Immunomodulatory Response of the Middle Ear Epithelial Cells in Otitis Media.

HYPOTHESIS: The middle ear (ME) epithelium transforms because of changed immunomodulation during infection. INTRODUCTION: The epithelial cells of the tympanic cavity represent the first line of defense in the context of otitis media. They can convert from a typical mucosal site into a respiratory epithelium and vice versa. Our goal is to depict the specific immune response of epithelial cells after infection at the molecular level. METHODS: The investigations were carried out on healthy and inflamed ME tissue, removed during surgical interventions in mouse and human models, and in a human in-vitro cell model in human ME epithelial cell line. We determined the epithelial localization of the protein expression of Toll- and NOD-like immune receptors and their associated signaling molecules using immunohistochemistry. In addition, we examined growth behavior and gene expression due to direct stimulation and inhibition. RESULTS: We found clinically and immunobiologically confirmed transformation of the inflamed ME epithelium depending on their origin, as well as differences in the distribution of Toll-like receptors and nucleotide-binding oligomerization domain-like receptors in the epithelial cell lining. Dysregulated gene and protein expression of the inflammatory and apoptotic genes could be modulated by stimulation and inhibition in the epithelial cells. CONCLUSIONS: The local ME mucosal tissue is believed to modulate downstream immune activity after pathogen invasion via intrinsic cellular mechanism. Using translation approaches to target these molecular pathways may offer more reliable clinical resolution of otitis media in the future.

Hearing rehabilitation and microbial shift after middle ear surgery with Vibrant Soundbridge in patients with chronic otitis media.

INTRODUCTION: Patients with otitis media (OM) encounter significant functional hearing impairment with conductive, or a combined hearing loss and long-term sequelae involving impaired speech/language development in children, reduced academic achievement and irreversible disorders of middle and inner ear requiring a long time therapy and/or multiple surgeries. In its persistent chronic form, Otitis media (COM) can often only be treated by undergoing ear surgery for hearing restoration. The persistent inflammatory reaction plays a major role, often caused by multi-resistant pathogens in the ear. Herein, we present outcomes of patients implanted with currently the only FDA approved active Middle Ear Implant Vibrant Soundbridge (VSB), suffering from persistent COM. METHODS: The study enrolled 42 patients, treated by performing middle ear (ME) surgery to different extents and implanted with the VSB to various structures in the ME. Included were 17 children and 25 adults that had recurrent and/or persisting OM and significant hearing loss. Preoperative and postoperative patients' audiometric data were evaluated and the benefit with VSB assessed using the Glasgow Benefit Inventory for adults and pediatric cohorts. The microbial spectrum of pathogens was assessed before and after surgery, exploring the colonization of the otopathogens, as well as the intestinal microbiome from individually burdened patients. RESULTS: The mean functional gain is 29.7 dB HL (range from 10 to 56.2 dB HL) with a significant improvement in speech intelligibility in quiet. Following VSB implantation, no significant differences in coupling were observed at low complication rates. Postoperatively patients showed significantly increased benefit with VSB compared to the untreated situation, including less otorrhea, pain, medical visits, and medication intake, with no recurrent OM and significant bacterial shift in otopathogens. The analysis of the intestinal microbiome displayed a high abundance of bacterial strains that might be linked to chronic and persistent inflammation. CONCLUSIONS: Functional ear surgery including rehabilitation with a VSB in patients suffering from COM present to be safe and effective. The successful acceptance accompanied by the improved audiological performance resulted in significant benefit with VSB, with a shift in the ear pathogens and altered microbiome and thus is a great opportunity to be treated.

Immunomodulation as a Protective Strategy in Chronic Otitis Media.

Introduction: Major features of the pathogenesis in otitis media, the most common disease in childhood, include hyperplasia of the middle ear mucosa and infiltration by leukocytes, both of which typically resolve upon bacterial clearance via apoptosis. Activation of innate immune receptors during the inflammatory process leads to the activation of intracellular transcription factors (such as NF-κB, AP-1), which regulate both the inflammatory response and tissue growth. We investigated these leading signaling pathways in otitis media using mouse models, human samples, and human middle ear epithelial cell (HMEEC) lines for therapeutic immunomodulation. Methods: A stable otitis media model in wild-type mice and immunodeficient KO-mice, as well as human tissue samples from chronic otitis media, skin from the external auditory canal and middle ear mucosa removed from patients undergoing ear surgery, were studied. Gene and protein expression of innate immune signaling molecules were evaluated using microarray, qPCR and IHC. In situ apoptosis detection determined the apoptotic rate. The influence of bacterial infection on immunomodulating molecules (TNFα, MDP, Tri-DAP, SB203580, Cycloheximide) in HMEEC was evaluated. HMEEC cells were examined after bacterial stimulation/inhibition for gene expression and cellular growth. Results: Persistent mucosal hyperplasia of the middle ear mucosa in chronic otitis media resulted from gene and protein expression of inflammatory and apoptotic genes, including NODs, TNFα, Casp3 and cleaved Casp3. In clinical chronic middle ear samples, these molecules were modulated after a specific stimulation. They also induced a hyposensitive response after bacterial/NOD-/TLR-pathway double stimulation of HMEEC cells in vitro. Hence, they might be suitable targets for immunological therapeutic approaches. Conclusion: Uncontrolled middle ear mucosal hyperplasia is triggered by TLRs/NLRs immunoreceptor activation of downstream inflammatory and apoptotic molecules.

[Immunomodulation in Cholesteatoma]. / Immunmodulation im Cholesteatom.

INTRODUCTION: The etiopathogenesis of chronic otitis media epitympanalis/cholesteatoma and its proliferative destructive course with possible complications such as destruction of bony structures with hearing loss, vestibular dysfunction, facial nerve paralysis and intracranial complications are still unexplained. Surgery is still the way to go. New studies are increasingly looking at the innate immune system. METHODS: Our studies were carried out in a mouse model in WT mice and immundeficient KO-mice, as well as in cholesteatoma and healthy ear canal skin and middle ear tissue, which was removed during ear surgery. The expression analyses were carried out at the gene and protein level using TNF as the major target for therapy evaluation. By means of TUNEL staining and immunohistochemistry the level of apoptosis was evaluated. RESULTS: The uncontrolled undirected cholesteatoma growth shows an immunomodulatory profile with up and down-regulation of various gene networks, especially those involved in TNF downstream and upstream signaling pathways. TNF in cholesteatoma is modulated both inflammatorily and apoptotically and therefore is suitable as a possible therapeutic approach in various models. CONCLUSIONS: Cholesteatoma might be immunomodulatory regulated.

[Effort-Reward Imbalance among otolaryngology residents in Germany]. / Psychosoziale Arbeitsbelastung von Ärzten in der HNO-Facharztweiterbildung.

INTRODUCTION: An increased psychosocial workload can have an negative impact on health. An effective way to record this is the effort reward imbalance model postulated by Siegrist. Values on this topic from ENT residents are missing, which is why the concept and corresponding questions were included in the survey on the current situation in further education. MATERIAL AND METHODS: An online survey on the current situation of the ENT residency including the recording of psychosocial workload was developed by ENT physicians on the basis of a well-known questionnaire of colleagues of the Alliance of Young Physicians. The short version of the validated questionnaire on the effort reward imbalance model according to Siegrist with 16 items was used. An online survey was carried out addressing all ENT residents in Germany known to the German society of Oto-Rhino-Laryngology, Head and Neck surgery. The survey was sent by e-mail and was available from April 1st to July 31st in 2019. RESULTS: 92,3 % of the participants had an effort-reward imbalance. The mean value of effort reward imbalance was 1.57 ± 0.43, adjusted 2.16 ±â€Š1.36. The effort scale was 10.71 ±â€Š1.40 (3-12), adjusted 85.72 ±â€Š15.52, reward scale 16.58 ±â€Š2.86 (7-28), adjusted 45.61 ±â€Š13.63, over commitment 17 ±â€Š3.37, adjusted 61.14 ±â€Š18.73. A high effort reward imbalance had positive significant correlations with regard to the duration of residency, the number of working hours per week and the number of duty hours per month. CONCLUSION: The effort and reward imbalance is comparable to other specialty physicians in residency. It is related to working hours, services and the progress of training. It can be improved through personal initiative and could be supplemented with the support of the hospital's internal stakeholders.

[Survey on current situation in otolaryngology residency]. / Umfrage der "Jungen HNO" zur aktuellen Situation der Weiterbildung von HNO-Ärzten.

BACKGROUND: Residents of ENT were asked about their situation in residency. A good and well structured training is the key for an attractive residency. METHODS: Between April 25-August 1, 2019, 691 residents registered with the German Society of Otorhinolaryngology, Head- and Neck Surgery ENT society were invited to anonymously participate in an online survey using SurveyMonkey® on the situation of the education in ENT and their working conditions. 25 of 80 questions were asked on the topics of structure and quality of the education in residency. RESULTS: The response rate was 36 % (n = 249). The participants attested their further training an average result. Mainly they see deficits in the further education and training structure and culture with a desire for improved feedback and improved surgical training. Participants were more dissatisfied with advanced further training time, regardless of ownership of the institution and level of care. CONCLUSIONS: The survey proposes concrete advice for improvement of ENT medical training in Germany. Suggestions for improvement are further development of the associated training and continuing education programs in cooperation with professional associations, structured feedback and supervision as well as transparent rotation plans and reliable working conditions.

[Survey on the need for an e-learning-platform for ENT residents]. / Umfrage zum Bedarf einer e-Learning-Plattform für Ärzte in der HNO-Facharzt-Weiterbildung.

OBJECTIVE: Interactive e-learning-platforms may replace the classical textbook in the future. Such media have the possible advantage of including video and audio files in a more comprehensive way, but ENT-specific platforms do not currently exist. So far, the actual needs and wishes of ENT residents are unclear and may be affected by the so called digital revolution. MATERIAL AND METHODS: An online survey was carried out addressing all ENT residents in Germany known to the German society of oto-rhino-laryngology, head and neck surgery. A 17-items survey was developed by ENT doctors receiving and providing training and distributed by e-mail. The survey was available to answer in April and May 2019. RESULTS: A total of 150 out of 671 ENT specialists and residents took part in the study. Of these, 80 % were residents and 20 % were ENT specialists. 63-80 % of the respondents already use online media in general at work, in preparation for the ENT specialist examination, for training purposes and for support as a clinician. 92-95 % of the participants indicated the willingness to use an interactive platform for their ENT specialist examination preparation and further training. On average, e-learning media are used by the responders to prepare for the ENT specialist examination or in clinical everyday life and for further training 108 or 130 min/week. The desire for surgical instruction videos is also very high. CONCLUSION: There is a high demand for a structured e-learning-platform especially for ENT. An interactive e-learning-platform would ensure, supplement and support qualified education and training.