Pathogenesis Of Otitis Media Research Articles

RNA Sequencing and Pathways Analyses of Middle Ear Epithelia From Patients With Otitis Media.

Otitis media (OM) is the most common pediatric diagnosis in the United States. However, our understanding of the molecular pathogenesis of OM remains relatively poor. Investigation of molecular pathways involved in OM may improve the understanding of this disease process and elucidate novel therapeutic targets. In this study, RNA sequencing (RNA-Seq) was used to discern cellular changes associated with OME compared to healthy middle ear epithelium (MEE). Ex vivo case-control translational. Middle ear epithelia was collected from five pediatric patients diagnosed with OME undergoing tympanostomy tube placement and five otherwise healthy pediatric patients undergoing cochlear implantation. Specimens underwent RNA-Seq and pathways analyses. A total of 1,292 genes exhibited differential expression in MEE from OME patients compared to controls including genes involved in inflammation, immune response to bacterial OM pathogens, mucociliary clearance, regulation of proliferation and transformation, and auditory cell differentiation. Top networks identified in OME were organismal injury and abnormalities, cell morphology, and auditory disease. Top Ingenuity canonical pathways identified were axonal guidance signaling, which contains genes associated with auditory development and disease and nicotine degradation II and III pathways. Associated upstream regulators included β-estradiol, dexamethasone, and G-protein-coupled estrogen receptor-1 (GPER1), which are associated with otoprotection or inflammation during insult. RNA-Seq demonstrates differential gene expression in MEE from patients with OME compared to healthy controls with important implications for infection susceptibility, hearing loss, and a role for tobacco exposure in the development and/or severity of OME in pediatric patients. 4 Laryngoscope, 131:2590-2597, 2021.

Nasopharyngeal Microbiota Analysis in Healthy and Otitis-prone Children: Focus on History of Spontaneous Tympanic Membrane Perforation.

Recurrent acute otitis media (RAOM) is common in children, and it may result in spontaneous tympanic membrane perforation (STMP), management of which is often challenging. In the upper respiratory tract (URT), resident microorganisms play a pivotal role in otitis media pathogenesis and prevention, as they are able to inhibit the colonization process and otopathogens growth. In particular, Dolosigranulum spp. and Corynebacterium spp. have been associated with respiratory health in several studies. This study aims at comparing both nasopharyngeal microbiota of children with RAOM versus matched controls and nasopharyngeal microbiota of children with a history of RAOM with STMP. Nasopharyngeal swabs were collected from 132 children, median age 3.51 (2.13-4.72), including 36 healthy children, 50 with RAOM without STMP, and 46 with RAOM with STMP. Bacterial DNA was subsequently extracted and 16S rRNA gene V3-V4 regions were polymerase chain reaction amplified and sequenced using Illumina MiSeq technology. A higher relative abundance of Dolosigranulum and Corynebacterium genera was detected in the nasopharynx of healthy children (16.5% and 9.3%, respectively) in comparison with RAOM without STMP (8.9% and 4.3%, respectively) and RAOM with STMP (5.2% and 2.8%, respectively). A decreasing pattern in relative abundance of these 2 pivotal genera through disease severity was detected. In all groups, the most abundant genera were Moraxella, Streptococcus and Haemophilus, followed by Dolosigranulum and Corynebacterium. Our study provides a characterization of the URT microbiota in otitis-prone children with and without history of recurrent STMP, suggesting that the role of Dolosigranulum and Corynebacterium in regulating the healthy URT microbiota should be further studied.

The Role of Serum Adhesion Molecules s-ICAM-1 and s-VCAM-1 in Chronic Otitis Media Pathogenesis: A Prospective Controlled Study.

The aim of this study was to determine the levels of soluble intracellular adhesion molecule-1 (s-ICAM-1) and soluble vascular cell adhesion molecule- 1 (s-VCAM-1) in patients with chronic otitis media (COM) according to the disease profile and to compare with ears without otitis media. Eighty-nine patients had ear surgery were included in the study prospectively. 78 patients who underwent tympanomastoidectomy included in the study group and 11 patients who underwent exploratory tympanotomy included in the control group prospectively. The level of s-ICAM-1 and s-VCAM-1 measured with ELISA technique. s-ICAM-1 and s-VCAM-1 levels compared between COM specific diseases group and with the control group. Levels of s-ICAM-1 and s-VCAM-1 measured as 584.5 ± 165.3ng/ml and 541.1 ± 237.3ng/ml in patients with COM, 384.4 ± 99.6ng/ml and 551.7 ± 336.4ng/ml in the control group respectively. The mean of s-ICAM-1 detected significantly higher in the COM group (p < 0.001). But the mean of s-VCAM-1 in the COM and control group was similar (p = 0.895). Also, s-ICAM-1 was significantly higher in patients with cholesteatoma, ossicular chain defects and tympanic membrane retraction (p = 0.037, 0.045 and 0.032, respectively). Although s-VCAM-1 level was not affected by cholesteatoma, ossicular chain defect and tympanic membrane retraction (p = 0.178, 0.243, p = 0.164, respectively). While the mean of s-ICAM-1 was detected significantly higher in COM and related pathologies therefore, increased serum levels may reflect the severity of the disease. But, s-VCAM-1 was not affected by COM and COM-specific diseases.

Upper Respiratory Tract Microbiome and Otitis Media Intertalk: Lessons from the Literature.

Otitis media (OM) is one of the most common diseases occurring during childhood. Microbiological investigations concerning this topic have been primarily focused on the four classical otopathogens (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pyogenes) mainly because most of the studies have been conducted with culture-dependent methods. In recent years, the introduction of culture-independent techniques has allowed high-throughput investigation of entire bacterial communities, leading to a better comprehension of the role of resident flora in health and disease. The upper respiratory tract (URT) is a region of major interest in otitis media pathogenesis, as it could serve as a source of pathogens for the middle ear (ME). Studies conducted with culture-independent methods in the URT and ME have provided novel insights on the pathogenesis of middle ear diseases through the identification of both possible new causative agents and of potential protective bacteria, showing that imbalances in bacterial communities could influence the natural history of otitis media in children. The aim of this review is to examine available evidence in microbiome research and otitis media in the pediatric age, with a focus on its different phenotypes: acute otitis media, otitis media with effusion and chronic suppurative otitis media.

Analysis of Inflammatory Signaling in Human Middle Ear Cell Culture Models of Pediatric Otitis Media.

Cell culture models are valuable tools for investigation of the molecular pathogenesis of diseases including otitis media (OM). Previous study indicates that age-, sex-, and race-associated differences in molecular signaling may impact disease pathophysiology. Currently, a singular immortalized middle ear epithelial (MEE) cell line exists, HMEEC-1, derived from an adult without known middle ear disease. In this study, HMEEC-1 and primary MEE cultures from pediatric patients with and without OM were stimulated with inflammatory cytokines or OM-pathogenic bacterial lysates to examine differences in the response of molecules associated with OM pathogenesis. Case-control series. MEE cultures were established from patients aged <6 years: two with recurrent OM (ROM), two with OM with effusion (OME), and one patient without OM who was undergoing cochlear implant surgery control undergoing cochlear implantation (Peds CI). Primary MEE cultures and HMEEC-1 cells were stimulated with tumor necrosis factor-α, interleukin (IL)-1β, or nontypeable Haemophilus influenzae lysate. TNFA, IL1B, IL6, IL8, IL10, and MUC5B were assayed via quantitative polymerase chain reaction. IL-8 was assayed by enzyme-linked immunosorbent assay. Gene/protein target expressions were frequently higher in pediatric OM lines than in HMEEC-1 and Peds CI. HMEEC-1 cells were frequently less responsive to stimuli than all pediatric lines. OME lines were often more responsive than ROM lines. OM may be associated with specific molecular phenotypes that are retained in primary cell culture. Adult-derived HMEEC-1 cells differ significantly in baseline expression and response of OM-associated molecules relative to pediatric MEE cells. Work is underway to immortalize pediatric OM MEE cultures as improved tools for the OM research community. 4 Laryngoscope, 131:410-416, 2021.

Genomics of Otitis Media (OM): Molecular Genetics Approaches to Characterize Disease Pathophysiology.

Otitis media (OM) is an infective and inflammatory disorder known to be a major cause of hearing impairment across all age groups. Both acute and chronic OM result in substantial healthcare utilization related to antibiotic prescription and surgical procedures necessary for its management. Although several studies provided evidence of genetics playing a significant role in the susceptibility to OM, we had limited knowledge about the genes associated with OM until recently. Here we have summarized the known genetic factors that confer susceptibility to various forms of OM in mice and in humans and their genetic load, along with associated cellular signaling pathways. Spotlighted in this review are fucosyltransferase (FUT) enzymes, which have been implicated in the pathogenesis of OM. A comprehensive understanding of the functions of OM-associated genes may provide potential opportunities for its diagnosis and treatment.

Vinpocetine Suppresses Streptococcus pneumoniae-Induced Inflammation via Inhibition of ERK1 by CYLD.

Otitis media (OM) is the most common bacterial infection in children. It remains a major health problem and a substantial socioeconomic burden. Streptococcus pneumoniae (S. pneumoniae) is one of the most common bacterial pathogens causing OM. Innate inflammatory response plays a critical role in host defense against bacterial pathogens. However, if excessive, it has a detrimental impact on the middle ear, leading to middle ear inflammation, a hallmark of OM. Currently, there has been limited success in developing effective therapeutic agents to suppress inflammation without serious side effects. In this study, we show that vinpocetine, an antistroke drug, suppressed S. pneumoniae-induced inflammatory response in cultured middle ear epithelial cells as well as in the middle ear of mice. Interestingly, vinpocetine inhibited S. pneumoniae-induced inflammation via upregulating a key negative regulator cylindromatosis (CYLD). Moreover, CYLD suppressed S. pneumoniae-induced inflammation via inhibiting the activation of ERK. Importantly, the postinfection administration of vinpocetine markedly inhibited middle ear inflammation induced by S. pneumoniae in a well-established mouse OM model. These studies provide insights into the molecular mechanisms underlying the tight regulation of inflammation via inhibition of ERK by CYLD and identified vinpocetine as a potential therapeutic agent for suppressing the inflammatory response in the pathogenesis of OM via upregulating negative regulator CYLD expression.

Reviewing the Pathogenic Potential of the Otitis-Associated Bacteria Alloiococcus otitidis and Turicella otitidis.

Alloiococcus otitidis and Turicella otitidis are common bacteria of the human ear. They have frequently been isolated from the middle ear of children with otitis media (OM), though their potential role in this disease remains unclear and confounded due to their presence as commensal inhabitants of the external auditory canal. In this review, we summarize the current literature on these organisms with an emphasis on their role in OM. Much of the literature focuses on the presence and abundance of these organisms, and little work has been done to explore their activity in the middle ear. We find there is currently insufficient evidence available to determine whether these organisms are pathogens, commensals or contribute indirectly to the pathogenesis of OM. However, building on the knowledge currently available, we suggest future approaches aimed at providing stronger evidence to determine whether A. otitidis and T. otitidis are involved in the pathogenesis of OM. Such evidence will increase our understanding of the microbial risk factors contributing to OM and may lead to novel treatment approaches for severe and recurrent disease.

Serum Interleukin-6 level a risk factor in pathogenesis of otitis media with effusion in children?

Objective: The aim of the study was to detect the serum level of cytokine interleukin-6 (IL-6) in children with persistent Otitis media with effusion (OME). Patients and methods: 50 children with OME divided into 3 groups, a group I consisted of 30 children who had persistent otitis media with effusion and did not improve by medical and surgical treatment. The age range of 5.8 ± 3. 4 years. Group (II) consisted of 20 children who had two or fewer OME episodes per year and improved by medical treatment and did not have a history of tubes insertion. The age range 6.3± 2.9 years. Group III consisted of 52 normal patients with similar age and sex as a control group. Results: There was no significant difference between group I and group II. There was a significance difference between each group and normal patients. Conclusion: The result of the present study suggesting that pro-inflammatory cytokine level Il-6 (IL-6) is significantly increased with persistent OME in children in comparison with normal patients.

Current Understanding of Host Genetics of Otitis Media.

The pathogenesis of otitis media (OM), an inflammatory disease of the middle ear (ME), involves interplay between many different factors, including the pathogenicity of infectious pathogens, host immunological status, environmental factors, and genetic predisposition, which is known to be a key determinant of OM susceptibility. Animal models and human genetics studies have identified many genes and gene variants associated with OM susceptibility: genes that encode components of multiple signaling pathways involved in host immunity and inflammatory responses of the ME mucosa; genes involved in cellular function, such as mucociliary transport, mucin production, and mucous cell metaplasia; and genes that are essential for Eustachian tube (ET) development, ME cavitation, and homeostasis. Since our last review, several new mouse models with mutations in genes such as CCL3, IL-17A, and Nisch have been reported. Moreover, genetic variants and polymorphisms in several genes, including FNDC1, FUT2, A2ML1, TGIF1, CD44, and IL1-RA variable number tandem repeat (VNTR) allele 2, have been identified as being significantly associated with OM. In this review, we focus on the current understanding of the role of host genetics in OM, including recent discoveries and future research prospects. Further studies on the genes identified thus far and the discovery of new genes using advanced technologies such as gene editing, next generation sequencing, and genome-wide association studies, will advance our understanding of the molecular mechanism underlying the pathogenesis of OM and provide new avenues for early screening and developing effective preventative and therapeutic strategies to treat OM.

Association Between Enlarged Adenoid and Otitis Media with Effusion in Children

Objectives: To assess the association between enlarged adenoid and otitis media with effusion in children.&#x0D; Methods: This cross sectional comparative study was carried out in the Department of Otolaryngology-Head &amp; Neck Surgery in Bangabandhu Sheikh Mujib Medical University, from July 2013 to June 2015. Thirty children with enlarged adenoids (case) and 30 children without enlarged adenoids (control) were included in this study. All patients subjected for history, local physical examination and evaluation of adenoid size by lateral X-ray of post nasal space. Tympanometry and pure tone audiometry are also done. Information’s recorded on a specially designed data sheet.&#x0D; Result: Among 30 case and 30 control, 12 (40.0%) and 2 (6.7%) patient had OME in case and control group respectively, mean age was 9.5 (2.76%) years and 9.96 (2.95%) in case and control group respectively. Male were predominant (70%) than female (30.0%) in cases. Among cases, grade- I was 20.0%, grade II- was 33.3% and grade-III was 46.7%. Hearing loss was found in 14 (46.7%) children. According to tympanometry, type A curve was in 17 (56.7%) children, type B in 9 (30.0%) and type C in 4 (13.3%) cases.&#x0D; Conclusion: Enlarged adenoids can be relevant in the pathogenesis of otitis media with effusion.&#x0D; Bangladesh J Otorhinolaryngol; April 2019; 25(1): 47-53

High concentrations of middle ear antimicrobial peptides and proteins and proinflammatory cytokines are associated with detection of middle ear pathogens in children with recurrent acute otitis media.

Recurrent and chronic otitis media (OM) are often refractory to antibiotics due to bacterial persistence in biofilm within the middle ear. In vitro and in vivo studies have demonstrated that antimicrobial proteins and peptides (AMPs) are bactericidal against otopathogens, indicating potential therapeutic value for recalcitrant OM. We measured concentrations of 6 AMPs and 14 cytokines in middle ear effusion (MEE) from 67 children undergoing ventilation tube insertion for recurrent acute OM. Sixty one percent of children had bacterial otopathogens detected in their MEE, 39% by PCR and 22% by PCR and culture. Groups were defined as: PCR-negative/culture-negative (absence of bacterial otopathogen), n = 26; PCR-positive/culture-negative (presence of nonculturable bacterial otopathogen), n = 26; PCR-positive/culture-positive (presence of culturable bacterial otopathogen), n = 15. Age, antibiotic usage, day-care attendance, presence of respiratory viruses in MEE and number of AOM episodes were similar between groups. AMP and cytokine concentrations were higher in children with bacterial otopathogens in their MEE compared to those with no bacterial otopathogens. Median concentrations of AMPs (except HBD2) were 3 to 56-fold higher in MEE from children with bacterial otopathogens detected in their MEE (P ≤ 0.01). Similarly, median cytokine concentrations (except TGFβ) were >16-fold higher in MEE with bacterial otopathogens detected (P ≤ 0.001). This is the first study to measure AMPs in MEE and together with the cytokine data, results suggest that elevated AMPs and cytokines in MEE are a marker of inflammation and bacterial persistence. AMPs may play an important role in OM pathogenesis.

Panel 7 – Pathogenesis of otitis media – a review of the literature between 2015 and 2019

ObjectiveTo perform a comprehensive review of the literature from July 2015 to June 2019 on the pathogenesis of otitis media. Bacteria, viruses and the role of the microbiome as well as the host response are discussed. Directions for future research are also suggested. Data sourcesPubMed database of the National Library of Medicine. Review methodsPubMed was searched for any papers pertaining to OM pathogenesis between July 2015 and June 2019. If in English, abstracts were assessed individually for their relevance and included in the report. Members of the panel drafted the report based on these searches and on new data presented at the 20th International Symposium on Recent Advances in Otitis Media. ConclusionsThe main themes that arose in OM pathogenesis were around the need for symptomatic viral infections to develop disease. Different populations potentially having different mechanisms of pathogenesis. Novel bacterial otopathogens are emerging and need to be monitored. Animal models need to continue to be developed and used to understand disease pathogenesis. Implications for PracticeThe findings in the pathogenesis panel have several implications for both research and clinical practice. The most urgent areas appear to be to continue monitoring the emergence of novel otopathogens, and the need to develop prevention and preventative therapies that do not rely on antibiotics and protect against the development of the initial OM episode.

Panel 2- recent advance in otitis media bioinformatics

ObjectivesTo update the medical literature on recent large-scale studies employing bioinformatics data analysis tools in otitis media (OM) disease models with a principal focus on developments in the past 5 years. Data sourcesPubmed indexed peer-reviewed articles. Review methodsComprehensive review of the literature using the following search terms: ‘genomics, inflammasome, microRNA, proteomics, transcriptome, bioinformatics’ with the term ‘otitis media’, and ‘middle ear’. Included articles published in the English language from January 1, 2015–April 1, 2019. Implications for practiceLarge scale bioinformatics tools over the past five years lend credence to the paradigm of innate immune response playing a critical role in host defense against bacteria contributing to Otitis Media (OM) progression from acute to chronic. In total, genomic, miRNAomic, and proteomic analyses all point to the need for a tightly regulated innate immune and inflammatory response in the middle ear. Currently, there is an urgent need for developing novel therapeutic strategies to control immunopathology and tissue damage, improve hearing and enhance host defense for both acute and chronic OM based on full understanding of the basic molecular pathogenesis of OM.

Panel 4: Recent advances in understanding the natural history of the otitis media microbiome and its response to environmental pressures

ObjectiveTo perform a comprehensive review of otitis media microbiome literature published between 1st July 2015 and 30th June 2019. Data sourcesPubMed database, National Library of Medicine. Review methodsKey topics were assigned to each panel member for detailed review. Draft reviews were collated and circulated for discussion when the panel met at the 20th International Symposium on Recent Advances in Otitis Media in June 2019. The final draft was prepared with input from all panel members. ConclusionsMuch has been learned about the different types of bacteria (including commensals) present in the upper respiratory microbiome, but little is known about the virome and mycobiome. A small number of studies have investigated the middle ear microbiome; however, current data are often limited by small sample sizes and methodological heterogeneity between studies. Furthermore, limited reporting of sample collection methods mean that it is often difficult to determine whether bacteria detected in middle ear fluid specimens originated from the middle ear or the external auditory canal. Recent in vitro studies suggest that bacterial interactions in the nasal/nasopharyngeal microbiome may affect otitis media pathogenesis by modifying otopathogen behaviours. Impacts of environmental pressures (e.g. smoke, nutrition) and clinical interventions (e.g. vaccination, antibiotics) on the upper respiratory and middle ear microbiomes remain poorly understood as there are few data. Implications for practiceAdvances in understanding bacterial dynamics in the upper airway microbiome are driving development of microbiota-modifying therapies to prevent or treat disease (e.g. probiotics). Further advances in otitis media microbiomics will likely require technological improvements that overcome the current limitations of OMICs technologies when applied to low volume and low biomass specimens that potentially contain high numbers of host cells. Improved laboratory models are needed to elucidate mechanistic interactions among the upper respiratory and middle ear microbiomes. Minimum reporting standards are critically needed to improve inter-study comparisons and enable future meta-analyses.

Recent Perspectives on Gene-Microbe Interactions Determining Predisposition to Otitis Media.

A comprehensive understanding about the pathogenesis of otitis media (OM), one of the most common pediatric diseases, has the potential to alleviate a substantial disease burden across the globe. Advancements in genetic and bioinformatic detection methods, as well as a growing interest in the microbiome, has enhanced the capability of researchers to investigate the interplay between host genes, host microbiome, invading bacteria, and resulting OM susceptibility. Early studies deciphering the role of genetics in OM susceptibility assessed the heritability of the phenotype in twin and triplet studies, followed by linkage studies, candidate gene approaches, and genome-wide association studies that have helped in the identification of specific loci. With the advancements in techniques, various chromosomal regions and genes such as FBXO11, TGIF1, FUT2, FNDC1, and others have been implicated in predisposition to OM, yet questions still remain as to whether these implicated genes truly play a causative role in OM and to what extent. Meanwhile, 16S ribosomal RNA (rRNA) sequencing, microbial quantitative trait loci (mbQTL), and microbial genome-wide association studies (mGWAS) have mapped the microbiome of upper airways sites and therefore helped in enabling a more detailed study of interactions between host polymorphisms and host microbiome composition. Variants of specific genes conferring increased OM susceptibility, such as A2ML1, have also been shown to influence the microbial composition of the outer and middle ear in patients with OM, suggesting their role as mediators of disease. These interactions appear to impact the colonization of known otopathogens (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis), as well as Neisseria, Gemella, Porphyromonas, Alloprevotella, and Fusobacterium populations that have also been implicated in OM pathogenesis. Meanwhile, studies demonstrating an increased abundance of Dolosigranulum and Corynebacterium in healthy patients compared to those with OM suggest a protective role for these bacteria, thereby introducing potential avenues for future probiotic treatment. Incorporating insights from these genetic, microbiome, and host-pathogen studies will allow for a more robust, comprehensive understanding of OM pathogenesis that can ultimately facilitate in the development of exciting new treatment modalities.

Assessment of the role of otoendoscopy in evaluating Eustachian tube and middle ear status during myringoplasty

ObjectiveTo assess the role of otoendoscopy in evaluating Eustachian tube and middle ear status during myringoplasty.BackgroundEustachian tube function has been the center of focus as a prognostic factor for middle ear surgery success because of its primary role in the middle ear aeration and in the pathogenesis of otitis media. Otoendoscopic evaluation of Eustachian tube allows visualization of the protympanic segment of the Eustachian tube and hidden recesses of the middle ear.Patients and methodsIn this prospective study, patients with a persistent dry central tympanic membrane perforation were operated at Otorhinolaryngology Department of Menoufia University Hospital in the period from March 2017 to February 2019. All patients were divided into two groups: group A included 50 cases that underwent otoendoscopic-assisted microscopic myringoplasty, and group B had 50 cases that underwent microscopic myringoplasty.ResultsThis study included 100 patients, with a mean age of 30.2 years. Overall, 42% of the patients were male and 58% of the patients were female. Otoendoscopic examination of middle ear in group A showed 20% of cases with adhesions and secretions at tympanic orifice of the Eustachian tube opening plus 8% of cases with congested mucosa at middle ear apparatus. The success of graft uptake was 94% in group A and 84% in group B.ConclusionThe result of this study supports the use of otoendoscopy in traditional microscopic myringoplasty. Endoscopy could be utilized efficiently to improve the visibility of the Eustachian tube opening and middle ear apparatus and then dealing with any pathology affecting them.

NOD1/NOD2-mediated recognition of non-typeable Haemophilus influenzae activates innate immunity during otitis media.

Pathogen recognition following infection in mammals depends mainly on TLRs and NLRs. Herein, we evaluate the role of NOD1 and NOD2 signaling in the inflammatory responses of the middle ear (ME) mucosa and leukocytes recruitment to infection site during otitis media (OM). OM is a common pediatric disease with prevalent repercussions on hearing health. While many risk factors have been implicated to OM proneness, immunity and the triggering of inflammation are central to OM pathology. We observed that many genes encoding members of the NOD leucine-rich repeat and their downstream adaptor/effector molecules were strongly regulated during the course of OM. When compared to wild type C57BL/6 mice, NOD1- and NOD2-deficient mice were susceptible to prolonged OM infection by non-typeable Haemophilus influenza. NOD1-deficient mice appeared to have reduced macrophage enlistment with a delayed inflammatory response by neutrophils and prolonged mucosal hyperplasia, whereas NOD2 knockouts exhibited an overall reduction in the number of leukocytes recruited to the ME, leading to delayed bacterial clearance. Altogether, these data show that the NODs play a role in the pathogenesis and recovery of OM and reinforce the importance of innate immune signaling in the protective host response.

Antibiotic modulation of mucins in otitis media; should this change our approach to watchful waiting?

BackgroundGel-forming mucins (GFMs) play important roles in otitis media (OM) pathogenesis. Increased mucin expression is activated by pathogens and proinflammatory cytokines. Bacterial biofilms influence inflammation and resolution of OM and may contribute to prolonged mucin production. The influence of specific pathogens on mucin expression and development of chronic OM with effusion (OME) remains an area of significant knowledge deficit. ObjectivesTo assess the relationship between GFM expression, specific pathogens, middle ear mucosal (MEM) changes, biofilm formation, and antibiotic utilization. MethodsMixed gender chinchillas were inoculated with nontypeable Haemophilus influenzae (NTHi) strain 86028NP or Streptococcus pneumoniae (SP) strain TIGR4 via transbulla injection. Antibiotic was administered on day 3–5 post inoculation. GFM expression was measured by quantitative PCR. Biofilm formation was identified and middle ear histologic changes were measured. ResultsSP infection resulted in higher incidence of biofilm and ME effusion compared with NTHi infection. However, NTHi persisted in the ME longer than SP with no substantive bacterial clearance detected on day 10 compared with complete bacterial clearance on day 10 for 50–60% of the SP-infected chinchillas. Both infections increased MEM inflammatory cell infiltration and thickening. NTHi upregulated the Muc5AC, Muc5B and Muc19 expression on day 10 (p = 0.0004, 0.003, and 0.002 respectively). SP-induced GFM upregulations were trended toward significant. In both NTHi and SP infections, the degree of GFM upregulation had a direct relationship to increased MEM hypertrophy, inflammatory cell infiltration and biofilm formation. Antibiotic treatment reduced the incidence of ME effusion and biofilm, limited the MEM changes and reversed the GFM upregulation. In NTHi infection, the rate of returning to baseline level of GFMs in treated chinchillas was quicker than those without treatment. ConclusionsIn an animal model of OM, GFM genes are upregulated in conjunction with MEM hypertrophy and biofilm formation. This upregulation is less robust and more quickly ameliorated to a significant degree in the NTHi infection with appropriate antibiotic therapy. These findings contribute to the understanding of pathogen specific influences on mucin expression during OM pathogenesis and provide new data which may have implications in clinical approach for OM treatment.

Translating Recent Microbiome Insights in Otitis Media into Probiotic Strategies.

The microbiota of the upper respiratory tract (URT) protects the host from bacterial pathogenic colonization by competing for adherence to epithelial cells and by immune response regulation that includes the activation of antimicrobial and (anti-)inflammatory components. However, environmental or host factors can modify the microbiota to an unstable community that predisposes the host to infection or inflammation. One of the URT diseases most often encountered in children is otitis media (OM). The role of pathogenic bacteria like Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the pathogenesis of OM is well documented. Results from next-generation-sequencing (NGS) studies reveal other bacterial taxa involved in OM, such as Turicella and Alloiococcus Such studies can also identify bacterial taxa that are potentially protective against URT infections, whose beneficial action needs to be substantiated in relevant experimental models and clinical trials. Of note, lactic acid bacteria (LAB) are members of the URT microbiota and associated with a URT ecosystem that is deemed healthy, based on NGS and some experimental and clinical studies. These observations have formed the basis of this review, in which we describe the current knowledge of the molecular and clinical potential of LAB in the URT, which is currently underexplored in microbiome and probiotic research.