Recent prevalence of allergic rhinitis caused by house dust mites among the pediatric population in Fukui, Japan.

Background: Allergic rhinitis (AR) is an IgE-mediated type I allergic chronic nasal disease common among all age groups, including the pediatric population. House dust mites (HDMs) are globally ubiquitous and the most important indoor aeroallergen. However, the recent prevalence of HDM-caused AR (AR-HDM) in Japan remains unknown, especially after the COVID-19 pandemic. Objective: The objective of this study was to investigate the current prevalence of AR-HDM, its clinical features, and the current status of medical examinations in elementary school students. Methods: A survey of 41,000 elementary school students was conducted during July 2021 in Fukui Prefecture, Japan. Parents were asked to complete a questionnaire that examined allergic disease history and clinical background. Results: A total of 17,974 subjects were analyzed in the study. The results showed that the current prevalence of AR-HDM in elementary school children is 18.8%. We found that AR-HDM had already developed before entrance into elementary school in 68.3% of affected subjects. Among these subjects, 82.3% had received some form of treatment, such as prescription medications, whereas 4.2% were treated by allergen immunotherapy. Multiple logistic regression analysis of the onset of AR-HDM revealed that male sex, being the first-born child, comorbidity of bronchial asthma, atopic dermatitis, food allergy, and allergic conjunctivitis are associated with development of AR-HDM. Conclusions: The present study revealed the prevalence of AR-HDM in elementary school children. The results emphasize the importance of appropriate diagnosis and treatment from infancy through early childhood.

Endogenous opioids in the olfactory tubercle and their roles in olfaction and quality of life.

Olfactory dysfunctions decrease daily quality of life (QOL) in part by reducing the pleasure of eating. Olfaction plays an essential role in flavor sensation and palatability. The decreased QOL due to olfactory dysfunction is speculated to result from abnormal neural activities in the olfactory and limbic areas of the brain, as well as peripheral odorant receptor dysfunctions. However, the specific underlying neurobiological mechanisms remain unclear. As the olfactory tubercle (OT) is one of the brain's regions with high expression of endogenous opioids, we hypothesize that the mechanism underlying the decrease in QOL due to olfactory dysfunction involves the reduction of neural activity in the OT and subsequent endogenous opioid release in specialized subregions. In this review, we provide an overview and recent updates on the OT, the endogenous opioid system, and the pleasure systems in the brain and then discuss our hypothesis. To facilitate the effective treatment of olfactory dysfunctions and decreased QOL, elucidation of the neurobiological mechanisms underlying the pleasure of eating through flavor sensation is crucial.

[RECURRENT AND VIRTUAL EDUCATION FOR ALL DISCIPLINES AND OCCUPATIONS IN THE ALLERGY REALM : A SURVEY OF THE PARTICIPANTS FROM THE INITIATIVE 'OUTREACH LECTURES' TO CREATE EDUCATIONAL OPPORTUNITIES].

BACKGROUND: In the enhancement of allergy care involving multidisciplinary and multiple medical departments, there is a perceived need for education that targets not only specialists but also non-specialists. However, research on the need for and methods of such education remains inadequate. OBJECTIVE: To design a remote allergy care education program for all medical practitioners and to validate its necessity and utility. METHODS: The Empowering Next Generation Allergist/immunologist toward Global Excellence Task Force (ENGAGE-TF), supported by the Japanese Society of Allergology, initiated a virtual educational program called 'Outreach Lectures' in collaboration with Keio University and Fukui University. This initiative was widely promoted through social media and various institutions, and a survey was conducted through its mailing list. RESULTS: 1139 responses were obtained. More than half were physicians from non-allergy specialties, representing a diverse range of healthcare professions. Over 70% expressed being 'very satisfied,' and over 60% found the difficulty level 'appropriate.' Free-form feedback revealed differences in learning focus based on profession and learning approach based on years of experience. CONCLUSION: The high participation rate (90%) of non-specialist physicians underscores the demand for addressing allergic conditions in primary care. The effectiveness of virtual / recurrent education, particularly for healthcare professionals with over 11 years of experience, was implied. Further follow-up investigation focusing on quantitative and objective assessment of educational effectiveness is indispensable.

Middle meatus microbiome in patients with eosinophilic chronic rhinosinusitis in a Japanese population.

BACKGROUND: Chronic rhinosinusitis (CRS) is a common chronic inflammatory disease and is subdivided into eosinophilic and noneosinophilic forms. There are few reports investigating the nasal microbiome and its pathological functions in patients with CRS. OBJECTIVE: We sought to analyze factors contributing to variations of the nasal microbiome in CRS, and on the basis of these factors, to elucidate whether the bacterial metabolites were related to the pathogenesis. METHODS: Nasal swabs were collected, and the V3 to V4 variable region of the 16S ribosomal RNA gene was amplified and sequenced. Factors contributing to variations of the nasal microbiome in patients with CRS were compared. The most influential factor was whether CRS was eosinophilic, and we compared α- and ß-diversity, bacterial species, and predictive bacterial functions between the 2 patient groups. In addition, the metabolites of the key bacteria were extracted, and we evaluated the predicted bacterial functions in airway epithelial cells. RESULTS: In total, 110 patients with CRS and 33 control subjects were enrolled. On the basis of the factors of variation, it was found that patients with eosinophilic CRS (n = 65) had different microbiomes with weighted UniFrac ß-diversity and lower α-diversity compared with those with noneosinophilic CRS (n = 45). A higher abundance of Fusobacterium nucleatum and an increased LPS pathway were observed in patients with noneosinophilic CRS compared with those with eosinophilic CRS. In airway epithelial cells, LPS derived from F nucleatum suppressed the expression levels of ALOX15 induced by TH2 cytokines. CONCLUSIONS: The differences in the nasal microbiome may play a key role in the pathophysiology of CRS.

Liquid-based cytology (LBC) with immunocytochemical staining improves fine-needle aspiration cytology (FNA) performance for salivary gland tumors.

BACKGROUND: Liquid-based cytology (LBC), now used globally for the head and neck region, has been used at our hospital since 2011. This study was designed to analyze the efficacy of LBC with immunocytochemical staining on preoperative diagnosis of salivary gland tumors. METHODS: This retrospective analysis of fine-needle aspiration (FNA) performance for salivary gland tumors was conducted at Fukui University Hospital. Salivary gland tumor operations conducted during April 2006 - December 2010 (84 cases) were classified as the Conventional Smear (CS) group, which were diagnosed morphologically by Papanicolaou and Giemsa staining. Those done during January 2012 - April 2017 (112 cases) were classified as the LBC group, which were diagnosed using LBC samples with immunocytochemical staining. The FNA results and pathological diagnosis of both groups were analyzed to calculate the FNA performance. RESULTS: Compared to the CS group, cases of inadequate and indeterminate FNA sample were not reduced significantly by LBC with immunocytochemical staining. As for FNA performance, the accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of CS group were, respectively, 88.7%, 53.3%, 100%, 100%, and 87.0%. Those of LBC group were all 100%, representing significant improvement over the CS group. CONCLUSIONS: Analysis results indicated the usefulness of LBC with immunocytochemical staining for preoperative diagnosis of salivary gland tumors.

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.

Regulation of the Expression of SARS-CoV-2 Receptor Angiotensin-Converting Enzyme 2 in Nasal Mucosa.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has caused a global pandemic. Higher expression of the virus receptor angiotensin-converting enzyme 2 (ACE2) in the nasal mucosa may be associated with high transmissibility and asymptomatic infection. In COVID-19, the elucidation of the determinants of ACE2 expression at nasal tissue level is crucial. The development of strategies to downregulate ACE2 expression in nasal epithelial cells might reduce transmission and be useful as a novel therapeutic approach. OBJECTIVE: To verify ACE2 expression in the nasal mucosa of patients with seasonal allergic rhinitis induced by Japanese cedar pollen (SAR-JCP) and chronic rhinosinusitis with nasal polyp (CRSwNP) and to examine the effects of short-chain fatty acids (SCFAs) on ACE2 expression in airway epithelial cells. METHODS: We assessed ACE2 expression in the nasal mucosa of control subjects, patients with SAR-JCP, and those with CRSwNP using real-time polymerase chain reaction. We also quantified ACE2 gene expression in cultured airway epithelial cells. RESULTS: Although ACE2 expression was greatly increased in a few patients with SAR-JCP during the Japanese cedar pollen season, mean levels were not significantly increased. ACE2 mRNA expression was significantly decreased in nasal polyp tissue from patients with chronic rhinosinusitis compared with the expression in that from control subjects. SCFAs generated by gastrointestinal microbiota significantly reduced resting ACE2 expression in cultured airway epithelial cells. SCFAs also significantly suppressed the dsRNA-dependent upregulation of ACE2 expression in airway epithelial cells. CONCLUSION: Inflammatory endotype affects ACE2 expression in the nasal mucosa and influences susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In particular, type 2 inflammation could downregulate ACE2 expression in the nasal mucosa and reduces susceptibility to SARS-CoV-2 in patients with CRSwNP. Although in vivo experiments are required, administration of SCFAs to the nasal cavity might be worthy of consideration as a preventative or therapeutic strategy for the early-stage COVID-19.

Involvement of Activation of Mast Cells via IgE Signaling and Epithelial Cell-Derived Cytokines in the Pathogenesis of Pollen Food Allergy Syndrome in a Murine Model.

Murine models to elucidate the pathogenesis of pollen food allergy syndrome (PFAS), characterized by oral hypersensitivity symptoms induced by specific foods in patients previously sensitized with a pollen, are lacking. The study aimed to examine PFAS pathogenesis in a novel murine model. Birch pollen-immunized mice were orally administered apple extract, and oral symptoms were evaluated based on oral rubbing frequency following the challenge. The birch pollen-immunized mice orally challenged with apple extract exhibited PFAS-like symptoms, including oral rubbing and positive reaction of swelling by the prick test. The apple extract administered with a protease inhibitor reduced the oral rubbing frequency, which was also significantly reduced in the immunized Fcer1a -/- and mast cell-deficient mice compared with the immunized control mice. The oral rubbing frequency, serum IgE levels, and Th2-cytokine production by the cervical lymph node cells were significantly reduced in the immunized Il-33 -/- and thymic stromal lymphopoietin receptor-deficient (Crlf2 -/-) mice as compared with the immunized wild-type mice. IL-33 and thymic stromal lymphopoietin involve the pathogenesis of PFAS. The apple-extract stimulation did not lead to increased Th2-cytokine production in the oral mucosa or number of group 2 innate lymphoid cells or eosinophils. PFAS involves an early-phase response by mast cell degranulation via IgE signaling after the cross-reactivity of Bet v 1-specific IgE and the food allergen, and exacerbation of allergic symptom via proteases in food; PFAS does not involve a late phase with local Th2/eosinophilic inflammation in the oral mucosa. This novel murine model might be used for elucidating the pathogenesis and assessing new therapeutic strategies for PFAS.

Increased Thrombin-Activatable Fibrinolysis Inhibitor in Response to Sublingual Immunotherapy for Allergic Rhinitis.

OBJECTIVES/HYPOTHESIS: The objective of this study was to determine the role of thrombin-activatable fibrinolysis inhibitor (TAFI) as a candidate biomarker for therapeutic efficacy of sublingual immunotherapy (SLIT) and to identify the role of TAFI in the pathogenesis of allergic rhinitis (AR). STUDY DESIGN: Retrospective cohort study and laboratory study. METHODS: Serum was collected from patients with allergies to Japanese cedar pollen before, during, and after treatment with SLIT. We measured the levels of immunoreactive TAFI, C3a, and C5a in serum by enzyme-linked immunosorbent assay (ELISA) and assessed their relative impact on a combined symptom-medication score. We also examined the impact of TAFI on mast cells and fibroblasts in experiments performed in vitro. RESULTS: Serum levels of TAFI increased significantly in response to SLIT. By contrast, serum C3a levels decreased significantly over time; we observed a significant negative correlation between serum levels of TAFI versus C3a and symptom-medication score. Mast cell degranulation was inhibited in response to TAFI, as it was the expression of both CCL11 and CCL5 in cultured fibroblasts. CONCLUSIONS: High serum levels of TAFI may be induced by SLIT. TAFI may play a critical protective role in pathogenesis of AR by inactivating C3a and by inhibiting mast cell degranulation and chemokines expression in fibroblasts. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:2413-2420, 2021.

Comparison of sensitization and prevalence of Japanese cedar pollen and mite-induced perennial allergic rhinitis between 2006 and 2016 in hospital workers in Japan.

BACKGROUND: The prevalence of allergic rhinitis (AR) is increasing worldwide, mainly due to an increase in antigen exposure. We conducted an epidemiological study involving the staff of the University of Fukui Hospital and its associated hospital in 2006. There were 1540 participants aged ≥20 years, and the rates of Japanese cedar (JC) pollinosis and mite-induced perennial allergic rhinitis (PAR) were 36.8% and 15.8%, respectively. In 2016, we conducted a second survey. METHODS: The rate of sensitization to JC pollen and mites and the prevalence of JC pollinosis and mite-induced PAR were analyzed based on data from questionnaires and antigen-specific immunoglobulin E (IgE) levels. RESULTS: In the present study, we analyzed data of 1472 participants aged between 20 and 59 years. Total sensitization to JC pollen and total prevalence of JC pollinosis were 57.8% (851/1472) and 40.8% (601/1472), respectively. Total sensitization to mites and total prevalence of mite-induced PAR were 41.4% (610/1472) and 18.8% (276/1472), respectively. Total prevalence of JC pollinosis and mite-induced PAR increased significantly over a decade. Among the 334 people who participated in the 2006 and 2016 cross-sectional studies, 13% of JC pollinosis and 36% of mite-induced PAR experienced remission. However, since the number of new onset cases was higher that the number of remission cases, a slight increase in prevalence was observed over a decade. CONCLUSIONS: The prevalence of JC pollinosis and mite-induced PAR continues to show increasing trends, accompanied by an increase in antigen exposure. The remission rate of JC pollinosis was particularly low.

Elevated Serum Leptin Levels in Patients With Eosinophilic Chronic Rhinosinusitis.

Background: Eosinophilic chronic sinusitis (ECRS) is a subtype of CRS with nasal polyps (CRSwNP) that is frequently comorbid with asthma. Notably, ECRS patients often show a high recurrence of NPs after surgical resection. Leptin is a hormone produced by adipocytes that has been implicated in airway inflammatory diseases. However, to date, the role of leptin in ECRS has not been investigated. Objective: To determine whether the serum levels of leptin are altered in patients with ECRS. Methods: In total, 40 patients with ECRS, 15 patients with non-eosinophilic CRS (non-ECRS), and 12 individuals without CRS (control) were included in this study. Patient's serum leptin levels were assessed, and the number of eosinophils in their NPs were measured through a histological evaluation of the three densest areas with cellular infiltrate beneath the epithelial surface. Finally, nasal fibroblast cultures established from NPs were stimulated with varying concentrations of recombinant leptin in vitro to determine whether leptin affects eotaxin-3 (Chemokine (C-C motif) ligand 26 :26: CCL26) expression. Results: The serum leptin levels in both the ECRS and non-ECRS groups were significantly higher than those in the control subjects (p < 0.0001 vs. ECRS; p < 0.05 vs. non-ECRS). Furthermore, ECRS patients displayed significantly elevated serum leptin levels compared to non-ECRS patients (p < 0.001), although there was no difference in body mass index between the groups. Notably, serum leptin levels were correlated with the proportion of eosinophils in peripheral blood (r = 0.3575, p < 0.01) and the number of eosinophils in NPs (r = 0.5109, p < 0.0001). Serum leptin levels were also correlated with eotaxin-3 mRNA expression in NPs (r = 0.5374, p < 0.01). Finally, leptin significantly augmented eotaxin-3 expression in nasal fibroblasts established in vitro from NPs in a leptin receptor-dependent manner (p < 0.05). Conclusion: Leptin levels are elevated in ECRS patients and may both promote and indicate the severity of ECRS as well as systemic type 2-biased inflammatory responses. Combined, these data indicate that circulating leptin may play a significant role in the development of eosinophilic inflammation in NPs.

Baicalin suppresses type 2 immunity through breaking off the interplay between mast cell and airway epithelial cell.

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Japanese herbal medicine Shin'iseihaito was reported to ameliorate the airway type 2 inflammatory response in clinical and experimental studies. Airway type 2 inflammatory diseases, including bronchial asthma and eosinophilic chronic rhinosinusitis (ECRS), often coexist and interact with each other. However, it is still unclear how Shin'iseihaito exerts its pharmacological effects on cells involved in airway mucosa. AIM OF THE STUDY: This study aims to examine the direct effect of baicalin, a representative bioactive compound of Shin'iseihaito, on type 2 immune responses in human airway epithelial cells and mast cells. MATERIAL AND METHODS: We measured the plasma pharmacokinetics of flavonoids derived from Shin'iseihaito and investigated the effects of baicalin on type 2 immune responses in human airway epithelial cells and human mast cells. RESULTS: Baicalin, wogonin, and wogonoside were detected in the plasma. The maximum plasma concentration of baicalin was highest at 1610 ng/ml (3.6 µM). In the normal human bronchial epithelial cells treated with baicalin, with or without stimulation by IFN-γ, the IL-33 expression was significantly downregulated. However, baicalin treatment did not affect the levels of thymic stromal lymphopoietin and IL-25. We noted that IL-33-dependent expression of tryptase mRNA in mast cells was significantly inhibited by baicalin. Also, the expression of IL-5 in mast cells enhanced by stimulation with TSLP plus IL-1ß was significantly downregulated by baicalin treatment. Moreover, the enhancement of IL-13 expression in mast cells by IL-33 simulation was also significantly inhibited by baicalin. CONCLUSIONS: Our results prove that by breaking off the vicious circle of mast cells and airway epithelial cells, baicalin may be an effective alternative therapeutic option for the treatment of type 2 inflammatory diseases, such as ECRS and comorbid asthma.

Enhanced 15-Lipoxygenase 1 Production is Related to Periostin Expression and Eosinophil Recruitment in Eosinophilic Chronic Rhinosinusitis.

BACKGROUND: The pathological features of chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) tissues include an eosinophilic infiltration pattern (eosinophilic CRS (ECRS)) or a less eosinophilic pattern (non-ECRS). Recently, it has been suggested that 15-lipoxygenase 1 (15-LOX-1) may have significant roles in allergic disease; however, the significance of 15-LOX-1 in CRS is not well understood. The objective of this study was to demonstrate the expression of 15-LOX-1 in CRS. METHODS: The mRNA expression levels of 15-LOX-1 and periostin in nasal tissues were measured by quantitative real-time polymerase chain reaction. We also performed an immunofluorescence study of nasal tissues. Cells of the Eol-1 eosinophilic leukemic cell line were stimulated with interleukin-33 to test the induction of 15-LOX-1. RESULTS: The expression level of 15-LOX-1 mRNA in nasal polyps (NPs) was significantly higher in ECRS patients than in non-ECRS patients. The immunofluorescence study revealed that both airway epithelial cells and eosinophils in NPs expressed 15-LOX-1. A significant correlation was seen between the number of eosinophils and the mRNA expression levels of 15-LOX-1 and periostin in nasal polyps. Moreover, interleukin-33 enhanced 15-LOX-1 expression in Eol-1 cells. CONCLUSIONS: 15-LOX-1 was shown to be a significant molecule that facilitates eosinophilic inflammation in ECRS.

Adult-onset eosinophilic airway diseases.

Eosinophilic airway inflammation is one of the cardinal features of allergic airway diseases such as atopic asthma and allergic rhinitis. These childhood-onset conditions are mediated by allergen and allergen-specific IgE and often accompanied by other allergic diseases including food allergy and eczema. They can develop consecutively in the same patient, which is referred to as an allergic march. In contrast, some phenotypes of asthma, nonsteroidal anti-inflammatory drugs-exacerbated airway disease (N-ERD), chronic rhinosinusitis with nasal polyps (CRSwNP)/eosinophilic CRS and allergic bronchopulmonary aspergillosis/mycosis (ABPA/ABPM) are adult-onset airway diseases, which are characterized by prominent peripheral blood eosinophilia. Most of these conditions, except for ABPA/ABPM, are nonatopic, and the coexistence of multiple diseases, including an adult-onset eosinophilic systemic disease, eosinophilic granulomatosis with polyangiitis (EGPA), is common. In this review, we focus on eosinophil biology, genetics and clinical characteristics and the pathophysiology of adult-onset eosinophilic asthma, N-ERD, CRSwNP/eosinophilic CRS, ABPA/ABPM and EGPA, while exploring the common genetic, immunological and pathological conditions among these adult-onset eosinophilic diseases.

Galectin-10, the protein that forms Charcot-Leyden crystals, is not stored in granules but resides in the peripheral cytoplasm of human eosinophils.

A predominant protein of human eosinophils is galectin-10 (Gal-10), also known as Charcot-Leyden crystal protein (CLC-P) because of its remarkable ability to form Charcot-Leyden crystals (CLCs), which are frequently found in tissues from patients with eosinophilic disorders. CLC-P/Gal-10 is highly expressed in human eosinophils and considered a biomarker of eosinophil involvement in inflammation. However, the intracellular sites where large pools of CLC-P/Gal-10 constitutively reside are still unclear, and whether this protein is derived or not from eosinophil granules remains to be established. Here, we applied pre-embedding immunonanogold transmission electron microscopy combined with strategies for optimal antigen and cell preservation and quantitative imaging analysis to investigate, for the first time, the intracellular localization of CLC-P/Gal-10 at high resolution in resting and activated human eosinophils. We demonstrated that CLC-P/Gal-10 is mostly stored in the peripheral cytoplasm of human eosinophils, being accumulated within an area of ∼250 nm wide underneath the plasma membrane and not within specific (secretory) granules, a pattern also observed by immunofluorescence. High-resolution analysis of single cells revealed that CLC-P/Gal-10 interacts with the plasma membrane with immunoreactive microdomains of high CLC-P/Gal-10 density being found in ∼60% of the membrane area. Eosinophil stimulation with CCL11 or TNF-α, which are known inducers of eosinophil secretion, did not change the peripheral localization of CLC-P/Gal-10 as observed by both immunofluorescence and immuno-EM (electron microscopy). Thus, in contrast to other preformed eosinophil proteins, CLC-P/Gal-10 neither is stored within secretory granules nor exported through classical degranulation mechanisms (piecemeal degranulation and compound exocytosis).

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.