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.

Circulating extracellular vesicles are associated with pathophysiological condition including metabolic syndrome-related dysmetabolism in children and adolescents with obesity.

Obesity of children and adolescents (OCA) is often accompanied by metabolic syndrome (MetS), which often leads to adult obesity and subsequent complications, yet the entire pathophysiological response is not fully understood. The number and composition of circulating extracellular vesicles (EV) reflect overall patient condition; therefore, we investigated the pathophysiological condition of OCA, including MetS-associated dysmetabolism, using circulating EVs. In total, 107 children and adolescents with or without obesity (boys, n = 69; girls, n = 38; median age, 10 years) were enrolled. Circulating EV number and EV protein composition were assessed via flow cytometry and liquid chromatography tandem-mass spectrometry, respectively. In a multivariate analysis, relative body weight (standardized partial regression coefficient (SPRC) 0.469, P = 0.012) and serum triglyceride level (SPRC 0.548, P < 0.001) were detected as independent parameters correlating with circulating EV number. Proteomic analysis identified 31 upregulated and 45 downregulated EV proteins in OCA. Gene ontology analysis revealed upregulated proteins to be involved in various biological processes, including intracellular protein transport, protein folding, stress response, leukocyte activation, innate immune response, and platelet degranulation, which can modulate lipid and glucose metabolism, skeletal and cardiac muscle development, inflammation, immune response, carcinogenesis, and cancer progression. Notably, several identified EV proteins are involved in neuro-development, neurotransmitter release, and neuro-protective agents in OCA. Circulating EVs were derived from adipocytes, hepatocytes, B cell lymphocytes, and neurons. Circulating EV number is significantly associated with MetS-related dysmetabolism and the EV protein cargo carries a special "signature" that reflects the alteration of various biological processes under the pathophysiological condition of OCA. KEY MESSAGES: Circulating EV number correlates with physical and laboratory parameters for obesity in children and adolescents. Relative body weight and triglyceride are independent factors for increased circulating EVs. EV composition is significantly changed in obesity of children and adolescents. Identified EV composition changes associated with obesity and involves in metabolism, immune response, and cancer progression. Circulating EVs are partially derived from adipocyte, hepatocytes, B cells, and neurons.

Insights from the trends of omalizumab and mepolizumab utilization in patients with asthma: A population-based cohort study using the National Database in Japan.

BACKGROUND: Biologics are increasingly being used in patients with severe uncontrolled asthma. However, the trends in their use for treating severe asthma in Japan remain unclear. METHODS: The number of patients with asthma prescribed omalizumab or mepolizumab between April 2017 and March 2018 was estimated according to sex, age, and geographical region using data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan. RESULTS: Overall, 5,014, 3,449 and 7,977 patients were prescribed omalizumab, mepolizumab, or either combination, respectively. The total number of patients prescribed biologics displayed a bimodal distribution with peaks in their early teens and seventies. Biologics were most commonly used by male and female patients in their seventies. Prescription was 1.24 times higher in males than in females up to the teenage years, whereas it was 1.95 times higher in females than in males from their twenties onwards. Omalizumab was prescribed 1.45 times more frequently than mepolizumab, especially in pediatric patients, and was prescribed 1.96 times more often to female patients than to male patients. Regional differences were observed in the proportion of patients prescribed biologics. Correlation analysis suggested a weak relationship (r = 0.3226, p = 0.0270) between the proportion of patients prescribed biologics and board-certified allergists according to the geographic region. CONCLUSIONS: In Japan, biologics are prescribed more often to older patients with severe asthma compared to those in other countries. Thus, eliminating the regional disparities in asthma treatment by specialists is necessary to provide appropriate medical care to patients with severe asthma.

Evaluation of adrenaline auto-injector prescription profiles: A population-based, retrospective cohort study within the National Insurance Claims Database of Japan.

BACKGROUND: Adrenaline is the first-line medication for managing anaphylaxis. A better understanding of prescription trends for adrenaline auto-injectors (AAIs) is important to improving patient care as well as information on health education interventions and medical guidelines. However, it has been difficult to gather comprehensive data in a sustainable manner. Thus, we aimed to investigate trends in AAI prescriptions in Japan. METHODS: We searched the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB), a unique and comprehensive database of health insurance claims, and investigated prescriptions for AAIs for all ages (April 2017 to March 2018). We assessed the annual number of prescriptions per person as well as prescription rates per 100,000 population per year by age, sex, and geographic region. RESULTS: A total of 88,039 subjects (56,109 males, 31,930 female) and 116,758 devices (1.33 AAIs per patient per year) were prescribed AAIs at least once a year for all ages. The prescription rate for AAIs was 69.5 per 100,000 population-years. Patients aged 0-9 years were prescribed AAIs at the rate of 278.9 per 100,000 population-years. Patients aged 0-19 years were 6.4 times more likely to be prescribed AAIs than those over 20 years of age. Males were more frequently prescribed AAIs than females in all age groups, except for those aged 20-24 years. We also evaluated differences in prescription rates by geographic region. CONCLUSIONS: This comprehensive evaluation revealed trends in AAI prescriptions, thus helping develop preventive strategies with respect to anaphylaxis in Japan.

Squamous cell carcinoma antigens are sensitive biomarkers for atopic dermatitis in children and adolescents: a cross-sectional study.

BACKGROUND: We recently reported that squamous cell carcinoma antigen 2 (SCCA2) is a reliable biomarker for atopic dermatitis (AD). OBJECTIVE: To further clarify its utility, we investigated for effects of comorbid allergies and AD treatment on serum SCCA levels. METHODS: Volunteers <18 years old were recruited through our website. Their allergic status was elucidated using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. We also recruited pediatric patients who were hospitalized because of severe AD. The serum levels of SCCA1 and SCCA2 were measured by enzyme-linked immunosorbent assays. In the severe AD patients, the levels of thymus and activation-regulated chemokine (TARC), SCCA1, and SCCA2 were measured before and after hospitalization. The severity of AD was assessed using the severity scoring of atopic dermatitis (SCORAD). RESULTS: A total of 576 participants (547 volunteers and 29 patients) were enrolled in the study. The levels of SCCA1 and SCCA2 were significantly higher in volunteers with mild AD and patients with severe AD than in healthy volunteers without allergic diseases. The levels were not elevated in those who had mild bronchial asthma or allergic rhinitis without AD. TARC, SCCA1, and SCCA2 were decreased during the treatment in severe AD patients, reflecting clinical improvement in response to treatment. Linear regression analysis for predicting a decrease in the SCORAD index showed R2 values of 0.16, 0.38, and 0.48 for TARC, SCCA1, and SCCA2, respectively. CONCLUSION: SCCAs, especially SCCA2, are sensitive biomarkers for detecting AD in children and adolescents and for assessing the severity and response to treatment of severe AD.

Factors associated with outcome of egg allergy 1 year after oral food challenge: A good baseline quality of life may be beneficial.

BACKGROUND: Safely liberalizing the diet to include an allergenic food may accelerate resolution of food allergy. The outcome of liberalization, however, varies among patients. METHODS: We conducted a prospective observational study to identify factors associated with outcome for egg allergy 1 year after oral food challenge (OFC). We enrolled children <72 months old who had egg allergy and underwent OFC for determination of the safe intake quantity of egg allergen. Each child's baseline clinical background was recorded. Caregivers used the Food Allergy Quality of Life Questionnaire-Parent Form (FAQLQ-PF) to assess their children's QoL. Dietary advice based on the OFC result was provided to support safe egg consumption. At 1 year after OFC, the quantity of egg each child safely consumed in daily life was surveyed. We classified the outcome as Successful (Group S) if the quantity increased during the 1 year, or as Unsuccessful (Group U) if it did not. Factors associated with the outcome were investigated by multivariate logistic regression analysis. RESULTS: A total of 93 children were enrolled, and after 1 year, 57 finished in Group S and 36 in Group U. The mean FAQLQ-PF score at baseline was significantly lower (ie, a better QoL) in Group S than in Group U. Multivariate logistic regression analysis identified a good QoL and absence of comorbid asthma or atopic dermatitis as factors predicting a favorable outcome. CONCLUSION: QoL may affect food allergy outcome. Intervention focusing on the QoL may promote outgrowing of food allergies.

Strategic Outlook toward 2030: Japan's research for allergy and immunology - Secondary publication.

Strategic Outlook toward 2030: Japan's Research for Allergy and Immunology (Strategy 2030) is the national research strategy based on Japan's Basic Law on Measures Against Allergic Diseases, a first of its kind worldwide. This strategy was established by a multi-disciplinary committee consisting of administrators of the Ministry of Health, Labour and Welfare of Japan, young and senior experts from various research societies and associations, and representatives of patient and public groups. Whereas the issues of transition, integration, and international collaboration have yet to be solved in this research realm in Japan, identification of unmet needs, digitization of information and transparent procedures, and strategic planning for complex problems (a process dubbed MIERUKA by the Toyota Way) are crucial to share and tackle the same vision and goals. The committee developed three specific actions focusing on preemptive treatment, interdisciplinarity and internationality, and life stage. The real success of Strategy 2030 is made by the spontaneous contributions of doctors, dentists, veterinarians, and other medical professionals; basic and clinical research scientists, research supporters, and pharmaceutical/medical device companies; manufacturers of food, healthcare, and home appliances; and patients, their families, and the public. The hope is to establish a stable society in which people can live long, healthy lives, as free as possible from allergic and immunological diseases, at each individual life stage. This article is based on a Japanese review first reported in Arerugi, introduces the developmental process and details of Strategy 2030.

Three cases of severe adolescent asthma treated with mepolizumab: lung function trajectories.

Real-world experience with mepolizumab for pediatric asthma is still limited. We report 3 patients who were treated with mepolizumab for severe adolescent asthma. Two patients, a 12-year-old boy and a 14-year-old girl, responded well to mepolizumab and showed apparent improvement in lung function from a downward trend over time before treatment. The third patient, a 16-year-old boy, whose treatment was switched from omalizumab to mepolizumab, did not have satisfactory response. The 2 successful cases had eosinophil counts of 440 and 371/µL and multiple comorbid allergic diseases including food allergies. The clinical benefit to them included elimination of both exacerbation and exercise-induced asthma. Interestingly, the boy's food-induced gastrointestinal symptoms disappeared following start of mepolizumab treatment.

Basophil Activation Test Based on CD203c Expression in the Diagnosis of Fish Allergy.

PURPOSE: The basophil activation test (BAT) has been reported to be useful for the diagnosis of various food allergies, such as allergy to peanut, but not to fish. This study aimed to evaluate the diagnostic performance of the BAT for fish allergy. METHODS: We performed a retrospective review of patients with fish allergy who underwent the BAT using a panel of fish extracts (15 kinds) to examine the differential reactivity to several species of fish. The BAT score for each extract was expressed as the ratio of CD203chigh% with the extract to that with anti-IgE antibody. Clinical reactivity to each fish was confirmed by positive oral food challenge or a typical history of fish-induced immediate allergy symptoms. Receiver-operating-characteristic (ROC) analysis was performed to evaluate the diagnostic performance. RESULTS: Fifty-one patients with fish allergy were analyzed. Using extracts of 15 species of fish, the BAT was performed a total of 184 times on the patients. Clinical allergy to each species of fish was confirmed in 90 (48.9%) of those tests. ROC analysis yielded high areas under the curve for the BAT scores for the 5 most common fish species (0.72-0.88). The diagnostic accuracy ranged from 0.74 to 0.86. Using a tentative cutoff value of 0.3 deduced from the ROC analyses of the 5 fish species, the accuracy for other fish allergic reactions was generally high (0.6-1.0), except the fish tested in a small number of patients. CONCLUSIONS: The BAT score based on CD203c expression may be useful for fish allergy diagnosis, especially since a large variety of fish can be tested by the BAT using fish extracts prepared by a simple method.

Abdominal and Thigh Muscle Attenuation Is Associated With Visceral Fat and Age in Children and Adolescents With Obesity.

Objective. This study investigated relationships between adipose tissue deposition within skeletal muscle and morphological and biochemical variables in children with obesity. Methods. Fifty-one Japanese children (16 girls) aged 7 to 16 years were assigned to either mild (<20%), moderate (≥20% to <50%), or severe obesity groups (≥50%). Computed tomography images were taken to calculate the cross-sectional area (CSA) of muscle, subcutaneous and visceral adipose tissue (VAT, for abdomen only), and muscle signal intensities, as an index of intramuscular adipose tissue in the anterior, lateral, and posterior muscles of the abdomen and quadriceps, hamstring and adductor muscles in the thigh. Fasting blood samples were collected to measure plasma lipids, glutamate oxaloacetate transaminase, glutamate oxaloacetate transaminase, uric acid, glucose, and HbA1c. Results. Signal intensity in the severe obesity group was significantly lower than mild and moderate obesity groups in the abdomen and significantly lower than the moderate obesity group in the thigh. Stepwise regression analysis with signal intensity as dependent variable revealed that VAT CSA and age in abdominal muscles and VAT CSA, age, and triglycerides in thigh muscles are predictors of signal intensities. Conclusions. These results suggest that VAT CSA and age are predictors of intramuscular adipose tissue of the abdominal and thigh in children with obesity.

ß2 adrenergic agonist suppresses eosinophil-induced epithelial-to-mesenchymal transition of bronchial epithelial cells.

BACKGROUND: Epithelial-mesenchymal transition is currently recognized as an important mechanism for the increased number of myofibroblasts in cancer and fibrotic diseases. We have already reported that epithelial-mesenchymal transition is involved in airway remodeling induced by eosinophils. Procaterol is a selective and full ß2 adrenergic agonist that is used as a rescue of asthmatic attack inhaler form and orally as a controller. In this study, we evaluated whether procaterol can suppress epithelial-mesenchymal transition of airway epithelial cells induced by eosinophils. METHODS: Epithelial-mesenchymal transition was assessed using a co-culture system of human bronchial epithelial cells and primary human eosinophils or an eosinophilic leukemia cell line. RESULTS: Procaterol significantly inhibited co-culture associated morphological changes of bronchial epithelial cells, decreased the expression of vimentin, and increased the expression of E-cadherin compared to control. Butoxamine, a specific ß2-adrenergic antagonist, significantly blocked changes induced by procaterol. In addition, procaterol inhibited the expression of adhesion molecules induced during the interaction between eosinophils and bronchial epithelial cells, suggesting the involvement of adhesion molecules in the process of epithelial-mesenchymal transition. Forskolin, a cyclic adenosine monophosphate-promoting agent, exhibits similar inhibitory activity of procaterol. CONCLUSIONS: Overall, these observations support the beneficial effect of procaterol on airway remodeling frequently associated with chronic obstructive pulmonary diseases.

Montelukast suppresses epithelial to mesenchymal transition of bronchial epithelial cells induced by eosinophils.

Epithelial to mesenchymal transition (EMT) is a mechanism by which eosinophils can induce airway remodeling. Montelukast, an antagonist of the cysteinyl leukotriene receptor, can suppress airway remodeling in asthma. The purpose of this study was to evaluate whether montelukast can ameliorate airway remodeling by blocking EMT induced by eosinophils. EMT induced was assessed using a co-culture system of human bronchial epithelial cells and human eosinophils or the eosinophilic leukemia cell lines, Eol-1. Montelukast inhibited co-culture associated morphological changes of BEAS-2b cells, decreased the expression of vimentin and collagen I, and increased the expression of E-cadherin. Montelukast mitigated the rise of TGF-ß1 production and Smad3 phosphorylation. Co-culture of human eosinophils with BEAS-2B cells significantly enhanced the production of CysLTs compared with BEAS-2B cells or eosinophils alone. The increase of CysLTs was abolished by montelukast pre-treatment. Montelukast had similar effects when co-culture system of Eol-1 and BEAS-2B was used. This study showed that montelukast suppresses eosinophils-induced EMT of airway epithelial cells. This finding may explain the mechanism of montelukast-mediated amelioration of airway remodeling in bronchial asthma.

Differential activation of eosinophils by bacteria associated with asthma.

BACKGROUND: It has been suggested that there is a complex interaction between microbiota and various human diseases. Some bacteria have been reported to be involved in the inception and progression of asthma, and others in the protection against asthma. We know very little about the mechanisms by which bacteria do harm or good with regard to asthma. This study investigated whether bacteria exert differential effects on the functions of eosinophils, major effector cells in airway inflammation in asthma. METHODS: Eosinophils were purified from healthy adult volunteers by Percoll density gradient centrifugation and negative immunomagnetic bead selection using anti-CD16 microbeads. Three kinds of heat-killed bacteria that have been implicated in asthma, namely Staphylococcus aureus (SA), Haemophilus influenzae (HI) and a Prevotella sp. (PS), were tested for their effects on the secretion of eosinophil-derived neurotoxin (EDN), the generation of superoxides and the production of cytokines/chemokines. RESULTS: SA, but not HI or PS, induced significant EDN release in a dose-dependent manner. Superoxide generation was significantly enhanced by each of the bacterial species, but most strongly by SA, which induced significantly greater TNF-α production by eosinophils than either HI or PS. Conversely, interleukin 10, an anti-inflammatory cytokine, was more strongly induced by HI and PS than by SA. CONCLUSIONS: Bacteria exert differential effects on eosinophils. Based on these results, SA may be involved in the exacerbation of, and HI and PS in the inhibition of, eosinophilic inflammation in asthma.