Inflammatory molecular endotypes of nasal polyps derived from White and Japanese populations.

BACKGROUND: Emerging evidence suggests that chronic rhinosinusitis with nasal polyps (CRSwNP) is a highly heterogeneous disease with disparate inflammatory characteristics between different racial groups and geographies. Currently, little is known about possible underlying distinguishing factors between these inflammatory differences. OBJECTIVE: Our aim was to interrogate differences in CRSwNP disease between White/non-Asian patients and Japanese patients by using whole transcriptome and single-cell RNA gene expression profiling of nasal polyps (NPs). METHODS: We performed whole transcriptome RNA sequencing with endotype stratification of NPs from 8 White patients (residing in the United States) and 9 Japanese patients (residing in Japan). Reproducibility was confirmed by quantitative PCR in an independent validation set of 46 White and 31 Japanese patients. Single-cell RNA sequencing (scRNAseq) was used to stratify key cell types for contributory transcriptional signatures. RESULTS: Unsupervised clustering analysis identified 2 major endotypes that were present within both cohorts of patients with NPs and had previously been reported at the cytokine level: (1) type 2 endotype and (2) non-type 2 endotype. Importantly, there was a statistically significant difference in the proportion of these endotypes between these geographically distinct subgroups with NPs (P = .03). Droplet-based single-cell RNA sequencing further identified prominent type 2 inflammatory transcript expression: C-C motif chemokine ligand 13 (CCL13) and CCL18 in M2 macrophages, as well as cystatin SN (CST1) and CCL26 in basal, suprabasal, and secretory epithelial cells. CONCLUSION: NPs from both racial groups harbor the same 2 major endotypes, which we have determined to be present in differing ratios between each cohort with CRSwNP disease. Distinct inflammatory and epithelial cells contribute to the type 2 inflammatory profiles observed.

Retinoic acid promotes fibrinolysis and may regulate polyp formation.

BACKGROUND: Patients with aspirin-exacerbated respiratory disease (AERD) regularly exhibit severe nasal polyposis. Studies suggest that chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by excessive fibrin deposition associated with a profound decrease in epithelial tissue plasminogen activator (tPA). Retinoids, including vitamin A and its active metabolite retinoic acid (RA), are necessary for maintaining epithelial function and well-known inducers of tPA in endothelial cells. OBJECTIVES: This study sought to determine whether endogenous retinoids are involved in NP pathophysiology and disease severity in patients with CRSwNP and AERD. METHODS: NP tissue was collected from patients with AERD or CRSwNP, and concentrations of retinoids and fibrinolysis markers were measured using ELISA. Normal human bronchial epithelial cells were stimulated alone or in combination with RA and IL-13 for 24 hours. RESULTS: This study observed lower retinoid levels in nasal polyps of patients with AERD than those with CRSwNP or healthy controls (P < .01). Levels of the fibrin-breakdown product d-dimer were the lowest in AERD polyps (P < .01), which is consistent with lower tPA expression (P < .01). In vitro, all-trans RA upregulated tPA levels in normal human bronchial epithelial cells by 15-fold and reversed the IL-13-induced attenuation of tPA expression in cultured cells (P < .01). CONCLUSIONS: RA, a potent inducer of epithelial tPA in vitro, is reduced in tissue from patients with AERD, a finding that may potentially contribute to decreased levels of tPA and fibrinolysis in AERD. RA can induce tPA in epithelial cells and can reverse IL-13-induced tPA suppression in vitro, suggesting the potential utility of RA in treating patients with CRSwNP and/or AERD.

Dupilumab improves eosinophilic otitis media associated with eosinophilic chronic rhinosinusitis.

BACKGROUND: Eosinophilic otitis media (EOM) is a refractory condition associated with eosinophilic chronic rhinosinusitis and bronchial asthma. EOM is characterized by type-2 inflammation and is refractory to various treatments. We investigated the efficacy of dupilumab, interleukin-4 receptor alpha antagonist, for patients with EOM complicated by eosinophilic chronic rhinosinusitis (ECRS). METHODS: Between April 2017 and April 2022, we treated 124 patients with dupilumab for refractory CRS or bronchial asthma. Of these, 14 had EOM concurrently, and 10 of them who had been treated for >6 months were included in our study. We retrospectively evaluated the efficacy of dupilumab by the amount of systemic corticosteroid used, the frequency of exacerbations, severity score of EOM, computed tomography (CT) score of temporal bones, and pure tone audiometry. We also enrolled 8 EOM patients without dupilumab treatment as a control group. RESULTS: Dupilumab significantly improved the amount of systemic corticosteroid used and the frequency of exacerbation and compared with before dupilumab was used (p = 0.01 and <0.01, respectively). All patients could be weaned from systemic-corticosteroid therapy by 54 weeks of dupilumab use. The severity score of EOM and CT score for temporal bones were significantly lower than before the treatment (p = 0.01 and 0.01, respectively). Compared to the control group, the systemic corticosteroid used and severity scores were improved in the dupilumab group (p = 0.02 and < 0.01, respectively). CONCLUSIONS: Dupilumab could be used to wean patients from systemic corticosteroids with the improvement of severity score in EOM associated with ECRS and bronchial asthma.

Serum IgG4 as a biomarker reflecting pathophysiology and post-operative recurrence in chronic rhinosinusitis.

BACKGROUND: Type 2 chronic rhinosinusitis (CRS), especially eosinophilic CRS (ECRS), is an intractable upper airway inflammatory disease. Establishment of serum biomarkers reflecting the pathophysiology of CRS is desirable in a clinical setting. As IgG4 production is regulated by type 2 cytokines, we sought to determine whether serum IgG4 levels can be used as a biomarker for CRS. METHODS: Association between the serum IgG4 levels and clinicopathological factors was analyzed in 336 CRS patients. Receiver operating characteristics (ROC) analysis was performed to determine the cut-off value of serum IgG4 levels that can be used to predict the post-operative recurrence. RESULTS: Serum IgG4 levels were significantly higher in patients with moderate to severe ECRS versus those with non to mild ECRS. The levels were also significantly higher in asthmatic patients and patients exhibiting recurrence after surgery compared to controls. ROC analysis determined that the best cut-off value for the serum IgG4 level to predict the post-operative recurrence was 95 mg/dL. The corresponding sensitivity and specificity were 39.7% and 80.5%, respectively. When we combined the two cut-off values for the serum IgG4 and periostin, patients with high serum levels of either IgG4 or periostin exhibited a high post-operative recurrence (OR: 3.95) as compared to patients having low serum levels of both IgG4 and periostin. CONCLUSIONS: The present results demonstrate that the serum IgG4 level is associated with disease severity and post-operative course in CRS. In particular, the combination of serum IgG4 and periostin could be a novel biomarker that predicts post-operative recurrence.

Increased expression of L-plastin in nasal polyp of patients with nonsteroidal anti-inflammatory drug-exacerbated respiratory disease.

BACKGROUND: Most patients with nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (NERD) suffer from recurrence of nasal polyps. However, little is known about the specific cellular and molecular mechanisms contributing to the pathogenesis of nasal polyp development in patients with NERD in particular, especially at baseline when cyclooxygenase 1 inhibitors are not present. The objectives of this study were to identify proteins involved in the pathogenesis of nasal polyps in patients with NERD. METHODS: We collected nasal polyp tissue from patients with NERD and from patients with aspirin-tolerant chronic rhinosinusitis with nasal polyps (CRSwNP). Protein profiles were analyzed by 2-dimensional electrophoresis and identified several proteins, including L-plastin, as highly expressed. We examined L-plastin and tissue factor (TF) expression by immunohistochemical and immunofluorescence analyses. To examine the role of L-plastin in eosinophils, we knocked down L-plastin expression in Eol-1 cells by using siRNA transfection. RESULTS: L-plastin protein levels in nasal polyp tissue were increased in patients with NERD relative to those in patients with aspirin tolerant CRSwNP. Immunofluorescence analysis revealed that L-plastin was dominantly expressed in eosinophils and L-plastin and TF were co-expressed in eosinophils in NERD nasal polyp tissue. Knockdown of L-plastin in Eol-1 cells disrupted the cell surface distribution of TF by stimulation with granulocyte macrophage colony-stimulating factor. CONCLUSION: Increased expression of L-plastin by eosinophils may contribute to abnormal fibrin deposition through TF translocation to the eosinophil cell surface in NERD nasal polyp tissue, which in turn may contribute to the pathogenesis of NERD.

A case of falciparum malaria: Acute hearing loss as the initial symptom.

A 49-year-old healthy woman, who returned from Burkina Faso, visited an ear, nose, and throat clinic with complaints of left hearing loss, tinnitus, and dizziness. Pure tone audiometry demonstrated bilateral mild sensorineural hearing loss. Three days later, she was transported in an ambulance to a general hospital due to high fever and disturbance of consciousness. Plasmodium falciparum was found in the peripheral blood smear. After diagnosing severe falciparum malaria with cerebral involvement, quinine hydrochloride, clindamycin, and artemether/lumefantrine were administered. After recovery of consciousness, she was followed up at our department with bilateral hearing loss. After taking prednisolone for 10 days, there was improvement to normal hearing level. Furthermore, no neurologic sequelae were observed. In this case, acute sensorineural hearing loss occurred before administration of the antimalarial drug. Therefore, hearing loss was not drug-induced, but was caused by the malaria itself. In patients with acute hearing loss and who have history of travel to tropical regions, physicians should include malaria and other causes of acute deafness in the differential diagnoses.

Endoscopic modified medial maxillectomy for odontogenic cysts and tumours.

BACKGROUND: Odontogenic maxillary cysts and tumours originate from the tooth root and have traditionally been treated through an intraoral approach. Here, we report the efficacy and utility of endoscopic modified medial maxillectomy (EMMM) for the treatment of odontogenic maxillary cysts and a tumour. METHODOLOGY: We undertook EMMM under general anaesthesia in six patients: four had radicular cysts, one had a dentigerous cyst, and one had a keratocystic odontogenic tumour. RESULTS: The cysts and tumours were completely excised and the inferior turbinate and nasolacrimal duct were preserved in all patients. There were no peri- or postoperative complications, and no incidences of recurrence. CONCLUSION: Endoscopic modified medial maxillectomy appears to be an effective and safe technique for treating odontogenic cysts and tumours.

[Comparison of B-mode ultrasonography and computed tomography in the evaluation of maxillary sinusitis in pediatric patients].

The use of ultrasonography in the diagnosis of maxillary sinusitis in pediatric patients has been reported recently because of the improvement of the accuracy of ultrasound technology. We thus compared B-mode ultrasonography and computed tomography in the diagnosis of maxillary sinusitis in pediatric patients. Thirty-six maxillary sinuses in 18 patients (10 females, 8 males, ages ranging from 7-15 years with an average age of 10.4 years) were examined. Ultrasonography of the maxillary sinus was performed in the horizontal and the vertical direction. Paranasal computed tomography and B-mode ultrasonography were performed within a few days. In some of these patients the maxillary sinuses were examined with a fiberscope. Sensitivity, specificity, false-positive, false-negative, positive predictive value and negative predictive value of B-mode ultrasonography compared with computed tomography were 92.6%, 100%, 0%, 7.4%, 100% and 81.8%, respectively. It appeared that ultrasonography was more sensitive than X-ray imaging, because the sensitivity and specificity of X-ray imaging of the maxillary sinus in pediatric patients compared with CT was reportedly 70-80%. A meaningful correlation of ultrasonography and CT was accepted as an assessment of desease severity. There are some problems with diagnosis by ultrasonography. There is no differentiation of mucosal thicking, cyst and discharge and imaging are less useful in pediatric patients. Because of these reasons, clinical sign and views in the nose are important for a correct diagnosis in pediatric patients. Furthermore, the most suitable age range to diagnose maxillary sinusitis correctly in pediatric patients must be examined.

[A rare case of pharyngeal mesenchymoma demonstrating a variety of histopathological findings].

We encountered a 38-years-old female patient who was complaining of an unpleasant sensation of the left cervical area due to a recurrent tumor originating from the middle pharynx. She had a history of surgically resected neurofibroma and lipoma from the anterior oropharyngeal wall respectively 5 years and 11 years previously. The preoperative diagnosis of a benign, non-epithelial neoplasm was made based on the imaging studies and surgical treatment was scheduled. An extended surgical resection of the middle pharynx including normal mucosa and a part of the tongue base was successfully accomplished. To cover the pharyngeal defect, a right antero-lateral thigh musculo-cutaneous flap was used for reconstruction. Microscopically, the surgically resected tissue showed a mixed condition of mature cartilaginous, bony and fibroadipose tissue without atypia. The final diagnosis was a benign mesenchymoma which was thought to have developed from pluripotential mesenchymal cells. We considered that the past tumorous lesions had possibly originated in those cells. Because pluripotential mesenchymal cells cannot easily be identified with ordinary histopathological examination, the determination of optimal surgical margins is difficult. In the case of mesenchymoma, substantial marginal tissue should be resected in order to prevent recurrence even in the case of a pathologically-proven benign tumor.

A review of current biomarkers in chronic rhinosinusitis with or without nasal polyps.

INTRODUCTION: Chronic rhinosinusitis (CRS) is a heterogeneous disease with a variety of cellular and molecular pathophysiologic mechanisms. Biomarkers have been explored in CRS using various phenotypes, such as polyp recurrence after surgery. Recently, the presence of regiotype in CRS with nasal polyps (CRSwNP) and the introduction of biologics for the treatment of CRSwNP has indicated the importance of endotypes, and there is a need to elucidate endotype-based biomarkers. AREAS COVERED: Biomarkers for eosinophilic CRS, nasal polyps, disease severity, and polyp recurrence have been identified. Additionally, endotypes are being identified for CRSwNP and CRS without nasal polyps using cluster analysis, an unsupervised learning technique. EXPERT OPINION: Endotypes in CRS have still being established, and biomarkers capable of identifying endotypes of CRS are not yet clear. When identifying endotype-based biomarkers, it is necessary to first identify endotypes clarified by cluster analysis for outcomes. With the application of machine learning, the idea of predicting outcomes using a combination of multiple integrated biomarkers, rather than a single biomarker, will become mainstream.

Prevalence of middle ear malformation and outcomes of tympanoplasty and/or canalplasty in patients with and without congenital external auditory canal stenosis.

OBJECTIVE: To compare the prevalence of middle ear malformations between patients with and without congenital external auditory canal stenosis (CEACS) and to investigate the outcomes of tympanoplasty and/or canalplasty in terms of tympanic membrane (TM) size and external auditory canal (EAC) stenosis in patients with middle ear malformation. METHODS: Twenty-five patients who underwent primary tympanoplasty and/or canalplasty for middle ear malformation at a tertiary academic medical center were retrospectively reviewed. CEACS was defined as an EAC diameter of 4 mm or less. Intraoperative findings, including irregularity of the ossicles, facial nerve, or chorda tympani; size of the TM and EAC on computed tomography; and pre- and postoperative hearing level, were collected. RESULTS: We included 7 and 18 patients with and without CEACS, respectively. The malleus handle defect, anterior deviation of the chorda tympani, and small TM (≤7 mm) (p-values 0.015, <0.001, and 0.003, respectively; Fisher's exact test) had significantly higher prevalence in patients with CEACS than in those without. The mean postoperative air-bone gap (ABG) in patients with CEACS was not significantly different from that in patients with normal-sized EAC (20.6 dB and 19.5 dB, respectively; p-value, 0.121; Mann-Whitney U test). No difference was observed in mean postoperative ABG between patients with small TM and those with normal-sized TM (19.2 dB and 20.0 dB, respectively; p-value, 0.469; Mann-Whitney U test). CONCLUSION: Patients with CEACS were more likely to have malleus handle defect, anterior deviation of the chorda tympani, and small TM than those without CEACS. Hearing outcome of patients with CEACS and a malformed malleus and/or incus might be equivalent to that of patients without CEACS following tympanoplasty and/or canalplasty, regardless of the EAC or TM size.

Clinical epidemiological study of 553 patients with chronic rhinosinusitis in Japan.

BACKGROUND: The relationship between chronic rhinosinusitis (CRS) and asthma has been known for a long time. However, no large studies on the relationship between CRS and lower airway diseases have been reported to date in Japan. Additionally, eosinophilic chronic rhinosinusitis (ECRS) in Japan is considered to be a subgroup of CRS with nasal polyps (CRSwNP) characterized by eosinophil-dominant inflammation. However, the diagnostic criteria of ECRS have not been established. METHODS: To investigate clinical and epidemiological features of patients with CRS from the aspect of their associations with lower airway diseases, 553 patients with CRS who visited one of six local university hospitals were examined and interviewed. Local eosinophilic infiltration was evaluated pathologically by examining NPs. RESULTS: The prevalences of olfactory dysfunction (OD) in the patients with nasal polyps (NPs) and those without NPs were 57.0% and 13.7%, respectively (p < 0.0001). The prevalence of asthma in all patients was 23.1%. Furthermore, the prevalences of NPs and OD in the patients with asthma and those without asthma were 81.0% and 50.1% (p < 0.0001) and 64.2% and 35.7% (p < 0.0001), respectively. 97.4% of the patients with asthma had ≥ 15% mucosal eosinophils, and 87.9% of the patients without asthma had <15% mucosal eosinophils. CONCLUSIONS: Similar to the relationship between nasal allergy and asthma, CRSwNP may be applicable to the concept of "one airway, one disease".

A Covered Lateral and Posterior Wall Flap of the Maxillary Sinus Prevents Reocclusion of the Postoperative Maxillary Cyst.

Although the number of postoperative maxillary cyst (POMC) cases has declined recently, a few reports of refractory cases have also been reported. The indications for endoscopic sinus surgery (ESS) for POMC removal are broadening and attempts to prevent postoperative recurrence at the cyst opening site have been widely investigated. Here, we have advocated our original pedunculated mucoperiosteal flap (CLAP flap; covered lateral and posterior wall flap of the maxillary sinus), where the bony area exposed intraoperatively is covered, to prevent postoperative recurrence. We have also presented the method for creating the CLAP flap. We classified the POMC as being medial, lateral, or anterior superior type and performed ESS. We introduced the CLAP flap after 2015 for the lateral type and some of the medial types of POMCs. We examined the cyst opening rate using computed tomography, age, sex, cyst position, and a follow-up period in four patients (five sides) who did not undergo flap surgery, but who were managed in our hospital in 2015, and in eight patients (nine sides) who underwent the CLAP flap technique in our hospital. In the group with the CLAP flap, the cyst opening rate was significantly higher (P < 0.05). The CLAP flap was effective for preventing postoperative bony regrowth. It may be one of the options for covering the exposed bone surface as widely as possible. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12070-021-02658-x.

Predictors of Visual Acuity and Usefulness of a Treatment Algorithm in Rhinogenous Optic Neuritis.

Rhinogenous optic neuritis, which causes neuropathy associated with visual dysfunction, greatly reduces patient quality of life and requires suitable early treatment. This study aimed to analyze visual outcome predictors in patients with rhinogenous optic neuritis and to develop and investigate the usefulness of an algorithm to facilitate early treatment. Prospective and retrospective investigations were conducted at the Department of Otorhinolaryngology. The visual outcomes after sinus surgery of 24 of 53 patients suspected of having rhinogenous optic neuritis were analyzed. Furthermore, the usefulness of the treatment algorithm was evaluated in 27 of these 53 patients. Data from 24 patients who underwent surgery were included in a multiple regression analysis to investigate the associations between visual outcomes and concomitant symptoms and the time from symptom onset to surgery. The mean time from the initial examination to a request for otorhinolaryngological examination to assess the usefulness of the treatment algorithm was compared in 27 patients who did not undergo an initial otorhinolaryngological examination. Visual acuity improved in 23 participants who underwent surgery. Multivariate analysis identified the time from onset to surgery and headache as significant predictors of postoperative visual acuity. The mean time from the initial examination to a request for otorhinolaryngological examination was significantly shorter after the algorithm was introduced (1.13 days, 8 patients; P = .008). Early surgical treatment is essential to avoid further postoperative visual acuity decreases in patients with rhinogenous optic neuritis. Patients who experience headache may have poorer postoperative outcomes.

Comparison of Current Staging Systems for Sinonasal Inverted Papilloma.

BACKGROUND: A staging system is essential for determining the optimal surgical approach and predicting postoperative outcomes for inverted papilloma (IP). Although staging systems based on the extent to which the location is occupied by an IP have been widely used, an origin site-based classification of IP using unsupervised machine learning algorithms has recently been reported. OBJECTIVE: To determine the most appropriate of five staging systems for sinonasal IP by comparing recurrence rates for each stage according to each of those systems. METHODS: Eighty-seven patients with sinonasal IP were enrolled in the study. Their tumors were retrospectively categorized according to the Krouse, Oikawa, Cannady, and Han staging systems, which are based on the extent of IP, and the Meng system, which is based on the site of origin. The rates of recurrence for each stage of the five systems were compared. RESULTS: Seven of the 87 patients (8.0%) had recurrences during an average 45.5 months (12-138 months) of follow-up. There were significant differences in disease-free survival between the stages specified by Han and Meng (p = 0.027 and p < 0.001, respectively), but not between the stages specified by Krouse, Oikawa, and Cannady (p = 0.236, 0.062, and 0.130, respectively). Cox proportional hazard models revealed that Meng system (adjusted hazard ratio [aHR] 4.32, 95% confidence interval [CI] 1.10-17.04) and presence of dysplasia (aHR 7.42, 95% CI 1.15-47.85) were significantly associated with recurrence. CONCLUSION: The staging systems proposed by Han and Meng were found to be accurate in terms of tumor recurrence. We recommend use of the Han staging system before surgery and the Meng system after intraoperative identification of the origin of the tumor.

A Phase II, Multicenter, Randomized, Placebo-Controlled Study of Benralizumab, a Humanized Anti-IL-5R Alpha Monoclonal Antibody, in Patients With Eosinophilic Chronic Rhinosinusitis.

BACKGROUND: Strong eosinophil infiltration in chronic rhinosinusitis with nasal polyp (CRSwNP) is highly associated with recalcitrance and higher nasal polyp recurrence rate after surgery. The prevalence of eosinophilic CRSwNP (ECRS) is increasing in Asian countries including Japan. Benralizumab is a humanized anti-IL-5R alpha monoclonal antibody that depletes eosinophils by antibody-dependent cell-mediated cytotoxicity. OBJECTIVE: To assess the efficacy and safety of benralizumab in patients with ECRS. METHODS: This phase II, randomized, double-blind, placebo-controlled study was conducted in Japan. Patients were randomized 1:2:2 to placebo, a single administration of benralizumab 30 mg, or benralizumab 30 mg every 4 weeks (q4w) for a total of three doses. The primary endpoint was the change in nasal polyp score from baseline at Week 12. RESULTS: Overall, 56 patients were enrolled (placebo, n = 11; benralizumab single dose, n = 22; benralizumab q4w, n = 23). Although the mean total nasal polyp score began to decrease after the initiation of benralizumab treatment, there were no statistically significant differences in change in nasal polyp score from baseline at Week 12 between benralizumab and placebo (placebo, -0.5 ± 0.8; benralizumab single, -0.3 ± 0.8; benralizumab q4w, -0.5 ± 1.5). Post-hoc analysis showed that the administration of benralizumab decreased nasal polyp scores ≥2 points in 42.2% of ECRS patients and that patients with high blood eosinophil levels had a greater tendency to respond to benralizumab treatment. The safety profile was similar to that in previous studies and no unexpected adverse events were noted. CONCLUSION: Although benralizumab did not meet the primary efficacy endpoint, reductions of nasal polyp scores were seen in the benralizumab group compared with the placebo group over the whole study period, especially in patients with high levels of blood eosinophils.