BACKGROUND:Elderly asthma has distinct pathophysiologic and phenotypic characteristics compared with asthma in younger patients. However, a potential relationship between sex hormones and the severity of asthma remains unknown in the elderly population. The aim of the present study was to elucidate the relationship between the level of circulating free testosterone and severity of asthma among Japanese with elderly asthma. METHODS:The level of free testosterone was measured using sera from elderly patients with asthma aged ≥60 years (n = 192), and its association with the severity of asthma was examined after stratification by sex. RESULTS:Based on previous literature and our preliminary analysis showing that current oral corticosteroid (OCS) use might be a risk factor for a lower free testosterone level regardless of severity of asthma, analyzed patients were limited to those who were not currently using OCS (n = 164). Regarding elderly men who were not currently using OCS (n = 62), there was no significant association between free testosterone level and severity of asthma. However, in female counterparts (n = 102), a low free testosterone level was significantly associated with severe asthma even after adjustment for age (p for trend, 0.03). CONCLUSIONS:The present study showed a significant association between the serum free testosterone level and severity of asthma among elderly women who were not currently using OCS. Although the causal relationship is unclear, this finding may provide a clue to understand the sex difference in the mechanisms of severe asthma in elderly populations.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic vasculitis with hypereosinophilia that is preceded by asthma and chronic rhinosinusitis with nasal polyps. Since multiple organs may be involved in this disease, early treatment is required. In this regard, glucocorticoid (GC) therapy is often initiated before a definitive diagnosis is made. A biopsy of an injured organ is useful for a diagnosis but is not performed in all cases due to its invasiveness and, at times, diagnostic accuracy. Therefore, a comprehensive diagnosis is often made based on symptoms and clinical course of disease. However, it is sometimes difficult to distinguish EGPA from other hypereosinophilic diseases or vasculitides. In recent years, in addition to GC and immunosuppressive agents, anti-interleukin (IL)-5/IL-5 receptor alpha (IL-5Rα) antibodies targeting eosinophils have become increasingly important in the treatment of EGPA. However, accumulating data suggest that such anti-IL-5/IL-5Rα antibody therapy may have effects beyond those observed in eosinophils. This paper outlines the clinical features, diagnosis, pathogenesis, and current treatment of EGPA, a hypereosinophilic disease.

Aim: Despite the revolutionary impact of biologics (Bx) on severe asthma management, predicting individual treatment responses remains challenging. We aimed to characterize the heterogeneous nature of clinical status and disease activity in patients with severe asthma after biologic therapies through a comprehensive evaluation of real-world clinical outcomes. Methods: In this retrospective, multicenter study of 53 patients with severe asthma who received biologic therapies, hierarchical clustering analysis was performed based on three key parameters during treatment: exacerbation, maintenance oral corticosteroid (mOCS) dose, and lung function. Canonical correlation analysis and multinomial logistic regression were used to identify predictors of response patterns. Results: Clustering analysis revealed three distinct control groups: well-controlled (n = 23), moderately controlled (n = 22), and poorly controlled (n = 8). Well-controlled patients exhibited minimal exacerbations, no oral corticosteroid (OCS) use, and optimal or stabilized lung function. Moderately controlled patients showed minimal exacerbations and no mOCS use but variable lung function improvements. Poorly controlled patients exhibited persistent exacerbations, mOCS dependence, or both with limited lung function improvement. Baseline forced expiratory volume in 1 second (FEV1) %predicted (percent predicted FEV1) values and blood eosinophil counts independently differentiated well-controlled from moderately controlled patients, whereas baseline mOCS use distinguished moderately controlled from poorly controlled patients. Conclusions: Our findings reveal distinct patterns of disease control following biologic therapy in severe asthma, with baseline lung function, eosinophilic inflammation, and OCS use as key predictive factors. These results support the need for personalized treatment approaches in severe asthma management.

Background: Asthma is characterized by phenotypes of different clinical, demographic, and pathological characteristics. Identifying the profile of exhaled volatile organic compounds (VOCs) in asthma phenotypes may facilitate establishing biomarkers and understanding asthma background pathogenesis. This study aimed to identify exhaled VOCs that characterize severe asthma phenotypes among patients with asthma. Methods: This was a multicenter cross-sectional study of patients with severe asthma in Japan. Clinical data were obtained from medical records, and questionnaires were collected. Exhaled breath was sampled and subjected to thermal desorption gas chromatography-mass spectrometry (GC/MS). Results: Using the decision tree established in the previous nationwide asthma cohort study, 245 patients with asthma were divided into five phenotypes and subjected to exhaled VOC analysis with 50 healthy controls (HCs). GC/MS detected 243 VOCs in exhaled breath samples, and 142 frequently detected VOCs (50% of all samples) were used for statistical analyses. Cluster analysis assigning the groups with similar VOC profile patterns showed the highest similarities between phenotypes 3 and 4 (early-onset asthma phenotypes), followed by the similarities between phenotypes 1 and 2 (late-onset asthma phenotypes). Comparisons between phenotypes 1-5 and HC revealed 19 VOCs, in which only methanesulfonic anhydride showed p <0.05 adjusted by false discovery rate (FDR). Comparison of these phenotypes yielded several VOCs showing different trends (p < 0.05); however, no VOCs showed p <0.05 adjusted by FDR. Conclusions: Exhaled VOC profiles may be useful for distinguishing asthma and asthma phenotypes; however, these findings need to be validated, and their pathological roles should be clarified.

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.

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.

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 pheno-type 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 clas-sified using clinical and molecular variables (Registered in UMIN-CTR; UMIN000027776.)(c) 2022 Japanese Society of Allergology. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Biologics targeting the molecules associated with type 2 inflammation have significantly improved the outcomes of patients with severe eosinophilic asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). Chronic eosinophilic airway/lung diseases including chronic eosinophilic pneumonia, allergic bronchopulmonary aspergillosis/mycosis, eosinophilic bronchitis, and eosinophilic granulomatosis with polyangiitis share clinical features with eosinophilic asthma and CRPwNP, which are mostly adult-onset and may develop simultaneously or consecutively. These eosinophilic airway/lung diseases respond well to initial treatment with systemic corticosteroids, but often recur when the corticosteroids are tapered. The management of these "refractory" cases is an unmet need for clinicians. We first reviewed the standard treatments for these chronic eosinophilic airway/lung diseases, followed by the definition and prevalence of refractory diseases and the role of biologics in their management. The available evidence varies from case reports and case series to randomized control trials, depending on the type of disease; however, these studies provide not only a direction for clinical practice, but also insights into the pathophysiology of each disease. Physicians should discuss the efficacy and costs of biologics in patients with refractory eosinophilic airway/lung diseases to minimize not only the current symptoms, but future risks as well.

Effect of Mepolizumab on reducing ANCA levels in eosinophilic granulomatosis with polyangiitis: a case series and review of the literature Main text;To the editor, Eosinophilic granulomatosis with polyangiitis (EGPA) is anti-neutrophil cytoplasmic antibody (ANCA)associated vasculitis with eosinophilia 1 .Mepolizumab, an anti-IL-5 antibody, has been shown to maintain remission in EGPA patients, contribute to reduced use of oral steroids, and reduce the frequency of relapses 2 .However, the effect of mepolizumab on ANCA remains unclear, as only case reports have been published so far.Herein, we present a case series where the effect of mepolizumab on ANCA values in EGPA is evaluated and a synthesis report of the published cases.We conducted a retrospective cohort study at Sagamihara Hospital and Shonan Kamakura General Hospital.From April 2004 to March 2022, 710 cases with EGPA disease insurance coverage at these hospitals were identified, and 166 cases diagnosed as EGPA according to the American College of Rheumatology 1990 criteria and the International Chapel Hill Consensus Conference Nomenclature of Vasculitides (CHSS) were extracted using medical records (Figure 1).Of the 61 patients treated with mepolizumab, 44 cases who were ANCA-negative at onset and 6 cases whose ANCA levels were negative due to use of systemic steroids or immunosuppressants were excluded.The remaining 11 patients (nine with Myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO-ANCA), and two with Proteinase 3 anti-neutrophil cytoplasmic antibodies) were included in the study (Tables S1,S2).The blood eosinophil count was significantly lower after treatment, and many cases showed low values even before mepolizumab treatment (Figure 2A).On the other hand, ANCA (median and interquartile range U/mL) showed a clear decrease (p = 0.0014) after mepolizumab treatment (4.0 [1.0-7.1]U/mL) compared to ANCA levels before treatment (11.0 [6.3-28.7]U/mL) (Figures 2B-1 and 2B-2).Corticosteroid doses and Birmingham Vasculitis Activity Score (BVAS) decreased after mepolizumab treatment (Figure 2C, D), suggesting that mepolizumab improved EGPA activity and decreased ANCA levels, despite reduced corticosteroid levels (median and interquartile range mg/day before mepolizumab; 7.0 [4.0-10.0]U/mL, after mepolizumab; 4.0 [2.0-5.0]U/mL).Next, we created a synthesis report of the published cases (Supplementary Material).Of the 90 relevant articles, 16 articles that used biologics preparations other than mepolizumab, 58 articles in which ANCA