1, but not gene expression, was reduced in both iSGS and iLTS‐scar epithelium compared with controls (P = .0184 and P = .0125, respectively). Both iSGS and iLTS‐scar had reductions in Mucin 5AC gene expression (P = .0007 and P = .0035, respectively), an epithelial goblet cell marker, with reductions in secretory cells histologically (P < .0001).
Conclusions
Compared with non‐scar epithelium, the epithelium within iSGS and iLTS is morphologically abnormal. Although both iSGS and iLTS have reduced epithelial thickness, ciliary cells, and secretory cells, only iSGS had significant increases in pathological basal cell expression. These data suggest that the epithelium in iSGS and iLTS play a common role in the pathogenesis of fibrosis in these two etiologies of laryngotracheal stenosis.
Setting
Tertiary referral center (2017–2020).
Level of Evidence
NA Laryngoscope, 132:2194–2201, 2022
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