Sebaceous Carcinoma of the Middle Ear: A Case Report.

Here we present the first case of sebaceous carcinoma of the middle ear. We discuss the treatment course and post treatment results after 11 years of follow up. We further summarize the available literature of sebaceous carcinoma of the temporal bone, which prior to this case was exclusively limited to the external auditory canal. Laryngoscope, 2024.

Not just snot: Local inflammatory profiles in patients with aspirin-exacerbated respiratory disease differ from patients with aspirin-tolerant chronic rhinosinusitis.

KEY POINTS: IL-5, CCL2, and CXCL8 in sinus mucous are higher in patients with AERD relative to aspirin-tolerant patients with CRS These mediators are pleiotropic, leading to widescale inflammatory processes contributing to AERD AERD is not only a T2 disease but heterogeneous: this may explain the refractory nature of AERD.

Local cytokine levels associate with SNOT-22 and UPSIT scores in chronic rhinosinusitis.

KEY POINTS: Elevated IL-5, IL-13, IL-33, and CCL2 correlate with lower UPSIT scores in CRS and AERD patients. Elevated IL-5, IL-13, TNF-α, CCL2, and CXCL-8 correlate with higher SNOT-22 scores in CRS and AERD patients.

Increased epithelial mTORC1 activity in chronic rhinosinusitis with nasal polyps.

Background: The airway epithelium plays a central role in the pathogenesis of chronic respiratory diseases such as asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), but the mechanisms by which airway epithelial cells (EpCs) maintain inflammation are poorly understood. Objective: We hypothesized that transcriptomic assessment of sorted airway EpCs across the spectrum of differentiation would allow us to define mechanisms by which EpCs perpetuate airway inflammation. Methods: Ethmoid sinus EpCs from adult patients with CRS were sorted into 3 subsets, bulk RNA sequenced, and analyzed for differentially expressed genes and pathways. Single cell RNA-seq (scRNA-seq) datasets from eosinophilic and non-eosinophilic CRSwNP and bulk RNA-seq of EpCs from mild/moderate and severe asthma were assessed. Immunofluorescent staining and ex vivo functional analysis of sinus EpCs were used to validate our findings. Results: Analysis within and across purified EpC subsets revealed an enrichment in glycolytic programming in CRSwNP vs CRSsNP. Correlation analysis identified mammalian target of rapamycin complex 1 (mTORC1) as a potential regulator of the glycolytic program and identified EpC expression of cytokines and wound healing genes as potential sequelae. mTORC1 activity was upregulated in CRSwNP, and ex vivo inhibition demonstrated that mTOR is critical for EpC generation of CXCL8, IL-33, and CXCL2. Across patient samples, the degree of glycolytic activity was associated with T2 inflammation in CRSwNP, and with both T2 and non-T2 inflammation in severe asthma. Conclusions: Together, these findings highlight a metabolic axis required to support epithelial generation of cytokines critical to both chronic T2 and non-T2 inflammation in CRSwNP and asthma.

Type 2 inflammation drives an airway basal stem cell program through insulin receptor substrate signaling.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a type 2 (T2) inflammatory disease associated with an increased number of airway basal cells (BCs). Recent studies have identified transcriptionally distinct BCs, but the molecular pathways that support or inhibit human BC proliferation and differentiation are largely unknown. OBJECTIVE: We sought to determine the role of T2 cytokines in regulating airway BCs. METHODS: Single-cell and bulk RNA sequencing of sinus and lung airway epithelial cells was analyzed. Human sinus BCs were stimulated with IL-4 and IL-13 in the presence and absence of inhibitors of IL-4R signaling. Confocal analysis of human sinus tissue and murine airway was performed. Murine BC subsets were sorted for RNA sequencing and functional assays. Fate labeling was performed in a murine model of tracheal injury and regeneration. RESULTS: Two subsets of BCs were found in human and murine respiratory mucosa distinguished by the expression of basal cell adhesion molecule (BCAM). BCAM expression identifies airway stem cells among P63+KRT5+NGFR+ BCs. In the sinonasal mucosa, BCAMhi BCs expressing TSLP, IL33, CCL26, and the canonical BC transcription factor TP63 are increased in patients with CRSwNP. In cultured BCs, IL-4/IL-13 increases the expression of BCAM and TP63 through an insulin receptor substrate-dependent signaling pathway that is increased in CRSwNP. CONCLUSIONS: These findings establish BCAM as a marker of airway stem cells among the BC pool and demonstrate that airway epithelial remodeling in T2 inflammation extends beyond goblet cell metaplasia to the support of a BC stem state poised to perpetuate inflammation.

Nasal administration of anti-CD3 monoclonal antibody modulates effector CD8+ T cell function and induces a regulatory response in T cells in human subjects.

Background: Parenteral anti-CD3 Mab (OKT3) has been used to treat transplant rejection and parental administration of a humanized anti-CD3 Mab (Teplizumab) showed positive effects in diabetes. Nasal administration of anti-CD3 Mab has not been carried out in humans. Nasal anti-CD3 Mab suppresses autoimmune diseases and central nervous system (CNS) inflammation in animal models. We investigated the safety and immune effects of a fully humanized, previously uncharacterized nasal anti-CD3 Mab (Foralumab) in humans and its in vitro stimulatory properties. Methods: In vitro, Foralumab were compared to UCHT1 anti-human CD3 mAb. For human administration, 27 healthy volunteers (9 per group) received nasal Foralumab or placebo at a dose of 10ug, 50ug, or 250ug daily for 5 days. Safety was assessed and immune parameters measured on day 1 (pre-treatment), 7, 14, and 30 by FACS and by scRNAseq. Results: In vitro, Foralumab preferentially induced CD8+ T cell stimulation, reduced CD4+ T cell proliferation and lowered expression of IFNg, IL-17 and TNFa. Foralumab induced LAP, TIGIT, and KLRG1 immune checkpoint molecules on CD8+ and CD4+ T cells in a mechanism independent of CD8 T cells. In vivo, nasal Foralumab did not modulate CD3 from the T cell surface at any dose. Immune effects were primarily observed at the 50ug dose and consisted of reduction of CD8+ effector memory cells, an increase in naive CD8+ and CD4+ T cells, and reduced CD8+ T cell granzyme B and perforin expression. Differentially expressed genes observed by scRNAseq in CD8+ and CD4+ populations promoted survival and were anti-inflammatory. In the CD8+ TEMRA population there was induction of TIGIT, TGFB1 and KIR3DL2, indicative of a regulatory phenotype. In the memory CD4+ population, there was induction of CTLA4, KLRG1, and TGFB whereas there was an induction of TGF-B1 in naïve CD4+ T cells. In monocytes, there was induction of genes (HLA-DP, HLA-DQ) that promote a less inflammatory immune response. No side effects were observed, and no subjects developed human anti-mouse antibodies. Conclusion: These findings demonstrate that nasal Foralumab is safe and immunologically active in humans and presents a new avenue for the treatment of autoimmune and CNS diseases.

Human airway mast cells proliferate and acquire distinct inflammation-driven phenotypes during type 2 inflammation.

Mast cells (MCs) play a pathobiologic role in type 2 (T2) allergic inflammatory diseases of the airway, including asthma and chronic rhinosinusitis with nasal polyposis (CRSwNP). Distinct MC subsets infiltrate the airway mucosa in T2 disease, including subepithelial MCs expressing the proteases tryptase and chymase (MCTC) and epithelial MCs expressing tryptase without chymase (MCT). However, mechanisms underlying MC expansion and the transcriptional programs underlying their heterogeneity are poorly understood. Here, we use flow cytometry and single-cell RNA-sequencing (scRNA-seq) to conduct a comprehensive analysis of human MC hyperplasia in CRSwNP, a T2 cytokine-mediated inflammatory disease. We link discrete cell surface phenotypes to the distinct transcriptomes of CRSwNP MCT and MCTC, which represent polarized ends of a transcriptional gradient of nasal polyp MCs. We find a subepithelial population of CD38highCD117high MCs that is markedly expanded during T2 inflammation. These CD38highCD117high MCs exhibit an intermediate phenotype relative to the expanded MCT and MCTC subsets. CD38highCD117high MCs are distinct from circulating MC progenitors and are enriched for proliferation, which is markedly increased in CRSwNP patients with aspirin-exacerbated respiratory disease, a severe disease subset characterized by increased MC burden and elevated MC activation. We observe that MCs expressing a polyp MCT-like effector program are also found within the lung during fibrotic diseases and asthma, and further identify marked differences between MCTC in nasal polyps and skin. These results indicate that MCs display distinct inflammation-associated effector programs and suggest that in situ MC proliferation is a major component of MC hyperplasia in human T2 inflammation.

The Proposed Usage of Intranasal Steroids and Antihistamines for Otitis Media with Effusion.

PURPOSE OF REVIEW: To examine the role of allergy medications in the treatment of otitis media with effusion (OME), focusing on use of intranasal steroids and antihistamines. RECENT FINDINGS: There has been ongoing controversy regarding the role of allergy in the development of OME. Treatment of OME with medications commonly used for allergic symptomatology has been studied. Proposed treatment options include decongestants, mucolytics, oral steroids, topical steroids, antihistamines, and antibiotics. We begin by evaluating the proposed association between allergy and OME, and then evaluate intranasal steroids and oral antihistamine therapy in the treatment of OME. The role of the adenoid and concurrent nasal symptomatology is also addressed. The preponderance of data suggests that neither intranasal steroids nor antihistamines improve the long-term clearance of isolated OME and are therefore not recommended. However, data are notably limited with regard to improvement rates in OME in patients specifically with concurrent allergy and/or adenoid hypertrophy. Future studies of medications for OME would ideally incorporate study designs controlling for both allergic rhinitis and adenoid hypertrophy, to better understand the impact of these medications on OME in these subgroups of patients.

National Analysis of Risk Factors for Nasal Fractures and Associated Injuries in Trauma.

Nasal fractures account for up to 58% of facial fractures. However, the literature characterizing associated injuries and risk factors for nasal fractures is sparse and is mostly composed of single-center experiences. This study sought to provide a large descriptive analysis and identify associated injuries and risk factors for nasal fractures in trauma using a national database. A retrospective analysis of the National Trauma Data Bank (NTDB) from 2007 to 2015 was performed. Patients ≥18 years of age with nasal fractures were included. A multivariable logistic regression model was used to identify predictors for nasal fracture in trauma. Of 5,494,609 trauma patients in the NTDB, 255,533 (4.6%) had a nasal fracture. Most were male (74.8%) with a mean age of 45.6 years. Blunt trauma accounted for 90.5% of fractures, with motor vehicle accident being the most common mechanism (27.5%). Closed fractures occurred in 93.0% of patients. Concomitant injuries included traumatic brain injury (TBI; 56.9%), malar/maxillary fracture (27.9%), and open wound of the face (38.6%) and nose (9.5%). Of all patients, 10.1% underwent closed or open reductions at index hospitalization. The strongest associated injuries with nasal fracture included open wound of the nose (odds ratio [OR]: 8.71, 95% confidence interval [CI]: 8.49-8.94, p < 0.001), epistaxis (OR: 5.26, 95% CI: 4.59-6.02, p < 0.001), malar/maxillary fracture (OR: 4.38, 95% CI: 4.30-4.45, p < 0.001), and orbital fracture (OR: 3.99, 95% CI: 3.91-4.06, p < 0.001). Nasal fractures are common traumatic injuries with more than 90% occurring by blunt mechanism and over half suffering from a concomitant TBI. The strongest associated injury with nasal fracture is an open wound of the nose.

The Influence of Age on the Relationship Between Allergic Rhinitis and Otitis Media.

PURPOSE OF REVIEW: To examine the relationship between otitis media, allergic rhinitis, and age. RECENT FINDINGS: Otitis media and allergic rhinitis are prevalent conditions with a controversial relationship. Some data suggest that these entities are significantly associated, either through allergic rhinitis inducing Eustachian tube dysfunction or through allergic pathophysiology simultaneously occurring intranasally and in the ear. Other studies, however, have refuted this relationship. For example, treatment with antihistamines does not reliably improve OME, making causation and association challenging to establish. Age may have an effect on the nature of the relationship between allergic rhinitis and otitis media, by impacting both the individual conditions and their association. Epidemiological, immunological, and adenoidal studies have suggested that differences occur with age, and this review encapsulates the related data and publications. We begin by evaluating how allergic rhinitis and otitis media each are affected by age, then evaluate the role that age may have in the relationship between the two conditions. Adult and pediatric literature are evaluated so as to include the full impact of age across patients' lifespan. Age induces changes in immunity, patterns of inflammation, and susceptibility to both allergic rhinitis and otitis media with effusion. Age may also be an effect modifier which impacts the nature of the relationship between these two conditions. The influence of age on the association between these highly prevalent conditions remains a topic of active study.

Otitis Media with Effusion: Our National Practice.

Otitis media with effusion (OME) is the focus of an updated multidisciplinary clinical practice guideline published by the American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO-HNSF) and the American Academy of Pediatrics (AAP). Based on data from clinical trials, the guideline recommends against using antihistamines, antibiotics, oral steroids, and intranasal steroids for OME. To understand practice patterns related to these guidelines, we assessed nationally representative data. Despite controlling for age, sex, race/ethnicity, and other potential confounders individualized for each medication class, an increased risk of antihistamine (odds ratio [OR], 3.53), antibiotic (OR, 4.31), and intranasal steroid administration (OR, 3.58) was seen when OME was diagnosed. These analyses have demonstrated opportunities for quality improvement in the care of patients with OME, quantifying gaps in practice relevant to proposed quality measures. Education targeted according to practice setting may facilitate appropriate therapy and/or referral for definitive intervention in children with OME.

Medications for Allergic Rhinitis.

Objectives Adherence to the allergic rhinitis clinical practice guideline is being considered as a potential focus for national performance metrics. To help inform this discussion, we assessed patient- and clinician-reported medication administration among nationally representative populations of patients with allergic rhinitis. Study Design Cross-sectional analyses. Setting and Subjects Home health assessments, ambulatory visits. Methods Participants in the National Health and Nutrition Examination Survey and the National Ambulatory Medical Care Survey / National Hospital Ambulatory Medical Care Survey were assessed. The primary outcomes were the percentage of patients reporting receipt of antihistamines and/or nasal steroids among those with allergy-related symptoms and the percentage for whom a clinician administered these medications when diagnosing allergic rhinitis. Secondary outcomes included assessments of those with worse quality of life, confirmatory allergy testing, and leukotriene receptor antagonist use. Results Within the National Health and Nutrition Examination Survey, an estimated 29.2 million patients were diagnosed with "hay fever," while 92.2 million were diagnosed with "allergies." Patients with symptoms of allergic rhinitis reported that antihistamines or nasal steroids were prescribed in 21.1% to 24.0% of cases. Leukotriene receptor antagonists were given to 1.7% of those without asthma or use of other allergy medications. Within the National Ambulatory Medical Care Survey / National Hospital Ambulatory Medical Care Survey, observations representing 149.5 million visits for allergic rhinitis demonstrated that nasal steroids were administered in 29.6% of cases, while nonsedating and sedating antihistamines were given in 22.4% and 17.2%, respectively. Conclusions Despite a high prevalence of allergic rhinitis, per patient report and clinician entry, a substantial number of affected patients do not receive antihistamines and nasal steroids.

Oral Antibiotic Use for Otitis Media with Effusion: Ongoing Opportunities for Quality Improvement.

OBJECTIVES: (1) To evaluate the probability of antibiotic administration associated with ICD-9 diagnosis of otitis media with effusion (OME) in the absence of acute otitis media, (2) to determine whether usage varies according to visit setting, and (3) to ascertain if practice gaps are such that future practice changes might be measured. STUDY DESIGN: Cross-sectional analysis of an administrative database. SETTING: Ambulatory visits in the United States. SUBJECTS AND METHODS: National Ambulatory and Hospital Ambulatory Medical Care Surveys, 2005-2010; univariate, multivariate, and stratified analyses of antibiotic usage were performed. The study population was restricted to children without acute or unspecified otitis media. The primary outcome was the probability of oral antibiotic administration when OME was diagnosed. The impact of the location of service and subspecialty care was also analyzed. RESULTS: Data from 1,390,404,196 pediatric visits demonstrated that oral antibiotics were administered for 32% of visits with an OME diagnosis, even in the absence of acute otitis media (odds ratio, 4.31; 95% confidence interval: 2.88-6.44; P < .001). The highest antibiotic administration was seen in the emergency department (risk difference, 37.1%; number needed to harm, 3). No significant increased risk of antibiotic usage was seen during otolaryngology visits. Diagnoses of infections at nonotologic sites were associated with a 1.98 to 26.60 increase in odds of oral antibiotic administration. CONCLUSION: Oral antibiotics continue to be administered in children with OME in the absence of acute infection, with risk varying by location of service. There is a potential opportunity for quality improvement through reducing antibiotic administration for pediatric OME.

Age: An effect modifier of the association between allergic rhinitis and Otitis media with effusion.

OBJECTIVES/HYPOTHESIS: 1) To determine whether there is a significant relationship between allergic rhinitis and otitis media with effusion (OME), Eustachian tube dysfunction (ETD), or tympanic membrane retraction (TMR) in children in a nationally representative population; and 2) to determine whether age is an effect modifier of any such association because this hypothesis has yet to be tested. STUDY DESIGN: Retrospective analysis of cross-sectional national databases with limited potential for referral bias. SETTING AND SUBJECTS: National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey, 2005-2010. METHODS: Univariate, multivariate, stratified, and subgroup analyses were performed as defined a priori. The primary outcomes were OME, ETD, or TMR; the primary predictor variable was allergic rhinitis, with age evaluated as an effect modifier. RESULTS: Data representing 1,491,045,375 pediatric visits were examined and demonstrated that age was an effect modifier of the assessed association. More specifically, in children 6 years of age or older, the presence of allergic rhinitis significantly increased the odds of OME, ETD, or TMR (odds ratio [OR] 4.20; 95% confidence interval [CI] 2.17, 8.09; P < 0.001), whereas in children less than 6 years of age there was no significant association (OR 1.13; 95% CI 0.53, 2.46; P = 0.745). CONCLUSION: Age is an effect modifier of the association between allergic rhinitis and OME; a significant relationship is observed in children 6 years of age and older, whereas there is no significant association in younger children. LEVEL OF EVIDENCE: 2c. Laryngoscope, 126:1687-1692, 2016.

Suprathreshold asymmetries in human motion perception.

Detection of asymmetries has been a mainstay of using vestibular reflexes to assess semicircular canal function. However, there has been relatively little work on how vestibular stimuli are perceived. Suprathreshold vestibular perception was measured in 13 normal healthy controls by having them compare the relative sizes of two yaw (vertical-axis rotation) or sway (right-left translation) stimuli. Both stimuli were 1.5 s in duration with a staircase used to adjust the relative size of the stimuli to find a pair of stimuli perceived as equal. Motion stimuli were delivered in darkness using a hexapod motion platform, and visual stimuli simulating motion were presented on a screen in the absence of platform motion. Both same direction (SD) and opposite direction (OD) stimuli were delivered in separate runs. After a two-interval stimulus, subjects reported which movement they perceived as larger. Cumulative distribution functions were fit to the responses so that the relative magnitudes of the two stimuli perceived as equal could be determined. For OD trial blocks, a directional asymmetry index was calculated to compare the relative size of perceived rightward and leftward motion. For all trial blocks, a temporal asymmetry index (TAI) was used to compare the relative size of the first and second intervals. Motion OD stimuli were perceived as equal in all subjects in yaw and all but one in sway. For visual OD stimuli, two subjects had slightly asymmetric responses for both sway and yaw. The TAI demonstrated asymmetry in 54% in yaw, in which the second interval was perceived to be larger in all but one subject who had an asymmetry. For sway, only two subjects had a significant asymmetry. Visual stimuli produced a similar rate of asymmetry. The direction and magnitude of these asymmetries were not significantly correlated with those seen for motion stimuli. Asymmetries were found in a fraction with the TAI in SD stimuli for motion in yaw (42%) and sway (33%), as well as for vision in yaw (60%) and sway (43%). The precision at discriminating SD motion stimuli decreased significantly with age, but there was no difference in OD motion or visual stimuli.

Directional asymmetries and age effects in human self-motion perception.

Directional asymmetries in vestibular reflexes have aided the diagnosis of vestibular lesions; however, potential asymmetries in vestibular perception have not been well defined. This investigation sought to measure potential asymmetries in human vestibular perception. Vestibular perception thresholds were measured in 24 healthy human subjects between the ages of 21 and 68 years. Stimuli consisted of a single cycle of sinusoidal acceleration in a single direction lasting 1 or 2 s (1 or 0.5 Hz), delivered in sway (left-right), surge (forward-backward), heave (up-down), or yaw rotation. Subject identified self-motion directions were analyzed using a forced choice technique, which permitted thresholds to be independently determined for each direction. Non-motion stimuli were presented to measure possible response bias. A significant directional asymmetry in the dynamic response occurred in 27% of conditions tested within subjects, and in at least one type of motion in 92% of subjects. Directional asymmetries were usually consistent when retested in the same subject but did not occur consistently in one direction across the population with the exception of heave at 0.5 Hz. Responses during null stimuli presentation suggested that asymmetries were not due to biased guessing. Multiple models were applied and compared to determine if sensitivities were direction specific. Using Akaike information criterion, it was found that the model with direction specific sensitivities better described the data in 86% of runs when compared with a model that used the same sensitivity for both directions. Mean thresholds for yaw were 1.3±0.9°/s at 0.5 Hz and 0.9±0.7°/s at 1 Hz and were independent of age. Thresholds for surge and sway were 1.7±0.8 cm/s at 0.5 Hz and 0.7±0.3 cm/s at 1.0 Hz for subjects <50 and were significantly higher in subjects >50 years old. Heave thresholds were higher and were independent of age.

Cervical vestibular evoked myogenic potentials (cVEMPs) in patients with superior canal dehiscence syndrome (SCDS).

OBJECTIVE: To determine the usefulness of both amplitude and threshold data from tone-burst cervical vestibular evoked myogenic potential (cVEMP) testing for the evaluation of superior canal dehiscence syndrome (SCDS). STUDY DESIGN: Case series with chart review. SUBJECTS AND METHODS: Sixty-seven patients underwent cVEMP testing. We correlated mean tone burst cVEMP amplitude and threshold data with temporal bone CT findings. Patients were excluded for Ménière's disease, middle ear disease, or otologic surgery. RESULTS: Superior canal dehiscence patients had higher mean cVEMP amplitudes (SCDS 173.8 microV vs non-SCDS 69.7 microV, P=0.031) and lower mean thresholds (SCDS 72.8 dB nHL vs non-SCDS 80.9 dB nHL) at 500 Hz. CONCLUSION: Patients with SCDS have larger amplitudes and lower thresholds on cVEMP testing at 500 Hz. This study supports the utility of tone burst cVEMPs for the evaluation of SCDS and is one of few large single-center studies to establish normative data.