Higher Prevalence and Severity of Eosinophilic Otitis Media in Patients with Asthma-COPD Overlap Compared with Asthma Alone.

INTRODUCTION: Eosinophilic otitis media (EOM) is well-known to frequently co-exist with adult-onset asthma. Both diseases are similar type 2 inflammation and are considered to have a "one airway, one disease" relationship. Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO), characterized by airway obstruction caused by airway wall thickening (AWT), is a severe condition with a higher incidence of mortality compared to asthma alone or COPD alone. Based on the "one airway, one disease" concept, we hypothesized that the inflammatory pathophysiology of EOM differs depending on its comorbidity with ACO or with asthma alone. METHODS: A total of 77 chronic rhinosinusitis (CRS) patients with asthma were enrolled in this study. The subjects were divided into 2 groups: a group with comorbid asthma alone (asthma group; 46 patients), and a group with comorbid ACO (ACO group; 31 patients). The 2 groups were compared and assessed with regard to various factors, including the patients' clinical characteristics, prevalence rate of EOM, EOM severity, EOMs relationships with smoking and AWT, and the eosinophil and neutrophil cell counts in the middle ear effusion (MEE). RESULTS: The ACO group included significantly more males (p < 0.05), was significantly older (p < 0.05), and showed significantly lower lung function values (FEV1 [L], FEV1 [%pred]) (p < 0.01) compared with the asthma group. The ACO group also had a significant history of smoking as shown by the Brinkman index (p < 0.01) and greater AWT as assessed by high-resolution computed tomography (p < 0.05). The EOM prevalence rate was significantly higher in the ACO group (p < 0.05), especially with increased ACO severity (p < 0.05). The EOM severity was also significantly higher in the ACO group (p < 0.05) and also correlated with the ACO severity (p < 0.05). The pretreatment ear clinical characteristics score and the average air conduction hearing level were significantly higher in the ACO group (p < 0.05). The eosinophil percentage in the MEE/otorrhea was significantly lower in the ACO group (25.3%) than in the asthma group (54.7%) (p < 0.05). Conversely, the neutrophil percentage was significantly higher in the ACO group (75.7% vs. 41.9%) (p < 0.05). CONCLUSIONS: Our findings suggest that, in CRS patients with asthma, comorbidity with ACO may be a clinical factor leading to increased EOM prevalence and severity, as well as a higher neutrophil infiltration percentage in the middle ear. Cessation of smoking and early therapeutic intervention for ACO may mitigate progression of bronchial remodeling (i.e., reduce AWT) and help reduce the prevalence and severity of EOM.

Characteristics of patients with severe asthma who experienced treatment failure with omalizumab.

BACKGROUND: Omalizumab, an anti-IgE antibody, has been widely used in many countries, including Japan. However, some patients do not respond to omalizumab, and the cause of treatment failure has not been fully elucidated. OBJECTIVE: This study aimed to evaluate the characteristics of adult asthma patients who failed to achieve disease control with omalizumab in a real-world setting. METHODS: We retrospectively reviewed the medical records of patients in Tokyo Women's Medical University Hospital between March 2009 and May 2016. The patient characteristics and factors for treatment failure with omalizumab were evaluated, as were treatment alternatives after discontinuation of omalizumab. RESULTS: In total, 59 patients were included in this study. The omalizumab-ineffective group had a significantly higher number of patients with eosinophilic sinusitis (P = 0.001) and eosinophilic otitis media (P = 0.023) than the omalizumab-effective group. A multivariate analysis revealed that both eosinophilic chronic rhinosinusitis (odds ratio: 23.4; P = 0.011) and eosinophilic otitis media (odds ratio: 6.71; P = 0.039) were associated with treatment failure with omalizumab. Most patients with eosinophilic comorbidities of the ear, nose, and throat (ENT) in the omalizumab-ineffective group received mepolizumab or benralizumab as alternative therapy, following which disease control was achieved. CONCLUSION: Eosinophilic comorbidities of the ENT may affect treatment failure with omalizumab in patients with severe asthma. Anti-interleukin-5 antibody or anti-interleukin-5Rα antibody rather than anti-IgE antibody should be considered as an additional therapy for patients with severe asthma who have eosinophilic comorbidities of the ENT.

Increased Expression of Activation-Induced Cytidine Deaminase in Sinus Mucosa from IgG4-Related Disease Patients with Comorbid Chronic Rhinosinusitis.

OBJECTIVE: IgG4-related disease (IgG4-RD) is a systemic condition characterized by an elevated serum IgG4 level, localized infiltration of IgG4-positive plasma cells, and lesions in various organs. IgG4-RD also shows high rates of complication with allergic diseases and is often accompanied by elevated serum IgE levels. Reports in recent years have also shown high rates of complication with chronic rhinosinusitis (CRS) and its characteristic nasal manifestations. Accordingly, we speculate that there may be a distinct form of CRS that, as an IgG4-RD, differs from other CRS. Here, we investigated whether the elevated levels of factors that are thought to be important in the pathogenesis of IgG4-RD are also seen in the sinus mucosa of IgG4-RD-associated CRS patients. METHODS: Ethmoid sinus mucosa specimens from 9 IgG4-RD (6 Mikulicz disease and 3 Küttner's tumor) patients with elevated serum IgG4 and IgE and from 22 control CRS patients were examined immunohistochemically for Treg cytokines (IL-10 and TGF-ß), activation-induced cytidine deaminase (AID), and immunocompetent cells. The 22 control CRS patients were divided into 3 subgroups based on the serological findings for IgG4 and IgE. Quantitative real-time PCR was performed to examine the expression of AID. RESULTS: The ethmoid sinus mucosa from patients with IgG4-RD-associated CRS showed, in comparison with the 3 CRS control subgroups, significantly elevated AID production. Their mucosa also showed significantly increased infiltration of CD-20-positive immunocompetent cells compared with the controls. On the other hand, immunohistochemical examination found no significant differences in the number of IL-10- or TGF-ß-positive cells. CONCLUSION: Ethmoid sinus mucosa from IgG4-RD-associated CRS patients showed clearly increased AID production, suggesting AID involvement in class-switching to IgG4 in those local sites. This implies the existence of a distinct form of CRS that is an IgG4-RD.

Eosinophilic otitis media is associated with asthma severity and smoking history.

PURPOSE: Eosinophilic otitis media (EOM) is an intractable otitis media characterized by an accumulation of eosinophils in the middle ear and a strong association with asthma. We investigated the relationship between EOM and asthma severity, asthma risk factors, lung function, and airway structural changes assessed by high-resolution computed tomographic (HRCT) scanning. MATERIALS AND METHODS: Forty-one asthma patients with chronic rhinosinusitis (18 men and 23 women; mean age 56 years; age range 25-82 years) were included in this study. EOM was diagnosed according to the published diagnostic criteria. Asthma severity and risk factors for asthma, such as smoking history (Brinkman index, BI), were examined. Airway wall thickness and emphysema were assessed with HRCT scanning by a blinded respiratory specialist using a validated method. Lung function was measured using standard procedures. RESULTS: EOM was diagnosed in 34% of the patients. Asthma severity, BI and airway wall thickness were each statistically greater in patients with EOM than in patients without EOM. CONCLUSION: There was a close relationship between EOM and asthma severity in asthma patients with chronic rhinosinusitis. Cessation of smoking might help prevent EOM by reducing airway wall thickness.

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.

Optimal control of asthma improved eosinophilic otitis media.

BACKGROUND: Eosinophilic otitis media (EOM) is often associated with comorbid asthma. The middle ear cavity is part of the upper airway. Therefore, EOM and asthma can be considered to be a crucial part of the "one airway, one disease" phenomenon. Based on the concept of one airway, one disease in the context of allergic rhinitis and asthma, optimal level of inhalation therapy for better asthma control leads to improvement in allergic rhinitis. OBJECTIVE: We conducted a pilot study to determine whether appropriate strengthening of inhalation therapy for asthma is effective for EOM. METHODS: Fifteen patients with EOM and comorbid asthma were enrolled in this study. Eight patients were randomly selected and administered appropriately strengthened inhalation therapy for asthma (strengthened group). The effect of the therapy on EOM was assessed by comparing a questionnaire for ear symptoms, clinical characteristic score, pure tone audiometry, blood tests and temporal bone computed tomography (CT) examination before and after the therapy. Seven other EOM + asthma patients without the above mentioned therapy were included as controls. RESULTS: In the strengthened group, the score of ear symptoms, clinical characteristics score, peripheral blood eosinophil count, CT score, and air conduction hearing level improved significantly after strengthening the inhalation therapy, but not in the control group. The lung function tests (forced vital capacity [%predicted], forced expiratory volume in 1 second [FEV1] [L], and FEV1 [%predicted]) significantly increased in the strengthened group after the therapy, but not in the control group. CONCLUSION: In this study we demonstrated that EOM improved along with improved lung function when appropriately optimal inhalation therapy was implemented in patients with EOM and asthma. Administration of optimizing therapy for asthma might be effective for concomitant EOM.

Treatment outcomes of sialendoscopy for submandibular gland sialolithiasis: The minor axis of the sialolith is a regulative factor for the removal of sialoliths in the hilum of the submandibular gland using sialendoscopy alone.

OBJECTIVE: To assess the general guidelines for the removal of sialoliths for submandibular gland sialolithiasis using sialendoscopy alone. METHODS: We analyzed 61 sialoliths treated using sialendoscopy in 42 patients with submandibular gland sialolithiasis. We evaluated the submandibular gland sialoliths and divided each case based upon the location: the Wharton's duct or the hilum. We measured the major and minor axes of the sialoliths using a soft tissue computed-tomography (CT) scan and evaluated the removal rate of the sialoliths using sialendoscopy alone. RESULTS: The removal rate of the sialoliths in the Wharton's duct (52.6%) was significantly higher than that in the hilum of the submandibular gland (26.1%) (P=0.042). The minor axis was significantly correlated to the treatment outcome of sialendoscopy alone for all cases (P=0.030). A significant correlation was observed for cases involving the hilum of the submandibular gland and the measurement of the minor axes of the sialoliths for the treatment outcome of sialendoscopy alone (P=0.009). The major axis showed no correlation with the treatment outcomes of sialendoscopy alone. CONCLUSION: The measurement of the minor axes of the sialoliths with a soft tissue CT scan was correlated with treatment outcome of sialendoscopy alone for all cases, particularly sialoliths in the hilum. The easurement of the major axis showed no correlation with outcomes of sialendoscopy alone.

Diagnostic and treatment effects of sialendoscopy for patients with swelling of the parotid gland when sialoliths are undetected with computed tomography.

Between August 2009 and May 2016, 74 patients underwent sialoendoscopic surgery. 32 patients had parotid gland disease and 9 patients had intermittent swelling of the parotid gland and sialoliths were not detected with CT imaging. 4 patients were diagnosed with idiopathic Stensen's duct stenosis. Sialendoscopy directly confirmed Stensen's duct stenosis in 2 patients. However, the sialendoscope was unable to be inserted in the other 2 patients, who had stenosis of the orifice of the Stensen's duct. Balloon expansion of the duct was performed in these 2 patients and a steroid drug was injected into the duct in one patient. Complete remission was archived in one patient treated with sialendoscopy. Three patients had sialolithiasis. Microsialoliths and/or white floating matter was observed and removed using sialendoscopy. All patients experienced complete remission. In cases of Sjögren syndrome and recurrent parotitis, sialendoscopic surgery was performed, but the symptoms showed no improvement. For patients with microsialoliths, sialendoscopy may be most useful for diagnosis and treatment when the sialoliths are not detected with CT imaging. At present, sialendoscopic surgery have limitation in the treatment of Stensen's duct stenosis and may similarly have limitation in the treatment of Sjögren's syndrome and recurrent parotitis.

The landmark for removal of sialoliths using sialendoscopy alone in parotid gland sialolithiasis.

OBJECTIVE: To assess the general guidelines for removal of sialoliths in parotid gland sialolithiasis using sialendoscopy alone. METHODS: We analyzed 34 sialoliths treated using sialendoscopy in 26 patients with parotid gland sialolithiasis. We divided the Stensen's duct and parotid gland into for parts using computed tomography findings: (A) front of the masseter, (B) anterior and lateral to the center (anterolateral) of the masseter, (C) posterior and lateral to the center (posterolateral) of the masseter, (D) behind of the masseter. The location and size of each sialolith was assessed. RESULTS: The removal rates of sialoliths in the different locations by sialendoscopy alone were as follows: front of the masseter, 68.8%; anterolateral of the masseter, 60.0%; posterolateral of the masseter, 0%; and behind of the masseter, 33.3%. The removal rate using sialendoscopy alone was significantly higher in the sections anterior to the center of the masseter than in those posterior to the center of the masseter (66.7% [14/21] vs. 20.0% [2/10]; P=0.019). The size of the sialolith was not correlated to the removal rate by sialendoscopy alone. CONCLUSION: Sialoliths of the parotid gland located in positions anterior to the center of the masseter are significantly easier to remove by sialendoscopy alone. The center of the masseter is a general landmark for removal of sialoliths from the parotid gland using sialendoscopy alone. The size of the sialolith is not correlated with removal, except rare huge sialoliths.

Basophils are increased and express increased levels of interleukin-4 in the parotid lesions of Kimura disease.

BACKGROUND: Kimura disease (KD) is a systemic soft-tissue disease that leads to formation of painless masses in lymph nodes, with the highest predilection for the head and neck and especially the parotid gland. KD lesions are characterized by marked eosinophil infiltration, production of IgE and increased expression of T-helper type 2 (Th2) cytokines (interleukin [IL]-4, IL-5, etc.). Skewing to a Th2 inflammation is also demonstrated in the peripheral blood, with elevated eosinophils and high IgE levels. It is thought that basophils may play important roles in orchestrating this Th2 inflammation via IL-4 production leading to the induction of IgE synthesis as well as eosinophil infiltration. However, there are no reports as yet on the role of basophils in KD. OBJECTIVE: The present study was performed to investigate the potential role of basophils in the pathogenesis of KD. In this context we also examined the expression of IL-4 in basophils in the KD lesions. METHODS: By immunohistochemistry using a monoclonal antibody against a basophil marker ProMBP1 we investigated the number and distribution of basophils in the KD lesions. By double immunohistochemistry we analyzed the colocalization of IL-4 in basophils. RESULTS: There was an increased number of basophils infiltrating the KD parotid gland lesions as compared to that in normal control parotid tissue. By double-immunofluorescence we found that approximately 7% of IL-4-positive cells in KD patients' parotid glands were basophils. CONCLUSION: Basophils may also play a role in the pathogenesis of KD, leading to the induction of IgE synthesis and eosinophil infiltration.