The link between allergic rhinitis and chronic otitis media with effusion in atopic patients

The significant incidence of atopy associated with otitis media with effusion (OME) has suggested a role of allergy in the pathogenesis of OME. Analysis of inflammatory mediators indicates that the mucosa of the middle ear can respond to antigen in the same way as does the mucosa of the lower respiratory tract. Recent characterization of the mucosa and effusion from atopic patients with OME reveals a Th2 cytokine and cellular profiles consistent with an allergic response, supporting the role of allergy in OME. In addition, animal studies demonstrate that inhibiting characteristic allergy cytokines can prevent the production of middle ear effusion. As the understanding of allergy and its role in the inflammation of OME continues to deepen, this will introduce focused treatments of OME in the atopic population.     

Direct evidence of bacterial biofilms in otitis media

OBJECTIVES/HYPOTHESIS: Bacteriologic studies of otitis media with effusion (OME) using highly sensitive techniques of molecular biology such as the polymerase chain reaction have demonstrated that traditional culturing methods are inadequate to detect many viable bacteria present in OME. The presence of pathogens attached to the middle-ear mucosa as a bacterial biofilm, rather than as free-floating organisms in a middle-ear effusion, has previously been suggested to explain these observations. The suggestion has been speculative, however, because no visual evidence of such biofilms on middle-ear mucosa has heretofore been collected. The hypotheses motivating the current study were: 1) biofilms of nontypable Hemophilus influenzae will form on the middle-ear mucosa of chinchillas in an experimental model of OME, 2) these biofilms will exhibit changes in density or structure over time, and 3) biofilms are also present on tympanostomy tubes in children with refractory post-tympanostomy otorrhea. The objective of this study was to collect visual evidence of the formation of bacterial biofilms in these situations. STUDY DESIGN: Laboratory study of bacteriology in an animal model and on medical devices removed from pediatric patients. METHODS: Experimental otitis media was induced in chinchillas by transbullar injection of nontypable H. influenzae. Animals were killed in a time series and the surface of the middle-ear mucosa was examined by scanning electron microscopy (SEM) for the presence of bacterial biofilms. Adult and fetal chinchilla uninfected controls were similarly examined for comparison. In addition, tympanostomy tubes that had been placed in children's ears to treat OME and removed after onset of refractory otorrhea or other problems were examined by SEM and by confocal scanning laser microscopy for bacterial biofilms, and compared with unused control tubes. RESULTS: Bacterial biofilms were visually detected by SEM on the middle-ear mucosa of multiple chinchillas in which H. influenzae otitis media had been induced. Qualitative evaluation indicated that the density and thickness of the biofilm might increase until at least 96 hours after injection. The appearance of the middle-ear mucosa of experimental animals contrasted with that of uninjected control animals. Robust bacterial biofilms were also visually detected on tympanostomy tubes removed from children's ears for clinical reasons, in contrast with unused control tubes. CONCLUSIONS: Bacterial biofilms form on the middle-ear mucosa of chinchillas in experimentally induced H. influenzae otitis media and can form on tympanostomy tubes placed in children's ears. Such biofilms can be directly observed by microscopy. These results reinforce the hypothesis that the bacterial aggregates called biofilms, resistant to treatment by antibiotics and to detection by standard culture techniques, may play a major etiologic role in OME and in one of its frequent complications, post-tympanostomy otorrhea.     

Efficacy of allergy immunotherapy as a treatment for patients with chronic otitis media with effusion

OBJECTIVE: Controversy persists over the significance of allergy as it might relate to chronic middle-ear disease as no controlled study of the efficacy of allergy immunotherapy has been published. The aim of this study was (1) to evaluate the atopic status of patients with intractable chronic otitis media with effusion or drainage from their middle ear and (2) to determine in this select population the efficacy of specific allergy immunotherapy in preventing or limiting the duration of their chronic middle-ear disease. METHODS: This was a prospective, cohort study of patients cared for in a private community practice. History, examination, audiogram, tympanometry and recurrence of effusion/infection were recorded on 89 patients (52 children <15 years old, 37 adults) referred with (1) effusion found to warrant myringotomy and ventilation tubes, or (2) chronic drainage from a perforation or tube. All were evaluated for allergy by intradermal skin testing according to criteria of the American Academy of Otolaryngic Allergy. A control cohort of 21 patients who refused therapy was included. Intervention consisted of immunotherapy for dust, pollen, and molds. Recurrence or persistence of fluid or drainage following 2-8 years of therapy was compared to the patient's pretreatment status. RESULTS: All 89 OME patients proved to be atopic. Most were allergic to dust (94%), animals (44%) and molds (88%) while 9% were allergic only to seasonal pollens. Associated allergic diseases included asthma (21%) and allergic rhinitis/sinusitis (63%). Otitis was the sole symptom among 37%. Immunotherapy provided complete resolution of effusion or drainage in 85% of 127 ears. CONCLUSION: Intradermal testing proved all 89 patients with intractable middle-ear disease in this study who presented with chronic effusion or chronic draining perforations or tubes to be atopic. Specific allergy immunotherapy significantly improved 5.5% and completely resolved 85% of chronic otitis media with effusion in these ears. None of the controls resolved spontaneously (p<0.001). This supports the hypothesis that in many, otitis media with effusion is an immune mediated allergic disease and suggests that these patients deserve consideration for aggressive evaluation and allergy treatment, as most respond to immunotherapy.     

变态反应性中耳炎动物模型的建立及Ⅰ型变态反应与分泌性中耳炎关系的探讨

目的探讨Ⅰ型变态反应、Th1、Th2类细胞因子在小鼠分泌性中耳炎中耳黏膜的表达情况。方法采用卵清白蛋白致敏并耳内激发小白鼠制成分泌性中耳炎(OME)模型。以免疫组织化学方法检测实验组、对照组中耳黏膜IL4、IL5、IFNγ、IL12的表达情况,同时作病理检查,了解嗜酸粒细胞浸润与各细胞因子的关系。结果实验组Th2类细胞因子IL4、IL5表达明显增加,伴相应的中耳黏膜嗜酸粒细胞浸润,而Th1类细胞因子IFNγ、IL12明显减少,且嗜酸粒细胞浸润与IL5呈正相关(γ=0.951,P<0.05)。结论Ⅰ型变态反应是OME发病的重要原因,而Th2类细胞因子在其发病过程中起着重要的作用。     

Anti-inflammatory effect of erythromycin on histamine-induced otitis media with effusion in guinea pigs

In this study, the anti-inflammatory effect of erythromycin was investigated in a model of histamine-induced otitis media with effusion (OME). OME was induced in guinea pigs by the transtympanic injection of histamine solution into the middle-ear cavity. Guinea pigs were randomly assigned to one of three groups: control, erythromycin treatment, or methylprednisolone treatment. After histamine injection, the animals were treated with intraperitoneal medication for five days consecutively. Afterwards, the animals were sacrificed and the temporal bones were removed. The samples were examined stereologically. In the erythromycin-treated group, it was observed that neutrophil infiltration was significantly inhibited when compared to the control group. This result shows that erythromycin may produce a significant anti-inflammatory effect in this model of OME.     

Association of Otitis Media With Effusion and Allergy as Demonstrated by Intradermal Skin Testing and Eosinophil Cationic Protein Levels in Both Middle Ear Effusions and Mucosal Biopsies

This study was performed to ascertain the role of allergy, as defined by skin testing and histochemical markers, in the pathogenesis of otitis media with effusion (OME). A historical perspective of allergy as it relates to OME is presented. The study included 89 patients: 48 with persistent effusion but no recent acute infection, 25 with purulent OME complicated by a superimposed infection, and 16 control subjects. All 89 patients had persistent effusion for more than 2 months and subsequently required the placement of tympanostomy tubes. Allergy was defined using the radioallergosorbent test (RAST), serum immunoglobulin E (IgE) levels, and skin tests. Allergies were present in 97% of the patients with nonacute OME. The relationship between allergy and OME was corroborated clinically in 89% of patients and was also substantiated by elevated levels of effusion eosinophil cationic protein (ECP) in 87.5% of OME patients. Histologically, polyclonal antibody staining for ECP demonstrated the presence of eosinophils in middle ear mucosal biopsy specimens. This study confirms that OME is a sign of allergic inflammation in the middle ear that is associated with an increase in eosinophils and a concomitant release of ECP into the effusion in individuals with allergy demonstrated by skin testing.     

Efficacy of an antiallergic drug on otitis media with effusion in association with allergic rhinitis. An experimental study.

The effect of an antiallergic drug on the evacuation of middle ear effusion (MEE) from the tubotympanum was investigated by means of an animal model with both otitis media with effusion (OME) and allergic rhinitis. Azelastine hydrochloride (AZ), an oral antiallergic drug, was administered and the presence of MEE was investigated. Serous MEE was seen in 12 of the 13 untreated control animals on the 11th day after the experimental OME was induced, whereas MEE was detected in 9 of the 13 animals administered 1 mg/kg of AZ, but only in 4 of the 13 animals administered 2 mg/kg of AZ. In addition, the effect of AZ on MEE production was also examined in an experimental OME animal model without allergic rhinitis. Middle ear effusion was observed in all OME animals that received 2 mg/kg AZ for 5 consecutive days, before and 3 days after the experimental OME was induced. Results of the present study indicate that AZ promotes the evacuation of MEE from the tubotympanum in the OME animal model associated with nasal allergy. These data suggest that an antiallergic drug may contribute to the therapy of OME patients in association with nasal allergy indirectly, by promoting evacuation of MEE due to inhibition of type I allergic reactions in the nasopharynx.     

Characterization of cytokines present in pediatric otitis media with effusion: comparison of allergy positive and negative

To investigate the possible relationship between allergy and otitis media with effusion (OME), we investigated the cytokine level in the middle ear effusion (MEE)s of children with persistent OME. Interleukin (IL)-2, IL-4, IL-6 and tumor necrosis factor (TNF)-alpha in the MEEs were measured by devised sensitive sandwich enzyme-linked immunosorbent assay (ELISA) and compared allergy positive group with allergy negative group. The mean levels of IL-4, IL-6 and TNF-alpha in MEE were significantly higher in allergy positive group than allergy negative group (P<0.05). Elevation of Th-2-driven cytokines (IL-4, IL-6) and TNF-alpha in MEEs may be a contributing factor in the persistence of OME with allergy.     

The role of allergy in otitis media with effusion

The role of allergy in chronic otitis media with effusion (OME) is controversial. New evidence from cellular biology and immunology explain the basics of allergic reactions and allow more accurate diagnosis of allergies and inflammatory disease throughout the unified airway. This article examines the epidemiologic, methodological, and immunologic studies of allergic causes of OME, including (1) evidence for and against OME as an allergic disease, (2) allergy as a cause for eustachian tube obstruction, (3) examination of the most sensitive diagnostic tests for allergy, and (4) the effect of treatment of underlying allergies in improving and resolving middle ear disease.     

Decreased miRNA-320e correlates with allergy in children with otitis media with effusion

ObjectiveOtitis media with effusion (OME) is a common childhood disease and the main cause of conductive hearing loss in this age group. Many factors predispose to OME but allergy is still widely disputed. The answer may lay in the molecular mechanisms of ear exudate formation and the recent studies showed miRNAs might take part in it. MiRNAs are also potent regulators of allergic response. As miRNAs are present in the middle ear, we hypothesized their expression differs between allergic and non-allergic patients and reflects the difference in pathomechanism of effusion formation between these two groups.Materials and methodsThis study aimed to establish the expression of 5 different miRNAs (miR-223-3p, miR-451a, miR-16-5p, miR-320e, miR-25-3p) in ear exudates in children diagnosed with OME. The allergy group consisted of 18 patients whereas the non-allergic group had 36 patients. MicroRNA was isolated from the middle ear fluid collected during myringotomy and transcribed into cDNA. MiRNA expression was measured with TaqMan™ MicroRNA Assays and analyzed with DataAssist software. The comparative CT method was used for calculating the relative quantification of gene expression based on the endogenous control gene expression (U6 snRNA-001973).ResultsMiR-320e expression was significantly decreased in allergic children with OME. Other studied miRNAs also showed reduced expression in allergic children, but the decrease was not significant.ConclusionsMiRNA expression differs between children with and without allergy in the course of OME, but further studies are needed to explain the exact role of miR-320e and its target genes in OME pathology in allergic patients.     

Nebulized surfactant as a treatment choice for otitis media with effusion: an experimental study in the rabbit.

Exogenous surfactant can improve eustachian tube function in experimentally induced otitis media with effusion (OME). Performing tympanometric recordings, the efficacy of inhaled nebulized surfactant, as compared with inhaled nebulized physiological saline was investigated, for the treatment of OME experimentally induced in the rabbit by intrabullar inoculation of heat-killed Streptococcus pneumoniae. In addition, the histological changes in middle ears after the treatment were investigated in order to establish whether the pathological findings correlated with the results. Middle-ear pressure values before, and after, treatment were analyzed by the Wilcoxon statistical method, and the Mann-Whitney U test was used to compare the post-treatment values between groups. In all ears with OME in the affected animals, which were treated with nebulized surfactant inhalation, a positively significant (p<0.05) increase of pressure more than 20 daPa was recorded. In the control group, after inhalation of nebulized physiological saline, there was no positive increase in the affected middle-ear pressures; on the contrary, more negative pressure changes were recorded. In the histological evaluation, middle-ear epithelia and sub-epithelial space were normal in surfactant-treated ears with OME, whereas mucosal thickening with an oedematous sub-epithelial space containing occasional inflammatory cells and increases in connective tissue and vascularity, and effusions on the epithelial surface were present in the ears with OME in the control group. The significant improvement in the negative middle-ear pressure after nebulized surfactant treatment and the histological findings shown in our study can support the theory that surface-active agents are of importance in eustachian tube function even under pathologic conditions, such as OME.     

Evidence of mast cell activity in the middle ears of children with otitis media with effusion

OBJECTIVES: This is the first study to report the presence of tryptase, a reflection of mast cell activity, in chronic middle ear effusion of patients whose atopic status was characterized. DESIGN AND METHODS: Mediator activity of mast cells and eosinophils was measured prospectively from effusion of 33 randomly selected patients and 5 control subjects with chronic otitis media with effusion (OME). Atopy was determined by enzyme-linked immunosorbent assay. Middle ear biopsies from a second group of 8 OME patients and 4 controls were fixed in plastic and stained immunohistochemically for mast cells. RESULTS: Sixty-one percent of patients had extensive activation of mast cells in their middle ears. Among those with elevated tryptase in their effusion, 95.6% were atopic and 94.7% also had elevated levels of effusion eosinophilic cationic protein (ECP). Tryptase levels were elevated only in the effusion of atopic patients, as compared with 5 controls (P < .01). Mast cells were present in 6 of 8 OME ears and absent in all 4 normal ears. CONCLUSION: Mast cells and its mediator tryptase, both indicators of a Th2-driven immune response, are present in a majority of ears that have chronic effusion. These findings support the hypothesis that middle ear mucosa is capable of an allergic response and that the inflammation within the middle ear of most OME patients is allergic in nature.     

腺样体肥大儿童伴变应性鼻炎与分泌性中耳炎的相关性分析

目的 分析腺样体肥大儿童伴分泌性中耳炎(ＯＭＥ)与变应性鼻炎(ＡＲ)发病的相关性。方法 回顾性分析12岁以下870例腺样体肥大患儿的病史,分析AR、咽鼓管功能不良及OME的相关性。结果 本组腺样体肥大患儿中AR发病率为30.11%,AR在不同年龄组中的发病率差异有统计学意义,随着年龄增加,发病率逐渐升高(P<0.01)。6岁以内发生咽鼓管功能障碍及OME的概率高,其中1~3岁组发生分泌性中耳炎的概率最大(P<0.01)。春季OME发病率高(P<0.001)。与不伴AR患者相比,伴有AR患儿患咽鼓管功能不良的概率增加了0.4倍(P=0.042);但患有OME的检出率减少了32%(P=0.0472)。结论 在腺样体肥大患儿中,多种因素使咽鼓管功能不良乃至OME高发。其中咽鼓管及其周围结构生理、病理、发育特点是最主要的因素,变态反应是次要影响因素。随着年龄增长,前者因逐渐发育完善,致病性降低,后者致病性增高,但总的发病率是逐渐降低的。     

IL-5 and Eotaxin Levels in Middle Ear Effusion and Blood from Asthmatics with Otitis Media with Effusion

Objective--The purpose of this study was to evaluate eosinophil infiltration as well as IL-5 and eotaxin levels in middle ear effusion (MEE) and blood from otitis media with effusion (OME) patients with asthma and to compare the findings with those from OME patients without asthma (control group). Material and methods--Levels of IL-5 and eotaxin in MEE and blood were measured by means of enzyme-linked immunosorbent assay. Results--IL-5 levels in MEE were significantly higher than those in blood in both groups of patients and in OME patients with asthma than in the control group. In addition, in OME patients with asthma, there was a significant correlation between the percentage of eosinophils and IL-5 levels in MEE. Eotaxin levels in blood were significantly higher than those in MEE in both groups of patients and in OME patients with asthma than in the control group. In addition, in OME patients with asthma, the percentage of eosinophils and eotaxin levels in blood tended to correlate, but did not reach statistical significance. Conclusion--These data suggest that, in OME patients with asthma, eosinophilia in MEE depends more on IL-5 than on eotaxin, and that eotaxin may play an important role in the mobilization of eosinophils from the bone marrow into the blood.     

Demonstration of RANTES and eosinophilic cataionic protein in otitis media with effusion with allergy

Regulated upon activation, normal T cell-expressed and -secreted (RANTES) is a chemokine which is an effective eosinophil and memory T cell chemoattractant and activator, and eosinophil is an important effector cell in allergic disease. It may contribute to the pathogenesis of otitis media with effusion (OME). Eosinophil cataionic protein (ECP), one of the major components of basic granules of eosinophils which is identified in middle ear effusion (MEE). We measured RANTES and ECP in MEEs of OME to determine whether RANTES is increased in the MEEs of OME with allergy. We also evaluated the correlation between RANTES and ECP to determine the role of RANTES as an eosinophil activator in the pathogenesis in OME with allergy. Both RANTES and ECP in MEE of OME with allergy were significantly higher than controls. There was a significant correlation between the contents of RANTES and ECP. Our results suggest the allergic role of chemokine in the pathogenesis of OME.     

Expression of matrix metalloproteinase-9 and -2 in pediatric chronic otitis media with effusion

OBJECTIVE: To evaluate the role of MMP-9 and MMP-2 in pediatric patients with middle ear effusion (MEE) and determine the pathogenesis of otitis media with effusion (OME) and allergy. METHODS: The MEE samples were collected from 25 patients with allergy and 20 patients without allergy as a control. The levels of MMP-9 and MMP-2 were measured using a commercially available enzyme-linked immunosorbent assay (ELISA). The activity of MMP-9 and MMP-2 were measured by gelatin-zymography. The Mann-Whitney U-test was used for comparisons between the allergy positive and control groups. RESULTS: The level of MMP-9 was significantly elevated in MEE from the allergy positive group compared to controls. The amount of MMP-9 activity significantly increased in the allergy positive group compared to controls. CONCLUSION: MMP-9 and MMP-2 are mediators of inflammation in the OME; in addition, MMP-9 may play a significant role in the pathophysiology of OME with allergy.     

The role of allergy in the pathogenesis of otitis media with effusion

To explain an allergic basis for the development of otitis media with effusion (OME), it was suggested that the middle ear mucosa can act as an allergic "shock organ." To evaluate this possibility, 16 juvenile rhesus monkeys were passively sensitized to pollen by intravenous injection of allergic human serum. All ears were then challenged by insufflation of pollen via the nose and eustachian tube (ET), twice daily, for four to five days. Daily tympanometry and otomicroscopy were performed, and on the last day of challenge, tympanocentesis was done to recover effusions. Five animals were killed and the middle ears were processed for histologic study. The results showed that none of the ears developed a middle ear effusion or OME. It is concluded that middle ear challenge with an appropriate pollen antigen in passively sensitized rhesus monkeys does not initiate an inflammatory reaction in the middle ear or induce OME.     

Effects of low humidity on the rat middle ear

Secretory otitis media is common in the winter, and the possible risk factors are numerous. This study examines the effect of low humidity on the middle ear using a Sprague-Dawley rat model: 23 test rats housed for 5 days in a low-humidity environment (10% to 12% relative humidity) and 23 control rats housed at 50% to 55% relative humidity. Microscopic ear examinations were graded for otitis media with effusion (OME) before testing and on test days 3 and 5. The mucosa of the middle ears and eustachian tubes was examined histopathologically. Significantly more effusions were observed in the low-humidity group on test days 3 (P = .003) and 5 (P = .01), but no intergroup histopathologic differences were noted. We conclude that a low-humidity environment contributed to the development of OME in the test animals, and that low-humidity warrants further investigation as a contributing factor in childhood middle ear disease.