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Objective: Due to the high postoperative recurrence rate in eosinophilic chronic rhinosinusitis (eCRS) patients, there is a need for an index to predict the postoperative outcomes. Group 2 innate lymphoid cells (ILC2s) are important effector cells for type 2 immune responses in eosinophilic airway inflammation. The aim of this study was to investigate whether the prevalence of ILC2s in sinonasal tissues or in peripheral blood is associated with the postoperative outcome in CRS patients.Methods: Twelve patients with eCRS and ten patients with non-eCRS were recruited. We examined the ILC2 prevalence in sinonasal tissues and in peripheral blood before and after endoscopic sinus surgery (ESS). Pre- and postoperative blood eosinophil counts were also examined. Lund-Mackay computed tomography (LMK-CT) scores were used to evaluate the disease severities and the postoperative outcomes; cases with more than 50% improvement were categorized into the good outcome group, and cases with less than 50% improvement were categorized into the poor outcome group.Results: The ILC2 prevalence in sinonasal tissues was correlated with that in preoperative blood in eCRS and non-eCRS patients. The ILC2 prevalence in sinonasal tissues and in preoperative blood was not correlated with the pre- or postoperative LMK-CT scores. Postoperatively, the ILC2 prevalence in blood was decreased in eCRS and non-eCRS patients, and blood eosinophil count was also decreased in eCRS patients but not in non-eCRS patients. The ILC2 prevalence in postoperative blood was decreased in the good outcome group but not in the poor outcome group. Blood eosinophil counts were not decreased postoperatively in both good and poor outcome groups.Conclusion: The decreased ILC2 prevalence in postoperative blood may be a predictive biomarker for evaluating postoperative outcomes in eCRS and non-eCRS patients. [ABSTRACT FROM AUTHOR]

Objective: Significant eosinophil infiltration and tissue remodeling are common characteristics of conditions associated with chronic airway inflammation, such as chronic rhinosinusitis with nasal polyp and bronchial asthma. This study was designed to elucidate the role of eosinophil-fibroblast interactions in tissue remodeling during chronic airway inflammation.Methods: Peripheral blood eosinophils or EoL-1 eosinophilic leukemia cells were cocultured with nasal polyp fibroblasts (NPFs). Coculture-induced release of exosomes, major components of extracellular vesicles (EVs), and a profibrotic cytokine, vascular endothelial growth factor (VEGF), were evaluated by enzyme-linked immunosorbent assay.Results: Eosinophil-NPF interactions stimulated the release of exosomes and VEGF into culture supernatants. Coculture-induced release of exosomes was stimulated earlier than VEGF release, at 3 h of incubation. The average size of the EVs released by NPFs was 133 ± 3.6 nm. NPF-derived EVs (exosome concentration: 25 pg/mL) significantly stimulated VEGF release from EoL-1 cells. Pretreatment of NPFs with exosome inhibitor, GW4869 or DMA attenuated the release of exosomes and VEGF from cocultured EoL-1 cells and NPFs.Conclusion: The results of this study indicate that eosinophil-fibroblast interactions are important in the pathophysiology of tissue remodeling in eosinophil-predominant airway inflammation and that NPF-derived exosomes play a crucial role in the release of VEGF. [ABSTRACT FROM AUTHOR]

Background: Group 2 innate lymphoid cells (ILC2s) play important roles in allergic inflammation. However, their roles in the pathophysiology of allergic rhinitis (AR) are poorly understood. Objective: Prevalence of ILC2s in the inferior nasal turbinate (INT) tissues and the activating mechanisms of ILC2s were examined in patients with house dust mite (HDM)‐induced AR. Methods: Eighteen patients with HDM‐induced AR and 13 control subjects were recruited. Fresh INT tissues and peripheral blood mononuclear cells (PBMCs) were analysed using flow cytometry. Nasal lavage fluids (NLF) were collected at 10 minutes after the nasal provocation test (NPT) with HDM disc, and released mediators were measured by ELISA. Sorted ILC2s were cultured and stimulated with mediators associated with AR. Results: The prevalence of ILC2s was significantly increased in nasal mucosa of patients with HDM‐induced AR, and it was positively correlated with the number of infiltrating eosinophils. ILC2s in the INT tissues expressed a prostaglandin D2 (PGD2) receptor, chemoattractant receptor‐homologous molecule‐expressed TH2 cells (CRTH2) and a cysteinyl leukotriene (cysLTs) receptor, CysLT1. After NPT, the number of eosinophils and concentrations of PGD2 and cysLTs were significantly increased in the NLF from AR patients. PGD2 and cysLTs significantly induced IL‐5 production from cultured PBMC‐derived ILC2s dose‐dependently. PGD2‐induced and cysLTs‐induced productions of IL‐5 and IL‐13 from ILC2s were completely inhibited by ramatroban, a dual CRTH2 and thromboxane receptor antagonist, and montelukast, a CysLT1 antagonist, respectively. Conclusions: PGD2‐CRTH2 and cysLTs‐CysLT1 axes may activate tissue‐resident ILC2s to produce Th2 cytokines, IL‐5 and IL‐13, leading to the development of allergic inflammation in AR. [ABSTRACT FROM AUTHOR]

We herein present three cases of abnormally expanded frontal sinuses (pneumoceles) with severe infection in patients with mental retardation and brain atrophy. Two patients previously underwent laryngotracheal separation surgery, and bacteriological examinations of purulent nasal discharge revealed infections caused by drug-resistant bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. As conservative medical treatments were ineffective, all three patients were treated by computed tomography-guided endoscopic sinus surgery. This navigation system is useful for safer surgery in the area of anatomic deformity. The clinical findings, possible etiologies and surgical treatment of these cases are discussed. [ABSTRACT FROM AUTHOR]

ILC2s represent a critical innate cellular source of type 2 cytokines and may play important roles in various diseases. We examined the role of ILC2s in the pathogenesis of two subgroups of CRSwNP: ECRS and non-ECRS. We analyzed the prevalence of ILC2s in sinonasal tissues and in blood from patients with ECRS, non-ECRS, CRSsNP, and control. The prevalence of ILC2s in nasal tissues was higher in patients with ECRS as compared to those with non-ECRS or CRSsNP. The prevalence of blood ILC2s was not different between patients with ECRS and non-ECRS. The prevalence of blood ILC2s was higher in patients with allergic rhinitis and elevated serum IgE levels. Alternaria -induced IL-33 secretion was increased in nasal epithelial cells derived from patients with ECRS as compared to those from patients with non-ECRS or CRSsNP. ILC2s may be involved in the pathogenesis of CRSwNP, in particular in patients with tissue eosinophilia (i.e., ECRS). [ABSTRACT FROM AUTHOR]

Objective Low-dose, long-term use of 14-membered macrolides is effective for treatment of patients with chronic airway inflammation such as diffuse panbronchiolitis or chronic rhinosinusitis. However, long-term use of macrolides can promote the growth of drug-resistant bacteria, and the development of anti-inflammatory macrolides that lack antibiotic effects is desirable. Previously, we developed EM900, a novel 12-membered erythromycin A derivative, which has potent anti-inflammatory and immunomodulatory activities and lacks any antibacterial activity. We examined the anti-inflammatory effects of EM900 on mucus secretion from airway epithelial cells. Methods To examine the in vivo effects of EM900 on airway inflammation, we induced hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium via intranasal instillation of lipopolysaccharides. In vitro effects of EM900 on airway epithelial cells were examined using cultured human airway epithelial (NCI-H292) cells. Mucus secretion was evaluated via enzyme-linked immunosorbent assays with an anti-MUC5AC monoclonal antibody. Results Oral administration of EM900 or clarithromycin (CAM) significantly inhibited LPS-induced mucus production from rat nasal epithelium. EM900, CAM, or erythromycin significantly inhibited MUC5AC secretion induced by tumor necrosis factor-α from NCI-H292 cells. MUC5AC mRNA expression was also significantly lower in EM900-treated cells. Conclusion These results indicated that a novel non-antibiotic macrolide, EM900 exerted direct inhibitory effects on mucus secretion from airway epithelial cells, and that it may have the potential to become a new anti-inflammatory drug for the treatment of chronic rhinosinusitis. [ABSTRACT FROM AUTHOR]

Objectives: Although some patients with postviral olfactory dysfunction (PVOD) recover spontaneously, many others are left with the degree of smell loss and there are no established drugs for the treatment of patients with PVOD. Valproic acid (VPA) has been widely used for the treatment of epilepsy. Its potential neuroregenerative effects have been shown via animal studies. This is the first study to treat PVOD patients with VPA. This open-label, single-arm, phase II study was conducted to investigate the effects of VPA in patients with PVOD. Methods: The patients received oral tablets of VPA 200 mg twice a day for 24 weeks. In total, 11 patients with PVOD were recruited. Oder scores of recognition and detection threshold (measured with a T&T olfactometer), and visual analog scale were examined during the treatment. Results: All odor scores significantly improved over time. Although the mean duration of olfactory dysfunction in this study was 11.5 months, both odor recognition threshold and odor detection threshold scores significantly improved 4 weeks after treatment initiation compared to the pre-treatment threshold scores. The olfactory recovery rates in patients treated with VPA were clearly better than those we previously reported in PVOD patients who received Toki-shakuyaku-san, the traditional treatment in Japan. The olfactory recovery rates of patients with PVOD at 12 weeks and 24 weeks of VPA treatment were both 77.8%, and the olfactory cure rates at 12 weeks and 24 weeks of VPA treatment were 33.3% and 44.4%, respectively. No serious adverse events were observed. Conclusions: VPA seems to be a safe treatment option in patients with PVOD. The effects of VPA treatment for PVOD patients should be studied with a controlled study design in the future. [ABSTRACT FROM AUTHOR]

Basal cell hyperplasia is commonly observed in nasal polyp epithelium of eosinophilic chronic rhinosinusitis (eCRS). We examined the function and mechanisms of basal cell hyperplasia in the pathophysiology of eCRS. We found that normal human bronchial epithelial (NHBE) cells obtained basal cell characteristics when cultured with PneumaCult™-Ex Plus Medium. Most of the cells passaged three times expressed basal cell surface markers CD49f and CD271 by flow cytometry, and basal cell nuclear marker p63 by immunohistochemical staining. We named these NHBE cells with basal cell characteristics cultured Basal-like cells (cBC), and NHBE cells cultured with BEGM™ cultured Epithelial cells (cEC). The characteristics of cBC and cEC were examined and compared by RNA sequencing, RT-PCR, ELISA, and cell proliferation studies. RNA sequencing revealed that cBC showed higher gene expression of thymic stromal lymphopoietin (TSLP), IL-8, TLR3, and TLR4, and lower expression of PAR-2 compared with cEC. The mRNA expression of TSLP, IL-8, TLR3, and TLR4 was significantly increased in cBC, and that of PAR-2 was significantly increased in cEC by RT-PCR. Poly(I:C)-induced TSLP production and LPS-induced IL-8 production were significantly increased in cBC. IL-4 and IL-13 stimulated the proliferation of cBC. Finally, the frequency of p63-positive basal cells was increased in nasal polyp epithelium of eCRS, and Ki67-positive proliferating cells were increased in p63-positive basal cells. Type 2 cytokines IL-4 and IL-13 induce basal cell hyperplasia, and basal cells exacerbate type 2 inflammation by producing TSLP in nasal polyp of eCRS. [ABSTRACT FROM AUTHOR]

Background: Allergic rhinitis (AR) impairs quality of life and affects nearly 40% of the Japanese population. Sublingual immunotherapy (SLIT) is the disease‐modifying treatment for AR, but requires the selection of a biomarker associate with clinical efficacy in patients with AR who are treated with SLIT. The present study sought to examine objective biomarkers used for assessing the clinical efficacy of SLIT. Methods: The authors examined the effects of 1 year of SLIT treatment with house dust mites (HDMs) using peripheral blood mononuclear cells (PBMCs) and serum from patients with AR. The prevalences of follicular regulatory T (Tfr), type 2 follicular helper T (Tfh2), type 2 helper T (Th2), conventional regulatory T (Treg), and type 1 regulatory T (Tr1) cells were examined by flow cytometry. Serum concentrations of HDM‐specific IgA, IgE, and IgG4 antibodies, and HDM‐induced production of interleukin (IL) 5 and IL‐10 from cultured PBMCs were evaluated by enzyme‐linked immunosorbent assay. Results: Following 1 year of SLIT, the prevalences of Tfr, conventional Treg, and Tr1 cells were significantly increased, whereas that of Th2 cells and Tfh2 cells were significantly decreased; the serum concentration of HDM‐specific IgG4 was significantly increased; and HDM‐induced production of IL‐5 from PBMCs was significantly decreased, while that of IL‐10 was significantly increased. The increase in the prevalence of Tfr cells after SLIT correlated positively with the improvement of clinical symptom scores. Conclusion: An increase in Tfr cells may play an important role in SLIT, and may be a useful indicator for the clinical efficacy of SLIT. [ABSTRACT FROM AUTHOR]

This article discusses the effects of sublingual immunotherapy (SLIT) on patients with Japanese cedar pollinosis, a common allergic disease in Japan. The study found that SLIT reduced clinical symptoms and decreased the avidity of antigen-specific IgE, which is associated with mast cell degranulation and anaphylaxis. The study also examined serum levels of antigen-specific IgE, IgA, IgG1, and IgG4, as well as Tfh cell subsets. The findings suggest that SLIT induces the production of low-affinity IgE and suppresses the production of high-affinity IgE, contributing to the therapeutic efficacy of SLIT. [Extracted from the article]

Abstract: Mucormycosis is a rapidly progressive fungal infection that usually occurs in patients with diabetes mellitus or in immunocompromised patients. Sinus involvement is the most common clinical presentation and the rates of mortality increase with the orbital extension. The treatment of mucormycosis includes aggressive surgical debridement and systemic antifungal therapy. Early diagnosis and prompt initiation of effective antifungal drugs are essential for successful outcome. However, the role of orbital exenteration for the case of orbital involvement remains controversial, and the drugs effective against mucormycosis are limited. We present a successfully treated case with rhino-orbital mucormycosis caused by Rhizopus oryzae in a diabetic and dialysis patient. The early diagnosis, surgical debridement and a new combination therapy with liposomal amphotericin B and micafungin were effective. This new combination antifungal therapy will be useful for the treatment of mucormycosis. [Copyright &y& Elsevier]

We examined the histopathological changes in the olfactory mucosa of cynomolgus and rhesus macaque models of SARS-CoV-2 infection. SARS-CoV-2 infection induced severe inflammatory changes in the olfactory mucosa. A major histocompatibility complex (MHC) class II molecule, HLA-DR was expressed in macrophage and supporting cells, and melanocytes were increased in olfactory mucosa. Supporting cells and olfactory neurons were infected, and SARS-CoV-2 N protein was detected in the axons of olfactory neurons and in olfactory bulbs. Viral RNA was detected in olfactory bulbs and brain tissues. The olfactory epithelium-olfactory bulb pathway may be important as a route for intracranial infection by SARS-CoV-2. • SARS-CoV-2 infection induces severe inflammatory changes in olfactory mucosa. • Supporting cells, olfactory neurons and olfactory bulbs are infected. • Supporting cells and macrophages express HLA-DR as antigen presenting cells. • Melanocytes increase in the infected olfactory mucosa. • Olfactory epithelium-olfactory bulb pathway as a route for intracranial infection. [ABSTRACT FROM AUTHOR]

Objectives: The aims of the present study were to clarify the time-course of olfactory recovery and the prognostic factors in PIOD patients treated with Toki-shakuyaku-san (TSS). Methods: A retrospective cohort study of patients with PIOD was conducted by reviewing patients' medical records. This study included patients who received TSS or a combination of TSS and zinc sulfate. Olfactory function was examined by T&T olfactometer at each 3-monthly follow-up visit. Patients with normal and mild olfactory dysfunction were excluded. Gender, age, treatment, duration of disease until the first visit and olfactory function scores of the T&T olfactometer at the first visit were analyzed as candidate clinical predictors of recovery. Results: A total of 82 PIOD patients with ages ranging from 16 to 79 years were included. The mean duration of follow-up was 14.5 months (range 3-45 months). The number of patients with olfactory recovery increased for 24 months and the cumulative recovery rate was 77.3%. In about 60% of patients, olfactory recovery occurred within 6 months. Multivariate analysis showed that younger age (<65 years) and residual olfactory function were significantly associated with good olfactory recovery. Conclusions: We revealed recovery rates over time in patients with PIOD. The recovery of olfactory function often occurred during the early period (≤6 months). However, the number of patients with olfactory recovery increased for a long-term of 24 months after the first visit. Residual olfactory function and younger age were prognostic factors exactly. TSS may be a useful therapeutic agent for patients with PIOD. We believe that these results provide important information that is useful for counseling patients with PIOD. [ABSTRACT FROM AUTHOR]

GLA-AF effect on T cell activator-induced IL-5 (M), IFN- (N) and IL-10 (O) secretion from memory CD4+ T cells from JCP patients. GLA-AF significantly inhibited the IL-5 secretion, and significantly stimulated the secretion of IFN- and IL-10 from these cells (Figure M-O). In addition, JC pollen-induced IL-5 secretion was suppressed in co-cultured CD11c SP + sp DCs and CD4 SP + sp T cells from the spleens of GLA-treated JC pollen-sensitized mice (Figure G). [Extracted from the article]

IL-25 likely has vital roles in initiating and activating type-2 immune responses in AR. We hypothesized that the molecules produced IL-25 by allergen-producing organisms such as JC is involved in the pathogenesis of AR. Participants included 13 patients with Japanese cedar pollinosis and 10 HCs. We measured the IL-25 protein concentration in nasal secretions and in culture supernatants of PNECs. NHBE cells were stimulated with pharmacological and immunological agents and JC. The IL-25 concentration in nasal secretions was significantly higher in patients with Japanese cedar pollinosis than in HCs. JC stimulated IL-25 production from PNECs. TNF-α, IL-4, and IL-13 significantly enhanced JC-induced IL-25 production ; their activation by serine proteases was sufficient to enhance IL-25 production. Furthermore, the NADPH oxidase activity, including JC enhanced IL-25 production. A better understanding of JC-induced IL-25 production by epithelial cells may allow the development of novel therapeutic and preventive strategies for Japanese cedar pollinosis. [ABSTRACT FROM AUTHOR]

Mucus hypersecretion and eosinophil infiltration are important characteristics of eosinophilic inflammation in upper airways, such as allergic rhinitis and chronic rhinosinusitis with nasal polyp. EGFR transactivation induces mucus and inflammatory cytokine secretion from airway epithelial cells. However, the roles of EGFR in eosinophilic inflammation in upper airways are still unknown. The purpose of the study is to elucidate the effects of the EGFR inhibitor AG1478 on eosinophilic airway inflammation. AG1478 significantly inhibited thrombin-induced GM-CSF secretion from nasal epithelial cells and thrombin-induced secretion of eotaxin-1 and RANTES from nasal fibroblasts. Intranasal instillation of AG1478 inhibited OVA-induced goblet cell metaplasia, mucus production and eosinophil/neutrophil infiltration in rat nasal epithelium, as did intraperitoneal injection of AG1478. These results indicate that EGFR transactivation plays an important role in eosinophilic airway inflammation. Intranasal instillation of an EGFR inhibitor may be a new therapeutic approach for the treatment of intractable eosinophilic inflammation in upper airways. [ABSTRACT FROM AUTHOR]

The epithelial cell-derived cytokines, thymic stromal lymphopoietin (TSLP), interleukin (IL)-25, and IL-33 induce T helper 2 type immune responses. In the present study, we investigate the role of these cytokines in the pathophysiology of eosinophilic chronic rhinosinusitis (ECRS). Nasal tissue specimens from chronic rhinosinusitis patients were assayed for the expression of TSLP, IL-25, IL-33, protease-activated receptor (PAR)-2, and P2Y2 receptor (P2Y2R). Cytokine production in cultured nasal epithelial cells (PNECs) was also examined. The mRNA levels of TSLP and IL-25 and the concentrations of IL-25 and IL-33 increased in PNECs from ECRS patients. Immunohistological staining demonstrated that TSLP, IL-25, and IL-33 were localized in the epithelial cells of nasal polyps, and that their expression was increased in ECRS. The mRNA levels of TSLP and IL-25 correlated with the clinical severity of ECRS, as indicated by the computed tomography score. The TSLP mRNA levels and IL-33 protein concentration correlated with the number of eosinophils in the nasal polyps of patients with ECRS. Airborne allergen-induced cytokine production increased in PNECs of these patients. Expression levels of the PAR-2 and P2Y2R increased in cultured PNECs and nasal polyps from patients with ECRS. The results indicate that increased induction and expression of TSLP, IL-25, and IL-33 from nasal epithelial cells contribute to the pathophysiology of ECRS. [ABSTRACT FROM AUTHOR]

Sublingual immunotherapy (SLIT) with Japanese cedar (JCe) pollinosis was expected to be effective for Japanese cypress (JCy) pollinosis. However, only a half of JCy pollinosis patients clinically improved. Therefore, we examined the immunological effect of SLIT for JCy pollinosis. Peripheral blood mononuclear cells (PBMCs) from patients with JCe and JCy pollinosis who did and did not receive SLIT were incubated with Cry j 1, Cha o 1 and Cha o 3 antigens. Basophil activation test (BAT) were performed. Production of IL-5 and IL-17 induced by antigens was inhibited in the SLIT group. Cry j 1-specific production of IL-10 was increased, and serum Cry j 1-specific IgE and -IgG4 were elevated. However, Cha o 1- or Cha o 3-specific production of IL-10 and specific IgG4 was not increased. Antigens-specific BAT did not decrease after SLIT. New SLIT with JCe and JCy is needed for patients with combined JCe and JCy pollinosis. • SLIT with JCe pollen inhibited production of IL-5 and IL-17 from PBMCs induced by JCe or JCy allergens. • SLIT with JCe pollen induced Cry j 1-specific production of IL-10, and serum levels of Cry j 1-specific IgE and IgG4. • SLIT with JCe pollen did not induce Cha o 1- or Cha o 3-specific production of IL-10 and specific IgG4. • Cry j 1-induced IL-10/IL-5 and Cry j 1-specific IgG4 were negatively correlated with the severity of clinical symptoms. [ABSTRACT FROM AUTHOR]

Abstract Background Epithelial cell-derived IL-33 has an important role in the initiation and activation of innate allergic inflammation. IL-33 acts as a cytokine through the ST2 receptor (ST2L) and it stimulates the production of Th2 cytokines. Soluble ST2 (sST2) may regulate Th2 responses by neutralizing the activity of IL-33. Basophils express ST2L and produce IL-5 in response to IL-33. However, the role of the epithelial cell–basophil interaction and sST2 in IL-5 production remains unclear. Methods Cultured human bronchial epithelial (hBE33) cells, that contained the human IL-33 gene (i.e., hBE33 cells) and a human basophilic cell line, KU812 cells, were used to study the epithelial cell–basophil interaction in the production of IL-5 induced by HDM. Results At 15 min after incubation, HDM stimulated the rapid release of IL-33 from cultured hBE33 cells. IL-33 and the supernatant of HDM-treated hBE33 cells stimulated IL-5 production from KU812 cells. Anti-IL-33 antibody and anti-ST2 antibody treatment of KU812 cells suppressed IL-5 production, which had been induced by the supernatant of HDM-treated hBE33 cells. The hBE33 cells secreted sST2 in a time-dependent manner. The production of sST2 by KU812 cells co-cultured with hBE33 cells was significantly increased, compared with KU812 cells cultured with the supernatant of hBE33 cells. Soluble ST2 suppressed IL-5 production by KU812 cells, which was induced by the supernatant of HDM-treated hBE33 cells. Conclusions Epithelial cell-derived IL-33 promoted IL-5 production by KU812 cells. The subsequently produced sST2 has important roles in regulating Th2 responses. [ABSTRACT FROM AUTHOR]