Genome-wide association study indicates novel associations of annexin A13 to secretory and GAS2L2 with mucous otitis media.

To evaluate the genetics of chronic nonsuppurative otitis media (OM). We performed a genome-wide association study of 429,599 individuals included in the FinnGen study using three different case definitions: combined chronic nonsuppurative OM (7034 cases) (included serous and mucous chronic OM), mucous chronic OM (5953 cases), and secretory chronic OM (1689 cases). Individuals without otitis media were used as controls (417,745 controls). We used immunohistochemistry (IHC) of the murine middle ear to evaluate the expression of annexin A13. Four loci were significantly associated (p < 1.7 × 10-8) with nonsuppurative OM. Three out of the four association signals included missense variants in genes that may play a role in otitis media pathobiology. According to our subtype-specific analyses, one novel locus, located near ANXA13, was associated with secretory OM. Three loci (near TNFRSF13B, GAS2L2, and TBX1) were associated with mucous OM. Immunohistochemistry of murine middle ear samples revealed annexin A13 expression at the apical pole of the Eustachian tube epithelium as well as variable intensity of the secretory cells of the glandular structure in proximity to the Eustachian tube. We demonstrated that secretory and mucous OM have distinct and shared genetic associations. The association of GAS2L2 with ciliary epithelium function and the pathogenesis of dysfunctional mucosa in mucous OM is suggested. The abundant expression of annexin A13 in the Eustachian tube epithelium, along with its role in apical transport for the binding and transfer of phospholipids, indicates the role of annexin A13 and phospholipids in Eustachian tube dysfunction.

Evaluation of Eustachian tube dimensions by temporal bone computed tomography in patients with chronic otitis media.

OBJECTIVE: To clarify the relationship between Eustachian tube dimensions and chronic otitis media aetiology using temporal bone computed tomography. METHODS: The data of 231 adults who had undergone surgery for unilateral chronic otitis media were reviewed retrospectively. Diseased and healthy ears were enrolled in groups 1 and 2, respectively. Group 1A included chronic otitis media with cholesteatoma (n = 28) and group 1B included chronic otitis media without cholesteatoma (n = 203). The Eustachian tube dimensions of groups 1 and 2 were compared, to clarify the relationship between the Eustachian tube dimensions and chronic otitis media aetiology. Groups 1A and 1B were compared to assess the effect of Eustachian tube dimensions on cholesteatoma development. RESULTS: The Eustachian tube was shorter, narrower and located more horizontally in ears with chronic otitis media. No significant difference was found between groups 1A and 1B. CONCLUSION: Eustachian tube dimensions are closely related to chronic otitis media aetiopathology, but are not related to cholesteatoma development.

Is the promontory a promising site to diagnose otitis media in paleopathology? A search for evidence.

OBJECTIVE: The promontory of the middle ear was recently suggested to be an appropriate site for diagnosing otitis media (OM) in archaeological bones by endoscopic inspection. The present study scrutinized the underlying assumption that a bulgy, irregular promontorial surface represents a pathological condition. MATERIALS: We compared an allegedly healthy individual and an allegedly diseased individual in skeletal remains of two human individuals from the early Medieval period in Germany. METHODS: The specimens were studied using microscopic analyses of thin ground sections. RESULTS: The osseous architecture of the three-layered promontorial wall was the same in both specimens. Both the contour of the resorption front of the middle layer and the thickness of the overlying outer periosteal layer showed some variation, resulting in an either smooth or a bulgy promontorial surface, while signs of resorptive or proliferative changes at the periosteal surface were missing in both cases. CONCLUSIONS: Our results suggest that an irregular promontorial surface represents normal variation in the development of the otic capsule rather than a pathological condition. We therefore conclude that the promontory is not an appropriate site for diagnosing OM in archaeological bone. SIGNIFICANCE: The study contributes to evidence-based diagnoses in paleo-otological studies. Our assumption is in line with clinical and experimental findings indicating that the otic capsule is protected against bone remodeling. LIMITATIONS: Only two specimens were studied. SUGGESTIONS FOR FURTHER RESEARCH: SEM-studies to detect more subtle changes to the promontorial surface.

Is pre-operative audiometry a reliable predictor of ossicular chain condition?

OBJECTIVE: Investigation of ossicular chain (OC) status before surgery is important for preoperative patient consultation. This research aimed to investigate the relationship between pre-operative audiometric values and intra-operative OC condition in a relatively large population of chronic otitis media (COM) surgeries. METHODS: In this descriptive-analytic cross-sectional study, we evaluated 694 patients who underwent COM surgeries. We analyzed pre-operative audiometric data and intraoperative findings including ossicular anatomy, ossicular mobility, and the condition of middle ear mucosa. RESULTS: The optimal cut-off values of pre-operative speech reception threshold (SRT), mean air-conduction (AC), and mean air-bone gap (ABG) for predicting OC discontinuity were 37.5 dB, 37.2 dB, and 28.4 dB, respectively. For the prediction of OC fixation, the optimal cut-off points of SRT, mean AC, and mean ABG were 37.5 dB, 40.3 dB, and 32.8 dB, respectively. The computing of Cohen's d (95 % confidence interval) demonstrated the greater mean ABG in ears with OC discontinuity in comparison with ears with normal ossicles in all types of pathologies. There was a descending trend of Cohen's d from cholesteatoma to tympanosclerosis and then to granulation tissue and hypertrophic mucosa. There was a substantial relation between the type of pathology and OC status (P < 0.001). Ears with tympanosclerosis plaque had the most fixed OC among all types of pathologies (40 ears, 30.8 %), and ears with no pathology had the most normal OC (135 ears, 83.3 %). CONCLUSIONS: The results supported the view that pre-operative hearing is a key determining factor for the prediction of OC status.

Automated multi-class classification for prediction of tympanic membrane changes with deep learning models.

BACKGROUNDS AND OBJECTIVE: Evaluating the tympanic membrane (TM) using an otoendoscope is the first and most important step in various clinical fields. Unfortunately, most lesions of TM have more than one diagnostic name. Therefore, we built a database of otoendoscopic images with multiple diseases and investigated the impact of concurrent diseases on the classification performance of deep learning networks. STUDY DESIGN: This retrospective study investigated the impact of concurrent diseases in the tympanic membrane on diagnostic performance using multi-class classification. A customized architecture of EfficientNet-B4 was introduced to predict the primary class (otitis media with effusion (OME), chronic otitis media (COM), and 'None' without OME and COM) and secondary classes (attic cholesteatoma, myringitis, otomycosis, and ventilating tube). RESULTS: Deep-learning classifications accurately predicted the primary class with dice similarity coefficient (DSC) of 95.19%, while misidentification between COM and OME rarely occurred. Among the secondary classes, the diagnosis of attic cholesteatoma and myringitis achieved a DSC of 88.37% and 88.28%, respectively. Although concurrent diseases hampered the prediction performance, there was only a 0.44% probability of inaccurately predicting two or more secondary classes (29/6,630). The inference time per image was 2.594 ms on average. CONCLUSION: Deep-learning classification can be used to support clinical decision-making by accurately and reproducibly predicting tympanic membrane changes in real time, even in the presence of multiple concurrent diseases.

Tuberculosis of the middle ear: A systematic review.

OBJECTIVE: Tuberculous otitis media (TOM) is a rare extrapulmonary manifestation of tuberculosis (TB) and remains challenging to diagnose due to non-specific symptoms. This systematic review identifies clinical characteristics, diagnostic evaluation, and outcomes in cases of TOM. METHODS: A comprehensive literature search utilizing the PubMed, CINAHL, Scopus, and Cochrane Library databases was conducted for relevant articles published between 2000 and 2021. Cases involving adult patients with TOM were included. Non-English studies, animal studies, and reviews were excluded. RESULTS: 41 case reports and 7 case series were included, comprising data from 67 patients. The mean age was 40 years (range, 19-87 years) and the majority were female (n = 46, 68.7 %). The mean symptom duration was 12.8 months (range, 0.25-120 months). Common symptoms included otorrhea (n = 60, 89.6 %), HL (n = 58, 86.6 %), otalgia (n = 19, 28.4 %), and FP (n = 18, 26.9 %). Otoscopy revealed tympanic membrane (TM) perforation in 45 patients (67.2 %). Most patients were diagnosed with tissue biopsy (n = 53, 79.1 %). Surgical interventions were performed in 48 patients (71.6 %) and 63 patients (94.0 %) were prescribed anti-TB chemotherapy. Long-term sequelae (e.g., HL, FP, and TM perforation) were noted in 39 patients (58.2 %) at a mean follow-up of 18.8 months (range, 1-120 months). CONCLUSION: TOM should be included in the differential diagnosis of chronic suppurative otitis media. Histopathological examination is a reliable diagnostic method. Early detection and management are recommended for optimizing outcomes. LEVEL OF EVIDENCE: 3b.

Patulous eustachian tube after balloon eustachian tuboplasty in a post-radiation patient.

BACKGROUND: Balloon eustachian tuboplasty (BET) is a minimally invasive surgical treatment that is effective and safe for obstructive eustachian tube dysfunction. However, BET complications include excessive widening of the eustachian tube, causing a patulous eustachian tube (PET). Herein, we report a case of PET following BET in a patient who underwent radiation therapy and reviewed the literature on considerations for reducing complications after BET. CASE PRESENTATION: A 63-year-old woman complained of bilateral ear fullness after concurrent chemoradiation therapy for nasopharyngeal lymphoma. BET was performed on the left side because the left-sided serous otitis media persisted. A left-sided PET was performed two weeks after the BET, along with eustachian tube silicone plug insertion on the left side. The patient became asymptomatic immediately after the surgery, with no recurrence reported after a 12-month follow-up period. CONCLUSIONS: To our knowledge, there has been no report of PET following BET in a post-radiation patient, and it was successfully treated via ET silicone plug insertion.

gom1 Mutant Mice as a Model of Otitis Media.

Otitis media (OM) disease is a common cause of hearing loss that is primarily the result of middle ear infection. At present, our understanding of the mechanisms leading to OM is limited due to the lack of animal models of OM with effusion (OME). Here, we report that the mice with genetic otitis media one (gom1) mutants are prone to OM. gom1 Mice were produced by the N-ethyl-N-nitrosourea (ENU) mutagenesis program as an animal model to study OM. These mice demonstrate many common features of OM, such as middle ear effusion and hearing impairment. We revealed that gom1 mice display various signs of middle ear and inner ear dysfunctions, including elevated thresholds of auditory-evoked brainstem response (ABR) and lack of cochlear microphonic responses. Decreased compliance in tympanometry measurements indicates tympanic membrane and ossicular chain malfunction. We confirmed through histological examinations of middle ear structures that 34/34 (100 %) of the mutant mice suffered from severe OME. While individual ears had different levels of effusion and inflammatory cells in the middle ear cavity, all had thickened middle ear mucosa and submucosa compared to control mice (B6). Moreover, the mutant mice displayed cochlear hair cell loss. These observations also suggested the craniofacial abnormalities in the gom1 mouse model. Together, these results indicate that gom1 mice could be valuable for investigating the genetic contribution to the development of middle ear disease.

Patulous Eustachian Tube Patients With Oculopharyngeal Muscular Dystrophy.

OBJECTIVES: To describe cases of patulous Eustachian tube (PET) or patent ET conditions in oculopharyngeal muscular dystrophy (OPMD). PATIENTS: Four cases of PET or patent ET conditions with OPMD. MAIN OUTCOME MEASURES: Clinical case records, objective ET function tests (tubo-tympano-aerodynamic graphy and sonotubometry), and swallowing function (videoendoscopic examination and Food Intake Level Scale) were analyzed. RESULTS: Two cases of definite PET, one case of possible PET, and one case lacking aural symptoms with findings of patent ET. All patients have ptosis, and three cases have dysphagia. Body mass index indicated that three cases were underweight. Magnetic resonance imaging in case 4 showed atrophy and fat replacement of palatine and masticatory muscles. CONCLUSIONS: It is important to consider PET or patent ET conditions when OPMD patients describe aural symptoms.

Bone Damage in Chronic Otitis Media.

The middle ear bone destruction in chronic otitis media is activated and regulated by inflammation. Chronic otitis media with granulation is a highly active inflammatory process in which many cytokines are released. The bone is degraded by osteoclasts but, at the same time, protected by cytokines, growth factors, adhesion molecules and osteotropic hormones. Tumor necrosis factor-α, interleukin (IL)-1, IL-6, and OPG/RANKL present in cholesteatoma and granulation accelerate bone lysis and increase the destructive effect on the middle ear.

Effects of cigarette smoke on Haemophilus influenzae-induced otitis media in a rat model.

Exposure to cigarette smoke (CS) is a factor that could delay or worsen the recovery of otitis media (OM) by causing inflammatory swelling of the Eustachian tube (ET). However, despite the suggested relationship, little is known about the association between OM and CS. Therefore, we aimed to evaluate the effects of CS on the development, progression, and recovery of OM, as well as the histological and molecular changes caused by CS exposure, by using a rat model of OM infected with non-typeable Haemophilus influenzae (NTHi). Eighty Sprague-Dawley rats with normal middle ears (MEs) were divided into four groups (n = 20 rats/group): control, CS, OM, and CS + OM. The CS and CS + OM groups were exposed to CS for 2 weeks. The inflammatory reaction to NTHi was more intense and lasted longer in the CS + OM group than in the other groups. Goblet cell proliferation and mucus secretion in the ET were more significant in the CS and CS + OM groups than in the other groups. These findings suggested that because CS directly affects the ET and ME mucosa, bacterial OM can become more severe and may resolve more slowly in the presence of CS exposure rather than in its absence.

IL13 May Play an Important Role in Developing Eosinophilic Chronic Rhinosinusitis and Eosinophilic Otitis Media with Severe Asthma.

A woman in her 50s was a super responder to benralizumab administered for the treatment of severe bronchial asthma (BA) with eosinophilic chronic rhinosinusitis with nasal polyp (ECRS) and eosinophilic otitis media (EOM). She exhibited the gradual exacerbation of ECRS/EOM despite good control of BA approximately 1 year after benralizumab initiation. Therefore, the treatment was switched to dupilumab, and the condition of the paranasal sinuses and middle ear greatly improved with the best control of her asthma. The patient reported that her physical condition was the best of her life. However, she developed a pulmonary opacity on chest computed tomography after 6 months. Histological examination of the lung parenchyma and cell differentiation of the bronchoalveolar lavage fluid indicated atypical chronic eosinophilic pneumonia, and treatment was switched to mepolizumab. Similarly to the period of benralizumab treatment, exacerbation of ECRS/EOM reduced her quality of life approximately 10 months after the administration of mepolizumab. Dupilumab was again introduced as a replacement for mepolizumab. The clinical course and consideration of the interaction between inflammatory cells led us to speculate that interleukin-13 could play a key role in the development of ECRS/EOM with severe BA.

The structure of nontypeable Haemophilus influenzae SapA in a closed conformation reveals a constricted ligand-binding cavity and a novel RNA binding motif.

Nontypeable Haemophilus influenzae (NTHi) is a significant pathogen in respiratory disease and otitis media. Important for NTHi survival, colonization and persistence in vivo is the Sap (sensitivity to antimicrobial peptides) ABC transporter system. Current models propose a direct role for Sap in heme and antimicrobial peptide (AMP) transport. Here, the crystal structure of SapA, the periplasmic component of Sap, in a closed, ligand bound conformation, is presented. Phylogenetic and cavity volume analysis predicts that the small, hydrophobic SapA central ligand binding cavity is most likely occupied by a hydrophobic di- or tri- peptide. The cavity is of insufficient volume to accommodate heme or folded AMPs. Crystal structures of SapA have identified surface interactions with heme and dsRNA. Heme binds SapA weakly (Kd 282 µM) through a surface exposed histidine, while the dsRNA is coordinated via residues which constitute part of a conserved motif (estimated Kd 4.4 µM). The RNA affinity falls within the range observed for characterized RNA/protein complexes. Overall, we describe in molecular-detail the interactions of SapA with heme and dsRNA and propose a role for SapA in the transport of di- or tri-peptides.

Comprehensive phenotypic analysis of the Dp1Tyb mouse strain reveals a broad range of Down syndrome-related phenotypes.

Down syndrome (DS), trisomy 21, results in many complex phenotypes including cognitive deficits, heart defects and craniofacial alterations. Phenotypes arise from an extra copy of human chromosome 21 (Hsa21) genes. However, these dosage-sensitive causative genes remain unknown. Animal models enable identification of genes and pathological mechanisms. The Dp1Tyb mouse model of DS has an extra copy of 63% of Hsa21-orthologous mouse genes. In order to establish whether this model recapitulates DS phenotypes, we comprehensively phenotyped Dp1Tyb mice using 28 tests of different physiological systems and found that 468 out of 1800 parameters were significantly altered. We show that Dp1Tyb mice have wide-ranging DS-like phenotypes, including aberrant erythropoiesis and megakaryopoiesis, reduced bone density, craniofacial changes, altered cardiac function, a pre-diabetic state, and deficits in memory, locomotion, hearing and sleep. Thus, Dp1Tyb mice are an excellent model for investigating complex DS phenotype-genotype relationships for this common disorder.

Shortwave infrared otoscopy for diagnosis of middle ear effusions: a machine-learning-based approach.

Otitis media, a common disease marked by the presence of fluid within the middle ear space, imparts a significant global health and economic burden. Identifying an effusion through the tympanic membrane is critical to diagnostic success but remains challenging due to the inherent limitations of visible light otoscopy and user interpretation. Here we describe a powerful diagnostic approach to otitis media utilizing advancements in otoscopy and machine learning. We developed an otoscope that visualizes middle ear structures and fluid in the shortwave infrared region, holding several advantages over traditional approaches. Images were captured in vivo and then processed by a novel machine learning based algorithm. The model predicts the presence of effusions with greater accuracy than current techniques, offering specificity and sensitivity over 90%. This platform has the potential to reduce costs and resources associated with otitis media, especially as improvements are made in shortwave imaging and machine learning.

Glycolytic Metabolism Is Critical for the Innate Antibacterial Defense in Acute Streptococcus pneumoniae Otitis Media.

Objective: Streptococcus pneumoniae (S.pn) is a common respiratory pathogen and a frequent cause of acute otitis media (AOM) in children. However, little is known about the immunometabolism during AOM. This study was to assess the presence of glucose metabolic reprogramming during AOM and its underlying mechanism affecting inflammatory response and middle ear injury. Methods: The levels of glycolytic metabolism were evaluated by measuring the expression of glycolysis-related genes and the production of metabolites. HE stain, immunofluorescence, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA) and Western blot were performed to measure the effect of glucose metabolic reprogramming on inflammatory response, pneumococcal clearance, hypoxia-inducible factor 1 alpha (HIF-1α) expression and cytokine secretion during AOM, respectively. Results: The analysis of microarray revealed an increase of the expression of glycolysis-related genes during S.pn-induced AOM, which was verified by real-time PCR. Increased glycolysis promoted the production of IL-1ß and TNF-α and facilitated the clearance of S.pn by enhancing phagocytosis and killing capability of neutrophils, but also aggravated the middle ear injury. Furthermore, these pathogenic effects could be reversed after glycolytic inhibitor 2DG treatment. Additionally, HIF-1α was observed to involve in glycolytic metabolism during AOM. Conclusion: S.pn infection induced increased glycolysis conversion during AOM, which promoted inflammatory responses and bacterial clearance, but also aggravated tissue damage.

The transcriptional landscape of the cultured murine middle ear epithelium in vitro.

Otitis media (OM) is the most common paediatric disease and leads to significant morbidity. Although understanding of underlying disease mechanisms is hampered by complex pathophysiology, it is clear that epithelial abnormalities underpin the disease. The mechanisms underpinning epithelial remodelling in OM remain unclear. We recently described a novel in vitro model of mouse middle ear epithelial cells (mMEECs) that undergoes mucociliary differentiation into the varied epithelial cell populations seen in the middle ear cavity. We now describe genome wide gene expression profiles of mMEECs as they undergo differentiation. We compared the gene expression profiles of original (uncultured) middle ear cells, confluent cultures of undifferentiated cells and cells that had been differentiated for 7 days at an air liquid interface (ALI). >5000 genes were differentially expressed among the three groups of cells. Approximately 4000 genes were differentially expressed between the original cells and day 0 of ALI culture. The original cell population was shown to contain a mix of cell types, including contaminating inflammatory cells that were lost on culture. Approximately 500 genes were upregulated during ALI induced differentiation. These included some secretory genes and some enzymes but most were associated with the process of ciliogenesis. The data suggest that the in vitro model of differentiated murine middle ear epithelium exhibits a transcriptional profile consistent with the mucociliary epithelium seen within the middle ear. Knowledge of the transcriptional landscape of this epithelium will provide a basis for understanding the phenotypic changes seen in murine models of OM.

Longitudinal optical coherence tomography to visualize the in vivo response of middle ear biofilms to antibiotic therapy.

Studying the impact of antibiotic treatment on otitis media (OM), the leading cause of primary care office visits during childhood, is critical to develop appropriate treatment strategies. Tracking dynamic middle ear conditions during antibiotic treatment is not readily applicable in patients, due to the limited diagnostic techniques available to detect the smaller amount and variation of middle ear effusion (MEE) and middle ear bacterial biofilm, responsible for chronic and recurrent OM. To overcome these challenges, a handheld optical coherence tomography (OCT) system has been developed to monitor in vivo response of biofilms and MEEs in the OM-induced chinchilla model, the standard model for human OM. As a result, the formation of MEE as well as biofilm adherent to the tympanic membrane (TM) was longitudinally assessed as OM developed. Various types of MEEs and biofilms in the chinchilla model were identified, which showed comparable features as those in humans. Furthermore, the effect of antibiotics on the biofilm as well as the amount and type of MEEs was investigated with low-dose and high-dose treatment (ceftriaxone). The capability of OCT to non-invasively track and examine middle ear conditions is highly beneficial for therapeutic OM studies and will lead to improved management of OM in patients.

Identifying distinct trajectories of acute otitis media in children: A prospective cohort study.

OBJECTIVES: To identify possibly distinct acute otitis media (AOM) trajectories in childhood and identify determinants associated with specific AOM trajectories. To explore which child will become prone to recurrent AOM episodes and which will not. DESIGN: Population-based prospective cohort study among 7863 children from birth until 10 years and their mothers. METHODS: This study was embedded in the Generation R Study: a population-based prospective cohort study. Data on AOM and determinants were collected by repeated parental questionnaires. Distinct AOM trajectories within the population were identified with latent-class analyses. Next, using multivariate analysis we checked whether specific determinants were associated with specific trajectories. RESULTS: Three distinct trajectories were identified; that is, non-otitis prone, early AOM-that is children who suffered AOM episodes until 3 years of age but not beyond, and persistent AOM-that is children who remained otitis-prone. Male gender (OR: 1.26, CI: 1.11-1.43) and day-care attendance (OR: 1.31, CI: 1.06-1.60) were associated with increased odds of early AOM. Breastfeeding was beneficial for children in both the early-AOM and persistent-AOM trajectories (OR: 0.78 and 0.77, respectively). Birth in the summer or autumn as compared with birth in the spring decreased odds of AOM only in the persistent-AOM trajectory. Half of all AOM-prone children recovered after the age of 3 years. CONCLUSION: Specific determinants are associated with different AOM trajectories. Future research is needed to better predict which child will remain otitis-prone and which recovers after the age of 3 years to better tailor treatment towards the needs of the individual child.

Endoscopic epitympanic exploration in mucosal chronic otitis media: is canal wall up mastoidectomy really needed?

OBJECTIVE: To compare endoscopic epitympanic exploration with conventional canal wall up (cortical) mastoidectomy for mucosal chronic otitis media in terms of post-operative outcomes. METHODS: Seventy-six patients diagnosed with chronic otitis media (mucosal variety) were randomly assigned to two treatment groups: endoscopic epitympanic exploration and conventional canal wall up (cortical) mastoidectomy. The groups were compared in terms of: post-operative anatomical outcomes (graft uptake), middle-ear physiological outcomes (post-operative tympanometry), audiological outcomes (air-bone gap), surgical time, post-operative pain, vertigo, and long-term complications such as retraction pocket and re-perforation. RESULTS: There was a statistically significant difference between the groups in terms of mean air-bone gap at 12 months, surgical time, and median post-operative pain measured at 6 hours (p < 0.05). No statistically significant differences were noted in terms of: graft uptake at 1, 3 and 6 months, mean air-bone gap at 3 and 6 months, tympanometry at 3, 6 and 12 months, vertigo at 1 week, or long-term complications. CONCLUSION: Endoscopic epitympanic exploration resulted in significantly better long-term audiological outcomes, shorter operating time and less pain compared with conventional canal wall up (cortical) mastoidectomy.