Practical guide for the diagnosis and management of primary ciliary dyskinesia.

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.

Executive summary: Japanese guidelines for allergic rhinitis 2020.

The Practical Guideline for the Management of Allergic Rhinitis, the fist guideline for allergic rhinitis in Japan, was prepared after a symposium held by the Japanese Society of Allergology in 1993. The current 9th edition was published in 2020 and is widely used today. The most recent collection of evidence from the literature was supplemented to the revised guideline to incorporate evidence-based medicine. The revised guideline includes updated epidemiology of allergic rhinitis in Japan, a figure representing the mechanisms of allergic rhinitis in both the onset and sensitization phases with the introduction of regulatory T cells and type 2 innate lymphoid cells, practical assessment for diagnosis, new pharmacotherapy agents such as anti-IgE mAb and a new drug delivery system for antihistamines, sublingual immunotherapy for children, dual sublingual immunotherapy for house dust mites and Japanese cedar pollen extract, new classification for surgery for allergic rhinitis, and treatment and prescriptions for older adults. An evidence-based step-by-step strategy for treatment is also described.

Surveillance of pollen-food allergy syndrome in elementary and junior high school children in Saitama, Japan.

BACKGROUND: Because few studies have epidemiologically evaluated pollen-food allergy syndrome (PFAS), relevant information about this disease is limited in children. OBJECTIVE: We wanted to clarify the epidemiological details of PFAS by creating a questionnaire which enables to distinguish class 2 food allergy from that of class 1. METHODS: We conducted a questionnaire survey for schoolchildren attending to public elementary and junior high schools. In this questionnaire, we asked about both the allergy to fruits and/or vegetables and allergic rhinitis (AR). PFAS was, then, defined as allergy for fruits and/or vegetable which occurred after the symptoms of AR appeared. RESULTS: A total of 2,346 children (median age, 10.6±2.5 years; 1,157 boys) were evaluated. The prevalence of PFAS was 6.9% among subjects. The mean ages in the onset of AR and PFAS were 4.59±2.76 and 7.38±3.17 years old, respectively. Various kinds of foods were shown to be causative, among which kiwifruits were the commonest. As high as approximately 30% of children with PFAS experienced systemic symptoms including cutaneous (21.8%) and respiratory symptoms (9.6%). Anaphylaxis was diagnosed in 5.8% children. CONCLUSION: Our results indicated that the prevalence of PFAS was getting higher and the mean age of onset was getting lower. These may be attributed to the increasing number of patients with AR and also to the lower age of onset of AR. We have to be careful to not only local but also systemic symptoms when examining children with PFAS.

Predictors of adherence to sublingual immunotherapy for Japanese cedar pollinosis: a prospective analysis.

BACKGROUND: Sublingual immunotherapy (SLIT) often has low adherence rates. OBJECTIVE: To provide effective support for SLIT continuation, we investigated potential predictors of SLIT adherence through a prospective analysis of patient characteristics. We excluded evaluation of treatment effect and symptoms during treatment, aiming instead to identify predictors of later dropout or insufficient adherence due to indolence or forgetfulness using only information obtained at initial examination. METHODS: We provided patients with a questionnaire and monitored self-reported adherence once every 6 months. Cases of dropout for clear reasons were excluded, but cases of dropout or insufficient adherence to SLIT for indolence or forgetfulness were included. RESULTS: Fifty-three patients receiving SLIT were assessed. Nine patients dropped out after providing a clear reason. Thirty-four patients maintained good adherence. Seven patients continued SLIT but with insufficient adherence, while three patients discontinued SLIT for unclear reasons (indolence or forgetfulness) and these ten individuals were classified as the poor-adherence group. Univariate analysis and multivariate logistic regression analysis of the good-adherence and poor-adherence groups showed age to be a significant predictor of SLIT adherence. Based on analysis of a receiver operating characteristic curve, age < 40.5 years was selected as the optimal cutoff value for predicting poor adherence to SLIT. CONCLUSIONS: To prevent treatment SLIT discontinuation on account of indolence or forgetfulness, the necessity of longterm treatment continuity should be communicated clearly prior to commencing treatment, especially for patients under 40 years of age.

Effectiveness of Glecaprevir/Pibrentasvir for Hepatitis C: Real-World Experience and Clinical Features of Retreatment Cases.

Glecaprevir/pibrentasvir (G/P) are direct-acting antivirals (DAAs) that achieve a high sustained virological response (SVR) rate for hepatitis C virus (HCV) infection. We investigated G/P effectiveness for HCV patients based on real-world experience and the clinical features of retreatment cases. HCV patients (n = 182) were compared for clinical features and outcomes between first treatment (n = 159) and retreatment (n = 23) G/P groups. Overall, 77 patients (42.3%) were male, the median age was 68 years, and 86/66/1/4 cases had genotype 1/2/1+2/3, respectively. An SVR was achieved in 97.8% (178/182) of cases by intention-to-treat analysis and 99.4% (178/179) of cases by per-protocol analysis. There were no remarkable differences between the first treatment and retreatment groups for male (42.8% vs. 39.1%, p = 0.70), median age (68 vs. 68 years, p = 0.36), prior hepatocellular carcinoma (5.8% vs. 8.7%, p = 0.59), or the fibrosis markers AST-to-platelet ratio index (APRI) (0.5 vs. 0.5, p = 0.80) and fibrosis-4 (FIB-4) index (2.2 vs. 2.6, p = 0.59). The retreatment group had a significantly more frequent history of interferon treatment (12.3% vs. 52.2%, p < 0.01) and the Y93H mutation (25.0% vs. 64.7%, p = 0.02). The number of retreatment patients who had experienced 3, 2, and 1 DAA treatment failures was 1, 3, and 19, respectively, all of whom ultimately achieved an SVR by G/P treatment. In conclusion, G/P was effective and safe for both HCV first treatment and retreatment cases despite the retreatment group having specific resistance mutations for other prior DAAs. As G/P treatment failure has been reported for P32 deletions, clinicians should consider resistance mutations during DAA selection.

Past history of hepatocellular carcinoma is an independent risk factor of treatment failure in patients with chronic hepatitis C virus infection receiving direct-acting antivirals.

Direct-acting antiviral (DAA) treatment can achieve a high sustained virological response (SVR) rate in patients with hepatitis C virus (HCV) infection regardless of a history of hepatocellular carcinoma (HCC [+]). We examined 838 patients (370 men, median age: 69 years) who were treated with DAAs for comparisons of clinical findings between 79 HCC (+) (9.4%) and 759 HCC (-) (90.6%) patients and associations with treatment outcome. Male frequency was significantly higher in the HCC (+) group (60.8% vs 42.4%, P = 0.006). There were significant differences between the HCC (+) and HCC (-) groups for platelet count (115 vs 152 ×109 /L, P < 0.001), baseline alpha fetoprotein (AFP) (9.9 vs 4.5 ng/mL, P < 0.001) and the established fibrosis markers of FIB-4 index (4.7 vs 3.0, P < 0.001), AST-to-platelet ratio index (APRI) (1.1 vs 0.7, P = 0.009), M2BPGi (3.80 vs 1.78 COI, P < 0.001) and autotaxin (1.91 vs 1.50 mg/L, P < 0.001). The overall SVR rate was 94.7% and significantly lower in the HCC (+) group (87.3 vs 95.5%, P = 0.001). Multivariate analysis revealed that a history of HCC was independently associated with DAA treatment failure (odds ratio: 3.56, 95% confidence interval: 1.32-9.57, P = 0.01). In conclusion, patients with chronic HCV infection and prior HCC tended to exhibit more advanced disease progression at DAA commencement. HCC (+) status at the initiation of DAAs was significantly associated with adverse therapeutic outcomes. DAA treatment for HCV should therefore be started as early as possible, especially before complicating HCC.

Current status of sublingual immunotherapy for allergic rhinitis in Japan.

Japanese cedar pollen (JCP) and house dust mite (HDM) are two major allergens that cause allergic rhinitis (AR) in Japan and the prevalence of AR is increasing. Pharmacothearpy is a commonly used treatment, but the level of patient satisfaction is very low. Allergen immunotherapy (AIT) is the only therapeutic modality that provides not only symptom relief but also quality of life improvement that leads to a high rate of satisfaction. In particular, sublingual immunotherapy (SLIT) is a safe and effective treatment for AR. Here we introduce a large-scale double-blind, placebo-controlled trial of SLIT in Japanese patients using JCP droplets or HDM tablets conducted in Japan. The immediate future of SLIT in Japan is also discussed.

A Very Rare Case of Hypereosinophilic Syndrome Secondary to Natural Killer/T-Cell Lymphoma.

Hypereosinophilic syndrome (HES) is a systemic disease characterized by an increased peripheral blood eosinophil count accompanied by systemic organ dysfunction. HES is classified into idiopathic HES, primary (neoplastic) HES (HESN), and secondary (reactive) HES (HESR). In this case report, a patient who developed peripheral blood eosinophilia and granulation tissue in the pharynx and paranasal sinus, which was initially diagnosed as chronic eosinophilic leukemia (CEL), categorized as HESN, but was eventually identified after the patient had died as natural killer/T-cell (NK/T) lymphoma, nasal type (ENKL), categorized as HESR, is presented. ENKL-induced HES is very rare but must be considered.

[ANALYSIS OF BACKGROUNDS AND LEVEL OF UNDERSTANDING OF TREATMENT OF POOR ADHERENCE AND DROPOUT CASES ON SUBLINGUAL IMMUNOTHERAPY FOR JAPANESE CEDAR POLLINOSIS IN THE FIRST FOLLOW-UP YEAR].

BACKGROUND: We considered the factors of poor adherence to and dropout from sublingual immunotherapy (SLIT) by verifying patient backgrounds 1 year after start of treatment. METHODS: We recruited 38 patients who began SLIT between November 2014 and September 2015. We analyzed their attributes and level of understanding of the treatment, and conducted a self-reported survey on factors behind dropout cases and poor adherence cases. RESULTS: Four patients dropped out 1 year after start of treatment. Three left for reasons related to anxiety about side effects. There were five cases of poor adherence. There was no significant difference between good adherence, poor adherence, and dropout regarding level of understanding of the treatment (p=0.59). In the comparison between good and poor adherence groups, except four dropout patients, the adherence tended to be poor in patients with short duration of disease, smoking patients, and young patients. Continuous rate of SLIT achieved about 90%, suggesting relatively high level of adherence. CONCLUSION: It appears possible that anxiety related to side effects could be a factor affecting dropout from SLIT. There was no significant difference regarding level of understanding of the treatment. The adherence tended to be poor in patients with short duration of disease, smoking patients, and young patients.

A single mouse monoclonal antibody, E58 modulates multiple IgE epitopes on group 1 cedar pollen allergens.

We recently described a dominant role for conformational epitopes on the group 1 allergen of the mountain cedar (Juniperus ashei, Cupressaceae), Jun a 1, in pollen hypersensitivity in South Central U.S.A. Since these epitopes are surface exposed and are likely to be flexible, they may be susceptible to molecular or physical perturbations. This may make Jun a 1 a potential target for new forms of therapy for cedar pollinosis. Here, we describe a mouse monoclonal antibody, termed E58, which binds to the group 1 allergens of the cedar pollens from three highly populated regions of the world (central U.S.A., France and Japan). Upon binding to these allergens, E58 strongly reduces the binding of patient's IgE antibodies to these dominant allergens. This characteristic of E58, and potentially other similar antibodies, suggests an opportunity to develop preventative or therapeutic agents that may inhibit cedar pollen sensitization or prevent their allergic reactions.

Guiding principles of sublingual immunotherapy for allergic rhinitis in Japanese patients.

OBJECTIVE: Sublingual immunotherapy (SLIT) appears to offer practical advantages for the treatment of allergic rhinitis (AR). Based on a review of the scientific literature, we present recommendations as guiding principles to administer SLIT safely. METHODS: Clinical questions concerning SLIT were prepared. Literature published between January 2003 and December 2012 was searched from PubMed, the Cochrane Library, and Japana Centra Revuo Medicina. Qualified studies were analyzed and the results were evaluated, consolidated, and codified. We answered 17 clinical questions and, based on this, presented evidence-based recommendations. RESULTS: Sublingual immunotherapy improved symptoms (e.g., quality of life [QOL]) and reduced medication scores in seasonal AR and perennial AR. Most SLIT-induced adverse effects were local oral reactions, although systemic adverse effects such as gastrointestinal symptoms, urticaria, and asthma are occasionally reported. There have been no reports of lethal anaphylactic reactions by SLIT. When SLIT is continued for 3-4 years, its effect persists long after discontinuation. CONCLUSION: A correct diagnosis of AR and sufficient informed consent from patients are required before initiating SLIT. Sublingual immunotherapy should be continued for 3 years or longer. The initial administration of SLIT during the uptitration of an allergen vaccine and the general condition of patients are critical for the safe performance of SLIT.

[Postural and Conditional Variations of Nasal Patency in Patients under General Anesthesia Approximating Sleep as Assessed with Acoustic Rhinometry].

Nasal obstruction is a known risk factor associated with obstructive sleep apnea (OSA). Multiple methods of measuring nasal abnormalities including anterior and posterior rhinomanometry and acoustic rhinometry (AR) have been used to better quantify the relationship. These measurements are usually used in the sitting and awakening situation, which differ from the situations in the supine position and while asleep. The goal of this study was to evaluate the nasal patency in patients under general anesthesia approximating sleep as assessed with AR. The nasal minimal cross-sectional area (MCSA) and nasal volume in 50 patients who underwent general anesthesia were compared with subjects in the sitting, supine, and supine position under general anesthesia using AR to measure the nasal dimensions and patency. MCSA and nasal volume decreased more significantly in the supine than in the sitting subjects and these decrements were shown more in the supine position under general anesthesia than in the supine position without anesthesia. Furthermore, regarding nasal volume, the difference between in the sitting and in the supine was larger than the difference between in the supine position with and without general anesthesia. These results suggested that the decrements regarding nasal volume under positional change were greater than those under conditional change. The positional variation can affect the airway patency hydrodynamically and these alterations indicate the relationship of the pathophysiology in patients with OSA.

Patient Background Factors Affecting the Therapeutic Outcomes in Response to Eszopiclone in Adult Patients with Chronic Insomnia: A Post Hoc Analysis of a Double-Blind Phase III Study in Japan.

STUDY OBJECTIVE: To identify whether baseline demographic factors or subjective sleep variables are associated with the outcomes following treatment with eszopiclone using data from a recent randomized controlled trial of 78 Japanese subjects with insomnia who were treated with 2 mg eszopiclone per day. METHODS: We performed a post hoc analysis of factors including sleep latency (SL), wake time after sleep onset (WASO) (both assessed via sleep diaries), and several demographic variables. Subjects with a SL or WASO > 30 min at baseline and with evaluable SL/WASO data at Week 4 were included in SL and WASO remitter analyses, respectively; those with a SL or WASO ≤ 30 min at Week 4 were defined as SL or WASO remitters, respectively. Threshold baseline SL and WASO values for identification of remitters were determined. RESULTS: No relationships between subjectively assessed therapeutic outcomes and demographic factors were identified. Patients with shorter SL and lower WASO values at baseline showed better outcomes following treatment with eszopiclone in terms of SL and WASO changes, respectively. Baseline SL of 75 min and baseline WASO of 80 min were selected as arbitrary cutoff values for determination of SL and WASO remitters/non-remitters, respectively. CONCLUSION: These findings may help clinicians to predict their patients' outcomes in response to standard doses of eszopiclone in clinical practice.

[Two cases of allergic fungal rhinosinusitis with bone destruction].

We report herein two cases of allergic fungal rhinosinusitis accompanied by bone destruction of the adjacent nasal sinuses. The first case involved a 21-year-old man who presented with left exophthalmos. Computed tomography (CT) showed soft tissue lesions in the left paranasal sinuses and destruction of the left lamina papyraceae, as well as infiltration of the lesion into the orbit. In the second case, a 39-year-old man, CT showed bone destruction of the skull base and medial wall of the left orbit. In both cases, total serum immunoglobulin (Ig)E level was >1000 IU/mL and fungus-specific IgEs were increased. Fungal hyphae were identified within the mucus on histopathological examination in both cases; however, no fungal invasion of the mucosa was apparent. Final diagnosis was allergic fungal rhinosinusitis (AFRS) in both cases. AFRS is a relatively new disease concept that was proposed in the early 1980s, with disease characteristics very similar to eosinophilic rhinosinusitis. Occasionally, AFRS must be differentiated from malignant disease or invasive fungal rhinosinusitis, so an understanding of the clinical features is important.

KIR3DL1-HLA-Bw4 combination and IL28B polymorphism predict response to Peg-IFN and ribavirin with and without telaprevir in chronic hepatitis C.

Natural killer cells play a key role in the immune control of viral infections. Killer immunoglobulin-like receptors (KIRs) regulate natural killer cell activation and inhibition through the recognition of their cognate HLA class I ligands. We assessed the predictive factors of a sustained virological response (SVR) in 200 Japanese patients with chronic genotype 1b hepatitis C who were treated with telaprevir (TVR), pegylated-interferon-α2b (PEG-IFN), and ribavirin (RBV) triple therapy (92 patients) or PEG-IFN/RBV therapy alone (108 patients). Sixteen KIR genotypes, HLA-A, -B and -C ligands, and an interleukin (IL) 28B polymorphism (rs8099917) were analyzed. We observed that triple therapy, white blood cell count, hemoglobin value, hepatitis C viral load, a rapid virological response (RVR), IL28B TT genotype, and KIR3DL1-HLA-Bw4 genotype were associated with an SVR. In multivariate regression analysis, we identified an RVR (P < 0.000001; odds ratio [OR] = 20.95), the IL28B TT genotype (P = 0.00014; OR = 5.53), and KIR3DL1-HLA-Bw4 (P = 0.004, OR = 3.42) as significant independent predictive factors of an SVR. In conclusion, IL28B and KIR3DL1/HLA-Bw4 are independent predictors of an SVR in Japanese patients infected with genotype 1b HCV receiving TVR/PEG-IFN/RBV or PEG-IFN/RBV therapy.

Guiding principles of subcutaneous immunotherapy for allergic rhinitis in Japan.

OBJECTIVE: In anticipation of the development of guidelines for antigen-specific subcutaneous immunotherapy (SCIT), we present recommendations that can serve as guiding principles based on a review of the scientific literature. METHODS: Clinical questions (CQs) concerning SCIT were prepared. Literature searches for publications between January 1990 and February 2011 were performed in PubMed, the Cochrane Library, and Japana Centra Revuo Medicina Web version 4. Qualified studies were analyzed and the results were evaluated, consolidated, and codified. RESULTS: We present answers for 13 CQs on the indications, methods, effectiveness and mechanisms of SCIT, with evidence-based recommendations. CONCLUSION: The guiding principles are intended to be applied to children (≤15 years old) and adults (≥16 years old) with allergic rhinitis (AR). These principles can be used by otorhinolaryngologists for diagnosis of AR, evaluation of severity and rhinoscopic findings, performance of antigen challenge tests, and management of systemic anaphylactic reactions associated with SCIT.

Lung functions of Japanese patients with chronic rhinosinusitis who underwent endoscopic sinus surgery.

BACKGROUND: Chronic rhinosinusitis (CRS), which is clinically classified into CRS without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP), shows considerable geographic differences and heterogeneity. Eosinophilic (E) CRS with nasal polyps (ECRSwNP) has a higher degree of disease severity and higher frequency of comorbid asthma. Epidemiologic studies in different ethnic populations have improved understanding of the pathophysiology of the disease. Here we report the clinical characteristics of Japanese patients with medically refractory CRS undergoing endoscopic sinus surgery (ESS). METHODS: We recruited a total of 210 CRS patients and assessed them by nasal endoscopy, the Lund-Mackay score using computed tomography (CT), peripheral eosinophilia and smoking status. We also examined the comorbidity of asthma, effects of age and lung functions in the patients. RESULTS: In this study, 13% of CRSwNP patients and 20% of CRSwNP patients with peripheral blood eosinophilia exhibited obstructive lung dysfunction (FEV1/FVC <70%) despite the absence of an asthma diagnosis. Among elderly nonsmoker patients (≥ 60 years) who had never been diagnosed with asthma, 50% of CRSwNP patients with peripheral blood eosinophilia showed decreased FEV1/FVC <70%. CONCLUSIONS: Our findings suggest that asthma is under-diagnosed in CRS patients who undergo ESS, especially the elderly. Although the association between CRS and asthma has been recognized, increased attention to the comorbidity of obstructive airway diseases such as asthma is still needed for management of medically refractory CRS.

[Effect of posterior nasal neurectomy combined with the inferior turbinate surgery for Japanese cedar pollinosis].

INTRODUCTION: Up to 30% of the Japanese population suffers from Japanese cedar pollinosis, and some of these patients also have severe perennial allergies or other pollen allergies. Posterior nasal neurectomy has recently been reported as effective treatment for severe perennial allergic and intrinsic rhinitis. However, the efficacy of this surgery for seasonal allergic rhinitis has not been shown. In this study, the effectiveness of posterior nasal neurectomy combined with inferior turbinate surgery for patients with Japanese cedar pollinosis with concomitant intractable perennial allergies was evaluated with a questionnaire. SUBJECTS AND METHODS: Nine patients with Japanese cedar pollinosis, who also had perennial allergies, and undergone posterior nasal neurectomy combined with inferior turbinate surgery from April in 2005 to July in 2008, were enrolled. A numeric rating scale (NMR) was used to evaluate clinical symptoms in the pre- and post-surgery periods. The frequency of medication (oral administration and nasal spray) during the cedar pollinosis season was also evaluated. RESULTS: The NMR scores for all nasal and eye symptoms during cedar pollinosis season were significantly reduced after the surgery. The frequency of medication during the season was dramatically decreased after surgery. CONCLUSION: The present study demonstrates that posterior nasal neurectomy combined with inferior turbinate surgery is a highly effective treatment for Japanese cedar pollinosis. Since the Japanese cedar pollinosis season is limited to 2 to 3 months, such surgery is indicated for patients who suffer from severe perennial allergies and are also sensitized to some allergens such as Japanese cedar and ragweed pollen.

Five adult laryngeal venous malformation cases treated effectively with sclerotherapy.

OBJECTIVES/HYPOTHESIS: Laryngeal venous malformation is a comparatively rare condition in adults. It presents as a livid or bluish mass that may cause bleeding, hoarseness, stridor, and even difficulty in breathing. So far, treatment has largely consisted of laser therapy and surgical removal. Five cases of adult laryngeal venous malformations that were treated by sclerotherapy (local injection of monoethanolamine oleate solution) are reported. All lesions disappeared after one or two treatment sessions, and two of the five cases that presented recently were cured in the outpatient clinic setting with no sequelae. Sclerotherapy with monoethanolamine oleate is a safe, easy, and effective treatment for laryngeal venous malformations.