Metagenomic gut microbiome analysis of Japanese patients with multiple chemical sensitivity/idiopathic environmental intolerance.

BACKGROUND: Although the pathology of multiple chemical sensitivity (MCS) is unknown, the central nervous system is reportedly involved. The gut microbiota is important in modifying central nervous system diseases. However, the relationship　between the gut microbiota and MCS remains unclear. This study aimed to identify gut microbiota variations associated with MCS using shotgun metagenomic sequencing of fecal samples. METHODS: We prospectively recruited 30 consecutive Japanese female patients with MCS and analyzed their gut microbiomes using shotgun metagenomic sequencing. The data were compared with metagenomic data obtained from 24 age- and sex-matched Japanese healthy controls (HC). RESULTS: We observed no significant difference in alpha and beta diversity of the gut microbiota between the MCS patients and HC. Focusing on the important changes in the literatures, at the genus level, Streptococcus, Veillonella, and Akkermansia were significantly more abundant in MCS patients than in HC (p < 0.01, p < 0.01, p = 0.01, respectively, fold change = 4.03, 1.53, 2.86, respectively). At the species level, Akkermansia muciniphila was significantly more abundant (p = 0.02, fold change = 3.3) and Faecalibacterium prausnitzii significantly less abundant in MCS patients than in HC (p = 0.03, fold change = 0.53). Functional analysis revealed that xylene and dioxin degradation pathways were significantly enriched (p < 0.01, p = 0.01, respectively, fold change = 1.54, 1.46, respectively), whereas pathways involved in amino acid metabolism and synthesis were significantly depleted in MCS (p < 0.01, fold change = 0.96). Pathways related to antimicrobial resistance, including the two-component system and cationic antimicrobial peptide resistance, were also significantly enriched in MCS (p < 0.01, p < 0.01, respectively, fold change = 1.1, 1.2, respectively). CONCLUSIONS: The gut microbiota of patients with MCS shows dysbiosis and alterations in bacterial functions related to exogenous chemicals and amino acid metabolism and synthesis. These findings may contribute to the further development of treatment for MCS. TRIAL REGISTRATION: This study was registered with the University Hospital Medical Information Clinical Trials Registry as UMIN000031031. The date of first trial registration: 28/01/2018.

Uncovering Severe Patient Group With Pollen-Related Extrarespiratory Allergic Symptoms: A Year-Long Diary Survey in Japan.

BACKGROUND: The most common symptoms of pollen allergy are rhinitis and conjunctivitis. However, in real-world clinical practice, we sometimes encounter patients with pollen allergy suffering from severe extrarespiratory symptoms including skin, gastrointestinal, or flu-like symptoms in relation to exposure to sensitized pollen. OBJECTIVE: To elucidate the extrarespiratory symptoms in patients with pollen allergy. METHODS: We performed a non-drug-focused prospective study of patients with pollen allergy (n = 384). During the 1-year observational period, they were asked to complete a weekly electronic diary consisting of visual analog scale (VAS) scores to assess all symptoms experienced in various organs over the past week. An association between seasonal pollen levels and seasonal increase in VAS scores was evaluated using a mixed-effects model for repeated measures. A k-means cluster analysis was performed to identify a group of patients experiencing stronger extrarespiratory symptoms. RESULTS: In patients sensitized to grass or birch pollen, higher seasonal levels of these pollen grains were associated with higher VAS scores for headache, gastrointestinal symptoms, skin symptoms, and fatigue. A cluster analysis identified a group of severe pollen-allergic patients with higher extrarespiratory symptoms (n = 42). This group was characterized by a higher frequency of comorbid food allergy/atopic dermatitis, higher rate of IgE sensitization to pollens, and higher impaired activity and work productivity. CONCLUSIONS: This 1-year survey identified a small but nonnegligible group of patients with pollen-related extrarespiratory symptoms. More attention should be paid to this patient group considering their impaired activity and work productivity.

Anisakis allergy versus gastric anisakiasis: A case of repeated Anisakis-associated symptoms.

A 53-year-old patient experienced 2 Anisakis-induced allergic episodes: the first with anaphylaxis, the second presenting with gastric symptoms and progressing to systemic anaphylaxis. The case could suggest a common pathophysiology involving allergic reactions in gastric anisakiasis and Anisakis allergy.

Clinical characteristics of allergic bronchopulmonary mycosis caused by Schizophyllum commune.

BACKGROUND: Allergic bronchopulmonary mycosis (ABPM) is an allergic disease caused by type I and type III hypersensitivity to environmental fungi. Schizophyllum commune, a basidiomycete fungus, is one of the most common fungi that causes non-Aspergillus ABPM. OBJECTIVE: Herein, we attempted to clarify the clinical characteristics of ABPM caused by S. commune (ABPM-Sc) compared with those of allergic bronchopulmonary aspergillosis (ABPA). METHODS: Patients with ABPM-Sc or ABPA were recruited from a nationwide survey in Japan, a multicenter cohort, and a fungal database at the Medical Mycology Research Center of Chiba University. The definition of culture-positive ABPM-Sc/ABPA is as follows: (1) fulfills five or more of the 10 diagnostic criteria for ABPM proposed by Asano et al., and (2) positive culture of S. commune/Aspergillus spp. in sputum, bronchial lavage fluid, or mucus plugs in the bronchi. RESULTS: Thirty patients with ABPM-Sc and 46 with ABPA were recruited. Patients with ABPM-Sc exhibited less severe asthma and presented with better pulmonary function than those with ABPA (p = 0.008-0.03). Central bronchiectasis was more common in ABPM-Sc than that in ABPA, whereas peripheral lung lesions, including infiltrates/ground-glass opacities or fibrotic/cystic changes, were less frequent in ABPM-Sc. Aspergillus fumigatus-specific immunoglobulin (Ig)E was negative in 10 patients (34%) with ABPM-Sc, who demonstrated a lower prevalence of asthma and levels of total serum IgE than those with ABPM-Sc positive for A. fumigatus-specific IgE or ABPA. CONCLUSIONS: Clinical characteristics of ABPM-Sc, especially those negative for A. fumigatus-specific IgE, differed from those of ABPA.

Leukotriene antagonists reduce epileptic seizures-related hospitalization in older adult populations with allergic rhinitis or asthma: A population-based cohort study using the Shizuoka Kokuho database: The Shizuoka study.

OBJECTIVE: Managing the risk of epileptic seizures in older adults is increasingly important as the population ages. Leukotriene receptor antagonists (LTRAs) are commonly used to treat asthma or allergic rhinitis. Preclinical studies suggest that LTRAs have antiepileptic effects; however, few population-based etiological studies on this topic have been available. Our study explored whether LTRAs reduce hospitalization risk associated with epileptic seizures in older individuals with asthma or allergic rhinitis. METHODS: We conducted a new-user design analysis using the Shizuoka Kokuho database. We included all individuals aged 60-89 years who had at least one episode of allergic rhinitis or asthma during the study period. We compared individuals who newly started LTRAs with those who did not take LTRAs. Propensity score matching was used to balance the baseline characteristics of the participants. We compared the hazard ratios for seizure-related hospitalization between new LTRA users and non-users and performed subgroup analyses. RESULTS: Our matched cohorts consisted of 64 724 new users and non-users of LTRAs who were aged 60-89 years and had asthma or allergic rhinitis. During the observation period, 377 (0.58%) and 595 (0.92%) incidents were observed in the LTRA new-user and non-user groups, respectively. The hazard ratio for seizure-related hospitalization was 0.75 (95% confidence interval [CI]: 0.62-0.92) in the LTRA new-user group compared with the non-user group. Subgroup analysis revealed that the hazard ratio was weak in diabetic patients (1.31; 95% CI: 0.72-2.38). SIGNIFICANCE: This study indicated that LTRAs reduced seizure-related hospitalization in older adult patients with allergic rhinitis or asthma. We could not evaluate the severity and related diseases of epileptic seizures during LTRAs. Further studies, including observational studies, detailed multicenter prospective studies, and clinical trials, are needed to validate these findings. PLAIN LANGUAGE SUMMARY: This study examined if leukotriene receptor antagonists (LTRAs), commonly used for asthma or allergies, could lower seizure risk in older adults. Analyzing health records of 60-89 year-olds with asthma or allergies, we found a reduced rate of seizure-related hospitalizations in those starting LTRAs, though this was not as evident in diabetic patients. Our results suggest potential benefits of LTRAs in preventing seizures in older adults with respiratory issues, but further research is needed to confirm these findings.

Serum MMP3 and IL1-RA levels may be useful biomarkers for detecting asthma and chronic obstructive pulmonary disease overlap in patients with asthma.

Background: Asthma and chronic obstructive pulmonary disease (COPD) overlap (ACO) is characterized by concurrent features of asthma and COPD. Since disease pathogenesis, severities, and treatments differ between asthma and ACO, it is important to differentiate them. Objective: To clarify and compare the characteristics of ACO and asthma and identify the serum biomarkers for differentiating them, especially in older patients. Methods: This study used the data of 639 participants from the nationwide cohort study, the NHOM-Asthma study, an asthma registry in Japan, with complete information on smoking history, respiratory function, and serum biomarkers. ACO was defined as the self-reported comorbidity of COPD or emphysema, or with obstructive pulmonary function and smoking history (pack-years≥10). The clinical characteristics of patients with ACO and asthma without COPD were compared. The serum biomarkers for differentiation were examined using receiver operating characteristic curves and multivariable analysis. The associations between the biomarkers and age were also analyzed. Results: Of the 639 asthma patients, 125 (19.6%) were diagnosed with ACO; these patients were older and male-dominant and had a higher prevalence of comorbidities such as hypertension, diabetes, and stroke. Among the serum biomarkers that were significantly different between ACO and asthma without COPD, the YKL-40/CHI3L1, MMP3, and IL-1RA levels showed a high area under the curve for discriminating ACO. Only the MMP3 and IL-1RA levels were significantly higher among ACO patients, regardless of age and sex; the YKL-40/CHI3L1 levels were not different due to the effect of age. Conclusion: MMP3 and IL-1RA may be useful serum biomarkers for distinguishing ACO from asthma.

Sensitization pattern to environmental allergens in a Japanese population.

Background: We previously described the prevalence of allergen-specific IgE in a general population of Japanese adults. Objective: We sought to elucidate allergen sensitization patterns in this population. Methods: Serum samples had been obtained from 800 blood donors aged 20 to 59 years and living in Tokyo, Japan, in 2005 and stored in the Japanese Red Cross Society. These samples were examined for IgE levels, total and specific for 23 allergens or allergen sources correlated with allergic airway diseases using the ImmunoCAP method. Exploratory and confirmatory factor analyses were performed to uncover the relationship among allergen-specific IgE based on their titers. Hierarchical cluster analysis was executed using Ward's method based on standardized factor scores identified through factor analysis. Results: Exploratory factor analysis revealed 6 categories of allergen-specific IgE: specific to 2 types of animals (insects and Dermatophagoides pteronyssinus/animal dander), 2 types of pollens (group 1 [Japanese cedar and cypress] and group 2 [alder, grass, and weeds]), and 2 types of microorganisms (fungi and commensal microorganisms on the skin). The Japanese population was categorized into 3 clusters: (A) nonatopic type, (B) house dust mite-dominant sensitization type, and (C) panatopic type. The panatopic group could be further classified into 2 subclusters positive and negative for fungal sensitization. Conclusions: This study demonstrated that a Japanese population could be divided into 3 clusters according to the sensitization pattern to 6 types of allergens.

Phenotype characterization and biomarker evaluation in moderate to severe type 2-high asthma.

BACKGROUND: There are two major pathological phenotypes of asthma, type 2 (T2)-high and T2-low asthma, which are important in determining treatment strategies. However, the characteristics and phenotypes of T2-high asthma have not yet been fully identified. OBJECTIVE: This study aimed to identify the clinical characteristics and phenotypes of patients with T2-high asthma. METHODS: This study used data from a nationwide asthma cohort study in Japan, NHOM Asthma Study. T2-high asthma was defined as a blood eosinophils count ≥ 300 /µL and/or fractional exhaled nitric oxide level ≥ 25 ppb, and the clinical characteristics and biomarkers were compared between T2-high and T2-low asthma. Furthermore, T2-high asthma was phenotyped via hierarchical cluster analysis using Ward's method. RESULTS: Patients with T2-high asthma were older, less likely to be female, had longer asthma duration, had lower pulmonary function, and had more comorbidities, including sinusitis and SAS. Patients with T2-high asthma showed higher serum thymus and activation-regulated chemokine and urinary leukotriene E4 levels and lower serum ST2 levels than those with T2-low asthma. There were four phenotypes among patients with T2-high asthma: Cluster 1 (youngest, early-onset, and atopic), Cluster 2 (long duration, eosinophilic, and low lung function), Cluster 3 (elderly, female-dominant, and late-onset), and Cluster 4 (elderly, late-onset, and asthma-COPD overlap-dominant). CONCLUSIONS: Patients with T2-high asthma have distinct characteristics and four distinct phenotypes, in which eosinophil-dominant Cluster 2 is the most severe phenotype. The present findings may be useful in precision medicine for asthma treatment in the future.

Prevalence of Allergic Diseases across All Ages in Japan: A Nationwide Cross-Sectional Study Employing Designated Allergic Disease Medical Hospital Network.

Introduction: Allergic diseases affect both children and adults, but generation-specific prevalence rates are unclear. Methods: An online questionnaire was used from December 2021 to January 2022 to survey the prevalence of allergic diseases among staff and their families of designated allergic disease medical hospitals in Japan. In this study, bronchial asthma (BA), atopic dermatitis (AD), food allergies (FAs), allergic rhinitis (AR), allergic conjunctivitis (AC), metal allergies (MAs), and drug allergies (DAs) were the allergic diseases surveyed. Results: In total, 18,706 individuals were surveyed (median age, 36 years; quartile range, 18-50). Allergic disease was reported in 62.2% of respondents. Across all ages, prevalence rates were as follows: BA (14.7%), AD (15.6%), FAs (15.2%), AR (47.4%), AC (19.5%), MAs (1.9%), and DAs (4.6%). The prevalence of BA and AR was higher in male children, whereas that of FAs and AC was higher in adult females. The prevalence of MAs and DAs peaked during adulthood and predominated among females. Conclusions: Our results suggest that approximately two-thirds of the Japanese population may have an allergic disease, with AR being the most prevalent.

Computed tomography findings of paranasal sinuses in patients with eosinophilic granulomatosis with polyangiitis: Comparison with other eosinophilic sinus diseases and clinical relevance of their severity.

BACKGROUND: Although paranasal sinuses are one of the most representative organs affected by eosinophilic granulomatosis with polyangiitis (EGPA), they have not been studied sufficiently. The aim of this study was to compare computed tomography (CT) findings in paranasal sinuses of EGPA with those of other eosinophilic sinus diseases and elucidate the clinical relevance of their severity. METHODS: CT findings of paranasal sinuses in EGPA patients prior to therapeutic intervention (n = 30) were evaluated using the Lund-Mackay staging (LMS) system and compared with those of three control diseases [(NSAID-exacerbated respiratory disease (N-ERD), aspirin-tolerant asthma, and eosinophilic chronic rhinosinusitis without asthma (ECRS)]. We divided EGPA patients into three groups based on their LMS scores and examined their association with disease manifestation. RESULTS: Total scores of the LMS system in EGPA were significantly lower than those of N-ERD and ECRS without asthma. There was a large variation in total LMS scores in EGPA, suggesting considerable heterogeneity of their sinus lesions. Although EGPA with low LMS system scores showed only minor findings in maxillary and anterior ethmoid regions, those with high LMS system scores were characterized by high scores in the ostiomeatal complex. However, the frequencies of patients with a Five-Factor Score ≥2 and with cardiac involvement were significantly higher for EGPA with low LMS system scores. CONCLUSIONS: Although paranasal sinus lesions in EGPA were less severe than those of other eosinophilic sinus diseases, their milder CT findings may be associated with a higher frequency of extra-respiratory organ involvement.

Omalizumab ameliorates extrarespiratory symptoms in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: Omalizumab, an anti-IgE antibody, has clinical efficacy against respiratory symptoms of aspirin-exacerbated respiratory disease (AERD). However, some patients with AERD also present with extrarespiratory (chest, gastrointestinal, and/or cutaneous) symptoms, which are resistant to conventional treatment but can be alleviated by systemic corticosteroids. OBJECTIVE: We evaluated the efficacy of omalizumab on extrarespiratory symptoms related to AERD. METHODS: In study 1, a total of 27 consecutive patients with AERD initially prescribed omalizumab at Sagamihara National Hospital between July 2009 and March 2019 were retrospectively studied. Frequency of exacerbations of AERD-related extrarespiratory symptoms was compared before and after omalizumab treatment. In study 2, we reported 3 AERD cases with aspirin challenge-induced extrarespiratory symptoms among patients studied in our previous randomized trial (registration UMIN000018777), which evaluated the effects of omalizumab on hypersensitivity reactions during aspirin challenge to AERD patients. Extrarespiratory symptoms induced during the aspirin challenge were compared between placebo and omalizumab phases. RESULTS: In study 1, omalizumab treatment was associated with decrease in frequency of exacerbation of chest pain (no. [%] of patients with exacerbation frequency ≥1 time per year, 6 [22.2%] vs 0; P < .001), gastrointestinal symptoms (9 [33.3%] vs 2 [7.4%]; P = .016), and cutaneous symptoms (16 [59.3%] vs 2 [7.4%]; P < .001), even under conditions of treatment-related reduction in systemic corticosteroid dose. Omalizumab also attenuated all the extrarespiratory symptoms during aspirin challenge in study 2. CONCLUSION: Omalizumab ameliorated extrarespiratory symptoms at baseline (without aspirin exposure) and during aspirin challenge.

Characterization and cluster analyses of elderly asthma in comparison with nonelderly patients with asthma in Japan.

BACKGROUND: Asthma is a heterogeneous disease with multiple phenotypes that are useful in precision medicine. As the population ages, the elderly asthma (EA, aged ≥ 65 years) population is growing, and EA is now a major health problem worldwide. OBJECTIVE: To characterize EA and identify its phenotypes. METHODS: In adult patients with asthma (aged ≥ 18 years) who had been diagnosed with having asthma at least 1 year before study enrollment, 1925 were included in the NHOM-Asthma (registered in UMIN-CTR; UMIN000027776), and the data were used for this study, JFGE-Asthma (registered in UMIN-CTR; UMIN000036912). Data from EA and non-EA (NEA) groups were compared, and Ward's minimum-variance hierarchical clustering method and principal component analysis were performed. RESULTS: EA was characterized by older asthma onset, longer asthma duration and smoking history, more comorbidities, lower pulmonary function, less atopic, lower adherence, and more hospital admissions because of asthma. In contrast, the number of eosinophils, total immunoglobulin E level, oral corticosteroid use, and asthma control questionnaire scores were equivalent between EA and NEA. There were 3 distinct phenotypes in EA, which are as follows: EA1: youngest, late onset, short duration, mild; EA2: early onset, long duration, atopic, low lung function, moderate; and EA3: oldest, eosinophilic, overweight, low lung function, most severe. The classification factors of the EA phenotypes included the age of onset and asthma control questionnaire-6. Similarities were observed between EA and NEA phenotypes after principal component analysis. CONCLUSION: The EA in Japan may be unique because of the population's high longevity. Characterization of EA phenotypes from the present cohort indicated the need for distinct precision medicine for EA. TRIAL REGISTRATION: JFGE-Asthma registered in UMIN-CTR (https://www.umin.ac.jp/ctr/); UMIN000036912.

Classifications of moderate to severe asthma phenotypes in Japan and analysis of serum biomarkers: A Nationwide Cohort Study in Japan (NHOM Asthma Study).

BACKGROUND: Asthma is a heterogeneous disease, and phenotyping can facilitate understanding of disease pathogenesis and direct appropriate asthma treatment. This nationwide cohort study aimed to phenotype asthma patients in Japan and identify potential biomarkers to classify the phenotypes. METHODS: Adult asthma patients (n = 1925) from 27 national hospitals in Japan were enrolled and divided into Global Initiative for Asthma (GINA) steps 4 or 5 (GINA 4, 5) and GINA Steps 1, 2, or 3 (GINA 1-3) for therapy. Clinical data and questionnaires were collected. Biomarker levels among GINA 4, 5 patients were measured. Ward's minimum variance hierarchical clustering method and tree analysis were performed for phenotyping. Analysis of variance, the Kruskal-Wallis, and chi-square tests were used to compare cluster differences. RESULTS: The following five clusters were identified: 1) late-onset, old, less-atopic; 2) late-onset, old, eosinophilic, low FEV1; 3) early-onset, long-duration, atopic, poorly controlled; 4) early-onset, young, female-dominant, atopic; and 5) female-dominant, T1/T2-mixed, most severe. Age of onset, disease duration, blood eosinophils and neutrophils, asthma control questionnaire Sum 6, number of controllers, FEV1, body mass index (BMI), and hypertension were the phenotype-classifying variables determined by tree analysis that assigned 79.5% to the appropriate cluster. Among the cytokines measured, IL-1RA, YKL40/CHI3L1, IP-10/CXCL10, RANTES/CCL5, and TIMP-1 were useful biomarkers for classifying GINA 4, 5 phenotypes. CONCLUSIONS: Five distinct phenotypes were identified for moderate to severe asthma and may be classified using clinical and molecular variables (Registered in UMIN-CTR; UMIN000027776.).

Identification of asthma cases in Japan using health insurance claims data: Positive and negative predictive values of proposed discrimination criteria: A single-center study.

BACKGROUND: Asthma cases have been increasingly investigated using claims data. However, the validity of defining asthma cases using health insurance claims in Japan is unclear. This study aims to assess the positive and negative predictive values of our proposed discrimination criteria for asthma. METHODS: We developed discrimination criteria for asthma based on both the International Statistical Classification of Diseases and Related Health Problems (ICD)-10 disease codes for asthma and health insurance claims data for prescriptions and the treatment of asthma. Inclusion criteria were patients aged ≥16 years with at least one health insurance claim from April 2018 to March 2019 in all departments of our hospital. Physician-diagnosed asthma documented in the charts was used as the reference standard. Positive and negative predictive values of the discrimination criteria for physician-diagnosed asthma were estimated and compared with those estimated from discrimination criteria based solely on ICD-10 codes. RESULTS: The new discrimination criteria had a high positive predictive value (PPV) of 86.0%, which was significantly higher than the PPV for the criteria defined solely by the ICD-10 codes (61.5%) (P < 0.01). The negative predictive values for both criteria were 100%. Allergic rhinitis and chronic cough were frequently misclassified as asthma using the discrimination criteria based solely on ICD-10 codes but were more likely to be appropriately classified using our proposed criteria. CONCLUSIONS: Our proposed criteria adequately identified asthma subjects using health insurance claims data in Japan with a high PPV. Further studies are needed for external validation of these criteria.

Frailty and muscle weakness in elderly patients with asthma and their association with cumulative lifetime oral corticosteroid exposure.

BACKGROUND: Frailty is a geriatric syndrome of age-related physiological decline, which is associated with higher mortality and decreased healthy life expectancy, and muscle weakness is one of the presentations of frailty. We investigated an association between lifetime oral corticosteroid (OCS) exposure with frailty and muscle weakness among elderly patients with asthma. METHODS: We studied 203 consecutive elderly outpatients with asthma aged ≥60 years old. They were classified into three groups according to their cumulative lifetime OCS dose (lifetime non-users, lower-dose users, and higher-dose users), which was retrospectively estimated from the response to a structured questionnaire. The prevalence of frailty determined by the Kihon Checklist was compared between the three groups. Hand-grip strength, and lean mass index were also measured as markers of muscle strength. RESULTS: Thirty-seven percent of the patients studied were considered frail. Higher cumulative lifetime OCS exposure was associated with a significantly higher prevalence of frailty (33% in lifetime non-users, 59% in lower-dose users, and 68% in higher-dose users; P for trend <0.005). This was also associated with lower hand-grip strength in both sexes (P for trend; 0.012 in men, and 0.020 in women), and lower lean mass index in men (P for trend 0.002). However, current doses of OCS were not significantly associated with these outcomes. CONCLUSIONS: Cumulative lifetime OCS exposure was associated with a higher prevalence of frailty and muscle weakness. These findings emphasize the importance of minimizing lifetime OCS exposure for the prolongation of healthy life expectancy in patients with asthma.