Interferon and IL-27 antagonize the function of group 2 innate lymphoid cells and type 2 innate immune responses.

Group 2 innate lymphoid cells (ILC2 cells) are type 2 cytokine-producing cells of the innate immune system with important roles in helminth infection and allergic inflammation. Here we found that tissue-resident ILC2 cells proliferated in situ without migrating during inflammatory responses. Both type I and type II interferons and interleukin 27 (IL-27) suppressed ILC2 function in a manner dependent on the transcription factor STAT1. ILC2-mediated lung inflammation was enhanced in the absence of the interferon-γ (IFN-γ) receptor on ILC2 cells in vivo. IFN-γ effectively suppressed the function of tissue-resident ILC2 cells but not that of inflammatory ILC2 cells, and IL-27 suppressed tissue-resident ILC2 cells but not tissue-resident TH2 cells during lung inflammation induced by Alternaria alternata. Our results demonstrate that suppression mediated by interferon and IL-27 is a negative feedback mechanism for ILC2 function in vivo.

Aggregated eosinophils and neutrophils characterize the properties of mucus in chronic rhinosinusitis.

BACKGROUND: Airway obstruction caused by viscous mucus is an important pathophysiologic characteristic of persistent inflammation, which can result in organ damage. OBJECTIVE: We investigated the hypothesis that the biophysical characteristics of accumulating granulocytes affect the clinical properties of mucus. METHODS: Surgically acquired nasal mucus samples from patients with eosinophilic chronic rhinosinusitis and neutrophil-dominant, noneosinophilic chronic rhinosinusitis were evaluated in terms of computed tomography density, viscosity, water content, wettability, and protein composition. Isolated human eosinophils and neutrophils were stimulated to induce the formation of extracellular traps, followed by the formation of aggregates. The biophysical properties of the aggregated cells were also examined. RESULTS: Mucus from patients with eosinophilic chronic rhinosinusitis had significantly higher computed tomography density, viscosity, dry weight, and hydrophobicity compared to mucus from patients with noneosinophilic chronic rhinosinusitis. The levels of eosinophil-specific proteins in mucus correlated with its physical properties. Eosinophil and neutrophil aggregates showed physical and pathologic characteristics resembling those of mucus. Cotreatment with deoxyribonuclease and heparin, which slenderizes the structure of eosinophil extracellular traps, efficiently induced reductions in the viscosity and hydrophobicity of both eosinophil aggregates and eosinophilic mucus. CONCLUSIONS: The present study elucidated the pathogenesis of mucus stasis in infiltrated granulocyte aggregates from a novel perspective. These findings may contribute to the development of treatment strategies for eosinophilic airway diseases.

Revised ISHAM-ABPA working group clinical practice guidelines for diagnosing, classifying and treating allergic bronchopulmonary aspergillosis/mycoses.

BACKGROUND: The International Society for Human and Animal Mycology (ISHAM) working group proposed recommendations for managing allergic bronchopulmonary aspergillosis (ABPA) a decade ago. There is a need to update these recommendations due to advances in diagnostics and therapeutics. METHODS: An international expert group was convened to develop guidelines for managing ABPA (caused by Aspergillus spp.) and allergic bronchopulmonary mycosis (ABPM; caused by fungi other than Aspergillus spp.) in adults and children using a modified Delphi method (two online rounds and one in-person meeting). We defined consensus as ≥70% agreement or disagreement. The terms "recommend" and "suggest" are used when the consensus was ≥70% and <70%, respectively. RESULTS: We recommend screening for A. fumigatus sensitisation using fungus-specific IgE in all newly diagnosed asthmatic adults at tertiary care but only difficult-to-treat asthmatic children. We recommend diagnosing ABPA in those with predisposing conditions or compatible clinico-radiological presentation, with a mandatory demonstration of fungal sensitisation and serum total IgE ≥500 IU·mL-1 and two of the following: fungal-specific IgG, peripheral blood eosinophilia or suggestive imaging. ABPM is considered in those with an ABPA-like presentation but normal A. fumigatus-IgE. Additionally, diagnosing ABPM requires repeated growth of the causative fungus from sputum. We do not routinely recommend treating asymptomatic ABPA patients. We recommend oral prednisolone or itraconazole monotherapy for treating acute ABPA (newly diagnosed or exacerbation), with prednisolone and itraconazole combination only for treating recurrent ABPA exacerbations. We have devised an objective multidimensional criterion to assess treatment response. CONCLUSION: We have framed consensus guidelines for diagnosing, classifying and treating ABPA/M for patient care and research.

EQUAL ABPA Score 2024: A Tool to Measure Guideline Adherence for Managing Allergic Bronchopulmonary Aspergillosis.

OBJECTIVES: Allergic bronchopulmonary aspergillosis (ABPA) is a complex lung disease associated with significant morbidity. The ABPA Working Group (AWG) of the International Society for Human and Animal Mycology (ISHAM) revised their management guidelines in 2024, but there is currently no standardised tool to assess adherence to these recommendations. METHODS: We extracted key recommendations from the updated 2024 ISHAM-AWG guidelines, focusing on critical areas: screening and diagnosis of ABPA, managing acute and treatment-dependent ABPA, and monitoring treatment response. Each item was assigned a score ranging from zero to three. We assigned negative scores to interventions not recommended by the guidelines. RESULTS: We identified 38 items indicative of optimal clinical care for patients with ABPA. The score for screening asthmatics for ABPA was set at three points. For diagnosing ABPA, 16 items were included, with a score ranging from 12 to 16 points, depending on the specific components used (predisposing conditions, serum A. fumigatus-specific IgE and IgG, serum total IgE, blood eosinophil count and chest computed tomography). The management of acute ABPA comprised 11 items, with a maximum score of three points. For treatment-dependent ABPA, there were nine items (scores ranging from -3 to 6). Follow-up care comprised 10 items with a maximum score of 10-13 points, covering imaging, spirometry, testing serum total IgE levels and therapeutic drug monitoring. CONCLUSIONS: The EQUAL ABPA score has been developed as a comprehensive tool to quantify guideline adherence. Future studies will evaluate to which extent guideline adherence is associated with improved clinical outcomes for patients with ABPA.

High attenuation mucus in bronchi with allergic bronchopulmonary mycosis.

BACKGROUND: High-attenuation mucus (HAM) is a specific manifestation of allergic bronchopulmonary mycosis (ABPM) on chest computed tomography (CT). OBJECTIVES: To compare the diagnostic accuracy of the two definitions of HAM and to clarify the clinical and radiographic characteristics of HAM-positive and HAM-negative ABPM. METHODS: CT images at the diagnosis of ABPM using Asano's criteria were retrospectively analysed. In Study #1, radiographic data obtained using the same CT apparatus in a single institute were analysed to determine the agreement between the two definitions of HAM: a mucus plug that is visually denser than the paraspinal muscles or that with a radiodensity ≥70 Hounsfield units. In Study #2, HAM was diagnosed by comparison with the paraspinal muscles in patients with ABPM reporting to 14 medical institutes in Japan. RESULTS: In Study #1, 93 mucus plugs from 26 patients were analysed. A substantial agreement for HAM diagnosis was observed between the two methods, with a κ coefficient of 0.72. In Study #2, 60 cases of ABPM were analysed; mucus plugs were present in all cases and HAM was diagnosed in 45 (75%) cases. The median A. fumigatus-specific IgE titre was significantly lower in HAM-positive patients than in HAM-negative patients (2.5 vs. 24.3 UA /mL, p = .004). Nodular shadows were observed more frequently in the airways distal to HAM than in those distal to non-HAM mucus plugs (59% vs. 32%, p < .001). CONCLUSION: In conclusion, agreement between the two methods to diagnose HAM was substantial. HAM was associated with some immunological and radiographic characteristics, including lower levels of sensitization to A. fumigatus and the presence of distal airway lesions.

Eosinophilic mucus diseases.

Eosinophilic inflammation is primarily characterized by type 2 immune responses against parasitic organisms. In the contemporary human being especially in developed countries, eosinophilic inflammation is strongly associated with allergic/sterile inflammation, and constitutes an undesired immune reaction. This situation is in stark contrast to neutrophilic inflammation, which is indispensable for the host defense against bacterial infections. Among eosinophilic inflammatory disorders, massive accumulation of eosinophils within mucus is observed in certain cases, and is often linked to the distinctive clinical finding of mucus with high viscosity. Eosinophilic mucus is found in a variety of diseases, including chronic allergic keratoconjunctivitis, chronic rhinosinusitis encompassing allergic fungal sinusitis, eosinophilic otitis media, eosinophilic sialodochitis, allergic bronchopulmonary aspergillosis/mycosis, eosinophilic plastic bronchitis, and eosinophilic asthma. In these pathological conditions, chronic inflammation and tissue remodeling coupled with irreversible organ damage due to persistent adhesion of toxic substances and luminal obstruction may impose a significant burden on the body. Eosinophils aggregate in the hyperconcentrated mucus together with cell-derived crystals, macromolecules, and polymers, thereby affecting the biophysical properties of the mucus. This review focuses on the clinically significant challenges of mucus and discusses the consequences of activated eosinophils on the mucosal surface that impact mucus and persistent inflammation.

Aspergillus fumigatus extract modulates human eosinophils via NOD2 and oxidative stress.

BACKGROUND: Aspergillus fumigatus is a pathogenic fungus known to be associated with severe asthma and allergic bronchopulmonary mycosis. However, the precise mechanisms underlying airway inflammation remain unclear. In this study, we investigated the direct modulation of human eosinophils by A. fumigatus and identified the specific mechanism of airway inflammation. METHODS: Eosinophils isolated from healthy subjects were stimulated with extracts of A. fumigatus. Multi-omics analysis, comprising transcriptomic and proteomic analyses, was performed. The expression of specific factors was evaluated using quantitative real-time polymerase chain reaction and flow cytometry. Mechanistic analyses were performed using NOD2 inhibitor and N-acetyl-l-cysteine (NAC). RESULTS: The A. fumigatus extract changed the expression of adhesion molecules (CD62L and CD11b) and CD69 on the surface of eosinophils, without affecting their viability, via nucleotide-binding oligomerization domain-containing protein 2 (NOD2) but not protease activity. Investigation using kinase inhibitors showed that A. fumigatus extract-induced modulation was partly mediated via p38 mitogen-activated protein kinases. Multi-omics analysis revealed that A. fumigatus-induced gene and protein expression profiles were characterized by the upregulation of oxidative stress-related molecules, including heat shock proteins (HSP90AA1, HSP90AB1, SRXN1, and HMOX1). NOD2 inhibitor and NAC differentially inhibited A. fumigatus-induced inflammatory changes. Additional multi-omics analysis identified that NOD2 signaling induced gene signatures different from those of interleukin (IL)-5 and elicited synergistic change with IL-5. CONCLUSIONS: A. fumigatus modulates human eosinophils via NOD2 and oxidative stress-mediated signaling. NOD2 signaling potentiated IL-5-induced activation, suggesting its pathogenic role in type 2 inflammation. NOD2 inhibitors and antioxidants can have therapeutic potential against A. fumigatus-related allergic disorders.

Allergic bronchopulmonary aspergillosis with atopic, nonatopic, and sans asthma-Factor analysis.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) develops in the presence or absence of asthma, either atopic or nonatopic. We have tried to explore the essential components in the pathogenesis of the disease, which are either consistent and variable according to the presence and type of asthma. METHODS: Non-cystic fibrosis ABPA cases satisfying Asano's criteria were extracted from a prospective registry of ABPA and related diseases in Japan between 2013 and 2023. According to the type of preceding asthma, ABPA was classified into three groups: ABPA sans asthma (no preceding asthma), ABPA with atopic asthma, and ABPA with nonatopic asthma. Exploratory and confirmatory factor analyses were performed to identify the components that determined the clinical characteristics of ABPA. RESULTS: Among 106 cases of ABPA, 25 patients (24%) had ABPA sans asthma, whereas 57 (54%) and 24 (23%) had ABPA with atopic and nonatopic asthma, respectively. Factor analysis identified three components: allergic, eosinophilic, and fungal. Patients with atopic asthma showed the highest scores for the allergic component (p < .001), defined by total and allergen-specific IgE titers and lung opacities, and the lowest scores for the fungal component defined by the presence of specific precipitin/IgG or positive culture for A. fumigatus. Eosinophilic components, including peripheral blood eosinophil counts and presence of mucus plugs/high attenuation mucus in the bronchi, were consistent among the three groups. CONCLUSION: The eosinophilic component of ABPA is considered as the cardinal feature of ABPA regardless of the presence of preceding asthma or atopic predisposition.

Risk factors for poor adherence to inhaled corticosteroid therapy in patients with moderate to severe asthma.

BACKGROUND: Poor adherence to inhaled corticosteroid (ICS) therapy is a common reason for worsened asthma control. OBJECTIVE: We investigated the characteristics of patients with moderate to severe asthma who showed poor adherence to therapy, to identify the barriers for optimal ICS therapy in a real-world observational cohort. METHODS: We enrolled patients aged ≥20 years presenting with moderate to severe asthma who were enrolled at 18 hospitals in Japan. According to the Global Initiative for Asthma 2018 steps 3-5, the patients were considered as moderate to severe asthmatic. At inclusion, clinical information was obtained using a self-completed questionnaire. Poor adherence was defined as skipping the ICS therapy for more than once a week or inability to recognize the necessity of daily ICS therapy. Adherence Starts with Knowledge 20 (ASK-20) questionnaire was used to evaluate the cause of therapy incompliance. RESULTS: Of the total 85 participants, 19 (22%) showed poor adherence. The median age at diagnosis in the poor adherence group was 10.0 years (interquartile range [IQR], 3.0-50.0), and that in the good adherence group was 41.0 years (18.5-51.5; P = 0.050). The scores for the ASK-20 items related to the "resistance to taking too much medicine" and "compliance with the number of dosing" demonstrated statistically significant differences between patients diagnosed with asthma during their childhood and others. CONCLUSIONS: Age at diagnosis is an independent risk factor to predict poor ICS adherence among adults with moderate to severe asthma.

Treatments of refractory eosinophilic lung diseases with biologics.

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.

Nationwide survey of refractory asthma with bronchiectasis by inflammatory subtypes.

RATIONALE: Bronchiectasis and bronchiolitis are differential diagnoses of asthma; moreover, they are factors associated with worse asthma control. OBJECTIVE: We determined clinical courses of bronchiectasis/bronchiolitis-complicated asthma by inflammatory subtypes as well as factors affecting them. METHODS: We conducted a survey of refractory asthma with non-cystic fibrosis bronchiectasis/bronchiolitis in Japan. Cases were classified into three groups, based on the latest fractional exhaled NO (FeNO) level (32 ppb for the threshold) and blood eosinophil counts (320/µL for the threshold): high (type 2-high) or low (type 2-low) FeNO and eosinophil and high FeNO or eosinophil (type 2-intermediate). Clinical courses in groups and factors affecting them were analysed. RESULTS: In total, 216 cases from 81 facilities were reported, and 142 were stratified: 34, 40 and 68 into the type 2-high, -intermediate and -low groups, respectively. The frequency of bronchopneumonia and exacerbations requiring antibiotics and gram-negative bacteria detection rates were highest in the type 2-low group. Eighty-seven cases had paired latest and oldest available data of FeNO and eosinophil counts; they were analysed for inflammatory transition patterns. Among former type 2-high and -intermediate groups, 32% had recently transitioned to the -low group, to which relatively low FeNO in the past and oral corticosteroid use contributed. Lastly, in cases treated with moderate to high doses of inhaled corticosteroids, the frequencies of exacerbations requiring antibiotics were found to be higher in cases with more severe airway lesions and lower FeNO. CONCLUSIONS: Bronchiectasis/bronchiolitis-complicated refractory asthma is heterogeneous. In patients with sputum symptoms and low FeNO, airway colonisation of pathogenic bacteria and infectious episodes are common; thus, corticosteroids should be carefully used.

Moldy odor from air conditioners in the residences of Japanese participants with and without asthma.

Fungi, a major allergen associated with asthma onset and severity, can contaminate air conditioners if not properly maintained. We surveyed the prevalence and risk factors associated with fungal contamination of air conditioners and patient behavior to reduce this contamination. Japanese adults aged ≥30 years registered in the database of an Internet research company were asked to participate in an online survey. A moldy odor from the air conditioners in their residences was used as an indicator of fungal contamination. Among a total of 1006 adults, including 631 patients with asthma, 37.1% reported a moldy odor from air conditioners. The prevalence was higher in residences with indoor condensation and in air conditioners used for ≥6 years or frequently during the summer, but was lower in air conditioners with an auto-cleaning function. The risk of indoor condensation was higher in apartments, in the presence of an aquarium, and in the absence of a 24-h ventilation system. These risk factors did not differ between the residences or air conditioners of participants with and without asthma. Asthmatic patients were conscious of indoor air quality; however, do not necessarily take appropriate measures to reduce indoor mold contamination, possibly due to a lack of knowledge. In conclusion, appropriate patient education is required to reduce environmental fungal contamination and improve asthma control.

Clinical Utility of the Electrocardiographic P-Wave Axis in Patients with Chronic Obstructive Pulmonary Disease.

BACKGROUND: The vertical P-wave axis on electrocardiography (ECG) is a useful criterion for screening patients with chronic obstructive pulmonary disease (COPD). This study aimed to investigate the clinical characteristics of patients with COPD with a vertical P-wave axis as they have not yet been elucidated. METHODS: Keio University and its affiliated hospitals conducted an observational COPD cohort study over 3 years. We analyzed 201 patients using ECG and chest computed tomography. RESULTS: The severity of airflow limitation was higher in patients with a P-wave axis >75° than in those with a P-wave axis ≤75°. Patients with a P-wave axis >75° exhibited significantly higher total COPD assessment test scores and increased St. George's Respiratory Questionnaire total, activity, and impact scores than those with a P-wave axis ≤75°. The incidence of exacerbations over 1 and 3 years was significantly higher in patients with a P-wave axis >75° than in those with a P-wave axis ≤75°. The optimal cutoff for the P-wave axis for a percentage of the predicted forced expiratory volume in 1 s <50% and future exacerbations over 3 years was 70° (the areas under the curve [AUC]: 0.788; sensitivity: 65.3%; specificity: 78.3%) and 79° (AUC: 0.642; sensitivity: 36.7%; specificity: 92.6%). The ratio of the low attenuation area was also significantly higher in patients with a P-wave axis >75° than in those with a P-wave axis ≤75°. However, the ratio of the airway wall area did not differ between the 2 groups. CONCLUSIONS: Patients with COPD with a vertical P-wave axis exhibited severe airflow limitation and emphysema, a worse health status, and more frequent exacerbation than patients without a vertical P-wave. Detection of the vertical P-wave axis by ECG is beneficial for the management of patients with COPD.

New clinical diagnostic criteria for allergic bronchopulmonary aspergillosis/mycosis and its validation.

BACKGROUND: There are several clinical diagnostic criteria for allergic bronchopulmonary aspergillosis (ABPA). However, these criteria have not been validated in detail, and no criteria for allergic bronchopulmonary mycosis (ABPM) are currently available. OBJECTIVE: This study proposes new diagnostic criteria for ABPA/ABPM, consisting of 10 components, and compares its sensitivity and specificity to existing methods. METHODS: Rosenberg-Patterson criteria proposed in 1977, the International Society for Human and Animal Mycology (ISHAM) criteria proposed in 2013, and this new criteria were applied to 79 cases with pathological ABPM and the control population with allergic mucin in the absence of fungal hyphae (n = 37), chronic eosinophilic pneumonia (n = 64), Aspergillus-sensitized severe asthma (n = 26), or chronic pulmonary aspergillosis (n = 24). These criteria were also applied to the 179 cases with physician-diagnosed ABPA/ABPM in a nationwide Japanese survey. RESULTS: The sensitivity for pathological ABPM with Rosenberg-Patterson criteria, ISHAM criteria, and this new criteria were 25.3%, 77.2%, and 96.2%, respectively. The sensitivity for physician-diagnosed ABPA/ABPM were 49.2%, 82.7%, and 94.4%, respectively. The areas under the curve for the receiver-operating characteristic curves were 0.85, 0.90, and 0.98, respectively. The sensitivity for ABPM cases that were culture-positive for non-Aspergillus fungi were 13.0%, 47.8%, and 91.3%, respectively. CONCLUSIONS: The new diagnostic criteria, compared with existing criteria, showed better sensitivity and specificity for diagnosing ABPA/ABPM.

Prevalence of inhaled allergen-specific IgE antibody positivity in the healthy Japanese population.

BACKGROUND: Measurement of allergen-specific IgE antibodies to inhaled allergens is important for the diagnosis and risk evaluation of allergic diseases such as asthma and allergic rhinitis. This study aimed to elucidate the prevalence of allergen sensitization among the healthy population in Japan using serum samples stocked in the Japanese Red Cross for blood donation. METHODS: Age- and gender-stratified serum samples (n = 800) from residents in Tokyo aged 20-59 years were randomly selected from the stocked serum obtained for blood donation in 2005. Total and specific IgE antibodies to 17 inhaled allergens were measured by the ImmunoCAP method. Individuals with positive (≥0.35 UA/mL) specific IgE antibodies to at least one inhaled allergen were defined as atopic. Stocked serums from donors aged 20-29 years in Sapporo, Osaka, Fukuoka, and Okinawa (n = 200 each) were also obtained for the measurement of IgE to six common inhaled allergens, to evaluate regional differences in the rate of positivity. RESULTS: Among residents in Tokyo, the prevalence of atopy was 78.0% and highest in men aged 20-29 years (94.0%), which decreased with age. The prevalence of specific IgE antibodies was highest for Japanese cedar pollen (66.8%), followed by cypress pollen (46.8%), Dermatophagoides pteronyssinus (38.3%), and moths (30.1%). Examination of IgE to Japanese cedar pollen, D. pteronyssinus, and moths identified 97.6% of atopic subjects in Tokyo. There were substantial regional differences in the prevalence of pollen IgE positivity. CONCLUSIONS: This study demonstrated an extremely high prevalence of positivity in inhaled allergen-specific IgE antibodies among healthy adults in Japan.

Diversities of allergic pathologies and their modifiers: Report from the second DGAKI-JSA meeting.

In October 2021, researchers from the German Society of Allergy and Clinical Immunology (DGAKI) and from the Japanese Society of Allergology (JSA) focused their attention on the pathological conditions and modifiers of various allergic diseases. Topics included 1) the pathophysiology of IgE/mast cell-mediated allergic diseases; 2) the diagnosis and prevention of IgE/mast cell-mediated diseases; 3) the pathophysiology, diagnosis, and treatment of eosinophilic airway diseases; and 4) host-pathogen interaction and allergic diseases. This report summarizes the panel discussions, which highlighted the importance of recognizing the diversity of genetics, immunological mechanisms, and modifying factors underlying allergic diseases.

Real-Time Detection of Glyphosate by a Water-Gated Organic Field-Effect Transistor with a Microfluidic Chamber.

This paper reports the development of a real-time monitoring system utilizing the combination of a water-gated organic field-effect transistor (WG-OFET) and a microfluidic chamber for the detection of the herbicide glyphosate (GlyP). For the realization of the real-time sensing with the WG-OFET, the surface of a polymer semiconductor was utilized as a sensing unit. The aqueous solution including the target analyte, which is employed as a gate dielectric of the WG-OFET, flows into a designed microfluidic chamber on the semiconductor layer and the gate electrode. As the sensing mechanism, the WG-OFET-based sensor utilizes the competitive complexation among carboxylate-functionalized polythiophene, a copper(II) (Cu2+) ion, and GlyP. The reversible accumulation and desorption of the positively charged Cu2+ ion on the semiconductor surface induced a change in the electrical double-layer capacitance (EDLC). The optimization of the microfluidic chamber enables a uniform water flow and contributes to real-time quantitative sensing of GlyP at a micromolar level. Thus, this study would lead to practical real-time sensing in water for various fields including environmental assessment.

Optimal Aspergillus fumigatus and Asp f 1 serum IgG cut-offs for the diagnosis of allergic bronchopulmonary aspergillosis.

BACKGROUND: The presence of IgG antibodies (Abs) to Aspergillus fumigatus (Af) is a crucial diagnostic criterion for allergic bronchopulmonary aspergillosis (ABPA). Although precipitation is traditionally used to document IgG Abs, anti-Af serum IgG levels can also be measured by enzyme immunoassay (EIA). However, there are insufficient data on the optimal cut-offs to assess diagnostic performance of the EIA method. This study aimed to determine cut-off levels of IgG binding crude Af extracts or recombinant Asp f 1 (by ImmunoCAP®) and to compare their efficacy for ABPA diagnosis with Af-precipitating Abs. METHODS: The age distribution of levels of IgG to crude extracts of Af (Af-IgG) and recombinant Asp f 1 (Asp f 1-IgG) was established using sera from 694 healthy controls (HC). Receiver operating characteristic analysis for Af-IgG and Asp f 1-IgG levels for the purpose of ABPA diagnosis was performed in 306 Af-sensitized asthma patients (including 49 ABPA), and cut-offs were determined. RESULTS: An age-dependent decline in the levels of Af-IgG was observed in HC. Thus, cut-offs for Af-IgG levels were determined separately by age as 60 mg/L for patients aged <55 years, and 45 mg/L for those aged ≥55 years. For Asp f 1-IgG, 6.6 mg/L was set as the cut-off regardless of age. Although such IgG testing by EIA allowed a sufficiently good diagnostic performance, Af-precipitating Abs had better diagnostic applicability for ABPA. CONCLUSIONS: We determined cut-offs for Af-IgG and Asp f 1-IgG measured by EIA, which can be useful in clinical settings where precipitating Abs are unavailable.

Clinical characteristics of patients with not well-controlled severe asthma in Japan: Analysis of the Keio Severe Asthma Research Program in Japanese population (KEIO-SARP) registry.

BACKGROUND: Multiple phenotypes exist within the classification of severe asthma. However, characteristics of patients with not well-controlled severe asthma have not been well identified. METHODS: Japanese patients with asthma (age ≥ 20 years) were enrolled at the Keio University Hospital and its affiliated hospitals in this observational study (Keio Severe Asthma Research Program). Among them, patients with severe asthma (those undergoing Global Initiative for Asthma [GINA] 2018 step 4 or 5 treatment) were included in this analysis and investigated clinical characteristics based on asthma control status. RESULTS: Of the 154 patients (men, 46.8%; age, 60.1 ± 14.9 years), 87 (56.5%) had not well-controlled (partly controlled and uncontrolled) asthma (GINA step 4, 42 patients; step 5, 45 patients). Overall, there were no significant differences in clinical characteristics between patients with well-controlled and not well-controlled asthma. However, cluster analysis revealed that distinct 5 clusters (cluster 1, well-controlled; cluster 2, eosinophilic; cluster 3, non-type 2 inflammation; cluster 4, high periostin; and cluster 5, late-onset type 2 inflammation), and clusters 2-5 were not well-controlled. Among them, cluster 3 was characterized by low eosinophil counts, low periostin levels, and less frequent olfactory disturbance, and this cluster had the worst asthma control. CONCLUSIONS: Japanese patients with severe asthma were divided into well-controlled and not-well controlled asthma, and we confirmed heterogeneity of not well-controlled severe asthma. These patients, especially non-type 2 phenotype, require a further therapeutic approach. (University Hospital Medical Information Network Clinical Trials Registry, UMIN000002980).

Adult-onset eosinophilic airway diseases.

Eosinophilic airway inflammation is one of the cardinal features of allergic airway diseases such as atopic asthma and allergic rhinitis. These childhood-onset conditions are mediated by allergen and allergen-specific IgE and often accompanied by other allergic diseases including food allergy and eczema. They can develop consecutively in the same patient, which is referred to as an allergic march. In contrast, some phenotypes of asthma, nonsteroidal anti-inflammatory drugs-exacerbated airway disease (N-ERD), chronic rhinosinusitis with nasal polyps (CRSwNP)/eosinophilic CRS and allergic bronchopulmonary aspergillosis/mycosis (ABPA/ABPM) are adult-onset airway diseases, which are characterized by prominent peripheral blood eosinophilia. Most of these conditions, except for ABPA/ABPM, are nonatopic, and the coexistence of multiple diseases, including an adult-onset eosinophilic systemic disease, eosinophilic granulomatosis with polyangiitis (EGPA), is common. In this review, we focus on eosinophil biology, genetics and clinical characteristics and the pathophysiology of adult-onset eosinophilic asthma, N-ERD, CRSwNP/eosinophilic CRS, ABPA/ABPM and EGPA, while exploring the common genetic, immunological and pathological conditions among these adult-onset eosinophilic diseases.