堀口 高彦

BACKGROUND: The genetic factors contributing to exacerbations in type 2-low asthma are not well understood. OBJECTIVE: We sought to clarify the association between variants in gasdermin B/orosomucoid-like 3 (GSDMB/ORMDL3) on 17q21 and exacerbations in type 2-low asthma. METHODS: This follow-up study of the multicenter Kinki Hokuriku Airway disease Conference (KiHAC) enrolled adults with asthma who were receiving inhaled corticosteroids. It examined associations between asthma exacerbations requiring systemic corticosteroids over 2 years and clinical and genetic factors in patients with the type 2-low endo-genotype, defined by serum periostin levels lower than 95 ng/mL and the IL4RA rs8832 A allele. Exacerbation risks were also evaluated in patients with the type 2-low genotype, defined by both the POSTN rs3829365 C allele and the IL4RA rs8832 A allele, using the KiHAC and replication cohorts. The genetic variant rs7216389 in GSDMB was the primary focus for assessing genetic risk. RESULTS: A total of 115 patients with the type 2-low endo-genotype were analyzed (mean age, 62 years; 76.5% female). During the 2-year follow-up, 32 patients experienced 1 or more exacerbation. Multivariate analysis identified the rs7216389 TT genotype, recent exacerbations, female sex, and higher body mass index as independent risk factors for asthma exacerbations in patients with the type 2-low endo-genotype. The association between the rs7216389 TT genotype and exacerbations was confirmed in patients with the type 2-low genotype in the KiHAC (n = 89) and replication (n = 125) cohorts. CONCLUSIONS: The rs7216389 TT variant on 17q21 may be an independent risk factor for exacerbations in adults with type 2-low asthma, highlighting the role of GSDMB in its pathophysiology.

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.

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.

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.

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.

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.

There is a concern that persons with underlying respiratory disease may have increased susceptibility to COVID-19 and/or increased severity/mortality if infected. However, information regarding such patients during the first wave of the epidemic is lacking in Japan. We surveyed chest physicians nationwide, and collected anonymous data concerning 1444 patients. Among COVID-19 patients, the prevalence of asthma, chronic obstructive pulmonary disease (COPD), and interstitial lung diseases (ILD) was 3.4%, 4.8%, and 1.5%, respectively. Among COVID-19 patients with these 3 comorbidities, exacerbation of the comorbidity occurred in 12.2%, 18.8%, and 36.4%, respectively, and mortality (6.2% overall) was 4.1%, 13.0%, and 31.8%, respectively. The prevalence of asthma among COVID-19 patients was not higher than that for the general population, and mortality in COVID-19 patients with asthma was not higher than mortality in COVID-19 patients without underlying respiratory disease. COVID-19 patients having COPD or ILD had relatively high mortality, especially for ILD.

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.

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.

69歳男性。3ヵ月前からの発熱、咳嗽を主訴に近医を受診し、胸部X線にて右中下肺野の腫瘤影を指摘され、当院へ紹介となった。胸部CTでは右下葉に内部不均一な90×88mm大の腫瘤が認められ、CT下経皮針生検を2回旋行するも確定診断とはならなかった。血液検査では炎症反応の上昇を認め、膿胸の疑いで抗菌薬治療を開始するも症状や画像所見は改善せず、経気管支肺生検を行った結果、肺扁平上皮癌と診断された。診断後は抗癌剤治療を提案したが、患者が緩和ケアを希望したため、緩和ケア科のある総合病院へ転院となった。