Alpha/Beta Gliadin MM1 Is a Novel Antigen for Wheat-Dependent Exercise-Induced Anaphylaxis.

INTRODUCTION: Screening for ω-5 gliadin specific IgE antibody (sIgE) has high diagnostic utility in cases of suspected wheat-dependent exercise-induced anaphylaxis (WDEIA); however, negative cases may require confirmatory tests, such as the oral challenge test. Thus, newly identified allergens that can be used for the serological diagnosis of WDEIA are needed. This study aimed to identify additional sIgE biomarkers of WDEIA. METHODS: Forty-two patients with WDEIA (5 negative/37 positive for ω-5 gliadin sIgE) were enrolled. For comparison, 8 patients with immediate-type wheat allergy without WDEIA and 20 healthy controls without wheat allergy were also enrolled. Extracted wheat proteins were separated by 2D-PAGE. Proteins that reacted with serum IgE antibody in 2D Western blotting (2D-WB) were identified using mass spectrometry. Recombinant proteins were synthesized in Escherichia coli, and the antigenicity was tested using ELISA and the basophil activation test. RESULTS: In 2D-WB, nine proteins reacted with the serum IgE antibody from at least 60% of patients with WDEIA (n ≥ 25/42). ELISA revealed that alpha/beta gliadin MM1 exhibited the highest positive immunoreactivity in 23 of 26 patients who were positive for ω-5 gliadin sIgE (88%) and in 5 of 5 patients who were negative for ω-5 gliadin sIgE (100%). Alpha/beta gliadin MM1 exhibited significantly higher basophil activation in 14 patients with WDEIA when compared to 5 individuals without a wheat allergy. CONCLUSIONS: Alpha/beta gliadin MM1 sIgE exhibited the highest seropositivity, even among patients who were negative for ω-5 gliadin sIgE. The inclusion of alpha/beta gliadin MM1 in allergen-sIgE tests may improve the sensitivity for diagnosing WDEIA.

Executive summary: Japanese guidelines for adult asthma (JGL) 2021.

Asthma is characterized by chronic airway inflammation, variable airway narrowing, and sensory nerve irritation, which manifest as wheezing, dyspnea, chest tightness, and cough. Longstanding asthma may result in airway remodeling and become intractable. Despite the increased prevalence of asthma in adults, asthma-associated deaths have decreased in Japan (0.94 per 100,000 people in 2020). The goals of asthma treatment include the control of symptoms and reduction of future risks. A functional partnership between physicians and patients is indispensable for achieving these goals. Long-term management with medications and the elimination of triggers and risk factors are fundamental to asthma treatment. Asthma is managed via four steps of pharmacotherapy ("controllers"), ranging from mild to intensive treatments, depending on disease severity; each step involves daily administration of an inhaled corticosteroid, which varies from low to high dosage. Long-acting ß2 agonists, leukotriene receptor antagonists, sustained-release theophylline, and long-acting muscarinic antagonists are recommended as add-on drugs. Allergen immunotherapy is a new option that is employed as a controller treatment. Further, as of 2021, anti-IgE antibody, anti-IL-5 and anti-IL-5 receptor α-chain antibodies, and anti-IL-4 receptor α-chain antibodies are available for the treatment of severe asthma. Bronchial thermoplasty can be performed for asthma treatment, and its long-term efficacy has been reported. Algorithms for their usage have been revised. Comorbidities, such as allergic rhinitis, chronic rhinosinusitis, chronic obstructive pulmonary disease, and aspirin-exacerbated respiratory disease, should also be considered during the treatment of chronic asthma. Depending on the severity of episodes, inhaled short-acting ß2 agonists, systemic corticosteroids, short-acting muscarinic antagonists, oxygen therapy, and other approaches are used as needed ("relievers") during exacerbation.

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.

Serological analysis of sensitization in allergic bronchopulmonary aspergillosis: a study on allergen components and interspecies relationships.

Background: Serological testing for immunoglobulin (Ig) E or IgG is useful for diagnosing allergic bronchopulmonary aspergillosis (ABPA), as it detects type I and III allergic reactions to Aspergillus species. However, few reports have investigated the allergen component and cross-reactivity among Aspergillus species. We aimed to measure and analyze the levels of IgGs specific to each Aspergillus species and investigate the prevalence of IgEs specific to each allergen component of A. fumigatus (Af) in ABPA patients.Methods: Serum samples were collected from 12 ABPA patients who visited our hospital between February and December 2017, and 16 with Af-sensitized asthma and 41 with Af-unsensitized asthma were controls. Immuno-CAP was performed to analyze the IgEs and IgGs specific to Af, A. niger, A flavus and A. terreus, and IgEs specific to allergen components Asp f 1, 2, 3, 4 and 6.Results: The ABPA group was significantly more frequently sensitized to Asp f 1 and 2 than the control groups. Af-specific IgEs were significantly positively correlated to the IgEs specific to A. flavus, A. niger and A. terreus. Af-specific IgGs were positively correlated to the IgGs specific to all the other species.Conclusions: Tests using allergen components were useful for ABPA diagnosis. Both IgE and IgG were highly cross-reactive among the Aspergillus species. There were many patients apart from asthmatic patients with ABPA, who displayed high Aspergillus IgG values.

Japanese guidelines for adult asthma 2020.

Bronchial asthma is characterized by chronic airway inflammation, which manifests clinically as variable airway narrowing (wheezes and dyspnea) and cough. Long-standing asthma may induce airway remodeling and become intractable. The prevalence of asthma has increased; however, the number of patients who die from it has decreased (1.3 per 100,000 patients in 2018). The goal of asthma treatment is to control symptoms and prevent future risks. A good partnership between physicians and patients is indispensable for effective treatment. Long-term management with therapeutic agents and the elimination of the triggers and risk factors of asthma are fundamental to its treatment. Asthma is managed by four steps of pharmacotherapy, ranging from mild to intensive treatments, depending on the severity of disease; each step includes an appropriate daily dose of an inhaled corticosteroid, which may vary from low to high. Long-acting ß2-agonists, leukotriene receptor antagonists, sustained-release theophylline, and long-acting muscarinic antagonists are recommended as add-on drugs, while anti-immunoglobulin E antibodies and other biologics, and oral steroids are reserved for very severe and persistent asthma related to allergic reactions. Bronchial thermoplasty has recently been developed for severe, persistent asthma, but its long-term efficacy is not known. Inhaled ß2-agonists, aminophylline, corticosteroids, adrenaline, oxygen therapy, and other approaches are used as needed during acute exacerbations, by selecting treatment steps for asthma based on the severity of the exacerbations. Allergic rhinitis, eosinophilic chronic rhinosinusitis, eosinophilic otitis, chronic obstructive pulmonary disease, aspirin-exacerbated respiratory disease, and pregnancy are also important conditions to be considered in asthma therapy.

Staphylococcus aureus enterotoxin sensitization involvement and its association with the CysLTR1 variant in different asthma phenotypes.

BACKGROUND: Sensitization to Staphylococcus aureus enterotoxin (SE) is a known risk factor for asthma susceptibility and severity. However, how SE sensitization is involved in asthma, particularly nonatopic asthma and/or late-onset asthma, remains uncertain. OBJECTIVE: To clarify the involvement of SE sensitization in nonatopic and/or late-onset asthma and its association with a polymorphism of the cysteinyl leukotriene receptor 1 gene (CysLTR1), which was examined because CysLT signaling is closely associated with late-onset eosinophilic asthma. METHODS: We assessed associations between sensitization to SE (A and/or B) and clinical indexes in 224 patients with asthma (mean age, 62.3 years; 171 women) from a cohort of the Kinki Hokuriku Airway Disease Conference, particularly those with nonatopic asthma (not sensitized to common aeroallergens) and/or late-onset asthma. Associations between SE sensitization and CysLTR1 polymorphism (rs2806489), a potential regulatory variant for atopic predisposition in women, were also assessed in a sex-stratified manner. RESULTS: A total of 105 patients (47%) with asthma were sensitized to SE. Among patients with nonatopic asthma (n = 67) or with late-onset asthma (n = 124), those sensitized to SE had significantly higher serum total IgE and periostin levels than those not sensitized. In nonatopic patients, a rapid decrease in forced expiratory volume in 1 second was associated with SE sensitization. In women with asthma, rs2806489 was associated with sensitization to SEB and age at asthma onset. CONCLUSION: SE sensitization contributes to TH2 inflammation in nonatopic and/or late-onset asthma. In women with asthma, the CysLTR1 variant might be associated with sensitization to SEB and age at asthma onset.

Effectiveness of training patients using DVD in the accurate use of inhalers for the treatment of bronchial asthma.

BACKGROUND: Inhalants are the standard treatment for patients with bronchial asthma. Inaccurate inhaler use leads to inadequate therapeutic effects and unnecessary dosage increases. However, it is a challenge for practitioners to master the various devices available and train patients on the accurate use of inhalers. Thus, establishing a system to instruct patients on how to accurately use inhalers is essential. We prepared a DVD and accompanying user manual explaining the operation of each inhaler device used in Japan. This pilot study aimed to examine the efficacy of these materials. METHODS: The subjects were 33 outpatients with bronchial asthma who received treatment in our facility for asthma and had already received conventional inhalant training. The oral medication and inhalants used by the patients were not changed. The patients were randomly assigned to a DVD viewing group or non-viewing group; various parameters were comparatively examined after 4 weeks. RESULTS: Significant improvements in Asthma Control Test scores, inhalation technique, forced vital capacity, forced expiratory volume in 1 s, impulse oscillometry resonant frequency, and induced sputum eosinophil count were observed in the DVD viewing group at 4 weeks post training. CONCLUSIONS: Pulmonary function and inflammatory parameters improved significantly in the DVD viewing group. These findings suggest that unnecessary step-up of asthma treatment can be avoided, leading to treatment cost reduction. Training patients with asthma in accurate inhaler use improves quality of life and therefore has great clinical significance. Hence, this method should be used more extensively in Japan and worldwide.

Increased periostin associates with greater airflow limitation in patients receiving inhaled corticosteroids.

BACKGROUND: Periostin, an extracellular matrix protein, contributes to subepithelial thickening in asthmatic airways, and its serum levels reflect airway eosinophilic inflammation. However, the relationship between periostin and the development of airflow limitation, a functional consequence of airway remodeling, remains unknown. OBJECTIVE: We aimed to determine the relationship between serum periostin levels and pulmonary function decline in asthmatic patients on inhaled corticosteroid (ICS) treatment. METHODS: Two hundred twenty-four asthmatic patients (average age, 62.3 years) treated with ICS for at least 4 years were enrolled. Annual changes in FEV1, from at least 1 year after the initiation of ICS treatment to the time of enrollment or later (average, 16.2 measurements over 8 years per individual), were assessed. At enrollment, clinical indices, biomarkers that included serum periostin, and periostin gene polymorphisms were examined. Associations between clinical indices or biomarkers and a decline in FEV1 of 30 mL or greater per year were analyzed. RESULTS: High serum periostin levels (≥ 95 ng/mL) at enrollment, the highest treatment step, higher ICS daily doses, a history of admission due to asthma exacerbation, comorbid or a history of sinusitis, and ex-smoking were associated with a decline in FEV1 of 30 mL or greater per year. Multivariate analysis showed that high serum periostin, the highest treatment step, and ex-smoking were independent risk factors for the decline. Polymorphisms of periostin gene were related to higher serum periostin levels (rs3829365) and a decline in FEV1 of 30 mL or greater per year (rs9603226). CONCLUSIONS: Serum periostin appears to be a useful biomarker for the development of airflow limitation in asthmatic patients on ICS.

A prospective study exploring the predictors of response to benralizumab in patients with refractory bronchial asthma.

OBJECTIVE: This study aimed to evaluate the predictors of response to benralizumab therapy in patients with refractory bronchial asthma. METHODS: After 16 weeks of benralizumab therapy, 32 patients with refractory bronchial asthma were assigned to two groups based on the response to treatment as indicated by changes in the asthma control test score (responders and non-responders) and evaluated for clinical characteristics. RESULTS: Overall, 25 responders and 7 non-responders were identified at week 16. Logistic regression analysis identified a peripheral eosinophil count of >300/µL during benralizumab treatment and a maximal peripheral eosinophil count of >300/µL in the past year as predictors of response. CONCLUSIONS: The predictors of response to benralizumab included a peripheral eosinophil count of >300/µL during treatment and a maximal peripheral eosinophil count of >300/µL in the past year. These findings could improve patient selection and reduce medical costs in the future.

Impact of initial empirical antimicrobial choice and cause of in-hospital death in patients with nursing and healthcare-associated pneumonia (NHCAP): A retrospective study.

Objectives: To examine the differences in antimicrobial selection outcomes in nursing and healthcare-associated pneumonia (NHCAP) patients with and without risk factors for drug-resistant pathogen (RDRP) infection, and to identify the cause of in-hospital death after improvement of NHCAP. Methods: We conducted a retrospective analysis of the medical records of hospitalized adult patients with NHCAP. NHCAP patients were divided into the RDRP and non-RDRP groups. The RDRP group was further classified into the narrow and broad subgroups according to the type of empirical antimicrobial agent selected. The difference in mortality between these subgroups was then examined. The cause of all in-hospital deaths was also evaluated. Results: e evaluated 220 patients with NHCAP. There was no difference in mortality between the narrow and broad subgroups (11.8% vs. 15.4%, p=0.655). Among the group with improved NHCAP, 11.3% (n=23/203) died in hospital before discharge. Although the causes of death in patients who improved after NHCAP were diverse, the most common was recurrence of pneumonia. Conclusions: Empirical antimicrobial therapy for NHCAP may not always require selection of broad-spectrum antimicrobial agents, as has been previously reported. Patients with NHCAP may die from other causes, even after NHCAP has improved.

Seasonal variation in the prevalence of Gram-negative bacilli in sputum and urine specimens from outpatients and inpatients.

Objectives: To determine whether the prevalence of gram-negative bacilli (GNB; Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli) in sputum and urine specimens from outpatients and inpatients differed by season and according to temperature and humidity changes. Methods: In this retrospective study, microbiologic data for adult patients from 2008 to 2019 were retrieved from the electronic database of a hospital in Japan. Data were categorized by specimen type (sputum and urine) and specimen collection (outpatient and inpatient). Associations between variables were assessed using Spearman's rank correlation coefficients. Differences between groups were assessed using Pearson's chi-square test and analysis of discrete variance. Results: Among inpatients, the frequencies of P. aeruginosa and K. pneumoniae isolation from sputum specimens were higher in summer and autumn. The frequency of P. aeruginosa isolation from urine specimens was higher in autumn. These seasonal trends were observed in specimens from both outpatients and inpatients. No seasonal trend was observed in the frequency of E. coli isolation. Mean monthly temperature was positively correlated with the frequency of isolating P. aeruginosa (r=0.2198, p=0.0081) and K. pneumoniae (r=0.3443, p=0.00002) from sputum as well as with the frequency of isolating K. pneumoniae (r=0.1905, p=0.0222) from urine. Mean monthly humidity was positively correlated with the frequency of isolating K. pneumoniae (r=0.2602, p=0.0016) from sputum. Conclusions: GNB were isolated more frequently in summer and autumn than in other seasons. These seasonal trends were observed for both outpatient and inpatient specimens. Seasonality should be considered for optimal infection control of GNB in hospitals.

Long-term monotherapy with suplatast tosilate in patients with mild atopic asthma: a pilot comparison with low-dose inhaled fluticasone.

BACKGROUND AND OBJECTIVE: Suplatast tosilate is a Th2 cytokine inhibitor that is effective for controlling persistent asthma. However, the long-term efficacy of suplatast is unknown. We compared the clinical efficacy of long-term monotherapy with suplatast tosilate with a low dose of inhaled steroids in patients with mild atopic asthma. METHODS: A total of 32 patients with mild atopic asthma were randomly assigned to receive suplatast (n=15) or fluticasone (n=17). In the suplatast group, 100 mg of suplatast was given orally 3 times a day (total daily dose = 300 mg) for 2 years. In the fluticasone group, 100 pg of fluticasone was inhaled twice a day (total daily dose = 200 tg) for 2 years. RESULTS: In the suplatast group, the improvements in peak expiratory flow (PEF) rate and forced expiratory volume in 1 second (FEV1) and the changes in the symptom diary scale and frequency of beta2 stimulant inhalation were generally similar to those in the fluticasone group, and efficacy was maintained for 2 years. Improvements in inflammatory indices, such as the sputum eosinophil cationic protein (ECP) level and exhaled nitric oxide concentration, were comparable in the suplatast and fluticasone groups. The improvement in airway hyperresponsiveness was also similar in the 2 groups. The peripheral blood eosinophil percent change, serum ECP level, and total IgE antibody titer improved only in the suplatast group. CONCLUSIONS: Long-term treatment with suplatast significantly improved symptoms and inflammatory indices in patients with mild atopic asthma. Along with fluticasone, suplatast is considered a useful drug for the management of mild atopic asthma.

Long-term clinical effects of an inhaler guidance DVD in patients with bronchial asthma.

OBJECTIVES: Erroneous use of inhalers is a serious problem. Given the multitude of devices currently available, it can be difficult to convey the correct methods for their efficient use to patients. We previously generated an educational DVD that visually and audibly explains the proper use of all inhaler types available in Japan to provide inhalation guidance to patients. Herein, we report the 1-year follow-up of patients who received or did not receive the DVD guidance. METHODS: Sixty-nine bronchial asthma patients undergoing outpatient treatment who received inhalation guidance from a pharmacist using a standard package insert were randomly allocated to a DVD group (n=35) or a no-DVD group (n=34). Their current oral or inhalant drug regimens were unchanged. Various parameters were measured 12 months later. Frequencies of aggravation during the 12-month period were also determined. RESULTS: Compared with the no-DVD group, there were significant improvements in asthma control test scores, forced vital capacity, FEV1, impulse oscillometry, resonant frequency, induced sputum eosinophil count, and FeNO in the DVD group after 12 months. Pulmonary function and inflammation parameters improved significantly with the use of the instructive DVD in addition to the package inserts. The frequency of asthma aggravation significantly decreased in the DVD group during the 12-month study period, likely because inhalation procedures were performed accurately. CONCLUSIONS: A DVD that provides accurate inhalation guidance enhances the quality of life of asthma patients and has substantial clinical ramifications. Thus, this tool would be beneficial for patients in Japan and worldwide.

Use of Assist Devices to Actuate Pressurized Metered-Dose Inhalers in Elderly Patients with Asthma.

INTRODUCTION: Some elderly patients experience difficulty when attempting to use pressurized metered-dose inhalers (pMDIs) due to reduced finger muscle strength. However, no studies have investigated the finger muscle strength required for pMDI actuation. Therefore, we created a modified pMDI pinch gauge and examined the finger muscle strength in elderly asthmatic patients with and without the use of a pMDI assist device to push the canister. METHODS: We measured the finger muscle strength (N) required to spray pMDI formulations (Adoair®, Alvesco®, Flutiform®, and Breztri®) using one hand in healthy individuals. We then similarly measured the finger muscle strength when using the modified pinch gauge in older adults aged 65 years or older with bronchial asthma who used pMDI formulations. RESULTS: The finger muscle strength required to actuate these devices was 29.4 N or more in healthy individuals. In the older patients with asthma, the finger muscle strength was 38.45 ± 5.80 N in men and 31.34 ± 9.94 N in women. The finger muscle strength was ≤ 29.4 N in 6.6% of men and 40.0% of women. CONCLUSIONS: Finger muscle strength should be considered when selecting a device for older patients with asthma, and the use of a pMDI assist device to push the canister is recommended in patients with weaker finger muscles.

The impact of the COVID-19 pandemic on asthma treatment in Japan: Perspectives based on doctors' views.

The coronavirus disease 2019 (COVID-19) pandemic has had a great influence on medical practice in Japan. In this study, an online questionnaire-based survey was conducted among doctors routinely involved in the treatment of asthma. The questions included in the survey pertained to their thoughts on asthma treatment amidst COVID-19, changes in their clinical approach toward patients with asthma, and the behavioral changes in patients in the pandemic era. The results revealed a significant impact of the pandemic on asthma treatment. Regardless of whether or not they were directly involved in the treatment of patients with COVID-19, the doctors had avoided using nebulizers in outpatient wards/clinics and routine pulmonary function testing. An increase in canceled appointments and inappropriate/non-adherence to treatment among their patients were noticeable. Furthermore, the survey revealed an extensive impact of the pandemic on the doctors engaged in asthma treatment irrespective of the differences in their medical backgrounds.

Evaluation of the pneumococcal urinary antigen test (PUT): a retrospective study.

OBJECTIVES: To determine the usefulness of the pneumococcal urinary antigen test (PUT) and to describe the characteristics of pneumococcal pneumonia. METHODS: In this retrospective study, we examined the effects of prior antibiotic treatment, pneumonia onset period, and sputum quality on the results of PUT. Clinical information was collected via medical records from all adult patients who were hospitalized at the Fujita Health University Bantane Hospital with "pneumonia" as a new diagnosis from April 2015 to March 2018. RESULTS: A total of 482 patients with pneumonia were included, of whom 103 had pneumococcal pneumonia. The frequency of PUT positivity did not differ significantly in patients with a pneumonia onset period of ≥3 days compared with those with a period of ≤2 days (P=0.514). Patients with a history of prior antimicrobial therapy had a significantly lower rate of positive sputum culture vs those with no such history (P=0.005); however, PUT positivity in the two groups did not differ significantly (P=0.367). CONCLUSIONS: Our results showed that urinary antigen testing for pneumococcal pneumonia is useful for diagnosis regardless of prior antibiotic treatment and time since symptom onset.