Primary tracheal adenoid cystic carcinoma: A case report and analysis of the tumor immune microenvironment using single cell RNA sequencing.

BACKGROUND: Tracheal adenoid cystic carcinoma (ACC) is a slow growing yet aggressive malignancy with high rates of local recurrence as well as distant metastasis. Tracheal ACC exhibit a low mutation burden along with high mutational diversity, and generally do not respond well to chemotherapeutics. METHODS: We present a rare case of primary tracheal ACC initially presenting with nonspecific cervicalgia and globus sensation that was ultimately treated with tracheal resection followed by chemoradiation. Immune profiling of intratumoral T-cell receptor (TCR) repertoire was subsequently performed using single cell RNA sequencing (scRNAseq). RESULTS: We describe a rare case of primary tracheal adenoid cystic carcinoma highlighting several management principles as well as providing new insights into intratumor T cell populations. CONCLUSIONS: Primary tracheal ACC is most commonly treated with surgical resection followed by adjuvant therapy. Further characterization of the tumor immune microenvironment is necessary to better understand ACC disease biology and to identify potential therapeutic targets.

A Comprehensive Flow Cytometry Panel for Analysis of Idiopathic Subglottic Stenosis.

OBJECTIVE: To present a comprehensive flow cytometry panel for idiopathic subglottic stenosis (iSGS). STUDY DESIGN: Controlled ex vivo cohort study. SETTING: Tertiary care academic hospital in a metropolitan area. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

#OtoTwitter: The Top 75 Twitter Influencers in Otolaryngology and Association With Academic Impact.

OBJECTIVES: Social media has enabled discussion of relevant topics within otolaryngology. With increasing academic discourse occurring on virtual platforms, it is important to examine who is influencing these discussions. This study thus aims to: (1) identify the top Twitter influencers in otolaryngology and (2) assess the relationship between Twitter influence and academic impact. STUDY DESIGN: Cross-sectional analysis. SETTING: Twitter. METHODS: The Right Relevance program was used to identify and rank the top 75 Twitter influencers, excluding organizations, according to the search terms "otolaryngology," "head and neck surgery," "ear nose throat," "rhinology," "head and neck," "laryngology," "facial plastics," and "otology." Demographic data and h-index were collected for each influencer. Correlational analyzes were performed to assess the relationships between Twitter rank and geographic location, sex, subspecialty, and h-index. RESULTS: The majority of the top 75 influencers were otolaryngologists (87%), female (68%), and located in the United States (61%). General otolaryngology (n = 20, 31%) was more well-represented than any individual subspecialty including facial plastics (n = 10, 15%), rhinology (n = 10, 15%), and neurotology (n = 9, 14%). There was a significant relationship between Twitter rank and h-index (Spearman ρ value of -0.32; 95% confidence interval: -0.51 to -0.01; P = .006). Twitter rank was not significantly correlated with subspecialty, sex, or geographic location (P > .05). CONCLUSION: The majority of Twitter influencers within otolaryngology were otolaryngologists, female, and located in the United States. Social media influence is positively associated with academic impact among otolaryngologists.

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

OBJECTIVES: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:3260-3266, 2024.

Removal of Metal Tracheal Stent: A Difficult Foreign Body.

INTRODUCTION: With its introduction in 1986, the use of metal tracheal stents gained favor due to relative ease of deployment and reduced risk of stent migration and mucus plugging. However, adverse events associated with metal stenting led the FDA to publish a recommendation against its use for benign airway stenosis in 2005. We present a case which illustrates the difficulty in removal of a metal stent from the airway. CASE REPORT: Our patient is a 47-year-old woman with a history of postintubation tracheal stenosis. She underwent multiple interventions with Thoracic Surgery at an outside facility, including stenting with an Ultraflex expandable metal stent. Her course was complicated by recurrent intraluminal granulation tissue, which led to placement of additional metal stents, as well as a tracheostomy due to obstructive proximal granulation tissue. On presentation at our institution, removal of the stents was recommended due to recurrent tracheitis and proximity of stent fragments to the innominate artery on CT imaging. She underwent direct microlaryngoscopy and bronchoscopy, and stent fragments were removed using a hemostat through the trach stoma. Postoperative imaging has confirmed retained stent fragments, and additional procedures have been required for further removal. DISCUSSION/CONCLUSION: Removal of metal stents from the trachea is challenging for several reasons. Neoepithelization of respiratory mucosa makes identification of fragments difficult. Furthermore, growth of granulation tissue through the metal lattice framework, as well as the stents' tendency to fracture, complicates extraction. This case illustrates the dangers of metal stenting for benign airway stenosis. Laryngoscope, 134:3977-3980, 2024.

A Single Center Description of Adult and Pediatric Endoscopic Posterior Costal Cartilage Grafting.

OBJECTIVE: Posterior glottis impairment alters breathing, voicing, and swallowing. Bilateral vocal fold movement impairment (BVFMI) occurs when the vocal cords are fixed/remain midline. Studies inadequately assessed endoscopic posterior costal cartilage grafting (enPCCG) for BVFMI across broad ages. We aim to assess decannulation and prosthesis free airway in children and adults who have undergone enPCCG. STUDY DESIGN: Retrospective cohort. SETTING: Referral center. METHODS: This study included adults and children who received enPCCG for BVFMI (2010-2018) and were followed for 35 months on average. The main outcome was successful decannulation of patients, or airway improvement in those without tracheostomy. Data on comorbidities, surgical complications, and interventions following surgery were collected. RESULTS: Ten children and 11 adults underwent enPCCG for BVFMI. Eighty-one percent of patients had a tracheostomy at surgery; adults were more likely to have a tracheostomy at surgery (P = 0.035), and to undergo double-staged procedure (P = 0.035) and stent (P = 0.008). Average stent duration was 29.7 days. Overall decannulation rate was 76% (90% for children; 70% for adults). Children were more likely to receive postoperative intensive care unit care (P = 0.004). Adults had mean 4.4 post-enPCCG interventions per patient compared to children's mean 3.91 interventions. The most common interventions were steroid injection (17.6%) and balloon dilation (16%). Preliminary analysis suggests postoperative dysphonia was reported in 66.7% of patients; postoperative dysphagia was rare. CONCLUSION: EnPCCG was more successful at achieving decannulation in children. Adults required additional interventions. A double-staged operation with prolonged stenting is recommended for adult patients. A majority of patients were decannulated at last follow-up.

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.

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. LEVEL OF EVIDENCE: 5 Laryngoscope, 134:865-872, 2024.

Association between Estrogen Exposure and Idiopathic Subglottic Stenosis.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:825-830, 2024.

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

OBJECTIVES: 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. STUDY DESIGN: Ex vivo molecular study of airway scar and healthy mucosa from iSGS patients. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. LEVEL OF EVIDENCE: NA; Basic science Laryngoscope, 133:3506-3511, 2023.

Low Gut Microbial Diversity Augments Estrogen-Driven Pulmonary Fibrosis in Female-Predominant Interstitial Lung Disease.

Although profibrotic cytokines, such as IL-17A and TGF-ß1, have been implicated in the pathogenesis of interstitial lung disease (ILD), the interactions between gut dysbiosis, gonadotrophic hormones and molecular mediators of profibrotic cytokine expression, such as the phosphorylation of STAT3, have not been defined. Here, through chromatin immunoprecipitation sequencing (ChIP-seq) analysis of primary human CD4+ T cells, we show that regions within the STAT3 locus are significantly enriched for binding by the transcription factor estrogen receptor alpha (ERa). Using the murine model of bleomycin-induced pulmonary fibrosis, we found significantly increased regulatory T cells compared to Th17 cells in the female lung. The genetic absence of ESR1 or ovariectomy in mice significantly increased pSTAT3 and IL-17A expression in pulmonary CD4+ T cells, which was reduced after the repletion of female hormones. Remarkably, there was no significant reduction in lung fibrosis under either condition, suggesting that factors outside of ovarian hormones also contribute. An assessment of lung fibrosis among menstruating females in different rearing environments revealed that environments favoring gut dysbiosis augment fibrosis. Furthermore, hormone repletion following ovariectomy further augmented lung fibrosis, suggesting pathologic interactions between gonadal hormones and gut microbiota in relation to lung fibrosis severity. An analysis of female sarcoidosis patients revealed a significant reduction in pSTAT3 and IL-17A levels and a concomitant increase in TGF-ß1 levels in CD4+ T cells compared to male sarcoidosis patients. These studies reveal that estrogen is profibrotic in females and that gut dysbiosis in menstruating females augments lung fibrosis severity, supporting a critical interaction between gonadal hormones and gut flora in lung fibrosis pathogenesis.

Human Leukocyte Antigen Genotyping of Idiopathic Subglottic Stenosis.

OBJECTIVE: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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. LEVEL OF EVIDENCE: NA, basic science Laryngoscope, 133:2533-2539, 2023.

Low Gut Microbial Diversity Augments Estrogen-driven Pulmonary Fibrosis in Female-Predominant Interstitial Lung Disease.

Although profibrotic cytokines such as IL-17A and TGF-ß1 have been implicated in interstitial lung disease (ILD) pathogenesis, interactions between gut dysbiosis, gonadotrophic hormones and molecular mediators of profibrotic cytokine expression, such as phosphorylation of STAT3, have not been defined. Here we show by chromatin immunoprecipitation sequencing (ChIP-seq) analysis of primary human CD4+ T cells that regions within the STAT3 locus are significantly enriched for binding by the transcription factor estrogen receptor alpha (ERa). Using the murine model of bleomycin-induced pulmonary fibrosis, we found significantly increased regulatory T cells compared to Th17 cells in the female lung. Genetic absence of ESR1 or ovariectomy in mice significantly increased pSTAT3 and IL-17A expression in pulmonary CD4+ T cells, which was reduced after repletion of female hormones. Remarkably, there was no significant reduction in lung fibrosis under either condition, suggesting that factors outside of ovarian hormones also contribute. Assessment of lung fibrosis among menstruating females in different rearing environments revealed that environments favoring gut dysbiosis augment fibrosis. Furthermore, hormone repletion following ovariectomy further augmented lung fibrosis, suggesting pathologic interactions between gonadal hormones and gut microbiota on lung fibrosis severity. Analysis in female sarcoidosis patients revealed a significant reduction in pSTAT3 and IL-17A levels and a concomitant increase in TGF-ß1 levels in CD4+ T cells, compared to male sarcoidosis patients. These studies reveal that estrogen is profibrotic in females and that gut dysbiosis in menstruating females augments lung fibrosis severity, supporting a critical interaction between gonadal hormones and gut flora in lung fibrosis pathogenesis.

Association of Educational Intervention With Knowledge of Airway Injury After Endotracheal Intubation and Tube Size Selection.

In this nonrandomized controlled trial, an educational intervention for emergency medicine residents was developed to increase knowledge of airway injury following prolonged intubation and reduce the proportion of large-for-height endotracheal tubes placed in the emergency department.

Myeloid Phenotypes in Tracheostomy-Associated Granulation Tissue.

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+FSClow SSClow ) 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+CD14high CD16low ) 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.

Characterizing the Macrophage Population in Patients With Idiopathic Subglottic Stenosis.

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.

Endotracheal Tube Size in Critically Ill Patients.

Importance: Many patients who survive critical illness are left with laryngeal functional impairment from endotracheal intubation that permanently limits their recovery and quality of life. Although the risk for laryngeal injury increases with larger endotracheal tube sizes, there are no data delineating the association of smaller endotracheal tube sizes with survival or acute recovery from critical illness. Objective: To determine if smaller endotracheal tubes are noninferior to larger endotracheal tubes with respect to critical illness outcomes. Design, Setting, and Participants: This propensity score-matched retrospective cohort study included all adult patients who underwent endotracheal intubation in the emergency department or intensive care unit and received mechanical ventilation for at least 12 hours from June 2020 to November 2020 at a single tertiary referral academic medical center. Exposures: Endotracheal intubation. Main Outcomes and Measures: Propensity score-matched analyses were performed with respect to the primary end point of 30-day all-cause in-hospital survival as well as the secondary end points of duration of invasive mechanical ventilation, length of hospital stay, mean peak inspiratory pressure, 30-day readmission, need for reintubation, and need for tracheostomy or gastrostomy tube placement. Results: Overall, 523 participants (64%) were men and 291 (36%) were women. Of these, 814 patients were categorized into 3 endotracheal tube groups: small for height (n = 182), appropriate for height (n = 408), and large for height (n = 224). There was not a significant difference in 30-day all-cause in-hospital survival between groups ([HR, 1.1; 95% CI, 0.7-1.7] for small vs appropriate; [HR, 1.1; 95% CI, 0.7-1.6] for large vs appropriate). Patients with small-for-height endotracheal tubes had longer intubation durations (mean difference, 32.5 hrs [95% CI, 6.4-58.6 hrs]) compared with patients with appropriate-for-height tubes. Conclusions and Relevance: Despite differences in intubation duration, the results of this cohort study suggest that smaller endotracheal tube sizes are not associated with impaired survival or recovery from critical illness. They support future prospective exploration of the association of smaller endotracheal tube sizes with recovery from critical illness.