A core outcome set for research on the management of otitis media with effusion in otherwise-healthy children.

INTRODUCTION: A Core Outcome Set (COS) is an agreed list of outcome domains to be reported by all studies investigating a condition. A COS for Otitis Media with Effusion (OME) in children with cleft palate exists (called MOMENT), but there isn't one for otherwise-healthy children. This study investigates whether the MOMENT COS could also be applicable to otherwise-healthy children. METHODS: A long list of potential outcomes was generated (independently of MOMENT) via three methods: literature review to establish which outcomes are reported by OME studies, a review of outcomes contained in OME questionnaires, and a focus group asking parents of children with OME what matters to them. The long list drawn up using these sources identified no outcomes additional to ones in the MOMENT long list. An online questionnaire was subsequently undertaken, asking parents/guardians and professionals/researchers whether they think that the MOMENT final list outcomes would also be applicable to otherwise healthy children. RESULTS: A total of 134 people took part: 53 parents/guardians (recruited through UK NHS hospitals) and 81 professionals/researchers (recruited internationally). Overall, 128 (95.5%) agreed that the MOMENT outcomes can also apply to otherwise healthy children (100% parents/guardians, 92.6% professionals/researchers). CONCLUSIONS: The outcome domains identified in the COS for OME management in children with cleft palate can also be used in otherwise-healthy children.

OMQ-14 and ECLiPS questionnaires: Potential adjuncts in the assessment of otitis media with effusion?

OBJECTIVE: To assess the capacity of two parental report questionnaires, OMQ-14 and ECLiPS, to support clinical-decision making in children affected by Otitis Media with Effusion (OME). DESIGN: OMQ-14 and ECLiPS were administered twice to 90 children aged 2-12 years, three months apart, or 3 months after surgery to insert ventilation tubes (VT). Children were subdivided according to clinical diagnosis into VT (n = 25) and Active Observation (AO; n = 20), and compared with healthy control children (n = 45). Data were analyzed at group level using repeated measures ANOVA, and at individual level using Receiver Operator Characteristics (ROC) curves and confusion matrices. RESULTS: Both OMQ-14 and ECLiPS were sensitive to the presence of OME, and also to improvements in hearing post-surgery. Both were also good at classifying children into their clinically-established diagnostic groups based on score cut-offs determined using Receiver Operator Characteristics (ROC) curves. However, outputs from confusion matrices suggest only around 50% of children after VTs would be indistinguishable from controls following VT surgery. Differences were observed in which children were identified as still having problems according to the questionnaires. OMQ-14 is more sensitive to disease-related hearing loss, while the ECLiPS is more sensitive to developmental difficulties. CONCLUSIONS: Despite being developed with different aims in mind, the OMQ-14 and ECLiPS were similarly sensitive both to symptoms of disease-related hearing difficulty and also to treatment-related improvements in hearing. A significant number of VT children continue to have poor OMQ-14 and ECLiPS scores relative to control children. ECLiPS scores do not always change in a way that hearing improvements would predict, suggesting the ECLiPS is sensitive to wider developmental difficulties. Parental report in the form of narrow or broad-based questionnaires may complement history-taking and audiometry to enhance the quality of discussion between carers and clinicians about OME management.

Evaluation of combinations of putative anti-biofilm agents and antibiotics to eradicate biofilms of Staphylococcus aureus and Pseudomonas aeruginosa.

Objectives: To evaluate potential anti-biofilm agents for their ability to enhance the activity of antibiotics for local treatment of localized biofilm infections. Methods: Staphylococcus aureus and Pseudomonas aeruginosa in vitro biofilm models were developed. The putative antibiotic enhancers N-acetylcysteine, acetylsalicylic acid, sodium salicylate, recombinant human deoxyribonuclease I, dispersin B, hydrogen peroxide and Johnson's Baby Shampoo (JBS) were tested for their anti-biofilm activity alone and their ability to enhance the activity of antibiotics for 7 or 14 days, against 5 day old biofilms. The antibiotic enhancers were paired with rifampicin and clindamycin against S. aureus and gentamicin and ciprofloxacin against P. aeruginosa. Isolates from biofilms that were not eradicated were tested for antibiotic resistance. Results: Antibiotic levels 10× MIC and 100× MIC significantly reduced biofilm, but did not consistently eradicate it. Antibiotics at 100× MIC with 10% JBS for 14 days was the only treatment to eradicate both staphylococcal and pseudomonal biofilms. Recombinant human deoxyribonuclease I significantly reduced staphylococcal biofilm. Emergence of resistance of surviving isolates was minimal and was often associated with the small colony variant phenotype. Conclusions: JBS enhanced the activity of antibiotics and several other promising anti-biofilm agents were identified. Antibiotics with 10% JBS eradicated biofilms produced by both organisms. Such combinations might be useful in local treatment of localized biofilm infections.

Anti-confocal assessment of middle ear inflammation.

To improve the diagnostic prediction of recurrence of otitis media with effusion after surgery, an anti-confocal system combined with spectroscopic measurements is proposed to reject unwanted signals from the eardrum and assess the blood content. The anti-confocal system was experimentally evaluated on both optical middle ear phantom and human skin. Results showed effective rejection of signals from the eardrum using a central stop replacing the confocal pinhole, while still detecting signals from the middle ear mucosa. The system is sensitive to changes in blood content, but scattering and absorption characteristics of the eardrum can distort the measurement. Confocal detection of eardrum properties was shown to be a promising approach to correct measurements.

Which outcome measures are reported by clinical trials investigating OME treatment? A case for standardised reporting.

INTRODUCTION: Many different OME treatment trials have been published using different outcomes measures to evaluate the success of particular interventions. We set out to identify the variation in reporting of outcome measures in OME trials that exists at present. This has been achieved by reviewing published trials to determine which outcome measures have been reported. METHOD: The literature review was carried out using PUBMED database (1980 to 2013). Data were collected on the treatment outcomes reported, with particular focus on the methods of assessment and the number of treatment outcomes used in each study. RESULTS: The 171 studies identified used 12 broad treatment outcome measures. The most common outcome measure was OME resolution (48%) followed by hearing level (36%). Only 95 studies used a single outcome measure, with 76 studies using between 2 and 4 outcome measures. The method of assessment varied between studies that used the same treatment outcome measures. CONCLUSION: OME treatment trials report a wide range of measures and comparison across studies is thus difficult. Establishing a core set of outcome measures to be reported by all trials in the future could be useful, and would allow comprehensive comparison of different studies and minimise potential for reporting bias.

Anti-confocal versus confocal assessment of the middle ear simulated by Monte Carlo methods.

The ability to monitor the inflammatory state of the middle ear mucosa would provide clinical utility. To enable spectral measurements on the mucosa whilst rejecting background signal from the eardrum an anti-confocal system is investigated. In contrast to the central pinhole in a confocal system the anti-confocal system uses a central stop to reject light from the in-focus plane, the eardrum, with all other light detected. Monte Carlo simulations of this system show an increase in detected signal and improved signal-to-background ratio compared to a conventional confocal set-up used to image the middle ear mucosa. System parameters are varied in the simulation and their influence on the level of background rejection are presented.

Pitch Discrimination: An Independent Factor in Cochlear Implant Performance Outcomes.

OBJECTIVE: To assess differences in pitch-ranking ability across a range of speech understanding performance levels and as a function of electrode position. STUDY DESIGN: An observational study of a cross-section of cochlear implantees. SETTING: Tertiary referral center for cochlear implantation. PATIENTS: A total of 22 patients were recruited. All three manufacturers' devices were included (MED-EL, Innsbruck, Austria, n = 10; Advanced Bionics, California, USA, n = 8; and Cochlear, Sydney, Australia, n = 4) and all patients were long-term users (more than 18 months). Twelve of these were poor performers (scores on BKB sentence lists <60%) and 10 were excellent performers (BKB >90%). INTERVENTION: After measurement of threshold and comfort levels, and loudness balancing across the array, all patients underwent thorough pitch-ranking assessments at 80% of comfort levels. MAIN OUTCOME MEASURE: Ability to discriminate pitch across the electrode array, measured by consistency in discrimination of adjacent pairs of electrodes, as well as an assessment of the pitch order across the array using the midpoint comparison task. RESULTS: Within the poor performing group there was wide variability in ability to pitch rank, from no errors, to a complete inability to reliably and consistently differentiate pitch change across the electrode array. Good performers were overall significantly more accurate at pitch ranking (p = 0.026). Consistent pitch ranking was found to be a significant independent predictor of BKB score, even after adjusting for age. Users of the MED-EL implant experienced significantly more pitch confusions at the apex than at more basal parts of the electrode array. CONCLUSIONS: Many cochlear implant users struggle to discriminate pitch effectively. Accurate pitch ranking appears to be an independent predictor of overall outcome. Future work will concentrate on manipulating maps based upon pitch discrimination findings in an attempt to improve speech understanding.

Update on otitis media - prevention and treatment.

Acute otitis media and otitis media with effusion are common childhood disorders, a source of significant morbidity, and a leading cause of antibiotic prescription in primary health care. Although effective treatments are available, some shortcomings remain, and thus better treatments would be welcome. Recent discoveries within the field of otitis media research relating to its etiology and pathogenesis have led to further investigation aimed at developing novel treatments. This article provides a review of the latest evidence relating to the understanding of acute otitis media and otitis media with effusion, current treatment strategies, their limitations, new areas of research, and novel strategies for treatment.

Development of a porous poly(DL-lactic acid-co-glycolic acid)-based scaffold for mastoid air-cell regeneration.

OBJECTIVES/HYPOTHESIS: To develop a porous, biodegradable scaffold for mastoid air-cell regeneration. STUDY DESIGN: In vitro development of a temperature-sensitive poly(DL-lactic acid-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) scaffold tailored for this application. METHODS: Human mastoid bone microstructure and porosity were investigated using micro-computed tomography. PLGA/PEG-alginate scaffolds were developed, and scaffold porosity was assessed. Human bone marrow mesenchymal stem cells (hBM-MSCs) were cultured on the scaffolds in vitro. Scaffolds were loaded with ciprofloxacin, and release of ciprofloxacin over time in vitro was assessed. RESULTS: Porosity of human mastoid bone was measured at 83% with an average pore size of 1.3 mm. PLGA/PEG-alginate scaffold porosity ranged from 43% to 78% depending on the alginate bead content. The hBM-MSCs proliferate on the scaffolds in vitro, and release of ciprofloxacin from the scaffolds was demonstrated over 7 to 10 weeks. CONCLUSIONS: The PLGA/PEG-alginate scaffolds developed in this study demonstrate similar structural features to human mastoid bone, support cell growth, and display sustained antibiotic release. These scaffolds may be of potential clinical use in mastoid air-cell regeneration. Further in vivo studies to assess the suitability of PLGA/PEG-alginate scaffolds for this application are required.

National Institute for Clinical Excellence guidelines on the surgical management of otitis media with effusion: are they being followed and have they changed practice?

OBJECTIVE: UK National Institute of Clinical Excellence (NICE) guidelines on surgical management of otitis media with effusion (OME) in children call for an initial 3 month period of observation, with ventilation tube (VT) insertion considered for children with persistent bilateral OME with a hearing level in better ear of 25-30 dB HL or worse ("core criteria"), or for children not meeting those audiologic criteria but when OME has significant impact on developmental, social or educational status (exceptional circumstances). We aimed to establish whether guidelines are followed and whether they have changed clinical practice. METHODS: Retrospective case-notes review in five different centres, analysing practice in accordance with guidelines in all children having first VT insertion before (July-December 06) and after (July-December 08) guidelines introduction. RESULTS: Records of 319 children were studied, 173 before and 146 after guidelines introduction. There were no significant differences in practice according to guidelines before and after their introduction with respect to having 2 audiograms 3 months apart (57.8 vs. 54.8%), OME persisting at least 3 months (94.8 vs. 92.5%), or fulfilment of the 25 dB audiometric criteria (68.2 vs. 61.0%). Practice in accordance with the core criteria fell significantly from 43.9 to 32.2% (Chi squared p=0.032). However, if the exceptional cases were included there was no significant difference (85.5 vs. 87.0%), as the proportion of exceptional cases rose from 48.3 to 62.2% (Chi squared p=0.021). CONCLUSION: This study shows that 87.0% of children have VTs inserted in accordance with NICE guidelines providing exceptional cases are included, but only 32.2% comply with the core criteria. A significant number have surgery due to the invoking of exceptional criteria, suggesting that clinicians are personalising the treatment to each individual child.

Biofilm eradication with biodegradable modified-release antibiotic pellets: a potential treatment for glue ear.

OBJECTIVE: To develop a biodegradable, modified-release antibiotic pellet capable of eradicating biofilms as a potential novel treatment for biofilm infections. DESIGN: Pellets containing poly(DL-lactic-co-glycolic acid) microparticles, rifampin and clindamycin hydrochloride (3.5%, 7%, or 28% antibiotic by weight), and carrier gel (carboxymethylcellulose or poloxamer 407) were tested in vitro. Drug release was assessed using serial plate transfer testing and high-performance liquid chromatography, and pellets were tested against biofilms in an in vitro model of Staphylococcus aureus biofilm grown on silicone. RESULTS: Serial plate transfer testing demonstrated continuing bacterial inhibition for up to 21 days for all pellets studied. High-performance liquid chromatography showed high levels of drug release for 2 to 4 days, with greatly reduced levels subsequently; continued measurable clindamycin (but not rifampin) release for up to 21 days was achieved. Pellets made with poloxamer released higher drug levels for a longer period. Irrespective of the carrier gel used, pellets containing 7% and 28% (but not 3.5%) antibiotic eradicated biofilms successfully. CONCLUSIONS: Antibiotic pellets can release antibiotics for up to 21 days and are able to eradicate biofilms in an in vitro model. Use of modified-release antibiotic formulations in the middle ear as a treatment for biofilms appears to be a potentially promising new therapy for otitis media with effusion.

Role of ciclosporin in steroid-responsive sudden sensorineural hearing loss.

CONCLUSIONS: A subgroup of patients with idiopathic sensorineural hearing loss (SNHL) will have steroid-dependent symptoms which can be confirmed using pure-tone audiometry. Long-term treatment with high-dose corticosteroids exposes patients to potentially serious adverse effects. Immunosuppression with ciclosporin can be an effective and well-tolerated treatment for steroid-responsive sudden SNHL. OBJECTIVE: To highlight ciclosporin as a therapeutic option in the treatment of steroid-responsive sudden SNHL. MATERIAL AND METHODS: A 39-year-old male with idiopathic sudden SNHL that was responsive to corticosteroids was treated with ciclosporin for 18 months. RESULTS: Steroid-dependent SNHL was confirmed on audiological evaluation. Ciclosporin was administered, allowing corticosteroid therapy to be discontinued. Ciclosporin was effective at controlling all symptoms of SNHL. Remission was confirmed objectively with pure-tone audiometry.

Evidence of T-helper cell 2 cytokine regulation of chronic otitis media with effusion.

Cytokine and cellular patterns of effusions may reflect stages of middle ear inflammation. The local interplay between IL-2 and -4 is likely to play a crucial role in the switching of inflammation in the chronic stage. The T-helper cell 2 (Th2) cytokines IL-4, -5 and -13 and the Th2/Th1 cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) regulate the cellular and molecular processes of chronic inflammation in the middle ear and therefore the chronic condition of otitis media with effusion (OME). Early identification of the cytokine and cellular patterns of effusions can be helpful in directing the clinical treatment of OME.We hypothesized that IL-2 and the group of Th2 cytokines regulate chronic inflammation in the middle ear and chronic OME. Effusions from children with persistent OME were analysed to determine the presence of cytokines (the Th1 cytokine IL-2, the Th2 cytokines IL-4, -5 and -13 and the Th1/Th2 cytokine GM-CSF), inflammatory cells (CD4+ T cells, eosinophils, macrophages and neutrophils) and mucin. Cytokines were evaluated by means of a quantitative "sandwich"-type ELISA, inflammatory cells by means of alkaline phosphatase-anti-alkaline phosphatase immunocytostaining and mucin by means of a modified periodic acid-Schiff method based on a slot-blot technique. The cytokine pattern in effusions varied from patient to patient. GM-CSF correlated positively and IL-4 inversely with IL-2 and the increased level of IL-4 may have had an inhibitory effect on IL-2. IL-5 and -13 correlated with IL-4. Inflammatory cells correlated with cytokines as follows: CD4+ T cells with IL-2 and -4; macrophages and neutrophils with GM-CSF; and eosinophils with IL-5. Some cytokine-cellular correlations in effusions were reflected at the clinical level. The mucin content of effusions correlated with the concentrations of IL-4 (>10 pg/ml) and -13, suggesting involvement of IL-4 and -13 in upregulation of the middle ear mucin metabolism.

The immunoregulatory and allergy-associated cytokines in the aetiology of the otitis media with effusion.

Inflammation in the middle ear mucosa, which can be provoked by different primary factors such as bacterial and viral infection, local allergic reactions and reflux, is the crucial event in the pathogenesis of otitis media with effusion (OME). Unresolved acute inflammatory responses or defective immunoregulation of middle inflammation can promote chronic inflammatory processes and stimulate the chronic condition of OME. Cytokines are the central molecular regulators of middle ear inflammation and can switch the acute phase of inflammation in the chronic stage and induce molecular-pathological processes leading to the histopathological changes accompanying OME. In this review we present cytokines identified in otitis media, immunoregulatory [interleukin (IL)-2, IL-10, transforming growth factor-beta]) and allergy associated (IL-4, IL-5, granulocyte-macrophage colony-stimulating factor), as crucial molecular regulators, responsible for chronic inflammation in the middle ear and the chronic condition of OME.

LPS up-regulates mucin and cytokine mRNA expression and stimulates mucin and cytokine secretion in goblet cells.

Bacterial inflammation in mucosa is accompanied by morphological and proliferative changes in goblet cells and mucin hypersecretion. Main stimulators of bacterial inflammation are bacterial lipopolysaccharides (LPS). In vitro investigation of the LPS effect on the molecular processes in goblet cells, using the human mucin-secreting goblet cell line HT29-MTX, showed the following results. LPS up-regulated mucin and cytokine mRNA expression and secretion in goblet cells in a concentration and time-dependent manner, with a maximum output at an LPS concentration of 100 ng/ml. LPS (100 ng/ml) increased mRNA expression of MUC5AC (2.4x), MUC5B (2.1x), and IL-8 (2.3x) and stimulated secretion of mucins (MUC5AC up to 39%, MUC5B up to 31%) and the inflammatory cytokine IL-8 (up to 10x). A significant correlation was found between the LPS-induced IL-8 secretion and secretion of mucins. These results suggest: (1) goblet cells, responding to the direct stimulation of bacterial LPS by two inflammatory-related processes such as production and secretion of the gel-forming mucins and the inflammatory cytokine IL-8, can be considered as an important part of mucosal immunity and (2) LPS- induced goblet cell mucin secretion can occur partly via IL-8-dependent pathway.

Postural stability of preoperative acoustic neuroma patients assessed by sway magnetometry: are they unsteady?

OBJECTIVE: The objective was to evaluate the preoperative postural stability of acoustic neuroma patients using sway magnetometry. STUDY DESIGN: Prospective two-center study. METHODS: Fifty-one patients (mean age, 53 years) diagnosed with unilateral acoustic neuroma on magnetic resonance imaging at two tertiary referral centers were studied. Preoperatively, each patient had sway patterns (with eyes open and with eyes closed, and standing on foam) recorded for 120 seconds by sway magnetometry. Path length for 30 seconds was calculated. The Romberg coefficient (path length with eyes open divided by path length with eyes closed) was calculated. RESULTS: Forty-four percent of patients had abnormal path lengths with eyes open, and 49% with eyes closed. The Romberg coefficients were significantly lower than normal (P <.001; 95% CI, 0.19-0.87). Mean Romberg coefficient was 0.59 (normal value = 0.73), and all patients had a coefficient of less than 1. CONCLUSIONS: Half of preoperative acoustic neuroma patients are unsteady, exhibiting abnormal sway patterns based on path length measurements. The increase in sway path length demonstrable in normal subjects with eyes closed was significantly exaggerated in patients with acoustic neuroma.

Is gastric reflux a cause of otitis media with effusion in children?

OBJECTIVES/HYPOTHESIS: Otitis media with effusion is the most common cause of childhood deafness. Gastroesophageal reflux has been implicated in the disease pathogenesis; therefore, it is necessary to identify the presence or absence of gastric juice in the middle ear. STUDY DESIGN: Middle ear effusions were collected from children undergoing myringotomy. If gastric reflux has occurred, effusions should contain pepsin protein. METHODS: Total pepsin/pepsinogen protein, fibrinogen, and albumin content of effusions were measured in enzyme-linked immunosorbent assays using antibodies to porcine pepsin, human albumin, and human fibrinogen. Proteolytic activity of each effusion was measured at pH 2. The pH of effusions was measured. RESULTS: Fifty-nine of 65 effusion samples gave a positive result with the antipepsin antibody, which also recognized pepsinogen. Pepsin/pepsinogen levels ranged from 0.8 to 213.9 microg/mL (serum reference levels, 49.8-86.6 ng/mL). All effusions contained albumin and fibrinogen with respective ranges of 1.77 to 95.75 and 0.30 to 2.30 mg/mL (serum reference levels, 35-45 and 2.2 to 4.6 mg/mL, respectively). Acidic protease activity occurred in 19 of 65 effusion samples. The pH of effusion samples was 7 to 9. CONCLUSIONS: The majority of effusion samples contained pepsin/pepsinogen protein; only 29% were active. The pepsin level in effusion samples based on activity is substantially lower than levels based on antibody detection; however, the pH present would irreversibly inhibit pepsin, which would explain the low levels of active enzyme. Pepsin/pepsinogen levels in the effusion samples were up to 1000 times higher than serum levels, whereas albumin and fibrinogen levels were of the same magnitude. The pepsin in middle ear effusions is almost certainly due to reflux of gastric contents, and there may be a role for antireflux therapy in the treatment of otitis media with effusion.

Role of the pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6 and interleukin-8 in the pathogenesis of the otitis media with effusion.

Inflammation in the middle ear mucosa, caused usually by bacterial and viral pathogens, is the primary event in the middle ear predisposing the development of otitis media with effusion (OME). Numerous inflammatory mediators have been identified in OME. However, cytokines play a central role as initiators, mediators and regulators of middle ear inflammation and subsequent molecular-pathological processes in middle ear tissues, leading to histopathological changes in the middle ear cavity and the pathogenesis of OME. In this article, we aim to present an overview of current research developments in the pro-inflammatory cytokine involvement in the aetiology of otitis media with effusion.

In vitro study of IL-8 and goblet cells: possible role of IL-8 in the aetiology of otitis media with effusion.

One of the main characteristics of otitis media with effusion (OME) is the differentiation of basal cells into goblet cells with subsequent proliferation in a modified respiratory epithelium leading to the formation of mucin-rich effusion in the middle ear cleft. In order to determine the effect of pro-inflammatory cytokines identified in OME, e.g. IL-1beta, tumour necrosis factor (TNF)-alpha, IL-6 and IL-8, on goblet cells, and to clarify the role of IL-8 in particular, we used the human goblet cell line HT29-MTX, which secretes two OME-related mucins: MUC5AC and MUC5B. IL-1beta and TNF-alpha stimulated the secretion of IL-8 in HT29-MTX goblet cells. Dose- (2-200 ng/ml) and time- (0-5 days) response studies of IL-8-induced mucin secretion were carried out. IL-8 upregulated the secretion of MUC5AC and MUC5B mucins in a concentration-dependent manner, with a maximum response at an IL-8 concentration of 20 ng/ml. IL-8 (20 ng/ml)-mediated mucin secretion persisted for up to 5 days, with a peak response 72 h after the addition of cytokine. These results suggest that: (i) goblet cells are target cells for the pro-inflammatory cytokines IL-1beta, TNF-alpha and IL-8 and can contribute to the pathogenesis of OME by increasing both the concentration of IL-8 and the secretion of mucin; and (ii) IL-8 stimulates prolonged mucin secretion from goblet cells and may be involved in the maintenance of the disease in the chronic stage.