NaCl exposure results in increased expression and processing of IL-1ß in Meniere's disease patients.

Meniere's disease (MD) is a chronic disease that causes episodic vertigo, fluctuating hearing loss, and aural fullness, initially managed by dietary salt reduction, and use of diuretics. Our prior research in autoimmune inner ear disease (AIED) demonstrated that in peripheral blood mononuclear cell (PBMC) from corticosteroid-resistant AIED patients, increased production, processing and release of interleukin-1ß (IL-1ß) is observed and hearing could be improved with use of anakinra, an interleukin-1 receptor antagonist. We have further identified that in these AIED patients, IL-1ß is uniquely processed to a 28 kDa pro-inflammatory product by caspase-7. In the present study, we characterize the production, processing and release of the pro-inflammatory cytokines IL-1ß and IL-6 from PBMC of MD (n = 14) patients in response to sodium chloride (NaCl), and determined the effect of the diuretic triamterene-hydrocholothiazide (T-HCTZ), or anakinra in these patients. We observed that PBMC cultured with NaCl from MD patients show processing of IL-1ß to the 28 kDa product, and that this product is abrogated with T-HCTZ. Our observations are consistent with other autoimmune diseases where high concentrations of NaCl caused release of pro-inflammatory cytokines and may provide further insight as to the mechanism of disease progression in MD patients.

Immune-Mediated Sensorineural Hearing Loss in the Pediatric Population.

A case series with chart review of pediatric patients with immune-mediated sensorineural hearing loss, including sudden sensorineural hearing loss and autoimmune-mediated hearing loss, was performed. Ninety-eight patients with sensorineural hearing loss were reviewed, and 41 patients met the inclusion criteria, which included corticosteroid therapy for a decline in sensorineural hearing. The primary outcome was the corticosteroid response rate: 61% of patients responded. The secondary outcome was a sustained response following multiple courses of corticosteroids for additional hearing loss, which correlated with timely corticosteroid treatment: 57% showed sustained response with multiple treatments, but as anticipated, patients were more likely to respond when treated promptly. Sustained responses fell over time with multiple treatments. These data demonstrate pediatric immune-mediated sensorineural hearing loss is corticosteroid responsive in at a rate similar to their adult counterparts and should be considered for similar treatment approaches.

Direct SARS-CoV-2 infection of the human inner ear may underlie COVID-19-associated audiovestibular dysfunction.

BACKGROUND: COVID-19 is a pandemic respiratory and vascular disease caused by SARS-CoV-2 virus. There is a growing number of sensory deficits associated with COVID-19 and molecular mechanisms underlying these deficits are incompletely understood. METHODS: We report a series of ten COVID-19 patients with audiovestibular symptoms such as hearing loss, vestibular dysfunction and tinnitus. To investigate the causal relationship between SARS-CoV-2 and audiovestibular dysfunction, we examine human inner ear tissue, human inner ear in vitro cellular models, and mouse inner ear tissue. RESULTS: We demonstrate that adult human inner ear tissue co-expresses the angiotensin-converting enzyme 2 (ACE2) receptor for SARS-CoV-2 virus, and the transmembrane protease serine 2 (TMPRSS2) and FURIN cofactors required for virus entry. Furthermore, hair cells and Schwann cells in explanted human vestibular tissue can be infected by SARS-CoV-2, as demonstrated by confocal microscopy. We establish three human induced pluripotent stem cell (hiPSC)-derived in vitro models of the inner ear for infection: two-dimensional otic prosensory cells (OPCs) and Schwann cell precursors (SCPs), and three-dimensional inner ear organoids. Both OPCs and SCPs express ACE2, TMPRSS2, and FURIN, with lower ACE2 and FURIN expression in SCPs. OPCs are permissive to SARS-CoV-2 infection; lower infection rates exist in isogenic SCPs. The inner ear organoids show that hair cells express ACE2 and are targets for SARS-CoV-2. CONCLUSIONS: Our results provide mechanistic explanations of audiovestibular dysfunction in COVID-19 patients and introduce hiPSC-derived systems for studying infectious human otologic disease.

Biologics for Immune-Mediated Sensorineural Hearing Loss.

Immune-mediated hearing losses include autoimmune inner ear disease, sudden sensorineural hearing loss, and Meniere's disease. Standard therapy for an acute decline in hearing is timely use of corticosteroids. Although 60% to 70% of patients are initially corticosteroid-responsive, that responsiveness is lost over time. In corticosteroid-resistant patients, increased expression of interleukin (IL)-1 is observed, and these patients may benefit from IL-1 inhibition. Autoinflammatory diseases are characterized by dysregulation of the innate immune response, clinically include sensorineural hearing loss, and benefit from IL-1 inhibition, thereby further establishing the relationship of IL-1 with immune-mediated sensorineural hearing loss.

The Correlation of Clinical Corticosteroid Responsiveness With Expression of IL-6 in Peripheral Blood Immune Cells (PBMC) in Patients With Autoimmune Inner Ear Disease (AIED).

HYPOTHESIS: Autoimmune inner ear disease (AIED) patients will differentially express interleukin (IL)-6 based on corticosteroid responsiveness. BACKGROUND: AIED is characterized by periods of acute sensorineural hearing loss (SNHL). In a majority of patients corticosteroid responsiveness is lost over time. The mechanisms that control corticosteroid responsiveness have not been fully elucidated. METHODS: Thirty-five AIED patients and 13 age-matched control subjects were enrolled in this study. Steroid responsive (n = 15) and steroid nonresponsive AIED patients (n = 20) were characterized based on audiometry before and after treatment for acute SNHL. Plasma and peripheral blood mononuclear cells (PBMC) were obtained at the time of acute SNHL to quantify plasma IL-6, soluble IL-6 receptor (sIL-6R), and C-C Motif Chemokine Ligand 3 (CCL3). PBMCs were stimulated with dexamethasone and release of soluble IL-6, sIL-6R, and CCL3 protein into conditioned supernatants was measured. Plasma IL-6 was also correlated to serum c-reactive protein (CRP), cardiac CRP, erythrocyte sedimentation rate. RESULTS: Statistically significant differences were observed in the plasma IL-6 between AIED patients and controls (2.37 versus 2.03 pg/ml, p < 0.01), plasma IL-6, and CCL3 between responders and nonresponders (0.136 versus 3.84 pg/ml, p < 0.005; 30.5 versus 32.4, p < 0.05) and released IL-6 from dexamethasone stimulated PBMC in AIED patients compared with controls (0.54 versus 1.12 pg/ml, p < 0.001). There was a correlation between plasma IL-6 levels of AIED patients to both serum CRP and cardiac CRP (R2 = 0.83, R2 = 0.88). CONCLUSIONS: We observed AIED patients, specifically nonresponders expressed greater levels of IL-6. Elevated IL-6 levels in AIED patients correlated with CRP levels, providing a commonly available laboratory test that may aid in rapid clinical decision-making in these patients.

Autoimmune inner ear disease patient-associated 28-kDa proinflammatory IL-1ß fragment results from caspase-7-mediated cleavage in vitro.

Interleukin-1ß (IL-1ß) is a key proinflammatory cytokine involved in the progression of many autoinflammatory and autoimmune diseases, including autoimmune inner ear disease (AIED). IL-1ß inhibition has been shown to result in clinical hearing improvement in a small cohort of corticosteroid-resistant patients with AIED. Canonical processing of pro-IL-1ß by caspase-1 generates an active 17-kDa fragment, capable of instigating a proinflammatory microenvironment. However, in response to LPS, PBMCs from patients with AIED uniquely express a 28-kDa IL-1ß fragment, as compared with PBMCs from control subjects. We synthesized and compared the biologic activity of the 28-kDa fragment to the 17-kDa IL-1ß product and the pro-IL-1 31-kDa protein. The 28-kDa IL-1ß fragment induces IL-6, TNF-α, and CCL3 in PBMCs. Uniquely, only caspase-7 treatment showed a dose- and time-dependent increase in 28-kDa band generation. Mass spectrometry confirmed the putative caspase-7 cleavage site of pro-IL-1ß, which was used to generate the 28-kDa fragment used for PBMC stimulation studies. Collectively, these results provide insight into the function of a poorly understood, processed 28-kDa form of IL-1ß in patients with AIED that is uniquely generated by caspase-7 and is capable of activating further downstream proinflammatory cytokines. Further investigation may provide novel pharmacologic targets for the treatment of this rare disease.

Medical and Audiological Indications for Implantable Auditory Devices.

Implantable auditory devices (IADs) are a viable hearing restoration option for patients with hearing loss. Conditions such as chronic otitis externa, congenital aural atresia, and chronic otitis media can be treated with a variety of implants. Progressive disease are also amenable to restoration with IADs, providing stabilized hearing. When considering the best rehabilitative options, the patient's preference, ease of surgery, ease of device use, quality of life, and the traditional alternatives (such as ossiculoplasty, hearing aids, and cochlear implants) need to be considered. Patients with conductive, mixed, and sensorineural losses, mild to severe in nature, can be candidates for IADs.

Idiopathic Sudden Sensorineural Hearing Loss Is Not a Sentinel Event for Acute Myocardial Infarction.

OBJECTIVE: Given ongoing debate about the suggested association, the primary objective was to determine if idiopathic sudden sensorineural hearing loss (ISSNHL) was a sentinel event for acute myocardial infarction (AMI) in adults. STUDY DESIGN: Case-control study. SETTING: United States MarketScan administrative health claims database. PATIENTS: Aged 18 years or older, had a diagnosis of ISSNHL on or after January 1st, 2011 and had sufficient follow-up data available to assess for AMI occurrence. INTERVENTION: N/A. MAIN OUTCOME MEASURES: Incidence rates (per 1,000 patient years) of AMI for cases and controls were computed. Adjusted and unadjusted Cox proportional hazards models were created to explore possible associations between ISSNHL and initial AMI. RESULTS: A total of 10,749 ISSNHL cases and 10,749 matched controls were included. There were no significant differences in the incidence rate of AMI between ISSNHL cases (8.29 events/1,000 person-years) and controls (9.25 events/1,000 person-years), nor were there differences within age groups, sex, or comorbidity status (overall incidence rate ratio 0.90; 95% confidence interval [CI] 0.70-1.15 p = 0.39). The unadjusted and adjusted Cox proportional hazards models did not demonstrate an association between ISSNHL and initial AMI (hazard ratio [HR]: 0.90, 95% CI: 0.70-1.15; HR: 0.86, 95% CI: 0.67-1.10, respectively). CONCLUSIONS: ISSNHL is not a predictor of an initial AMI in adult patients from the United States. Considerable inconsistencies in associations between cardiovascular risk factors and ISSNHL exist in the literature. Further work is needed to confirm or refute direct associations between cardiovascular disease risk factors and ISSNHL before definitive mechanistic conclusions can be made.

Characterization of newborn hearing screening failures in multigestational births.

OBJECTIVE: To define the rate and characterize the type of newborn hearing screening failures in multigestational births. METHODS: Retrospective chart review of all multigestational births that occurred in a 10-year period (2002-2012) in which at least one newborn failed newborn hearing screening at two tertiary care hospitals in the Northwell Health System. RESULTS: Out of 125,405 total births, we identified 2961 multigestational births, of which 59 (2.0%) newborns failed newborn hearing screening. None of their 66 twin/triplet siblings failed their newborn hearing screens. Of 43 newborns that returned for follow-up, 56.0% (24/43) had confirmed hearing loss, resulting in an overall rate of 0.81% in all multigestational newborns with hearing loss. Of 19 infants that passed repeat testing, two were judged to need myringotomy tube placement. Twenty-four infants had a confirmed hearing loss, 11 of which had sensorineural hearing loss (0.37%), and 13 with a conductive or mixed hearing loss (0.44%). CONCLUSIONS: We identified a greater than expected risk of conductive hearing loss, not attributable to otitis media, than sensorineural hearing loss in this population. These observations are consistent with the increased risk of birth defects in multigestational births.

The Balance of Tissue Inhibitor of Metalloproteinase-1 and Matrix Metalloproteinase-9 in the Autoimmune Inner Ear Disease Patients.

Tissue inhibitor of metalloproteinase-1 (TIMP-1) is a protein implicated in the control of inflammation in a number of autoimmune diseases. We hypothesized that the balance of TIMP-1 and matrix metalloproteinase-9 (MMP-9) may influence the control or perpetuation of inflammation in corticosteroid-responsive (RES) and corticosteroid-resistant (NR) autoimmune inner ear disease (AIED) patients. In the present study, we observed that plasma from AIED patients exhibited greater levels of TIMP-1 values compared with normal healthy controls. TIMP-1 abrogates lipopolysaccharide-mediated interleukin (IL)-1ß release from peripheral blood mononuclear cells in a dose-dependent manner. RES AIED patients have higher basal TIMP-1 levels and produce more TIMP-1 in response to IL-1ß. Conversely, consistent with our previous studies, we found that NR patients have higher basal MMP-9 levels and produce more MMP-9 levels in response to IL-1ß.

CHEER National Study of Chronic Rhinosinusitis Practice Patterns: Disease Comorbidities and Factors Associated with Surgery.

Objectives (1) Describe national patterns of chronic rhinosinusitis (CRS) care across academic and community practices. (2) Determine the prevalence of comorbid disorders in CRS patients, including nasal polyposis, allergic rhinitis, asthma, and cystic fibrosis. (3) Identify demographic, clinical, and practice type factors associated with endoscopic sinus surgery (ESS). Study Design Multisite cross-sectional study. Setting Otolaryngology's national research network CHEER (Creating Healthcare Excellence through Education and Research). Subjects and Methods A total of 17,828 adult patients with CRS were identified, of which 10,434 were seen at community practices (59%, n = 8 sites) and 7394 at academic practices (41%, n = 10 sites). Multivariate logistic regression was used to evaluate the association between demographic, practice type, and clinical factors and the odds of a patient undergoing ESS. Results The average age was 50.4 years; 59.5% of patients were female; and 88.3% were Caucasian. The prevalence of comorbid diseases was as follows: allergic rhinitis (35.1%), nasal polyposis (13.3%), asthma (4.4%), and cystic fibrosis (0.2%). In addition, 24.8% of patients at academic centers underwent ESS, as compared with 12.3% at community sites. In multivariate analyses, nasal polyposis (odds ratio [OR], 4.28), cystic fibrosis (OR, 2.42), and academic site type (OR, 1.86) were associated with ESS ( P < .001), while adjusting for other factors. Conclusions We describe practice patterns of CRS care, as well as demographic and clinical factors associated with ESS. This is the first study of practice patterns in CRS utilizing the CHEER network and may be used to guide future research.

AAO: Autoimmune and Autoinflammatory (Disease) in Otology: What is New in Immune-Mediated Hearing Loss.

OBJECTIVES: Autoinflammatory diseases are a family of immune-mediated, rare diseases, some of which, exhibit sensorineural hearing loss (SNHL), suggesting potentially similar mechanisms of molecular pathogenesis between autoinflammatory-mediated hearing loss and autoimmune inner ear disease (AIED) may exist. The purpose of this review is to compare the clinical features of autoimmune and autoinflammatory diseases that affect hearing, discuss the limitations of our knowledge, and highlight potential new disease mechanisms and therapeutics. DATA SOURCES: Pubmed Literature Review; Google Scholar Literature review. REVIEW METHODS: A focused comparison of AIED with a number of autoinflammatory diseases that manifest with sensorineural hearing loss was performed. The pathogenesis of these diseases is reviewed in the context of the innate and adaptive immune system, cytokine expression and genetic polymorphisms. RESULTS: AIED, since first described by Cogan and Lehnhardt and first clinically characterized by McCabe, has remained an enigmatic disease, with limited advances in both new diagnostics and new therapeutics. Since the discovery of autoinflammatory diseases, a number of systemic autoimmune diseases have either been re-classed as autoinflammatory diseases or identified to have features of autoinflammatory disease. CONCLUSION: AIED has clinical features of both autoimmune and autoinflammatory disease. It is critical that autoinflammatory diseases be correctly identified, as failure to do so may result in systemic amyloidosis and kidney damage.

The experience of bilateral cochlear implantation in a child with LEOPARD syndrome.

We present a 3-year old boy with Leopard syndrome. His clinical manifestations included a congenital bilateral sensorineural hearing loss. He underwent cochlear implantation on the right side at age 1 year and on the left side at age 1.5 years. The patient is doing very well and mainstreamed in a regular pre-school program with a teacher of the deaf and home based speech therapy. Bilateral cochlear implantation in the case of a child with Leopard syndrome can be successful.

Thyroid Disease and Surgery in CHEER: The Nation's Otolaryngology-Head and Neck Surgery Practice-Based Network.

OBJECTIVES: (1) Describe thyroid-related diagnoses and procedures in Creating Healthcare Excellence through Education and Research (CHEER) across academic and community sites. (2) Compare management of malignant thyroid disease across these sites. (3) Provide practice-based data related to flexible laryngoscopy vocal fold assessment before and after thyroid surgery based on the American Academy of Otolaryngology-Head and Neck Surgery Foundation's clinical practice guidelines. STUDY DESIGN: Review of retrospective data collection (RDC) database of the CHEER network using ICD-9 and CPT codes related to thyroid conditions. SETTING: Multisite practice-based network. SUBJECTS AND METHODS: There were 3807 thyroid patients (1392 malignant, 2415 benign) with 10,160 unique visits identified from 1 year of patient data in the RDC. Analysis was performed for identified cohort of patients using demographics, site characteristics, and diagnostic and procedural distribution. RESULTS: Mean number of patients with thyroid disease per site was 238 (range, 23-715). In community practices, 19% of patients with thyroid disease had cancer versus 45% in the academic setting (P < .001). While academic sites manage more cancer patients, community sites are also surgically treating thyroid cancer and performed more procedures per cancer patient (4.2 vs 3.5, P < .001). Vocal fold function was assessed by flexible laryngoscopy in 34.0% of preoperative patients and in 3.7% postoperatively. CONCLUSION: This is the first overview of malignant and benign thyroid disease through CHEER. It shows how the RDC can be used alone and with national guidelines to inform of clinical practice patterns in academic and community sites. This demonstrates the potential for future thyroid-related studies utilizing the otolaryngology-head and neck surgery practice-based research network.

Ménière's Disease: A CHEER Database Study of Local and Regional Patient Encounter and Procedure Patterns.

OBJECTIVE: (1) Integrate practice-based patient encounters using the Dartmouth Atlas Medicare database to understand practice treatments for Ménière's disease (MD). (2) Describe differences in the practice patterns between academic and community providers for MD. STUDY DESIGN: Practice-based research database review. SETTING: CHEER (Creating Healthcare Excellence through Education and Research) network academic and community providers. SUBJECTS AND METHODS: MD patient data were identified with ICD-9 and CPT codes. Demographics, unique visits, and procedures per patient were tabulated. The Dartmouth Atlas of Health Care was used to reference regional health care utilization. Statistical analysis included 1-way analyses of variance, bivariate linear regression, and Student's t tests, with significance set at P < .05. RESULTS: A total of 2071 unique patients with MD were identified from 8 academic and 10 community otolaryngology-head and neck surgery provider centers nationally. Average age was 56.5 years; 63.9% were female; and 91.4% self-reported white ethnicity. There was an average of 3.2 visits per patient. Western providers had the highest average visits per patient. Midwest providers had the highest average procedures per patient. Community providers had more visits per site and per patient than did academic providers. Academic providers had significantly more operative procedures per site (P = .0002) when compared with community providers. Health care service areas with higher total Medicare reimbursements per enrollee did not report significantly more operative procedures being performed. CONCLUSION: This is the first practice-based clinical research database study to describe MD practice patterns. We demonstrate that academic otolaryngology-head and neck surgery providers perform significantly more operative procedures than do community providers for MD, and we validate these data with an independent Medicare spending database.

Tonsillectomy Bleed Rates across the CHEER Practice Research Network: Pursuing Guideline Adherence and Quality Improvement.

OBJECTIVES: (1) Compare postoperative bleeding in the CHEER network (Creating Healthcare Excellence through Education and Research) among age groups, diagnoses, and practice types. (2) Report the incidence of bleeding by individual CHEER practice site based on practice guidelines. STUDY DESIGN: Retrospective data collection database review of the CHEER network based on ICD-9 and CPT codes related to tonsillectomy patients. SETTING: Multisite practice-based network. SUBJECTS AND METHODS: A total of 8347 subjects underwent tonsillectomy as determined by procedure code within the retrospective data collection database, and 107 had postoperative hemorrhage. These subjects had demographic information and related diagnoses based on the CPT and ICD-9 codes collected. Postoperative ICD-9 and CPT codes were used to identify patients who also had postoperative bleed. Variables included age (<12 vs ≥12 years), diagnoses (infectious vs noninfectious), and practice type (community vs academic). Statistical analysis included multivariate logistic regression variables predictive of postoperative bleeding, with P < .05 considered significant. RESULTS: Thirteen sites contributed data to the study (7 academic, 6 community). There was postoperative bleeding for an overall bleed rate of 1.3%. Patients ≥12 years old had a significantly increased bleed rate when compared with the younger group (odds ratio, 5.98; 95% confidence interval: 3.79-9.44; P < .0001). There was no significant difference in bleed rates when practices or diagnoses were compared. CONCLUSION: A site descriptor database built to expedite clinical research can be used for practice assessment and quality improvement. These data were also useful to identify patient risk factors for posttonsillectomy bleed.

Variation in the Use of Vestibular Diagnostic Testing for Patients Presenting to Otolaryngology Clinics with Dizziness.

OBJECTIVE: We used a national otolaryngology practice-based research network database to characterize the utilization of vestibular function testing in patients diagnosed with dizziness and/or a vestibular disorder. STUDY DESIGN: Database review. SETTING: The Creating Healthcare Excellence through Education and Research (CHEER) practice-based research network of academic and community providers SUBJECTS AND METHODS: Dizzy patients in the CHEER retrospective database were identified through ICD-9 codes; vestibular testing procedures were identified with CPT codes. Demographics and procedures per patient were tabulated. Analysis included number and type of vestibular tests ordered, stratified by individual clinic and by practice type (community vs academic). Chi-square tests were performed to assess if the percentage of patients receiving testing was statistically significant across clinics. A logistic regression model was used to examine the association between receipt of testing and being tested on initial visit. RESULTS: A total of 12,468 patients diagnosed with dizziness and/or a vestibular disorder were identified from 7 community and 5 academic CHEER network clinics across the country. One-fifth of these patients had at least 1 vestibular function test. The percentage of patients tested varied widely by site, from 3% to 72%; academic clinics were twice as likely to test. Initial visit vestibular testing also varied, from 0% to 96% of dizzy patients, and was 15 times more likely in academic clinics. CONCLUSION: There is significant variation in use and timing of vestibular diagnostic testing across otolaryngology clinics. The CHEER network research database does not contain outcome data. These results illustrate the critical need for research that examines outcomes as related to vestibular testing.

Does an Otolaryngology-Specific Database Have Added Value? A Comparative Feasibility Analysis.

OBJECTIVES: There are multiple nationally representative databases that support epidemiologic and outcomes research, and it is unknown whether an otolaryngology-specific resource would prove indispensable or superfluous. Therefore, our objective was to determine the feasibility of analyses in the National Ambulatory Medical Care Survey (NAMCS) and National Hospital Ambulatory Medical Care Survey (NHAMCS) databases as compared with the otolaryngology-specific Creating Healthcare Excellence through Education and Research (CHEER) database. STUDY DESIGN: Parallel analyses in 2 data sets. SETTING: Ambulatory visits in the United States. SUBJECTS AND METHODS: To test a fixed hypothesis that could be directly compared between data sets, we focused on a condition with expected prevalence high enough to substantiate availability in both. This query also encompassed a broad span of diagnoses to sample the breadth of available information. Specifically, we compared an assessment of suspected risk factors for sensorineural hearing loss in subjects 0 to 21 years of age, according to a predetermined protocol. We also assessed the feasibility of 6 additional diagnostic queries among all age groups. RESULTS: In the NAMCS/NHAMCS data set, the number of measured observations was not sufficient to support reliable numeric conclusions (percentage standard error among risk factors: 38.6-92.1). Analysis of the CHEER database demonstrated that age, sex, meningitis, and cytomegalovirus were statistically significant factors associated with pediatric sensorineural hearing loss (P < .01). Among the 6 additional diagnostic queries assessed, NAMCS/NHAMCS usage was also infeasible; the CHEER database contained 1585 to 212,521 more observations per annum. CONCLUSION: An otolaryngology-specific database has added utility when compared with already available national ambulatory databases.

N-Acetylcysteine attenuates tumor necrosis factor alpha levels in autoimmune inner ear disease patients.

Autoimmune inner ear disease (AIED) is a poorly understood disease marked by bilateral, rapidly progressive hearing loss triggered by unknown stimuli, which is corticosteroid responsive in 60 % of patients. Although the mechanism of the disease is not precisely understood, a complex interaction of cytokines is believed to contribute toward the inflammatory disease process and hearing loss. Previously, we showed the role of TNF-α in steroid-sensitive and IL-1ß in steroid-resistant immune-mediated hearing loss. N-Acetylcysteine (NAC), a broad spectrum antioxidant, has been effective in other autoimmune disorders. Other studies have shown NAC to have a protective adjunct role in human idiopathic sudden hearing loss, where the addition of NAC resulted in better hearing recovery than with steroids alone, although the mechanism of this protection was not elucidated. In the present study, we observed PBMCs from AIED patients exhibited higher baseline TNF-α and MPO levels compared with normal healthy controls. NAC effectively abrogates LPS-mediated TNF-α release from PBMC of both AIED patients and controls. We demonstrated that in AIED patients, the TNF-α downstream signaling pathway appears aberrantly regulated, influencing both MPO and IL-8 expression. Given that NAC effectively abrogated LPS-mediated TNF-α release and exerted minimal effects on the downstream targets of this pathway, we feel NAC may be a rational adjunct therapy for this enigmatic disease, worthy of clinical exploration.

Early efficacy trial of anakinra in corticosteroid-resistant autoimmune inner ear disease.

BACKGROUND: Autoimmune inner ear disease (AIED) is a rare disease that results in progressive sensorineural hearing loss. Patients with AIED initially respond to corticosteroids; however, many patients become unresponsive to this treatment over time, and there is no effective alternative therapy for these individuals. METHODS: We performed a phase I/II open-label, single-arm clinical trial of the IL-1 receptor antagonist anakinra in corticosteroid-resistant AIED patients. Given that the etiology of corticosteroid resistance is likely heterogeneous, we used a Simon 2-stage design to distinguish between an unacceptable (≤10%) and an acceptable (≥30%) response rate to anakinra therapy. Subjects received 100 mg anakinra by subcutaneous injection for 84 days, followed by a 180-day observational period. RESULTS: Based on patient responses, the Simon 2-stage rule permitted premature termination of the trial after 10 subjects completed the 84-day drug period, as the target efficacy for the entire trial had been achieved. Of these 10 patients, 7 demonstrated audiometric improvement, as assessed by pure tone average (PTA) and word recognition score (WRS). In these 7 responders, reduced IL-1ß plasma levels correlated with clinical response. Upon discontinuation of treatment, 3 subjects relapsed, which correlated with increased IL-1ß plasma levels. CONCLUSION: We demonstrated that IL-1ß inhibition in corticosteroid-resistant AIED patients was effective in a small cohort of patients and that IL-1ß plasma levels associated with both clinical hearing response and disease relapse. These results suggest that a larger phase II randomized clinical trial of IL-1ß inhibition is warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT01267994. FUNDING: NIH, Merrill & Phoebe Goodman Otology Research Center, and Long Island Hearing & Speech Society.