Eosinophilic otitis media and comorbid asthma.

PURPOSE OF REVIEW: Eosinophilic otitis media (EOM) is an intractable otitis media characterized by numerous eosinophils infiltrating the middle ear cavity, which is part of the upper airway. EOM shows a high rate of comorbidity with asthma. They are considered to have a 'one airway, one disease' relationship. Here, we summarize our current knowledge regarding the characteristics of EOM, EOM's relationship with asthma and the efficacy of optimal treatments for EOM. RECENT FINDINGS: The greater the severity of asthma, the more pronounced the development of EOM. Asthma control is usually inadequate in asthmatics who develop EOM, and appropriate strengthening of asthma inhalation therapy leads to improvement in the EOM. EOM severity can be divided into mild, moderate, and severe. Intratympanic infusion therapy using a topical steroid such as triamcinolone acetone is effective for mild EOM, whereas moderate EOM requires a systemic steroid in addition to triamcinolone acetone, and severe EOM forms granulation tissue that requires surgical removal. Recently, the effectiveness of molecularly targeted drugs is being reported, but more data need to be accumulated. SUMMARY: EOM and asthma are closely related. Optimal asthma treatment is important for treating EOM. Treatments commensurate with the severity of EOM are being developed.

Endoscopic Evaluation of the Eustachian Tube: assessment of a novel tool for grading Eustachian tube inflammation.

BACKGROUND: Signs of inflammation are commonly encountered during endoscopic examination of the Eustachian tube (ET) region. The clinical applicability of these findings may be enhanced by use of a standardized assessment score. METHODS: Digital video recordings were obtained of 50 nasal endoscopy examinations of the nasopharyngeal portion of the ET. Four fellowship-trained rhinologists independently reviewed the videos with regard to specific physical findings: edema of the ET torus, erythema of the ET torus, exudate at the ET orifice, and presence of tubal tonsil. Scoring of this Endoscopic Evaluation of the Eustachian Tube (3ET) was reported using both 2-point and 3-point scales. Each reviewer repeated the scoring at a 10-day interval. Interrater and intrarater agreement were calculated for each item and the total scores. RESULTS: Interrater and intrarater agreement were greater for the 3-point scale than the 2-point scale. Interrater agreement for overall instrument using the 3-point scale was in the "acceptable" range for Krippendorff's alpha on both the first trial (0.6922) and second trial (0.7238). Intrarater agreement was generally "excellent" for individual items as well as the overall instrument. CONCLUSION: The 3ET comprising these 4 physical findings has acceptable interrater and intrarater reliability, and may be applied to future clinical studies of ET function and disease.

Deletion of the complement C5a receptor alleviates the severity of acute pneumococcal otitis media following influenza A virus infection in mice.

There is considerable evidence that influenza A virus (IAV) promotes adherence, colonization, and superinfection by S. pneumoniae (Spn) and contributes to the pathogenesis of otitis media (OM). The complement system is a critical innate immune defense against both pathogens. To assess the role of the complement system in the host defense and the pathogenesis of acute pneumococcal OM following IAV infection, we employed a well-established transtympanically-induced mouse model of acute pneumococcal OM. We found that antecedent IAV infection enhanced the severity of acute pneumococcal OM. Mice deficient in complement C1qa (C1qa-/-) or factor B (Bf -/-) exhibited delayed viral and bacterial clearance from the middle ear and developed significant mucosal damage in the eustachian tube and middle ear. This indicates that both the classical and alternative complement pathways are critical for the oto-immune defense against acute pneumococcal OM following influenza infection. We also found that Spn increased complement activation following IAV infection. This was characterized by sustained increased levels of anaphylatoxins C3a and C5a in serum and middle ear lavage samples. In contrast, mice deficient in the complement C5a receptor (C5aR) demonstrated enhanced bacterial clearance and reduced severity of OM. Our data support the concept that C5a-C5aR interactions play a significant role in the pathogenesis of acute pneumococcal OM following IAV infection. It is possible that targeting the C5a-C5aR axis might prove useful in attenuating acute pneumococcal OM in patients with influenza infection.

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.

Allergic rhinitis, histamine, and otitis media.

Otitis media (OM) is a common and costly medical condition, especially in children. Most episodes of OM are associated with an upper respiratory viral infection and are short-lived and self-limiting with or without medical treatment. However, chronic OM with effusion (OME) has significant sequelae, is refractory to most medical treatments, and frequently requires surgical intervention. The pathophysiology of OME is complex and involves both eustachian tube (ET) dysfunction and middle ear pressure dysregulation. OM likely results from an increase in blood flow to and, thus, gas loss from the middle ear, in combination with a dysfunctional ET that can not resupply that gas. These processes could be induced by viral and/or allergen-driven inflammation. A large body of epidemiologic and mechanistic evidence supports a role for allergic rhinitis as a risk for OM. Indeed, evidence also supports a role for histamine in both conditions. However, not all such evidence is supportive of this relationship and a causal relationship between the two conditions has not been definitively proven. Moreover, therapeutic trials using common allergy therapies have either not been conducted or showed no benefit in OM. This prompted the 2004 clinical practice guidelines on OM to conclude that no recommendations could be made for "... allergy management as a treatment for OME based on insufficient evidence of therapeutic efficacy or a causal relationship between allergy and OME." Nonetheless, given the strong likelihood of allergy as a risk factor for OM, allergic rhinitis patients should be evaluated for OM and patients with OME should be considered for an allergy evaluation. If significant allergic rhinitis is diagnosed in a patient with OME, it should be treated aggressively (as in any case of moderate to severe allergic rhinitis) until further studies are conducted. No definitive conclusions about a role for food allergy in causing or treating OM can be made. Clearly, more studies are needed to examine the relationship between these two important conditions.

Role of adenoids and adenoiditis in children with allergy and otitis media.

Adenoids and/or tonsil inflammation with concomitant obstructive hypertrophy is one of the oldest and most common pediatric problems. Adenoids are a component of Waldeyer's ring and because of their anatomic position can be relevant in the pathogenesis of otitis media when they are inflamed and/or enlarged. Adenoid pads can create mechanical eustachian tube obstruction. Therefore, in some cases, adenoidectomy may have a role in the clinical management of otitis media with effusion. However, eustachian tube dysfunction related to the adenoids may also have an allergy-related functional component. Allergic inflammation has been described for middle ear effusion, and some studies have reported that mast cells increase and allergic mediators release in adenoids as well. Nasal endoscopy has a key role in confirming a diagnosis of adenoid hypertrophy and/or adenoiditis and in detecting an association between adenoid inflammation/infection and otitis media with effusion, especially during infancy and early childhood.

Role of nasal allergy in chronic secretory otitis media.

Nasal allergy seems to be one of the important causes of chronic secretory otitis media (SOM) in children and adults. Chronic SOM is unequivocally related to disturbed function of the eustachian tube, which facilitates communication of the middle ear with the nasopharynx, nasal cavity, and indirectly with paranasal sinuses. The most serious consequences of chronic SOM are decreased elasticity of the tympanic membrane and hearing impairment. Allergic reactions in the nasal mucosa leading to release of various mediators result in development of three types of nasal response characterized predominantly by nasal obstruction. Eustachian tube functions can be affected directly by the mediators released in the nasal mucosa or indirectly by the nasal obstruction. Nasal challenges with allergens performed by rhinomanometry, combined with tympanometry and eventually audiometry, may be a useful diagnostic supplement for this disorder.

Is the healthy middle ear a normally sterile site?

OBJECTIVE: To systematically evaluate the presumption that the healthy middle ear becomes colonized with organisms via the patent eustachian tube using modern microbiologic techniques. STUDY DESIGN: Sterile saline washings were obtained from the middle ear of patients in a prospective fashion. SETTING: Tertiary/quaternary referral centers. PATIENTS: Pediatric and adult patients undergoing cochlear implantation surgery. INTERVENTION(S): Standard bacterial and viral cultures, and nucleic acid amplification techniques. MAIN OUTCOME MEASURE(S): Identification of organisms. RESULTS: Specimens were obtained from 13 children and 9 adults. No organisms were identified in any of the specimens, either through standard culture or PCR testing. CONCLUSION: The presumption that the healthy middle ear is colonized by bacteria from the nasopharynx is unsubstantiated.

Immune modulatory oligonucleotides in the prevention and treatment of allergen-induced eustachian tube dysfunction in the animal model.

This article reviews the current literature investigating the applications and success of immune modulatory oligonucleotides as immunotherapy to treat and prevent allergen-induced eustachian tube dysfunction in animal models. Synthetic DNA-based immunotherapy agents composed of unmethylated cytosine-guanine dinucleotides (CpG ODNs) that bind to Toll-like receptors have been found to have tremendous potential as therapeutic agents and adjuvants. CpG ODNs can induce a shift in the cytokine profile and immune response that favors the T-helper type 1 pathway and suppresses the T-helper type 2 pathway. This makes CpG ODNs promising candidates for treating allergic diseases. Current CpG ODN studies have demonstrated prevention and treatment of acute allergen inflammation of the eustachian tube in an animal model of otitis media. Immune modulatory oligonucleotides in immunotherapy, administered systemically or topically, have been shown to be safe and effective in the animal model.

Immune modulatory oligonucleotides in prevention of nasal allergen-induced Eustachian tube dysfunction in rats.

OBJECTIVES: Develop a model of nasal allergen-induced Eustachian tube dysfunction (ETD) in a rat and investigate the role of immune modulatory oligonucleotides (IMOs) in the prevention of nasal allergen-induced ETD. STUDY DESIGN AND SETTING: Prospective, randomized study. Brown Norway rats were sensitized to ova albumin (OVA) and randomized to receive pretreatment with IMOs or phosphate-buffered saline. All animals were challenged intranasally with aerosolized OVA. Dynamic measures of Eustachian tube (ET) function were analyzed. RESULTS: Animals that were OVA-sensitized and IMO-pretreated had significantly lower mean passive opening (95% confidence interval [95% CI] 15.0,19.4) and closing (95% CI 4.8,7.8) ET pressures compared with those of (95% CI 24.1,32.7) and (95% CI 12.1,18.8) OVA-sensitized untreated rats, respectively. In addition, the IMO-pretreated animals demonstrated the ability to actively clear a significantly higher proportion of negative pressure (95% CI 0.64,0.96) compared with the untreated animals (95% CI 0.09,0.39). IMO-pretreated animals also demonstrated significantly improved mean mucociliary clearance times in seconds (95% CI 115,195) than those in untreated animals (95% CI 308,668). CONCLUSIONS: Pretreatment with IMOs prevented allergen-induced allergic inflammation around the Eustachian tube (ET) and resulted in improved ventilatory function of the ET compared with sensitized untreated animals. IMOs offer considerable promise in the management of nasal allergic disease as well as otitis media with effusion.

Immune modulatory oligonucleotides in the prevention and treatment of OVA-induced eustachian tube dysfunction in rats.

BACKGROUND: Otitis media with effusion (OME) is often associated with allergies. Immune modulatory oligonucleotides (IMO) mediate allergic inflammation and may therefore be efficacious in the treatment of airway inflammation. OBJECTIVE: To evaluate the role of an IMO via transtympanic mucosal application in prevention and treatment of ovalbumin-induced OME. DESIGN: Forty brown Norway rats were divided into control and treatment groups. Eustachian tube dysfunction was evaluated by passive opening pressures, passive closing pressures, active clearance of negative pressure, and mucociliary clearance transit time. RESULTS: Rats who underwent IMO treatment required 50% less pressure to open and close the eustachian tube (P < 0.05) and were able to actively clear 50% more negative pressure than the ovalbumin-control rats (P < 0.001). The treatment rats' mucociliary clearance time was half that of the control group (P < 0.001). CONCLUSION: IMO via transtympanic application can prevent and treat allergy-induced eustachian tube dysfunction in rats. IMO may offer substantial promise in the future management of OME.

The role of immunomodulatory oligonucleotides in prevention of OVA-induced Eustachian tube dysfunction.

OBJECTIVE: To evaluate the potential role of immunomodulatory oligonucleotides (IMO) in the prevention of OVA-induced Eustachian tube dysfunction (ETD) in a rat model. METHODS: Brown-Norway rats were sensitized to ovalbumin (OVA) and randomized to receive pre-treatment with IMO or phosphate buffered saline (PBS). After systemic sensitization, subjects received a transtympanic OVA challenge followed by evaluation of the Eustachian tube's dynamic function. RESULTS: Pre-treatment of OVA sensitized animals with IMO normalized passive opening and closing Eustachian tube pressures, improved active clearance of negative pressure in the middle ear, and resulted in reduced mean mucociliary transit times compared to untreated OVA-sensitized animals (P<0.001). CONCLUSION: These data demonstrate that pre-treatment with IMO prevent OVA-induced ETD in the rat. IMO treatment in the future may offer considerable promise in the management of OME in children.

Expression of beta-defensins in the tubotympanum of experimental otitis media.

CONCLUSION: Since the expression levels of beta-defensins 2-4 were up-regulated in experimental otitis media, they may play a protective role in the pathogenesis of otitis media. OBJECTIVES: Defensins are antimicrobial peptides that play a major role in innate immunity. The goal of this study was to identify the expression of defensins in experimental otitis media of the mouse. MATERIALS AND METHODS: The expression of three alpha-defensins (cryptdins, cryptdin-related sequences 1-C (CRS1-C), and CRS4-C) and four beta-defensins (mBD1, mBD2, mBD3, and mBD4) was investigated in the tubotympanum of experimental otitis media in mice by a semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), and the expression levels of three beta-defensins (mBD2, mBD3, mBD4) were evaluated by Western blotting. RESULTS: The alpha-defensins were not expressed in the tubotympanum. mBD1 was expressed constitutively in normal middle ear mucosa and Eustachian tube mucosa, but up-regulated expression of mBD2, mBD3, and mBD4 was observed with RT-PCR and Western blotting in the tubotympanums in experimental otitis media, while the normal tubotympanums did not express them.

Eustachian tube possesses immunological characteristics as a mucosal effector site and responds to P6 outer membrane protein of nontypeable Haemophilus influenzae.

The eustachian tube (ET) plays an important role in the pathogenesis of otitis media (OM). To better understand its biology and to develop a nasal vaccine for preventing OM, mucosal lymphocytes in the ET were analyzed, and the ET's immunological function was investigated. Mononuclear cells were isolated from murine ET, and lymphocyte subsets were analyzed by flow cytometry. Antibody-producing cells were determined by enzyme-linked immunospot assay. The expression of cytokine mRNA in ET CD4(+) T cells was determined by RT-PCR. Results in naive mice showed that the ET contained many immunocompetent cells, including a relative large number of IgA-producing cells and Th2 cytokine-expressing T cells. Next, we investigated antigen-specific immune responses in the ET. Mice were immunized intranasally with the P6 outer membrane of nontypeable Haemophilus influenzae (NTHi) and cholera toxin (CT), and P6-specific immune responses in the ET were examined. P6-specific IgA producing cells markedly increased in the ET. Moreover, in vitro stimulation with P6 of purified CD4(+) T cells from immunized mice resulted in the proliferation of CD4(+) T cells that expressed Th2 cytokine mRNA. These results indicate that the ET might be characterized as a mucosal effector site and that antigen-specific IgA and Th2 immune responses could be induced in the ET by intranasal immunization. These findings suggest that the ET might be a key immunological organ in the pathogenesis of OM, and in the development of a nasal vaccine.

Evidence of allergic inflammation in the middle ear and nasopharynx in atopic children with otitis media with effusion.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Immunodetection of surfactant proteins in human organ of Corti, Eustachian tube and kidney.

The presence of surfactant proteins was investigated in the human organ of Corti, Eustachian tube and kidney tissues. It has previously been shown that lamellar bodies are present in hairy cells of organ of Corti, in the cytoplasm of secretory and lumen of tubal glands of Eustachian tube and kidney renal basement membrane. No evidence for the presence of surfactant proteins in the organ of Corti and kidney has been presented until now. The aim of this study was to find out if surfactant proteins were expressed in other epithelia such as organ of Corti, Eustachian tube and kidney. Surfactant proteins were identified using one-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting. On one-dimensional Western blots, bands for surfactant protein A in human Eustachian tube (SP-A, 34 kDa) and in kidney extracts, and for surfactant protein D (SP-D, 43 kDa) in Eustachian tube and in kidney extracts (SP-D, 86 kDa), and for surfactant protein B (SP-B, 8 kDa) in human Eustachian tube and organ of Corti extracts were detected. Bands corresponded to monomeric forms of lung surfactant proteins. These results indicate the presence of SP-A and SP-D in kidney epithelium, SP-A, SP-B and SP-D in Eustachian tube and SP-B in the organ of Corti.

Proliferating macrophages, dendritic cells, natural killer cells, T and B lymphocytes in the middle ear and Eustachian tube mucosa during experimental acute otitis media in the rat.

Although many studies focus on the increase of immunocompetent cells within the middle ear mucosa during acute otitis media it is poorly understood how this increase is mediated. The differentiation between two possible causes, i.e. immigration and local proliferation, would help to better understand the pathophysiology of this disease. Therefore, the number of proliferating macrophages, dendritic cells, natural killer cells and T and B lymphocytes was studied during acute otitis media in the rat middle ear mucosa (ME mucosa) and Eustachian tube mucosa (ET mucosa) by labelling proliferating leucocytes with the DNA precursor bromodeoxyuridine (BrdU). By removing the middle ear and Eustachian tube 24 h after BrdU injection, the contribution of immigrated newly formed cells was estimated. At this timepoint, many leucocytes in the ME and ET mucosa had incorporated BrdU (between 15 and 25% within the subsets). By analysing these tissues one hour after BrdU injection, the local proliferation rate was determined (between 2 and 9% within the subsets). Thus, the inflamed ME and ET mucosa are the destination of immunocompetent cells and, as our data show, the inflamed microenvironment supports local proliferation of immunocompetent cells.

Distribution of immunoglobulin isotypes and subisotypes in equine guttural pouch (auditory tube diverticulum).

To clarify the functions of the equine guttural pouch, the distribution of various immunoglobulin isotypes and subisotypes in the guttural pouch mucosa were examined in healthy horses. IgGa was present in the mucosa of guttural pouch, mucosal lymph nodules and submucosal lymph nodules. IgM was scattered in the mucosal lymph nodules and in the germinal centers of the submucosal lymph nodules. IgGc was recognized only in the submucosal lymph nodules. These immunoglobulin isotypes and subisotypes were found in lymphocytes and plasma cells. On the other hand, IgA was detected in glandular epithelial cells and the surface layer of the mucosal epithelium, as well as in free cells. This finding suggests that IgA is secreted through the glandular epithelium. Based on the above findings, we conclude that the guttural pouch has phylactic ability.