Pathogenesis Of Otitis Media With Effusion Research Articles

The role of allergic rhinitis in upper respiratory tract inflammatory diseases

SummaryThe number of patients with allergic rhinitis (AR) is increasing. Furthermore, patients with otitis media with effusion (OME) and chronic sinusitis (CS) are frequently complicated with AR. These findings suggest that AR has an impact on the pathogenesis of both OME and CS. The direct and indirect influence of AR on OME and CS was investigated by clinical and experimental studies to clarify the mechanism by which type I allergic reaction is associated with OME and CS. Clinical findings of patients with OME or CS complicated with AR were analysed and compared with those of nonallergic subjects. Samples such as sinus effusions and middle ear effusions (MEE) were collected from the patients and infiltration of inflammatory cells and concentrations of inflammatory cytokines determined. In addition, previous reports discussing the relationship between AR and OME or CS are reviewed. Eosinophil infiltration and oedema were remarkable in paranasal sinus mucosa of patients with CS complicated with AR, suggesting the presence of type I allergic reaction in sinus mucosa. However, there was little evidence of eosinophils in sinus effusions. Endotoxin was frequently detected in sinus effusions of patients with CS having AR as well as suppurative CS. Hypoxia was also considered an important factor inducing sinus pathology. Eosinophils and IgE antibodies in MEE were not increased in OME patients with AR. Anti‐allergic medicine was effective in OME patients complicated with AR and improvement of nasal symptoms significantly correlated with that of ear symptoms. AR might be directly and indirectly associated with the pathogenesis of OME and CS.

The occurrence of Chlamydia pneumoniae, Mycoplasma pneumoniae, and herpesviruses in otitis media with effusion

In a previous report we found Chlamydia (C.) pneumoniae to be present in middle ear fluids (MEE) from older children with otitis media with effusion (OME). However, OME is a disease of younger children the present study was conducted in toddlers. MEEs ( n = 150) and nasopharynx samples ( n = 83) from children with OME was analyzed by PCR for the presence of C. pneumoniae and Mycoplasma (M.) pneumoniae. C. pneumoniae was not present in any and M. pneumoniae only in one of the MEEs, and these pathogens could be demonstrated in one and two nasopharynx samples, respectively. Further, 133 MEEs were analyzed by PCR for the presence of the 8 human herpesviruses, and all samples were found to be negative. We conclude that neither C. pneumoniae or M. pneumoniae, or any of the 8 human herpesviruses seems to play a major role in the pathogenesis of OME in early childhood OME.

Cell adhesion molecules and cytokines in middle ear effusions in children with or without recent acute otitis media

Objectives We sought to compare the levels of cytokines and cell adhesion molecules in middle ear effusions (MEEs) of children with (group 1) or without (group 2) acute otitis media (AOM) within 3 months of obtaining MEE and to correlate these levels with hearing loss. Design and subjects MEE were collected from children (49 and 51 children composed groups 1 and 2, respectively) with otitis media with effusion (OME) undergoing tube placement who had an audiogram performed preoperatively. MEE was assessed as serous or mucoid. Cytokines and cell adhesion molecules were measured by enzyme-linked immunosorbent assay. Data were analyzed with the Student t test, χ 2 test, and the Pearson correlation test. Results Concentrations of interleukin (IL)-1, IL-6, and vascular cell adhesion molecules (VCAM) were greater in the MEE of the children in group 1 compared with those of group 2 children. ( P < 0.001 for IL-1 and IL-6; P < 0.05 for VCAM). The concentrations of IL-1, IL-6, VCAM, and E-selectin were greater in serous than in mucoid MEE. ( P < 0.05). Concentrations of IL-6 correlated with the concentrations of the other 2 cytokines and the 3 cell adhesion molecules. Only concentrations of IL-6 in MEE correlated with the degree of hearing loss ( P < 0.002). Conclusions The inflammatory response leading to OME involves multiple cytokines regardless of an AOM episode in the 3 months before obtaining MEE. IL-6 is an important cytokine in the pathogenesis of OME.

Evidence of Allergic Inflammation in the Middle Ear and Nasopharynx in Atopic Children with Otitis Media with Effusion

Otitis media with effusion (OME) occurs in the setting of eustachian tube (ET) dysfunction. Previous studies have demonstrated a predominance of T helper 2 (Th2) mediators in the middle ear effusions (MEEs) of atopic children, suggesting that allergy plays a role in the pathogenesis of OME. Given that the middle ear is contiguous with the upper airway, the allergic inflammation seen in the middle ear of atopic patients with OME may also have been observed in the nasopharynx. We hypothesize that atopic children have different cellular and cytokine profiles in MEE compared with nonatopic patients and that this allergic inflammation occurs in both the middle ear and the nasopharynx. Forty-five patients undergoing both ventilation tube placement for OME and adenoidectomy for adenoid hypertrophy were recruited. The atopic status was determined for each patient using standard skin testing. The cellular and cytokine profiles of the MEEs and the torus tubarius and adenoid tissues were investigated using immunocytochemistry and in situ hybridization. Our results indicate that, within the atopic patient, there is a similar cellular and cytokine profile within the three regions sampled, with a predominant expression of interleukin-4 (a Th2 cytokine) and an increased infiltration of eosinophils compared with the nonatopic patient. These findings confirm the association of allergy with MEE and support the hypothesis that the middle ear may be an integral part of the United Airway Concept.

Effect of inhibitors of leukotriene and/or platelet activating factor on killed H. influenzae induced experimental otitis media with effusion

Our previous studies have shown that leukotriene (LT) and platelet activating factor (PAF) are important inflammatory mediators (IMs) in the pathogenesis of otitis media with effusion (OME). The purpose of this study was to determine the effect of a LT-inhibitor and/or PAF-antagonist on experimentally induced OME by killed H. influenzae in chinchillas. LT-inhibitor SCH-37224 and/or PAF-antagonist WEB-2170 were systematically administered, each separately or in combination, 2 h prior and then at regular intervals after the injection of killed H. influenzae into the superior bullae. After 48 h, OME was completely prevented in the combination group while it was only partially prevented in the other two separately treated groups. Animals in the control group all developed OME. Findings of this study suggest the importance of LT and PAF in the pathogenesis of OME and the usefulness of their blockers in the prevention of OME suggesting possible future therapeutic implication.

Role of macrophage migration inhibitory factor in otitis media with effusion in adults.

Otitis media with effusion (OME) is one of the most common ear diseases. Bacterial endotoxins and several inflammatory cytokines appear to be involved in the pathogenesis of OME in children; however, little is known of the immunological aspects of the onset of OME in adults. We sought to determine the presence of macrophage migration inhibitory factor (MIF) as well as interleukin 1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), RANTES (regulated upon activation, normal T-cell expressed and presumably secreted), and endotoxin in middle ear effusions (MEEs) from adult patients with OME. In addition, the levels of MIF in MEEs from adults and children were compared. MEE was obtained from 95 adults and 11 children. The levels of MIF, IL-1beta, TNF-alpha, and RANTES were determined by enzyme-linked immunosorbent assay, and the concentrations of endotoxin and total protein were determined by the Endospec assay and bicinchoninic acid assay, respectively. MIF was detected in 97.9% of the MEEs from adults, while endotoxin, IL-1beta, TNF-alpha, and RANTES were detected in 96.8, 12.6, 5.3, and 43.9%, respectively. In addition, the level of MIF was significantly higher than those of endotoxin, IL-1beta, and TNF-alpha. A positive correlation between the levels of MIF and endotoxin was observed. MIF and endotoxin were detected in 81.8 and 72.7%, respectively, of the MEEs from the children. The level of MIF was significantly higher in the children, and conversely that of endotoxin was significantly higher in the adults. These results suggest that the interaction between MIF and endotoxin may promote fluid collection in the middle ear, particularly in adults.

Autoimmunity in the etiology of otitis media with effusion

Otitis media with effusion (OME) is one of the most common health problems seen in children. The role of autoimmunity in the etiology of OME has been discussed for a long time. The purpose of this investigation is to determine the role of circulating antibodies in the pathogenesis of OME. The presence of antibodies against rabbit tympanic bulla epithelium was investigated by indirect immunoflouresence in the serum samples of 25 patients with OME and serum samples of 25 healthy children as a control group. In the control group, positive staining was seen in only 1 case (4%), whereas 8 cases with OME were positively stained (%32). There was statistically significant difference between the 2 groups. The presence of antibodies against middle ear epithelium in the cases with OME suggest that autoimmunity might play a role in the formation of effusion in the tympanic cavity.

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.

T(H)2 cytokine expression in atopic children with otitis media with effusion.

Otitis media with effusion (OME) is more common in atopic children. Few studies have looked for the presence of inflammatory mediators in the middle-ear effusions of this population. We hypothesize that atopic children with OME have a different inflammatory cell and cytokine profile than nonatopic patients with the disease. Twenty-six patients with OME undergoing myringotomy and ventilation tube placement were recruited at the McGill University Hospital Center. The atopic status was determined for each patient by using standard skin testing. By means of immunocytochemistry, fluid specimens were assessed for T lymphocytes (CD3), eosinophils (major basic protein), neutrophils (elastase), mast cells (tryptase), and basophils (BB1). By using in situ hybridization, the expression of IL-4, IL-5, and IFN-gamma was assessed. There is a higher percentage of eosinophils and T lymphocytes in atopic patients with OME (n = 8) compared with that seen in nonatopic patients (n = 18, P <.01). There is a higher percentage of neutrophils in nonatopic patients with OME compared with that seen in atopic patients (P <.01). In examining cytokine profiles, there is a higher percentage of cells expressing IL-4 and IL-5 in atopic patients with OME compared with that seen in nonatopic patients (P <.01). The predominance of eosinophils, T lymphocytes, and T(H)2 mediators in the middle-ear effusions of atopic children provides evidence that allergy might play a role in the pathogenesis of OME.

Experimental otitis media with effusion induced by leukotriene D 4

Objective: inflammatory mediators such as prostaglandins (PGs), leukotrienes (LTs), and platelet-activating factor (PAF) have been identified in human middle ear effusions (MEEs), as well as in the experimentally induced MEEs of animals. However, the exact function of LTs in the middle ear cavity is still unknown. In this study, the role of LTs was investigated using an experimental model in which OME was induced by LTD 4. Methods: to examine whether leukotrienes (LTs) induce otitis media with effusion (OME), 2×10 −6, 2×10 −5, 1×10 −4 and 2×10 −4 M of LTD 4 was injected into the rat ear. The severity of OME was assessed based on the histological findings. The concentrations of IL1-β, TNF-α, and GRO/CINC-1 in MEE were also measured. Additionally the therapeutic efficacy of a specific LTs antagonist, pranlukast on experimental OME was investigated. Results: all ears developed middle ear effusion (MEE) within 24 h and about 50% of the animals continued to demonstrate MEE for 14 days in the 1×10 −4 and 2×10 −4 M groups. The cytokine levels seemed to correspond well with the persistence of OME. The oral administration of a specific LTs antagonist, pranlukast, was found to alleviate the experimental OME. Conclusion: these findings suggest that LTs appear to plays an important role in the pathogenesis of OME.

Concentration of nitric oxide metabolites in middle ear effusion

Free radicals such as nitric oxide (NO) seem to be important in the pathogenesis of otitis media with effusion (OME). NO can be quantitated by measuring its metabolites, nitrate (NO 3 −) and nitrite (NO 2 −). The purpose of this study is to determine the concentrations of NO in human middle ear effusion (MEE). Samples of human MEE were collected at the time of myringotomy and tympanostomy tube insertions. The type of MEE was classified as serous (SOM), mucoid (MOM) or purulent (POM) at the time of surgery. Samples of MEE were assayed for NO metabolites (nitrate and nitrite) with colorimetric assay (Griess method). Concentrations of NO metabolites were highest in MOM followed by SOM and POM. This study suggests that NO is present in human MEE and may play an important role in the pathogenesis of OME.

Otitis media with effusion: expectant management

OBJECTIVE: Despite the fact that chronic otitis media with effusion (OME) is an entity with a high prevalence among children, the real effectiveness of most treatments in use nowadays has not been completely established. Based on its natural course, we defend an expectant management as the initial treatment. METHODS: We undertook a review of the available data taking into consideration the natural history, epidemiology and therapeutic options for OME. We looked for a guideline concerning the best treatment for OME in children. RESULTS: The treatment of OME still remains controversial, in spite of many therapeutic options. In children, the best management still seems to be the observation, probably for a period of three to six months. However, interventionist treatment should be done earlier on those patients considered as high risk or in which a problem happened with their development, due to hearing loss secondary to OME. CONCLUSIONS: The understanding of the several factors involved in the pathogenesis of OME, as well as of the features in its evolutive course, encourage the idea of a conservative expectant approach at first or up to the moment in which an interventionist approach (clinical or surgical) is justified.

Intranasal surfactant aerosol therapy for otitis media with effusion.

To determine the effect of surfactant alone and with other medications delivered intranasally as a metered dose inhaler (MDI) aerosol on the resolution of experimentally induced otitis media with effusion (OME). Eustachian tube dysfunction is a primary factor in the pathogenesis of OME. Intranasal surfactant via MDI has been shown in this laboratory to reduce passive opening pressure of the eustachian tube in normal gerbils and mice. OME was developed in 35 gerbils by transtympanic injection of 10 microg lipopolysaccharide from Klebsiella pneumoniae. Pretreatment otomicroscopy and tympanometry were performed to exclude pre-existing middle ear disease, and postinfection evaluations were performed on alternate days for a period of 30 days. Five animals received no treatment (control group); four were treated with propellant only (placebo); seven received surfactant alone; eight received surfactant and betamethasone; and six received surfactant with phenylephrine. All medications were sprayed intranasally as an aerosolized MDI and administered daily from postinfection day 2 onward. OME resolved after 16.0 +/- 0.44 days (mean + SD) in controls. There was no difference seen in the placebo or the surfactant with phenylephrine groups. Treatment with surfactant yielded resolution in 10.57 +/- 0.37 days; this was reduced to 8.57 +/- 0.37 days with surfactant plus betamethasone. These differences are statistically significant. There was no recurrence of OME in any group. This study demonstrates that using an aerosolized MDI surfactant with and without betamethasone decreases the duration of OME in this in vivo gerbil model.

中耳炎とサイトカイン

To elucidate the pathogenesis of otitis media with effusion (OME), the role of cytokines was investigated by analyzing the middle ear effusion (MEE) obtained from patients with this disease and from experimental animal models. Enzyme-linked immunosorbent assay (ELISA) of the MEE revealed that levels of IL-1β and IL-8 were higher in the mucoid type MEE than in the serous type MEE and were significantly increased in neutrophil-rich groups. Gene targets of those cytokines were also detected in pellets of the MEE by RT-PCR. However, the incidence of IL-6 and IL-8 detected by RT-PCR was lower than that detected by ELISA, suggesting that those cytokines were produced by the middle ear mucosa as well as inflammatory cells infiltrating the MEE.In the animal experiment, OME was induced in mice by intra-tympanic inoculation with an endotoxin, and the levels of IL-1β in the MEE were significantly increased. Intra-tympanic inoculation with rIL-1β also produced the MEE and the cytological findings of the MEE as well as the histological findings of the middle ear mucosa were similar to those found in endotoxin-induced OME. Furthermore, an intra-tympanic injection with anti-IL-1 receptor antibodies reduced the incidence of OME induced by an endotoxin or rIL-1β, suggesting that IL-1β may play an important role in the pathogenesis of OME.This clinical study demonstrated that macrolide was effective for OME and decreased the levels of inflammatory cytokines in the MEE including IL-1β and IL-8. Animal experiments also showed that co-administration of macrolide reduced the incidence of endotoxin-induced OME and the concentration of IL-1β in the MEE.These findings suggest that cytokines play an important role in the pathogenesis of OME and that a cycle of the cytokine network might be associated with the persistence of this disease.

Clinical, bacteriological, and histological study of adenoids in children

Purpose: The adenoid has long been recognized as an important factor in the pathogenesis of otitis media with effusion (OME). However, there is still considerable debate concerning how the condition of the adenoid tissue is involved in the cause of OME. The purpose of this study is to investigate whether the adenoid is an active agent of OME. Patients and Methods: One hundred forty-six patients aged from 3 to 6 years who underwent adenoidectomy at Oita Medical University (Japan) were retrospectively compared with patients with and without OME regarding macroscopic size of the adenoid, adenoidal-nasopharyngeal ratio (AN ratio), incidence of sinusitis and nasal allergy, bacteriological examination of adenoid tissues, reticular formation of the epithelium, and the percent of ciliated epithelium. Results: There was no significant difference in the size of adenoids. Haemophilus influenzae (HI) was cultured more frequently in adenoid specimens from patients with OME. A tendency toward increased stratified squamous epithelium and decreased ciliated epithelium was apparent in patients with OME. Reticular epithelium extension was greater in patients with than without OME. Conclusion: Adenoid inflammation is implicated in the pathogenesis of OME and the adenoids have an important role in the cause of OME by being a reservoir for HI.

Expression of Vascular Endothelial Growth Factor in Otitis Media

Increased vascular permeability and endothelial cell growth are important in the pathogenesis of otitis media with effusion (OME) and the vascular endothelial growth factor (VEGF) is known to play an important role in the increased vascular permeability and angiogenesis. To date, at least five isoforms of the VEGF family have been identified as VEGF transcripts, encoding polypeptides of 206, 189, 165, 145 and 121, but their physiological roles are unclear. The purpose of this study was to investigate the expression of VEGF, in both endotoxin-induced OME of the rat and human otitis media. We instilled endotoxin and saline as a control into the middle ear cavity of the rat. Middle ear mucosa were taken at 0 h, 1 h, 3 h, 6 h, 12 h, 1 day, 3 days, 7 days and 14 days and the expression of VEGF mRNA and VEGF protein was evaluated using semi-quantitative RT-PCR and immunohistochemistry. Expression of VEGF164 mRNA and VEGF120 mRNA was first identified 1 h after endotoxin instillation and was dramatically increased over the period 6 h-1 day and then progressively decreased by day 7. The level of expression of VEGF120 mRNA was slightly higher than that of VEGF164 mRNA and that of VEGF164 mRNA was much higher than that of VEGF188 mRNA. Immunostaining revealed expression of VEGF during 6 h to day 3 and its expression was localized to ciliated cells and some inflammatory cells. We also performed RT-PCRs of cDNA from middle ear fluids of 8 human OME patients and middle ear mucosa of 4 chronic otitis media patients for the identification of VEGF mRNA expression. VEGF121 mRNA was highly expressed in all samples compared with VEGF165 mRNA. These results suggest that VEGF may be primarily responsible for increased vascular permeability and endothelial cell growth in OME and that VEGF seems to play a significant role in the pathogenesis of OME.

Soluble adhesion molecules in middle ear effusions from patients with chronic otitis media with effusion

Soluble forms of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) have been identified in the peripheral blood and other body fluids. These soluble adhesion molecules have been reported to reflect the upregulation of cell surface ICAM-1 and VCAM-1 expression in inflammatory diseases. The levels of soluble ICAM-1 and soluble VCAM-1 in 37 middle ear effusions from 37 patients with chronic otitis media with effusion (OME) were quantitatively determined with enzyme-linked immunosorbent assays. The levels of soluble ICAM-1 in mucoid effusions were significantly higher than those in serous effusions, but the levels of soluble VCAM-1 did not differ significantly between the two types of effusion. The levels of soluble VCAM-1 in effusions from atopic patients were significantly higher than those from non-atopic patients, whereas the levels of soluble ICAM-1 in samples from atopic patients were significantly lower than those from non-atopic patients. Therefore, our data suggest that an increase in soluble VCAM-1 plays a more important role in the pathogenesis of OME in atopic patients than in non-atopic patients. In addition, soluble ICAM-1 is likely to play a more important role in the pathogenesis of OME in nonatopic patients than soluble VCAM-1.

The role of IL-1 beta in murine model of otitis media with effusion

Recent studies have demonstrated the presence of inflammatory cytokines such as IL-1 beta, TNF-alpha, IL-6, and IL-8 in the middle ear effusion (MEE) of patients with otitis media with effusion (OME). IL-1 beta is known to be produced from macrophages and monocytes in an early stage of inflammation by stimulation with microorganisms and endotoxins. Also, these studies have shown that endotoxins frequently are found in MEE and can induce OME in experimental animal model. These findings suggest that endotoxins in MEE cause a chain reaction of cytokines through IL-1 beta. However, the precise role of IL-1 beta in the pathogenesis of OME has not yet been clarified. In the present study, a murine model of OME was developed by intra-tympanic injection with endotoxin or recombinant mouse IL-1 beta (rIL-1 beta) and the effects of IL-1 beta on the production of MEE were investigated. OME was induced in specific pathogen-free male BALB/c mice by intra-tympanic inoculation with endotoxin purified from nontypeable Haemophilus influenzae or with rIL-1 beta. The presence of MEE in the subjects was observed through the ear drum under a microscope and samples of MEE were collected by aspiration and washing with phosphate-buffered saline. The concentrations of IL-1 beta in each sample of MEE were determined by ELISA and the histological changes were compared. The mice inoculated with endotoxin showed signs of the production of MEE and it was noted that the levels of IL-1 beta in MEE were significantly increased on day 3. Intra-tympanic inoculation with rIL-1 beta also produced MEE and these cytological findings of MEE as well as the histological findings of middle ear mucosa were similar to those found in the endotoxin-induced OME. Further, the influence of anti-IL-1 receptor antibodies on the production of OME was examined 3 days after intra-tympanic injection with anti-IL-1 receptor antibodies together with endotoxin or rIL-1 beta. The incidence of OME was lower in mice injected with anti-IL-1 receptor antibodies than that in mice injected with endotoxin or rIL-1 beta only. These findings suggest that IL-1 beta may play an important role in the pathogenesis of OME.

Detection of soluble interleukin‐2 receptor and soluble intercellular adhesion molecule‐1 in the effusion of otitis media with effusion

We measured sIL-2R, TNF-α and sICAM-1 in the sera and middle ear effusions (MEEs) of patients with otitis media with effusion (OME). Although there was no signmcant difference between the sIL-2R levels of the serous and mucoid MEEs, they were significantly higher than serum sIL-2R levels of OME patients and healthy controls. TNF-α levels of the mucoid MEEs were significantly higher than those of the serous type. However, TNF-α was rarely detected in the sera of OME patients or healthy controls. We observed significant differences between the serous and mucoid MEEs with respect to their sICAM-1 levels, which were also higher than serum slCAM-1 levels of OME patients and healthy controls. Our findings suggested that IL-2, TNF-α and ICAM-1 could be significantly involved in the pathogenesis of OME through the cytokine network.

The role of IgE-mediated hypersensitivity in otitis media with effusion

Introduction: The role of immunoglobin (Ig) E-mediated hypersensitivity in otitis media with effusion (OME) has been the subject of much controversy and personal bias. Uncontrolled studies report the incidence of respiratory allergy in children with OME to range from 4% to over 90%. Materials and Methods: Children 1 to 18 years old who had OME requiring a myringotomy and tubes from January 1, 1987, through July 1, 1988, were the subjects of this study. The history of allergic and radioallergosorbent test (RAST) analysis of specific serum IgE levels was undertaken for 26 allergens on 89 children in the study group and 59 children in the control group. Result: The incidence of allergen as diagnosed by RAST score was higher in children with OME than children in the control group ( P > f .05). There was no correlation between positive RAST scores and the number of polyethylene-ventilating (PE) tubes previously placed, history of tonsillectomy, history of adenoidectomy, or the character of the effusion (mucous v serous). Conclusion: Respiratory allergy is a factor involved in the pathogenesis of OME.