Publications by authors named "Chae-Seo Rhee"

175 Publications

DEP-induced ZEB2 promotes nasal polyp formation via epithelial-to-mesenchymal transition.

J Allergy Clin Immunol 2021 May 4. Epub 2021 May 4.

Obstructive Upper airway Research Laboratory, the Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Korea; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea. Electronic address:

Background: Diesel exhaust particles (DEPs) are associated with the prevalence and exacerbation of allergic respiratory diseases, including allergic rhinitis and allergic asthma. However, DEP-induced mechanistic pathways promoting upper airway disease and their clinical implications remain unclear.

Objective: We sought to investigate the mechanisms by which DEP exposure contributes to nasal polyposis using human-derived epithelial cells and a murine nasal polyp (NP) model.

Methods: Gene set enrichment and weighted gene coexpression network analyses were performed. Cytotoxicity, epithelial-to-mesenchymal transition (EMT) markers, and nasal polyposis were assessed. Effects of DEP exposure on EMT were determined using epithelial cells from normal people or patients with chronic rhinosinusitis with or without NPs. BALB/c mice were exposed to DEP through either a nose-only exposure system or nasal instillation, with or without house dust mite, followed by zinc finger E-box-binding homeobox (ZEB)2 small hairpin RNA delivery.

Results: Bioinformatics analyses revealed that DEP exposure triggered EMT features in airway epithelial cells. Similarly, DEP-exposed human nasal epithelial cells exhibited EMT characteristics, which were dependent on ZEB2 expression. Human nasal epithelial cells derived from patients with chronic rhinosinusitis presented more prominent EMT features after DEP treatment, when compared with those from control subjects and patients with NPs. Coexposure to DEP and house dust mite synergistically increased the number of NPs, epithelial disruptions, and ZEB2 expression. Most importantly, ZEB2 inhibition prevented DEP-induced EMT, thereby alleviating NP formation in mice.

Conclusions: Our data show that DEP facilitated NP formation, possibly via the promotion of ZEB2-induced EMT. ZEB2 may be a therapeutic target for DEP-induced epithelial damage and related airway diseases, including NPs.
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http://dx.doi.org/10.1016/j.jaci.2021.04.024DOI Listing
May 2021

Development of HIGH-INTENSITY FOCUSED ULTRASOUND(HIFU) Therapy in Inferior Turbinate Hypertrophy.

Clin Exp Otorhinolaryngol 2021 Mar 30. Epub 2021 Mar 30.

Department of Otorhinolaryngology- Head and Neck Surgery, Seoul National University Bundang Hospital, Seongnam, Korea.

Objectives: Inferior turbinate (IT) hypertrophy is the main cause of chronic nasal obstruction. We developed a high-intensity focused ultrasound (HIFU) ablation device to treat patients with IT hypertrophy.

Methods: First, computed tomography (CT) images of patients without any evidence of sinonasal disease were evaluated to measure and compared the IT, medial mucosal thickness (MT), and space between the nasal septum and IT according to clinical characteristics such as septal deviation. A HIFU prototype was developed based on human anatomical studies. The experimental study was performed in five pigs; the cross-sectional areas of the nasal cavity airway and histological changes at 1 and 4 weeks postoperatively were evaluated to compare the efficacy of HIFU turbinoplasty with that of radiofrequency turbinoplasty and control.

Results: The mean medial MT of the anterior, middle, and posterior portions of the IT were 4.66±1.14, 4.23±0.97, and 6.17±1.29 mm, respectively. The mean medial IT spaces was 2.65±0.79 mm. The diameter and focal depth of the prototype were 4 mm and 3 mm. HIFU showed no postoperative complications including bleeding or scar formation. After HIFU treatment, the cross-sectional area of the nasal airway increased by 196.62(7.8%) mm3 and 193.74(8.3%) mm3 at 1 week and 4 weeks, compared with the increase of 87.20(3.1%) mm3 and 213.81(9.0%) mm3, respectively, after radiofrequency therapy. Qualitative histologic analysis after radiofrequency turbinoplasty showed epithelial layer disruption at 1 week and increased fibrosis along with decreased glandular structure at 4 weeks. The HIFU group had an intact epithelial layer at 1 week postoperatively. However, significant differences were observed at 4 weeks, including increased fibrosis, and decreased glandular structure.

Conclusion: The efficacy and safety of HIFU turbinoplasty had been observed in an animal study. Our results warrant the need for further human clinical trials.
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http://dx.doi.org/10.21053/ceo.2020.02383DOI Listing
March 2021

Clinical characteristics of asymptomatic allergen sensitization with nasal septal deviation, often misdiagnosed as allergic rhinitis.

Eur Arch Otorhinolaryngol 2021 Mar 4. Epub 2021 Mar 4.

Department of Otorhinolaryngology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea.

Purpose: Allergic rhinitis (AR) is often defined based on symptoms accompanied by a positive allergen sensitivity test result. However, a positive skin prick test (SPT) does not always imply the occurrence of clinical symptoms. If an asymptomatic allergen-sensitized patient has nasal septal deviation (DSN) that could cause nasal obstruction, the condition could easily be confused with typical symptomatic AR. This study investigated the clinical and laboratory characteristics of asymptomatic allergen-sensitization with septal deviation (ASSD).

Methods: Patients from a nationwide AR cohort study, conducted in 8 university hospitals, were investigated. AR was diagnosed when there were at least 1 rhinitis symptom with a positive SPT result. The ASSD group included patients who had severe nasal obstruction with few other symptoms and a positive SPT, along with septal deviation. Clinical and laboratory characteristics were compared between the ASSD group and the true AR group.

Results: In total, 728 patients were included. The average age was 32.2 ± 12.7 and 66% of the patients had DSN. SPT indicated that ASSD patients were less sensitized to house dust mite (p = 0.019 for Dp and p = 0.021 for Df). There was a significant sex difference: the male-to-female ratio was higher in the ASSD than in the AR group (3.59 vs. 1.77, p = 0.012). However, no statistically significant differences in age, family history, and body mass index were found.

Conclusion: ASSD can mimic AR. When dealing with allergen-sensitized patients with a predominant symptom of nasal obstruction, DSN might also be considered before confirming a diagnosis of AR.
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http://dx.doi.org/10.1007/s00405-021-06725-5DOI Listing
March 2021

Non-association between low vitamin d levels and aeroallergen-positivity evaluated using multiple allergen simultaneous test in Korean adults.

Allergy Asthma Clin Immunol 2021 Feb 27;17(1):23. Epub 2021 Feb 27.

Sensory Organ Research Institute, Medical Research Center, Seoul National University, Seoul, Korea.

Background: Studies on the association between vitamin D levels and allergen sensitization have reported conflicting results. We aimed to evaluate the association between low vitamin D levels and sensitization to 59 aeroallergens in Korean adults.

Methods: We retrospectively reviewed serum 25-hydroxyvitamin D (25[OH]D) measurements of participants (n = 57,467) in a healthcare center between May 2003 and June 2020. Serum 25(OH)D levels were categorized as follows: severe deficiency (< 10 ng/mL), deficiency (10 to < 20 ng/mL), insufficiency (20 to < 30 ng/mL), and sufficiency (≥ 30 ng/mL). Among all subjects, 1277 simultaneously underwent the multiple allergen simultaneous test. Multiple linear and logistic regression analyses were used to estimate coefficients and odds ratios (ORs) with 95% confidence interval (CI) for the association between serum vitamin D deficiency and aeroallergen sensitization after adjustment for potential confounders. Subgroup analyses were conducted for the types of aeroallergen (house dust mites, pollens, animal dander, foods, cockroach, and fungus).

Results: Vitamin D deficiency, defined as serum 25(OH)D level < 20 ng/mL, was noted in 56.4% of participants. There were significant differences in serum 25(OH)D levels according to sex, age, season, and bone mineral density (all P < 0.001). In multiple linear regression analyses, serum 25(OH)D levels were significantly lower in young subjects (adjusted coefficient [95% CI], 0.188 [0.101, 0.275]) and during winter (- 4.114 [- 6.528, - 1.699]). However, no significant association was observed between serum 25(OH)D levels and allergen sensitization (adjusted coefficients [95% CI], - 0.211 [- 1.989, 1.567], P = 0.816). In multivariate logistic regression analyses, male sex, young age, and winter season were significant risk factors for vitamin D deficiency. However, allergen sensitization showed no significant association with 25(OD)D levels after adjusting for confounders (adjusted OR [95% CI], 1.037 [0.642, 1.674] in insufficiency; 0.910 [0.573, 1.445] in deficiency; 0.869 [0.298, 2.539] in severe deficiency groups, P for trend = 0.334). There were consistent findings across subgroups regarding type of aeroallergen sensitized.

Conclusion: Vitamin D deficiency was prevalent but was not significantly associated with aeroallergen sensitization in Korean adults. To the best of our knowledge, this is the first large-scale study to evaluate the association between vitamin D deficiency and sensitization to 59 different aeroallergens.
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http://dx.doi.org/10.1186/s13223-021-00525-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913436PMC
February 2021

Correlation between short-time and whole-night obstruction level tests for patients with obstructive sleep apnea.

Sci Rep 2021 Jan 15;11(1):1509. Epub 2021 Jan 15.

Department of Otorhinolaryngology-Head and Neck Surgery, Chungbuk National University College of Medicine, Chungbuk National University Hospital, Cheongju, Korea.

Identification of obstructive level is crucial for successful surgical outcomes in patients with obstructive sleep apnea (OSA). Unfortunately, most of the dynamic airway evaluations are performed for a short duration under drug-induced sleep; therefore, it is uncertain whether they represent airway events that occur during a whole night of sleep. This study was aimed to evaluate the correlation between obstructive levels that were identified by a short-time and a whole-night test in patients with OSA. Total 101 patients with OSA underwent drug-induced sleep fluoroscopy (DISF) and pressure manometry (PM). For DISF, the obstructive pattern was classified into one of three groups: soft palate, tongue-based, and a combined obstruction. PM was used to measure the proportion of retroglossal events out of total whole-night obstructive events in each patient. The mean age of the patients was 43.8 years. The obstructive pattern was identified as soft palate in 56 patients, combined in 38 patients, and tongue-based in 7 patients following DISF. Results from PM showed that the mean percentage of retroglossal obstructive events was 31.2 ± 30.7%. The average proportion of retroglossal obstructive events that were identified by PM in patients with soft palate, combined, and tongue-based obstruction was 27.2%, 32.1%, and 59.0%, respectively (p = 0.033). There are limitations of evaluating obstructive events that occur during a whole night with short-time tests. Surgeons should be aware the possibility of disagreement in the obstructive level between short-time and whole-night tests.
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http://dx.doi.org/10.1038/s41598-020-80825-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811006PMC
January 2021

Effect of lipopolysaccharide and polyinosinic:polycytidylic acid in a murine model of nasal polyp.

Sci Rep 2021 Jan 13;11(1):1021. Epub 2021 Jan 13.

Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehagro, Jongro-gu, Seoul, 03080, Korea.

Several factors, including bacterial and viral infections, have been associated with rhinosinusitis and nasal tissue remodelling that may result in nasal polyp formation. However, the potential role of bacterial or viral stimuli triggering polyp development is unclear. Here, we used lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid [poly(I:C)] in a murine model of allergic rhinosinusitis to compare different effects of bacterial- and virus-derived stimuli in the pathogenesis of nasal polyp formation. Briefly, BALB/c mice were sensitised and challenged with ovalbumin and staphylococcal enterotoxin, with or without LPS or poly(I:C), and the consequent histopathological profiles, cytokines, and systemic humoral responses were studied. While no significant differences in polyp formations and epithelial disruptions were observed among the experimental groups, the local cell recruitment patterns slightly differed in animals that received either LPS or poly(I:C). Additionally, the local immune environments generated by LPS or poly(I:C) stimulation varied. LPS stimulation induced a marked Th1/Th17 response and predominantly neutrophilic nasal polyp formations, whereas poly(I:C) induced a Th2-skewed environment in neutrophilic nasal polyp development. Overall, our findings show that both cell recruitment patterns and local immune environments induced by these two stimuli differ, which may have implications in the physiopathology of rhinosinusitis with nasal polyp.
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http://dx.doi.org/10.1038/s41598-020-80483-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806732PMC
January 2021

Correlation of site of obstruction between two dynamic evaluation modalities in obstructive sleep apnea patients: drug-induced sleep endoscopy and sleep videofluoroscopy.

Sleep Breath 2020 Oct 22. Epub 2020 Oct 22.

Department of Otorhinolaryngology-HNS, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Purpose: Drug-induced sleep endoscopy (DISE) and sleep videofluoroscopy (SVF) are two dynamic modalities for evaluating the upper airway in patients with obstructive sleep apnea (OSA). We evaluated the correlation of obstructive sites determined by DISE and SVF in OSA patients and elucidate findings that can improve the accuracy of upper airway assessment.

Methods: A consecutive series of 63 patients with OSA who underwent DISE and SVF were the subjects of this study. The DISE and SVF findings were divided according to the anatomical structure responsible for the collapse, including the soft palate (SP), oropharyngeal lateral walls (LW), tongue base (TB), and larynx (LX). The obstruction was graded on the three-point scale: 0, no obstruction; 1, partial obstruction; or 2, complete obstruction. Additionally, grade 1.5 TB obstruction was designated when the posterior displacement of the anterior tongue was detected during simultaneous retropalatal obstruction. The agreement rate and Cohen's kappa test between the two modalities were also assessed.

Results: The agreement rate between the two modalities was highest in LX (88.9%) followed by SP (85.7%), TB (76.1%), and LW (74.6%) (Cohen's kappa value = 0.757 in LX, 0.642 in SP, 0.637 in TB, 0.612 in LW, respectively). When grade 1.5 and 2 TB obstructions were combined, the agreement rate increased to 88.9% (Cohen's kappa value = 0.757).

Conclusions: We found a good overall agreement between the two dynamic airway evaluation modalities during drug-induced sleep, and this correlation may be improved if the posterior displacement of the anterior tongue during DISE is used as a sign of TB obstruction.
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http://dx.doi.org/10.1007/s11325-020-02225-8DOI Listing
October 2020

Human Rhinovirus Infection Enhances the Th2 Environment in Allergic and Non-allergic Patients with Chronic Rhinosinusitis.

Clin Exp Otorhinolaryngol 2021 May 11;14(2):217-224. Epub 2020 Sep 11.

Graduate School of Medicine, Seoul National University College of Medicine, Seoul, Korea.

Objectives: This study was conducted to determine whether patients with allergic rhinitis might be more susceptible to human rhinovirus (HRV) infection and whether the effects of infection on the elicited immune responses are different in allergic and non-allergic patients with chronic rhinosinusitis (CRS).

Methods: Uncinate process tissues were obtained from 61 CRS patients (of whom 39 had allergies and 22 did not) and were infected with HRV-16 using an air-liquid interface organ culture system. The expression levels of programmed cell death-ligand (PD-L)1, PD-L2, intracellular adhesion molecule 1, interferon-gamma (IFN-γ), interleukin (IL)-4, IL-5, and IL-10 were evaluated in the infected nasal mucosa.

Results: The HRV infection rates were not significantly different between the allergy (74.4%) and non-allergy (72.7%) groups. In the allergy group, the expression of PD-L1 (P=0.013) and IL-10 (P=0.040) was significantly elevated in the HRV-infected tissues, and there was a strong correlation between PD-L1 and IL-10 (r=0.868, P<0.001). In contrast, infected tissues from the non-allergy group displayed increased levels of IL-4 (P=0.039), IL-5 (P=0.023), and IFN-γ (P=0.031), as well as an increased IL-4/IFN-γ ratio, after HRV infection (P=0.043).

Conclusion: This study showed that HRV infection rates were similar in the nasal mucosa of patients with CRS regardless of the presence of allergic rhinitis. HRV infection enhanced the Th2 environment by modulating PD-L1 and PD-L2 expression levels in allergic mucosa and by increasing the IL-4/IFN-γ ratio in non-allergic mucosa.
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http://dx.doi.org/10.21053/ceo.2020.00444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111390PMC
May 2021

Polysomnographic phenotyping of obstructive sleep apnea and its implications in mortality in Korea.

Sci Rep 2020 08 6;10(1):13207. Epub 2020 Aug 6.

Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82 Gumi-ro 173th street, Bundang-gu, Seongnam, Gyeonggi-do, 13620, South Korea.

Conventionally, apnea-hypopnea index (AHI) is used to define and categorize the severity of obstructive sleep apnea. However, routine polysomnography (PSG) includes multiple parameters for assessing the severity of obstructive sleep apnea. The goal of this study is to identify and categorize obstructive sleep apnea phenotypes using unsupervised learning methods from routine PSG data. We identified four clusters from 4,603 patients by using 29 PSG variable and arranged according to their mean AHI. Cluster 1, spontaneous arousal (mean AHI = 8.52/h); cluster 2, poor sleep and periodic limb movements (mean AHI = 12.16/h); cluster 3, hypopnea (mean AHI = 38.60/h); and cluster 4, hypoxia (mean AHI = 69.66/h). Conventional obstructive sleep apnea classification based on apnea-hypopnea index severity showed no significant difference in cardiovascular or cerebrovascular mortality (Log rank P = 0.331), while 4 clusters showed an overall significant difference (Log rank P = 0.009). The risk of cardiovascular or cerebrovascular mortality was significantly increased in cluster 2 (hazard ratio = 6.460, 95% confidence interval 1.734-24.073) and cluster 4 (hazard ratio = 4.844, 95% confidence interval 1.300-18.047) compared to cluster 1, which demonstrated the lowest mortality. After adjustment for age, sex, body mass index, and underlying medical condition, only cluster 4 showed significantly increased risk of mortality compared to cluster 1 (hazard ratio = 7.580, 95% confidence interval 2.104-34.620). Phenotyping based on numerous PSG parameters gives additional information on patients' risk evaluation. Physicians should be aware of PSG features for further understanding the pathophysiology and personalized treatment.
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http://dx.doi.org/10.1038/s41598-020-70039-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411028PMC
August 2020

Double-Blind Placebo-Controlled Trial of Bepotastine Salicylate in Patients With Allergic Rhinitis.

Laryngoscope 2021 03 31;131(3):E702-E709. Epub 2020 Jul 31.

Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University College of Medicine, Seoul, South Korea.

Objectives/hypothesis: To evaluate the efficacy and safety of a slow-release form of bepotastine salicylate (HL151, Belion CR) in patients with perennial allergic rhinitis (PAR).

Study Design: Double-blind, placebo-controlled multicenter comparative study.

Methods: Two hundred seventy-two PAR patients (aged 19-65 years) were studied to determine the efficacy and safety of HL151 (20 mg once daily administration) relative to those of a placebo in terms of improvements in total and nasal symptom scores. The subjects were randomized to the placebo (n = 138) or HL151 group (n = 134, 20 mg orally once daily for 4 weeks), and reflective and instantaneous total nasal symptom scores (TNSS) were measured daily in comparison with baseline. Among 272 subjects, 229 subjects (119 in the placebo group, 110 in the HL151 group) who completed the study were included for efficacy analysis.

Results: Instantaneous and reflective TNSS and nasal symptoms such as rhinorrhea, nasal itching, and sneezing at 2 and 4 weeks showed that HL151 was superior to the placebo (all P < .05). There were no significant differences in terms of adverse events and adverse drug reactions between the two groups. Regarding serious adverse events, there was only one case of acute hepatitis B, which was reported not to be associated with HL151.

Conclusions: This multicenter trial showed that once-daily use of HL151 is efficacious and safe in adult patients with PAR and could improve compliance due to its convenience.

Level Of Evidence: 1b Laryngoscope, 131:E702-E709, 2021.
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http://dx.doi.org/10.1002/lary.28906DOI Listing
March 2021

Early Response of Specific IgE can Predict Satisfaction with Sublingual Immunotherapy.

Laryngoscope 2021 03 20;131(3):467-472. Epub 2020 Jun 20.

Department of Otorhinolaryngology, Seoul National University College of Medicine, Seoul, South Korea.

Objective: To investigate predictive parameters at baseline and during the early response to sublingual immunotherapy (SLIT) for house dust mites in allergic rhinitis patients.

Study Design: Retrospective cohort study.

Methods: Patients were treated with SLIT for at least 3 years and serological tests performed at baseline and at 1-year follow-up to investigate predictive parameters. Satisfaction with SLIT, 4 nasal symptoms, and quality of life were evaluated before and after 3 years of SLIT. Sixty-one patients were enrolled and divided into two groups depending on their satisfaction after 3 years of SLIT: 43 were satisfied (70.5%) and 18 were not (29.5%).

Results: Immunological parameters at baseline did not differ significantly between the satisfactory and unsatisfactory groups. However, changes in both Dermatophagoides pteronyssinus (Dp)- and D. farinae (Df)-specific IgEs were significantly higher in the unsatisfactory group than in the satisfactory group during the early response to SLIT (P = .006 and P = .045, respectively).

Conclusion: The changes in both Dp- and Df-specific IgE levels during early response may be indicators for favorable long-term treatment outcomes with SLIT. These results suggest that clinicians could measure these immunological parameters 1 year after Dp and Df SLIT to indicate potential responders versus nonresponders.

Level Of Evidence: 2b Laryngoscope, 131:467-472, 2021.
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http://dx.doi.org/10.1002/lary.28762DOI Listing
March 2021

House Dust Mite Sublingual Immunotherapy in Children Versus Adults With Allergic Rhinitis.

Am J Rhinol Allergy 2021 Jan 13;35(1):9-16. Epub 2020 Jun 13.

Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University College of Medicine, Seoul, Korea.

Background: There are only a few studies in which the clinical efficacy of SLIT has been compared between children and adults. In addition, there is a lack of research on other factors, associated with the treatment, including immunological parameters and quality of life (QOL).

Objective: To compare the effects of sublingual immunotherapy (SLIT) in adults and children on various factors: clinical efficacy, quality of life (QOL), satisfaction, immunological parameters, and adverse events.

Methods: Subjects who were sensitized to house dust mites and treated with SLIT for at least 2 years were enrolled. Seventy patients who completed questionnaires measuring nasal symptoms and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores and underwent serologic tests for immunological parameters at initial, 1-year, and 2-year follow-up were selected and divided into two groups based on age: a child group (age 4-12 years, n = 44) and an adult group (age 19-59 years, n = 26).

Results: The Total Nasal Symptom Score (TNSS) was significantly decreased after 2 years of SLIT in both the child and adult groups (, both); however, changes in TNSS from baseline did not significantly differ between the two groups (). More patients in adult group were satisfied with SLIT than those in child group (), and changes in RQLQ score from baseline tended to be larger in adult group (). The levels of immunological parameters at baseline were significantly higher in the child group than in the adult group; however, changes in the levels of these parameters were not significantly different.

Conclusion: Although more adult patients were satisfied with SLIT, the clinical effects of SLIT on nasal symptoms were comparable between child and adult groups. Despite different immunological values at baseline between the two groups, changing patterns of immunological parameters did not differ.
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http://dx.doi.org/10.1177/1945892420931713DOI Listing
January 2021

Characteristics of Obstructive Sleep Apnea Patients With a Low Body Mass Index: Emphasis on the Obstruction Site Determined by Drug-Induced Sleep Endoscopy.

Clin Exp Otorhinolaryngol 2020 Nov 29;13(4):415-421. Epub 2020 Apr 29.

Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.

Objectives: This study aimed to elucidate the patterns of upper airway collapse in obstructive sleep apnea (OSA) patients with a low body mass index (BMI).

Methods: We designed and conducted a retrospective cohort study. Consecutive patients diagnosed with OSA who underwent drug-induced sleep endoscopy (DISE) were included. Patients were classified into four groups according to their BMI. Age, sex, and polysomnography data were investigated. The patterns of upper airway collapse were characterized by the structures involved (soft palate, tongue base, lateral pharyngeal wall, and epiglottis). We compared the patterns of upper airway collapse in the supine and lateral decubitus position among the four BMI groups using the chi-square test and multivariate binary logistic regression analysis.

Results: A total of 627 patients (male, 517; mean age, 47.6±12.8 years) were included, consisting of 45, 79, 151, and 352 patients who were underweight or lower normal-weight (defined as the low BMI group), upper normal-weight, overweight, and obese, respectively. Severity indicators of OSA, such as the overall apnea-hypopnea index and duration of SaO2 below 90%, were significantly lower in patients with a low BMI than in obese patients, while their average oxygen saturation was significantly higher. The most common obstruction site in the supine position was the tongue base in patients with a low BMI (100%), whereas this obstruction site was significantly less common in obese patients (54.8%). Tongue base obstruction was mostly relieved in the lateral position, with no discernible obstruction in 86.7% of the low BMI patients.

Conclusion: Airway obstruction in OSA patients with a low BMI is mostly due to tongue base obstruction, which improves in the lateral position. These characteristics should be kept in mind when considering treatment options for this subgroup of OSA patients.
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http://dx.doi.org/10.21053/ceo.2019.00794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669311PMC
November 2020

Partial resection of hypertrophic torus tubarius for recurred snoring: Case series.

Medicine (Baltimore) 2020 Mar;99(10):e19329

Department of Otorhinolaryngology-Head and Neck Surgery, Chungbuk National University College of Medicine, Chungbuk National University Hospital, Cheongju, Korea.

Sleep-disordered breathing symptoms may recur in some children after successful adenoidectomy. A potential etiology that warrants consideration is torus tubarius hypertrophy (TTH) as well as residual or recurrent adenoid hypertrophy. Here, we report our experience and the treatment outcomes with microscopic coblator-assisted partial resection of TTH.Seven children who had undergone coblator-assisted partial resection of TTH under microscopy from April 2000 through January 2017 were retrospectively reviewed. The patient age at the time of initial adenotonsillectomy and the interval between the first operation and partial resection of TTH were identified. Lateral cephalometry and scores on the Korean version of the obstructive sleep apnea-18 (KOSA-18) questionnaire were reviewed.The median age at the time of the first operation was 3.0 years and the average time interval between the first operation and subsequent tubal tonsillectomy was 44.0 months. The average width between the torus tubarius was 2.1 mm preoperatively. Symptoms of sleep-disordered breathing were relieved in all patients after operation. Preoperative and postoperative KOSA-18 scores were 73.5 and 35.5, respectively (P = .024). On polysomnography, the preoperative and postoperative apnea-hypopnea index scores were 22.9 and 4.7, respectively (P = .068). The patients were followed up for an average of 1.3 years. One patient developed a recurrence of symptoms and underwent a revision operation. Complications such as bleeding and nasopharyngeal stenosis were not observed.Otorhinolaryngologists should keep TTH in mind as one of the differential diagnoses for recurrent upper airway obstruction symptoms after adenoidectomy. Microscopic coblator-assisted partial resection of TTH is likely to be safe and effective.
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http://dx.doi.org/10.1097/MD.0000000000019329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478779PMC
March 2020

Age-associated changes in chronic rhinosinusitis endotypes.

Clin Exp Allergy 2020 05 28;50(5):585-596. Epub 2020 Feb 28.

Department of Otorhinolaryngology-Head and Neck Surgery, Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea.

Background: Immunologic function in innate and adaptive immunity changes with the ageing process. Thus, age-related cytokine profiles in chronic rhinosinusitis (CRS) need to be investigated for precision medicine.

Objective: The objective of this study was to characterize age-related changes in immunologic profiles according to CRS subtypes.

Methods: Subjects in control (n = 29), CRS without nasal polyps (CRSsNP, n = 86), and CRS with nasal polyps (eosinophilic NP: ENP, n = 81; non-eosinophilic NP: NENP, n = 113) were enrolled in this study. Twenty markers for type 1/2/3 inflammation and other inflammatory processes were measured in homogenates of sinonasal tissues and statistically analysed.

Results: In control tissues, type 2/3 and proinflammatory mediators showed an inverse correlation with age. CRSsNP and NENP showed an age-related increase in type 2 cytokines and a decline in type 3 cytokines. Interestingly, the age-related decrease in type 3 mediators was associated with those of CT scores in NENP. ENP showed an age-related increase in type 3 cytokines with type 2 mediators sustained at high levels. Smokers with ENP demonstrated age-associated increases in type 1/2/3 mediators as well as CT scores. These age-related patterns in each CRS were confirmed by statistically adjusting atopy status, smoking history, and disease duration.

Conclusion: Age-associated cytokine changes differed among CRS subtypes and control tissues. CRSsNP and NENP demonstrated a decline in type 3 mediators and increase in type 2 mediators, whereas type 3 mediators increased with age in ENP.
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http://dx.doi.org/10.1111/cea.13586DOI Listing
May 2020

The clinical efficacy of relocation pharyngoplasty to improve retropalatal circumferential narrowing in obstructive sleep apnea patients.

Sci Rep 2020 02 7;10(1):2101. Epub 2020 Feb 7.

Department of Otorhinolaryngology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea.

Lateral pharyngeal wall appears to be a critical culprit of obstructive sleep apnea (OSA) subjects and relocation pharyngoplasty has been expected to be a promising surgical option to correct retropalatal circumferential narrowing in OSA patients. The purpose of our study is to evaluate the therapeutic outcomes of relocation pharyngoplasty and its clinical effectiveness in OSA patients with retropalatal circumferential narrowing. We performed relocation pharyngoplasty combined with nasal surgery in 133 OSA patients with the following characteristics: apnea-hypopnea index (AHI) over 10, retropalatal circumferential narrowing greater than grade I when awake, and redundant soft tissue around the lateral pharyngeal wall. The analysis of surgical success rate was performed with the data of 68 subjects who underwent pre and postoperative polysomnography. The objective success rate of relocation pharyngoplasty was 52.9%, and significant reduction of mean AHI with improvement of lowest SpO2 was seen in 69% of patients 3 months after the surgery. The median AHI was decreased from preoperative 37.3 to postoperative 21.4. Median lowest SpO2 changed from 78.4 to 84.1%. Total sleep time, daytime sleepiness, and visual analogue scale for snoring showed improvement as well. Postoperative complications including pain or bleeding were minimal in 133 subjects and a few patients complained of subtle taste loss. Our data demonstrate that relocation pharyngoplasty can be a favorable surgical option fighting against retropalatal circumferential narrowing.
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http://dx.doi.org/10.1038/s41598-020-58920-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005705PMC
February 2020

Clinical Characteristics Other Than Intralesional Hyperdensity May Increase the Preoperative Diagnostic Accuracy of Maxillary Sinus Fungal Ball.

Clin Exp Otorhinolaryngol 2020 May 2;13(2):157-163. Epub 2019 Nov 2.

Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.

Objectives: This study aimed to evaluate the clinical characteristics of maxillary sinus fungus ball (MFB) to increase the preoperative diagnostic accuracy.

Methods: A retrospective review of 247 patients who underwent endoscopic sinus surgery for unilateral maxillary sinusitis from January 2015 to December 2017 at a single institution was performed. Patients with pathologically proven MFB were compared to those with unilateral chronic maxillary sinusitis (CMS). Patient demographics and computed tomography (CT) findings were evaluated. The CT features were categorized as intralesional hyperdensity (calcification), the irregular lobulated protruding lesion (fuzzy appearance), maxillary sinus full haziness without mass effect, maxillary sinus full haziness with mass effect, and others. A regression tree analysis was performed.

Results: In total, 247 patients were analyzed; among them, 179 (72.5%) had MFB and 68 (27.5%) had CMS. MFB showed predominance in older individuals. Among the radiological features, intralesional hyperdensity was most commonly associated with MFB. The presence of a fuzzy appearance or full opacity with mass effect was also associated with MFB. The highest area under the curve was noted with the regression tree analysis based on the model, which included the presence of intralesional hyperdensity, demographic data (age), and presence of fuzzy appearance or maxillary sinus full haziness with mass effect in case of absence of intralesional hyperdensity (0.904).

Conclusion: A simple algorithm to optimize the preoperative diagnosis of MFB was developed. Physicians should be aware of such findings in the management of patients presenting with unilateral CMS.
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http://dx.doi.org/10.21053/ceo.2019.00836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248610PMC
May 2020

The Role of NF-κB in Chronic Rhinosinusitis With Nasal Polyps.

Allergy Asthma Immunol Res 2019 Nov;11(6):806-817

Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Purpose: Whereas the majority of nasal polyps observed in Western populations are eosinophilic, non-eosinophilic nasal polyps are significantly more frequent in Asian countries. Given the importance of nuclear factor-kappa B (NF-κB) in inflammation, this study focused on the role of NF-κB in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNPs) in Asian patients.

Methods: A total of 46 patients were enrolled in this study (22 diagnosed with CRSwNPs, 10 with chronic rhinosinusitis without nasal polyps [CRSsNP], and 14 control subjects). Nasal polyps and uncinate tissues (UTs) were collected and the tissues prepared for hematoxylin-eosin staining and immunohistochemistric (IHC) analysis. Total RNA was isolated for real-time polymerase chain reaction for p65, interleukin (IL)-6, IL-8, intracellular adhesion molecule (ICAM)-1, IL-1β, tumor necrosis factor (TNF)-α, and eotaxin.

Results: In the CRSwNPs group, 50% of nasal polyps were non-eosinophilic. IHC revealed a significantly higher fraction of NF-κB p65-positive cells in nasal polyps of the CRSwNPs group than in the UTs of control and CRSsNP groups. No difference in NF-κB p65-positive cell fraction was observed between eosinophilic and non-eosinophilic nasal polyps. The mRNA expression of p65, IL-6, IL-8, and eotaxin was significantly higher in nasal polyps of the CRSwNPs than in the UTs of control and CRSsNP group. However, no difference in expression was observed between eosinophilic and non-eosinophilic nasal polyps, with the exception of IL-1β expression.

Conclusions: Elevated expression of NF-κB- and NF-κB-associated inflammatory cytokines suggests NF-κB as the key factor for CRSwNPs pathogenesis in Asian patients. Understanding NF-κB-associated mechanisms will provide a deeper insight into CRSwNPs pathogenesis and ultimately improve therapeutic strategies for CRSwNPs.
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http://dx.doi.org/10.4168/aair.2019.11.6.806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761067PMC
November 2019

Does new sensitization correlate with nasal symptoms in children with allergic rhinitis?

Laryngoscope 2020 08 28;130(8):1864-1871. Epub 2019 Aug 28.

Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University College of Medicine, Seoul, Korea.

Objectives: To evaluate the correlation between the increased number of sensitized allergens and nasal symptoms in patients with allergic rhinitis who were sensitized to house dust mites (HDMs).

Methods: Among the patients who were enrolled in the Allergic Rhinitis Cohort Study for Kids, 174 children with rhinitis symptoms who were sensitized to HDMs were included in the analysis. Skin prick tests, serum total immunoglobulin E, eosinophil count, and bronchial provocation tests were carried out during the initial and 3-year follow-up visits. The patients were divided into two groups depending on the change in the number of sensitized allergens: increased number of sensitized allergens (group I) and maintained or reduced number of sensitized allergens (group II).

Results: In the analysis of allergen sensitization from baseline to the 3-year follow-up, no significant correlation was observed between the changes in the number of allergens and the total nasal visual analog scale score (R  < 0.001, P = .813). Furthermore, the comparison of demographic data and immunological factors between groups I and II did not show any significant differences. The changes in bronchial hyper-responsiveness were not significantly different between the two groups (P = 1.000).

Conclusion: New sensitization may not be correlated with nasal symptoms in patients in Asian countries where HDMs play a major role as a dominant allergen. Although further investigation must be conducted, the importance of new sensitization as an indicator of treatment outcome should be reconsidered in individuals in Asia.

Level Of Evidence: 2b Laryngoscope, 130: 1864-1871, 2020.
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http://dx.doi.org/10.1002/lary.28267DOI Listing
August 2020

Association of metabolic syndrome with the incidence of hearing loss: A national population-based study.

PLoS One 2019 26;14(7):e0220370. Epub 2019 Jul 26.

Department of Otorhinolaryngology-Head and Neck surgery, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Korea.

Background & Aims: Sensorineural hearing loss (HL) is one of the most common public health problems, and its prevalence increases with increasing life expectancy. An association between HL and metabolic syndrome (MetS) is suspected. Although previous epidemiological studies have investigated the association between the two variables, there have been conflicting conclusions. Therefore, we aimed to evaluate the association between the presence of MetS-and individual components of MetS-and HL, using a longitudinal design and a large-scale population.

Methods: A total of 17,513,555 individuals who underwent national health screening between January 2009 and December 2010 were identified. Subject data from the Korean Health Insurance Review and Assessment Service were reviewed. A total of 11,457,931 subjects were ultimately included in the analysis. Baseline comorbidities were defined according to the ICD-10 code from the Korean Health Insurance Review and Assessment Service data. If the participants had an ICD-10 code for HL during the follow-up, they were defined as having incident HL. Criteria for MetS adhered to the revised National Cholesterol Education Program Adult Treatment Panel III.

Results: There were 7,574,432 subjects without MetS and 3,883,499 with MetS. The incidence of HL in subjects without MetS and with MetS was 1.3% and 1.8% at 1 year, 4.1% and 5.2% at 3 years, and 6.8% and 8.6% at 5 years, respectively (P < 0.001). However, multivariate analyses revealed a negative association. Analyses according to the components of MetS demonstrated a positive association for those associated with dyslipidemia; however, the others exhibited an inverse association with HL. We also performed analyses using 4 groups according to the presence of MetS and the components of dyslipidemia. Univariate analysis revealed a positive association between the presence of MetS and HL; however, multivariate analysis revealed a positive association between the presence of dyslipidemia components and HL, regardless of the presence of MetS.

Conclusion: Among the components of MetS, the association between low HDL or high TG levels and HL was most apparent. It is useful to evaluate each MetS component in isolation, such as the presence of low HDL or high TG levels, rather than the presence of MetS as a cluster of components.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220370PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660075PMC
February 2020

Immunological Characteristics in Refractory Chronic Rhinosinusitis with Nasal Polyps Undergoing Revision Surgeries.

Allergy Asthma Immunol Res 2019 Sep;11(5):664-676

Department of Otorhinolaryngology-Head and Neck Surgery, Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea.

Purpose: Despite medical and surgical treatments, some cases of nasal polyps (NP) exhibit recidivism. However, the endotype of refractory chronic rhinosinusitis with NP (CRSwNP) remains unclear. Therefore, the objective of this study was to characterize the immunological profile of refractory CRSwNP.

Methods: The control (n =23), primary NP group (pNP, n =70) and refractory NP group (rNP, n =86) were enrolled in this study. Patients who underwent revision surgeries due to failed maximal medical treatment after primary surgery were defined as the rNP group. A total of 18 inflammatory markers were investigated in nasal tissues using multiplex cytokine assay or enzyme-linked immunosorbent assay.

Results: The clinical characteristics of rNP included more extensive disease and worse clinical course after surgery. Additionally, rNP subjects showed higher infection rate (mucopurulence and culture-positive rate), more frequent use of antibiotics and suffered from symptomatic bacterial infection, increased asthma morbidity compared to pNP. Cytokine profile analysis showed that levels of Th17-associated mediators (myeloperoxidase, interleukin (IL)-8, IL-17A and IL-23), B-cell activating factor (BAFF) and Th1 cytokine (interferon-γ) were up-regulated in rNP compared to controls and pNP. Human neutrophil elastase-positive cells were also enhanced in rNP compared with pNP. Upregulation of Th17/Th1mediators and BAFF were observed in rNP, regardless of tissue eosinophilia or asthmatic comorbidity. Interestingly, eosinophilic markers, such as eosinophil cationic protein and C-C motif chemokine ligand 24, were up-regulated in asthmatic rNP compared to pNP and controls. Levels of anti-dsDNA immunoglobulin (Ig) G and IgA were up-regulated in rNP and highest in asthmatic eosinophilic rNP among subtypes of rNP.

Conclusions: Our results suggest that Th17/Th1-associated mediators and BAFF may play a role and be a potential therapeutic target in refractory CRSwNP. Additionally, eosinophilic markers and autoantibodies may contribute to refractoriness in asthmatic rNP.
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http://dx.doi.org/10.4168/aair.2019.11.5.664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658403PMC
September 2019

Early-Life Environmental Factors Can Increase the Risk of Allergic Rhinitis.

Clin Exp Otorhinolaryngol 2019 Aug 8;12(3):239-240. Epub 2019 Jul 8.

Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

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http://dx.doi.org/10.21053/ceo.2019.00689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635708PMC
August 2019

Association between Sleep Duration and Chronic Rhinosinusitis among the Korean General Adult Population: Korea National Health and Nutrition Examination Survey.

Sci Rep 2019 05 9;9(1):7158. Epub 2019 May 9.

Department of Otorhinolaryngology-Head and Neck Surgery, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, South Korea.

An association between sleep duration and a wide spectrum of diseases has been reported, but little is known about its relationship with chronic rhinosinusitis (CRS). The present study aimed to investigate whether sleep duration was associated with CRS after adjusting for potential confounding factors in Korean adults. We analyzed data from the Korea National Health and Nutrition Examination Survey 2005-2009 and enrolled 24,658 participants aged ≥20 years. Data regarding sociodemographic characteristics, self-reported sleep duration, CRS, and other medical diseases were collected from questionnaires. Multiple logistic regression analyses were used to identify the relationship between sleep duration and CRS. The overall prevalence of CRS was 4.4%. Subjects with sleep duration ≤5 hours showed a highest prevalence for CRS (6.1%), compared to subjects with longer sleep duration (p = 0.02). After adjusting for covariates (age, sex, household income, residency, dwelling type, education, depression, alcohol, allergic rhinitis, chronic otitis media, angina or myocardial infarction, asthma, chronic obstructive pulmonary disease, bronchiectasis, and gastric ulcer), the sleep duration of ≤5 hours was significantly associated with CRS (OR = 1.502; 95% CI = 1.164-1.938). Only in older subgroup (≥50 years old), shorter sleep duration (≤5 hours) showed higher odds for CRS. These results suggested that sleep duration may be negatively associated with CRS in older Korean adults.
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http://dx.doi.org/10.1038/s41598-019-43585-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509136PMC
May 2019

Long-term Breastfeeding in the Prevention of Allergic Rhinitis: Allergic Rhinitis Cohort Study for Kids (ARCO-Kids Study).

Clin Exp Otorhinolaryngol 2019 Aug 18;12(3):301-307. Epub 2019 Apr 18.

Department of Otorhinolaryngology, Seoul National University College of Medicine, Seoul, Korea.

Objectives: There is a great deal of interest in the possibility that environmental factors may influence the risk of developing allergic rhinitis (AR) in early life. We investigated the simultaneous effects of mode of delivery and duration of breastfeeding on the development of AR in children.

Methods: Data from 1,374 children participating in the Allergic Rhinitis Cohort Study for kids (ARCO-kids study) was analyzed. All subjects were divided into AR or non-allergic rhinitis (NAR) groups. Data on environmental factors, mode of delivery and duration of breastfeeding were collected using a questionnaire.

Results: Compared with short-term breastfeeding (<6 months), long-term breastfeeding (≥12 months) was significantly associated with a lower prevalence of AR (adjusted odds ratio [aOR], 0.54; 95% confidence interval [CI], 0.34 to 0.88). Children in the AR group also had a higher cesarean delivery rate than those in the NAR group (39.1% vs. 32.8%, P=0.05). Regarding the combined effects of mode of delivery and duration of breastfeeding, long-term breastfeeding with a vaginal delivery strongly suppressed the development of AR, compared to short-term breastfeeding with a cesarean delivery (aOR, 0.47; 95% CI, 0.30 to 0.73).

Conclusion: Long-term breastfeeding (≥12 months) and a vaginal delivery are associated with a lower risk of developing childhood AR.
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http://dx.doi.org/10.21053/ceo.2018.01781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635702PMC
August 2019

Recovery period of sinonasal quality of life and its associated factors after endoscopic endonasal approach for anterior skull base tumors.

Acta Otolaryngol 2019 May 26;139(5):461-466. Epub 2019 Feb 26.

d Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Republic of Korea.

Background: Although endoscopic endonasal approach (EEA) for skull base tumors showed a good prognosis in sinonasal quality of life (QOL), what factors have influence on QOL is still in question. Aim/Objectives: To investigate the recovery of sinonasal QOL after EEA for anterior skull base tumors and find its prognostic factors.

Material And Methods: The study enrolled 250 patients undergoing EEA for anterior skull base tumors over 3 years. Sinonasal QOL was evaluated via sinonasal outcome test (SNOT-22) during 6 months. Age, gender, previous surgery, surgical extent, tumor pathology, combined surgical procedures, and surgical complications were analyzed.

Results: There were 101 male and 149 female with average 48.6 ± 16.1 years old. SNOT-22 increased from baseline (median 17.0; Q-Q 8.25-30.0) to postoperative 1 and 3 months (27.0; 15.0-36.0; p   <   .001 and 20.5; 11.0-32.0; p = .021, respectively) and it returned to the baseline within 6 months. Reconstruction with calcium hydroxyapatite and postoperative mucosal edema had a negative impact on the recovery (p  = .016 and .010, respectively), after adjustment for the baseline scores and postoperative months.

Conclusions And Significance: Sinonasal QOL was recovered within 6 months. Avoidance of calcium hydroxyapatite could prevent delayed recovery. Surgeons should carefully manipulate nasal mucosa to minimize postoperative mucosal edema.
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http://dx.doi.org/10.1080/00016489.2019.1574982DOI Listing
May 2019

The IFN-γ-p38, ERK kinase axis exacerbates neutrophilic chronic rhinosinusitis by inducing the epithelial-to-mesenchymal transition.

Mucosal Immunol 2019 05 25;12(3):601-611. Epub 2019 Feb 25.

Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.

Chronic rhinosinusitis (CRS) is a heterogeneous and multifactorial inflammatory disease characterized by involvement of diverse types of inflammatory cells. Asian CRS patients frequently show infiltration of neutrophils and an elevated level of interferon (IFN)-γ; by contrast, western patients exhibit eosinophil infiltration and enhanced levels of Th2-related cytokines. Neutrophilia in tissues decreases sensitivity to corticosteroids, but the mechanisms underlying the progression of neutrophilic CRS are unclear. In this study, we investigated the role of IFN-γ in CRS patients with marked neutrophil infiltration. We report that the IFN-γ level is upregulated in the tissues of these patients, particularly those with non-eosinophilic nasal polyps. The level of IFN-γ was significantly correlated with markers of the epithelial-to-mesenchymal transition (EMT). We further demonstrated that IFN-γ induced the EMT via the p38 and extracellular signal-regulated kinase (ERK) pathways in a manner distinct from the hypoxia-inducible factor (HIF)-1α, SMAD, and NF-κB signaling pathways. In a murine nasal polyp (NP) model, blocking the p38 and ERK signaling pathways prevented NP formation and chemotactic cytokine secretion by neutrophils but not eosinophils. Taken together, our results suggest that IFN-γ can induce the EMT in nasal epithelial cells, and thus blocking the p38 and ERK pathways could be an effective therapeutic strategy against neutrophil-dominant CRS.
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http://dx.doi.org/10.1038/s41385-019-0149-1DOI Listing
May 2019

The Prognostic Value of Albumin-to-Alkaline Phosphatase Ratio before Radical Radiotherapy in Patients with Non-metastatic Nasopharyngeal Carcinoma: A Propensity Score Matching Analysis.

Cancer Res Treat 2019 Oct 29;51(4):1313-1323. Epub 2019 Jan 29.

Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea.

Purpose: We first analyzed the prognostic power of albumin-to-alkaline phosphatase ratio (AAPR) before radical radiotherapy (RT) in non-metastatic nasopharyngeal carcinoma (NPC) patients.

Materials And Methods: The records of 170 patients with biopsy-proven, non-metastatic NPC treated by radical RT between 1998 and 2016 at our institution were retrospectively reviewed. Median follow-up duration was 50.6 months. All patients received intensity-modulated RT and cisplatin based chemotherapy before, during, or after RT. The major treatment of patients was based on concurrent chemoradiotherapy (92.4%). The AAPR was calculated by the last value of both albumin and alkaline phosphatase within 1 month immediately preceding RT. The optimal cut-off level of AAPR was determined by using Cutoff Finder, a web-based system. Propensity score matching (PSM) analysis was performed.

Results: The optimal cut-off level of AAPR was 0.4876. After PSM analysis of whole cohort, an AAPR was not related to survival outcomes. In PSM analysis for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC), an AAPR ≥ 0.4876 was related to better overall survival (OS), progression-free survival (PFS), and locoregional relapse-free survival (LRRFS) (OS: hazard ratio [HR], 0.341; 95% confidence interval [CI], 0.144 to 0.805; p=0.014; PFS: HR, 0.416; 95% CI, 0.189 to 0.914; p=0.029; and LRRFS: HR, 0.243; 95% CI, 0.077 to 0.769; p=0.016, respectively).

Conclusion: The AAPR, inexpensive and readily derived from a routine blood test, could be an independent prognostic factor for patients with LA-NPC. And it might help physicians determine treatment plans by identifying the patient's current status. Future prospective clinical trials to validate its prognostic value are needed.
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http://dx.doi.org/10.4143/crt.2018.503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790835PMC
October 2019

Intranasal Treatment With 1, 25-Dihydroxyvitamin D3 Alleviates Allergic Rhinitis Symptoms in a Mouse Model.

Allergy Asthma Immunol Res 2019 Mar;11(2):267-279

Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Purpose: Vitamin D is a potent immunomodulator. However, its role in the pathogenesis of allergic rhinitis is unclear.

Methods: The aim of this study was to evaluate the antiallergic effect of intranasally applied vitamin D in an allergic rhinitis mouse model. BALB/c mice were intraperitoneally sensitized with ovalbumin (OVA) and alum before they were intranasally challenged with OVA. Then, they were intranasally administered 1, 25-dihydroxyvitamin D3 (0.02 μg) or solvent. Allergic symptom scores, eosinophil infiltration, cytokine mRNA levels (interleukin [IL]-4, IL-5, IL-10, IL-13 and interferon-γ) in the nasal tissue, and serum total immunoglobulin E (IgE) and OVA-specific IgE, IgG1, and IgG2a were analyzed and compared with negative and positive control groups. Cervical lymph nodes (LNs) were harvested for flow cytometry analysis and cell proliferation assay.

Results: In the treatment group, allergic symptom scores, eosinophil infiltration, and mRNA levels of IL-4 and IL-13 were significantly lower in the nasal tissue than in the positive control group. The IL-5 level, serum total IgE, and OVA-specific IgE and IgG1 levels decreased in the treatment group; however, the difference was not significant. In the cervical LNs, CD86 expression had been down-regulated in CD11c⁺major histocompatibility complex II-high (MHCII) in the treatment group. Additionally, IL-4 secretion in the lymphocyte culture from cervical LNs significantly decreased.

Conclusions: The results confirm the antiallergic effect of intranasal 1,25-dihydroxyvitamin D3. It decreases CD 86 expression among CD11c⁺MHCII cells and T-helper type 2-mediated inflammation in the cervical LNs. Therefore, topically applied 1,25-dihydroxyvitamin D3 can be a future therapeutic agent for allergic rhinitis.
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http://dx.doi.org/10.4168/aair.2019.11.2.267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340801PMC
March 2019

Immunologic modification in mono- and poly-sensitized patients after sublingual immunotherapy.

Laryngoscope 2019 05 13;129(5):E170-E177. Epub 2018 Dec 13.

Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University College of Medicine, Seoul, Korea.

Objectives/hypothesis: To compare immunologic modification and treatment outcomes after 2 years of sublingual immunotherapy (SLIT) with house dust mite extracts (HDM) between monosensitized and polysensitized patients with allergic rhinitis.

Study Design: Retrospective cohort study.

Methods: Among the patients who were prospectively enrolled in the SLIT cohort study, patients with allergic rhinitis who were sensitized to HDM and treated with SLIT for at least 2 years were studied. All participants underwent serologic tests at baseline and after SLIT to evaluate changes in immunologic parameters. The total nasal symptom score (TNSS) was measured before and after SLIT, and effective and less effective responder groups were categorized depending on whether patients had a TNSS reduction of 50%, as compared with baseline.

Results: The increase in Dermatophagoides pteronyssinus and Dermatophagoides farinae specific immunoglobulin G4 levels was significantly higher in monosensitized patients than in polysensitized patients (P = .020 and P = .005, respectively). The TNSS significantly improved after SLIT in both the monosensitized and polysensitized groups (P < .001 in both groups). However, the difference in the changes in TNSS from baseline was not significant between the two groups (P = .374).

Conclusions: This study demonstrated different immunologic modifications after SLIT between monosensitized and polysensitized patients. However, patients in the polysensitized group who were treated with single-allergen SLIT experienced clinical improvement in TNSS that was comparable with that in the monosensitized group despite demonstrating different immunologic changes.

Level Of Evidence: 2b Laryngoscope, 129:E170-E177, 2019.
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http://dx.doi.org/10.1002/lary.27721DOI Listing
May 2019

Probable Roles of Coagulation Cascade and Fibrinolysis System in the Development of Allergic Rhinitis.

Am J Rhinol Allergy 2019 Mar 6;33(2):137-144. Epub 2018 Dec 6.

3 Department of Otorhinolaryngology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea.

Background: Dysregulation of the coagulation cascade and fibrinolysis system may play an etiologic role in many diseases. Allergic diseases such as bronchial asthma, atopic dermatitis, and conjunctivitis are also associated with fibrin accumulation caused by a change in hemostasis. However, only a few studies have dealt with the relationship between allergic rhinitis (AR) and the coagulation system.

Objective: We investigated the difference of coagulation and fibrinolysis cascade components between an AR mouse model and a control mice.

Methods: BALB/c mice were sensitized and challenged with ovalbumin. Multiple parameters of coagulation cascade and fibrinolysis system such as factors II, V, VII, X, and XIII; tissue-type plasminogen activator; urokinase-type plasminogen activator (u-PA); plasminogen activator inhibitor-1 (PAI-1); and fibrin were compared between the AR model group and the control group.

Results: The symptom scores and eosinophil counts were higher in the AR group than in the control group ( P < .01). The mRNA expression level of u-PA ( P = .040) was significantly lower, and the expression levels of factor II ( P = .038) and factor X ( P = .036) were significantly higher, in the AR group. Immunohistochemical staining revealed that most of the fibrinolysis system and coagulation cascade components were localized to the epithelium, endothelium, and submucosal glands of the nasal mucosa. u-PA was downregulated in the AR group, whereas fibrin deposition was more prominent in the AR group than in the control group.

Conclusion: In AR, particular components of the coagulation cascade were increased and fibrinolysis system was decreased compared to normal control. This difference may be associated with the fibrin deposition in the mucosa of AR mouse model.
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http://dx.doi.org/10.1177/1945892418816015DOI Listing
March 2019