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Kei Hosoya,1 Taro Komachi,2,* Katsunori Masaki,3,* Isao Suzaki,4 Hidehisa Saeki,5 Naoko Kanda,6 Makoto Nozaki,7 Yosuke Kamide,8 Yoshinori Matsuwaki,9 Yoshiki Kobayashi,10 Eriko Ogino,11 Shin-Ichi Osada,12 Norihiro Usukura,13 Toshikazu Kurumagawa,14 Junya Ninomia,15 Mikiya Asako,16 Keitaro Nakamoto,17 Hidenori Yokoi,18 Manabu Ohyama,19 Keiji Tanese,3 Sho Kanzaki,3 Koichi Fukunaga,3 Motohiro Ebisawa,8 Kimihiro Okubo13 1Nippon Medical School, Musashi Kosugi Hospital, Kanagawa, Japan; 2Department of Otolaryngology, Nippon Medical School, Chiba Hokusoh Hospital, Inzai, Chiba, Japan; 3Keio Allergy Center, Keio University Hospital, Tokyo, Japan; 4Department of Otorhinolaryngology, Head and Neck Surgery, Showa University, School of Medicine, Tokyo, Japan; 5Department of Dermatology, Nihon Medical School, Tokyo, Japan; 6Department of Dermatology, Nippon Medical School, Chiba Hokusoh Hospital, Inzai, Chiba, Japan; 7Wakaba-Hifuka Clinic, Tokyo, Japan; 8National Hospital Organization Sagamihara National Hospital, Clinical Research Center for Allergy and Rheumatology, Kanagawa, Japan; 9Matsuwaki Clinic Shinagawa, Tokyo, Japan; 10Allergy Center, Kansai Medical University, Hirakata, Japan; 11Kyoto Nose and Allergy Clinic, Kyoto, Japan; 12Department of Dermatology, Nippon Medical School Tama Nagayama Hospital, Tokyo, Japan; 13Department of Otolaryngology, Head and Neck Surgery, Nippon Medical School Hospital, Tokyo, Japan; 14Minamiosawa Medical Plaza, Tokyo, Japan; 15Nagase Clinic of Dermatology, Tokyo, Japan; 16Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University, Osaka, Japan; 17Department of Respiratory Medicine, Kyorin University Faculty of Medicine, Tokyo, Japan; 18Department of Otolaryngology, Head and Neck Surgery, Kyorin University Faculty of Medicine, Tokyo, Japan; 19Department of Dermatology, Kyorin University Faculty of Medicine, Tokyo, Japan*These authors contributed equally to this workCorrespondence: Kei Hosoya, Nippon Medical School, Musashi Kosugi Hospital, 1-383 Kosugimachi, Nakahara-ku, Kawasaki, Kanagawa, 211-8533, Japan, Tel +81-44-733-5181, Fax +81-44-711-8713, Email s00-073@nms.ac.jpPurpose: The status of dupilumab self-injection at home is not well understood. We therefore aimed to identify the barriers to adherence to dupilumab self-injection.Patients and Methods: This non-interventional open-label study was conducted between March 2021 and July 2021. Patients with atopic dermatitis, bronchial asthma, and chronic rhinosinusitis with nasal polyps receiving dupilumab, from 15 sites, were requested to complete a self-administered questionnaire regarding the frequency and effectiveness of dosing as well as their use and satisfaction with dupilumab. Barriers to adherence were assessed using the Adherence Starts with Knowledge-12.Results: We included 331 patients who used dupilumab for atopic dermatitis (n = 164), chronic rhinosinusitis with nasal polyps (n = 102), and bronchial asthma (n = 65). The median efficacy of dupilumab scored 9.3 on the visual analog scale. Overall, 85.5% of the patients self-injected dupilumab, and 70.7% perfectly complied with the established injection dates. The pre-filled pen was significantly superior to the conventional syringe in terms of usability, operability, ease of pushing the plunger, and patient satisfaction. However, the pre-filled pen caused more pain during self-injection than did the syringe. Multivariate logistic regression analysis showed that adherence decreased with longer dupilumab treatment duration (p = 0.017) and was not associated with age, sex, underlying disease, or device type. There was a difference in responses related to “inconvenience/forgetfulness” between the good and poor adherence groups.Conclusion: The pre-filled dupilumab pen was superior to the syringe in terms of usability, operability, ease of pushing the plunger, and satisfaction. Repetitive instructions are recommended for preventing poor adherence to dupilumab self-injection.Keywords: atopic dermatitis, biologics, bronchial asthma, chronic rhinosinusitis

Purpose of Review: Chronic rhinosinusitis (CRS) is a heterogeneous condition, so personalized treatment based on each patient's pathophysiology is essential, rather than a one-size-fits-all approach. Drug therapy for CRS has evolved significantly in recent years with the introduction of biologics, necessitating a reconsideration of the role of low-dose and long-term administration of a 14-membered ring macrolide (macrolide therapy) in the treatment of CRS. Recent research on the mechanisms of macrolide therapy and its proper use may assist physicians in improving patients' quality of life and reducing disease burden., Recent Findings: A classification of the pathogenesis of CRS based on endotype has been proposed, with type 2 inflammation playing a particularly important role as a refractory factor. Macrolide therapy improves CRS via immunomodulatory and anti-inflammatory effects rather than antimicrobial action, and it is expected to be effective in patients with neutrophil-dominant inflammation., Summary: Understanding the effectiveness and limitations of macrolide therapy is critical for making the best treatment decisions, especially when combined with surgery and other pharmacologic therapies. Therefore, selecting appropriate patients for macrolide therapy is critical for achieving adequate therapeutic efficacy., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: This randomised, double-blind, placebo-controlled, parallel-group, 52-week Phase III study (MERIT; NCT04607005) assessed mepolizumab efficacy and safety in patients with chronic rhinosinusitis with nasal polyps (CRSwNP)/eosinophilic CRS (ECRS) in Japan, Russia, and China, for which data are limited., Methodology: Eligible patients (enrolled at 60 centres) had blood eosinophil count >2%, endoscopic bilateral NP score ≥5, nasal obstruction visual analogue scale (VAS) score >5, ≥2 sinonasal symptoms, and either previous sinus surgery or systemic corticosteroid use/intolerance. Patients were randomised (1:1) to receive mepolizumab 100 mg subcutaneously or placebo every 4 weeks, plus standard of care. Co-primary endpoints: change from baseline in total endoscopic NP score (ENPS) (Week 52) and nasal obstruction VAS score (Weeks 49-52). Post hoc analyses conducted in a modified intent-to-treat (mITT) population excluded patients from two study sites, related to Good Clinical Practice violations by the Site Management Organisation overseeing these sites. These were considered the primary efficacy analyses., Results: In the mITT population, mepolizumab (n=80) versus placebo (n=83) significantly improved nasal obstruction VAS score from baseline to Week 49-52 and was associated with a trend of total ENPS improvements at Week 52. Mepolizumab/placebo on-treatment adverse events (AEs) occurred in 68/84 and 65/85 patients in the safety population (treatment-related AEs: 2/84 and 5/85, respectively), and on-treatment serious AEs in 0/84 and 4/85 patients, respectively (no fatalities reported)., Conclusions: Mepolizumab was effective and well-tolerated in patients with CRSwNP/ECRS from Japan, Russia, and China.

Seasonal allergic rhinitis caused by Japanese cedar pollen (SAR-JCP) is a serious social problem in Japan, affecting 38.8% of the population (1). Omalizumab, a recombinant humanised monoclonal anti-immunoglobulin (Ig)E antibody, reduces serum-free IgE levels by 84-99% (2). The reduction of serum-free IgE levels induced by omalizumab ultimately downregulates FcεRI expression in basophils and mast cells (3). Omalizumab significantly reduces nasal symptoms and improves the quality of life in patients with allergic rhinitis (4,5); however, other than a decrease in free IgE, its biomarker activity is unclear. Allergic rhinitis reactions are more pronounced in nasal secretions and mucosa than in serum; however, no studies have examined the changes in proteins in nasal secretions after omalizumab administration. In this study, we aimed to elucidate the pathophysiology of the effect of omalizumab. This may serve as a basis for the identification of new biomarkers through the examination of proinflammatory proteins in nasal secretions, which may reflect the pathophysiology more accurately than peripheral blood.

Objective: Primary ciliary dyskinesia (PCD) is a relatively rare genetic disorder that affects approximately 1 in 20,000 people. Approximately 50 genes are currently known to cause PCD. In light of differences in causative genes and the medical system in Japan compared with other countries, a practical guide was needed for the diagnosis and management of Japanese PCD patients., Methods: An ad hoc academic committee was organized under the Japanese Rhinologic Society to produce a practical guide, with participation by committee members from several academic societies in Japan. The practical guide including diagnostic criteria for PCD was approved by the Japanese Rhinologic Society, Japanese Society of Otolaryngology-Head and Neck Surgery, Japanese Respiratory Society, and Japanese Society of Pediatric Pulmonology., Results: The diagnostic criteria for PCD consist of six clinical features, six laboratory findings, differential diagnosis, and genetic testing. The diagnosis of PCD is categorized as definite, probable, or possible PCD based on a combination of the four items above. Diagnosis of definite PCD requires exclusion of cystic fibrosis and primary immunodeficiency, at least one of the six clinical features, and a positive result for at least one of the following: (1) Class 1 defect on electron microscopy of cilia, (2) pathogenic or likely pathogenic variants in a PCD-related gene, or (3) impairment of ciliary motility that can be repaired by correcting the causative gene variants in iPS cells established from the patient's peripheral blood cells., Conclusion: This practical guide provides clinicians with useful information for the diagnosis and management of PCD in Japan., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: Dupilumab, an anti-interleukin-4 receptor alpha monoclonal antibody, is a new treatment for severe uncontrolled chronic rhinosinusitis with nasal polyps. However, data on the effect of dupilumab on histological changes in nasal polyp tissue are lacking. We aimed to investigate the effect of dupilumab on real-life clinical conditions and nasal polyp tissues from patients with eosinophilic chronic rhinosinusitis (ECRS), which is a refractory subtype., Methods: We conducted an open-label, prospective, observational, single-centre study on 63 patients with refractory ECRS on the basis of the criteria of the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis Study. These patients had a history of surgery and received dupilumab for 24 weeks. Patient-reported sinonasal symptoms, T&T olfactometry and nasal polyp scores were prospectively evaluated. In 23 patients with residual nasal polyps following dupilumab treatment, changes in systemic and local periostin expression, and total collagen deposition in nasal polyp tissues were investigated before and after dupilumab administration., Results: Dupilumab rapidly improved sinonasal symptoms and reduced the nasal polyp score 24 weeks after initiation. 40 (63.5%) patients had resolution of nasal polyps, but the reduction was limited in the remaining 23 (36.5%) patients. Periostin expression in serum and nasal lavage fluid was decreased, whereas periostin and the total collagen deposition area in subepithelial tissues in residual nasal polyps were enhanced after dupilumab administration., Conclusion: Dupilumab improves sinonasal symptoms and reduces the nasal polyp score in refractory ECRS. Periostin-associated tissue fibrosis may be involved in the differential effect of dupilumab on nasal polyp reduction., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Sublingual immunotherapy is a widely used treatment, and serious adverse reactions such as anaphylaxis are rare. We report two cases of laryngeal edema as adverse reactions to sublingual immunotherapy, which could be continued due to a change in the administration method. Case 1 presents a 15-year-old male suspected to have had anaphylaxis due to the dust at the age of 6 years. He started treatment with Miticure ® and developed laryngeal edema 30 minutes after taking the 10000JAU dose on the 10th day. laryngeal edema was treated with intravenous infusion. Case 2 presents a 48-year-old woman. She started treatment with Cidacure ® and developed respiratory distress and laryngeal edema 1 hour after taking the 5000JAU dose on the 5th day. she had resolved mildly without therapeutic intervention. In both cases, the patients were switched to sublingual spitting, resumed with the initial dose cautiously, and were able to continue. Sublingual immunotherapy is a safe treatment, but sudden adverse reactions may occur. Laryngeal symptoms may be treated by changing to the sublingual spitting method, but laryngeal findings should be examined, and the dosage should be carefully increased.

Background: Olfactory dysfunctions (OD) and taste dysfunctions (TD) are widely recognized as characteristic symptoms of COVID-19; however, the frequency and mode of occurrence has varied depending on the viral mutation. The prevalence and characteristics of OD/TD in Japan have not been definitively investigated. The purpose of this study is to assess the prevalence of OD/TD in Japan during the Alpha variant epidemic, and measure symptom prolongation at 6 months and 1 year later following initial infection., Methods: Patients treated for COVID-19 between February to May 2021 were evaluated for OD/TD symptoms and provided with a QOL questionnaire. Olfactory tests and taste tests were performed using Open Essence and Taste Strips, respectively., Results: Among the 251 COVID-19 patients who participated, 119 underwent both olfactory and taste tests. Prevalence of subjective OD and TD at the time of survey was 57.8% and 40.2%, respectively. After 12 months, the prevalence fell to 5.8% for OD and 3.5% for TD. Among the OD/TD patients, 36.6% experienced parosmia, and 55.4% experienced parageusia. Prevalence of parosmia and parageusia was higher at 6 and 12 months than at the time of survey. Patients with long-lasting disease reported qualitative dysfunctions and scored significantly higher in food-related QOL problems. Most patients who were aware of their hyposmia had low scores on the olfactory test (83.1%). In contrast, only 26.7% of patients who were aware of their hypogeusia had low scores on the taste test., Conclusions: The prevalence of COVID-19-related OD and TD at the time of survey was 57.8% and 40.2%, respectively. Subjective symptoms of OD and TD persisted for one year in 5.8% and 3.5% of patients, respectively. More than half of the patients with OD or TD complained of qualitative dysfunction and a decrease in their QOL related to eating and drinking. Most patients with TD did not have true TD, but rather developed flavour disorders associated with OD. This conclusion is supported by the finding that patients with subjective OD had low scores on the olfactory test, whereas most patients with subjective TD had normal scores on the taste test.

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is a form of anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis characterized by eosinophil-rich granulomatous inflammation and small-to-medium vessel vasculitis associated with asthma, rhinosinusitis, and eosinophilia. EGPA is often difficult to distinguish from severe asthma and eosinophilic chronic rhinosinusitis (ECRS) in cases when there are no findings that suggest vasculitis. Dupilumab, an anti-IL-4Rα monoclonal antibody, is expected to be effective in eosinophilic airway inflammatory diseases, such as refractory asthma and chronic rhinosinusitis (CRS). Although transient eosinophilia and eosinophilic pneumoniae have been reported in patients with refractory asthma and CRS associated with dupilumab, few studies have examined the development of EGPA., Case Presentation: We report a case of a 61-year-old woman treated with dupilumab for refractory ECRS and eosinophilic otitis media (EOM) complicated by severe asthma. Although she had a previous history of eosinophilic pneumoniae and myeloperoxidase (MPO) ANCA positivity, there were no apparent findings of vasculitis before the initiation of dupilumab. After the second administration of dupilumab, several adverse events developed, including worsening of ECRS, EOM and asthma, and neuropathy. A blood test showed an eosoinophilia and re-elevation of MPO-ANCA levels after the administration of dupilumab. Therefore, dupilumab was discontinued owing to the development of EGPA, and prednisolone and azathioprine administration was initiated for a remission induction therapy., Conclusion: To the best of our knowledge, this is the first case report that suggests that dupilumab may directly trigger the manifestation of vasculitis in patients who were previously MPO-ANCA-positive. Although the precise mechanism of how dupilumab could trigger the development of EGPA requires further elucidation, measuring MPO-ANCA in patients with multiple eosinophilic disorders before the initiation of dupilumab might be helpful when considering the possibility of a latent EGPA. When administering dupilumab to patients with a previous history of MPO-ANCA positivity, clinicians must carefully monitor and collaborate with other specialists in the pertinent fields of study for appropriate usage., (© 2023. The Author(s).)

BACKGROUND Anosmia, which is loss of smell, is a recognized complication of coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which may persist after recovery from infection. Retronasal olfactory testing includes both subjective questionnaires and physiological tests that can be used to evaluate recovery of smell. This report presents the case of a 32-year-old man with persistent loss of smell following COVID-19 whose recovery was evaluated by retronasal olfactory testing. CASE REPORT The patient was a 32-year-old man with confirmed SARS-CoV-2 infection. He was aware of his olfactory dysfunction. Using the orthonasal test, a T&T Olfactometer 2 months after disease onset showed an olfactory threshold score of 2.2 points (mild decrease) and olfactory identification result of 3.4 points (moderate decrease). However, the retronasal intravenous olfactory test showed no response, indicating severe olfactory dysfunction. After 3 months of olfactory training and therapy with steroidal nasal drops (Fluticasone Furoate, 27.5 µg/day) and oral vitamins (Mecobalamin, 1500 µg/day), the patient's orthonasal test olfactory threshold score improved to 0.6 points (normal), and his olfactory identification result improved to 1.2 points (mild decrease). Although the retronasal intravenous olfactory test showed a weak response, a reaction did occur. At this time, the patient did not report any improvement in his symptoms. CONCLUSIONS This report has shown that in cases of persistent anosmia following COVID-19, retronasal olfactory testing can be used to evaluate recovery of the sense of smell.