Serum IL-28A/IFN-λ2 is linked to disease severity of COVID-19.

Type III interferons (IFNs) play an important role in respiratory viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This study aimed to determine whether the expression of serum type III IFNs predicted disease severity among patients with the coronavirus disease (COVID-19). A retrospective cohort study was conducted of patients admitted to a single hospital between March 21, 2020, and March 31, 2021. Patients were divided into mild to moderate I (MM) and moderate II to severe (MS) groups based on the COVID-19 severity classification developed by the Japanese Ministry of Health, Labor and Welfare. A total of 257 patients were included in the analysis. Human interleukin-28A (IL-28A/IFN-λ2) expression was significantly lower, and interleukin (IL)-6 expression was significantly higher in the MS group than in the MM group (both p < 0.001). In addition, IL-28A/IFN-λ2 was statistically significantly inversely correlated with the time from disease onset to negative SARS-CoV-2 PCR results (p = 0.049). Multivariable logistic regression analysis showed that IL-28A/IFN-λ2 was an independent predictor of disease severity (p = 0.021). The low expression of IL-28A/IFN-λ2 may serve as a serum biomarker that predicts the severity of COVID-19, possibly through the mechanism of delayed viral elimination.

Comprehensive Gene Expression Signature Using RNA-Seq in Airways of Mouse Model of Severe Asthma with Fungal Sensitization.

INTRODUCTION: Inhalation of fungal allergens induces airway epithelial damage following airway inflammation and excessive mucus secretion, which can lead to severe asthma with fungal sensitization (SAFS). Comprehensive gene expression analysis in Alternaria-exposed mouse airways, a model of SAFS, has not been conducted. METHODS: BALB/c mice received intranasal administration of Alternaria extract or phosphate-buffered saline twice a week for 6 weeks. Lung sections and bronchoalveolar lavage fluid were obtained to assess airway inflammation. RNA-Seq in the central airway was performed, and gene ontology (GO) analysis and gene set enrichment analysis (GSEA) were conducted for pathway analyses. An in vitro experiment using human airway epithelial cell 16HBE14o- was performed to validate the RNA-Seq findings. RESULTS: Eosinophilic airway inflammation with mucus overproduction and airway remodeling was observed in mice exposed to Alternaria. RNA-Seq analysis revealed 403 upregulated and 108 downregulated genes in airways of Alternaria-exposed mice. In GO analysis, the functions of immunoglobulin (Ig) receptor binding, Ig production, inflammatory response, and T-cell activation were upregulated, while those of keratinization and defense response to other organisms were downregulated. GSEA revealed positive enrichment in T-cell receptor complex, immunological synapse, antigen binding, mast cell activation, and Ig receptor binding, and negative enrichment in keratinization and cornification in Alternaria-exposed mice relative to control. Alternaria exposure to 16HBE14o- cells validated the downregulation of epithelial keratinization-related genes, including SPRR1A, SPRR1B, and KRT6B. CONCLUSION: RNA-Seq analysis showed that Alternaria exposure induced inflammatory response and impaired defense mechanisms in mice airway epithelium, which might be therapeutic targets for SAFS.

Mepolizumab improved airway hyperresponsiveness in a patient with allergic bronchopulmonary aspergillosis.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is a severe type of asthma characterized by hypersensitivity to Aspergillus fumigatus and lung infiltration with eosinophilia. The central pathogenesis of asthma is airway hyperresponsiveness (AHR), with eosinophils playing a critical role. Anti-interleukin (IL)-5 antibody therapy has been recently introduced to treat severe asthma, which reportedly inactivates and reduces eosinophil count. A recent case series highlighted the improvement in asthmatic symptoms associated with ABPA, but previous reports failed to demonstrate any improvement in AHR. OBJECTIVE: Herein, we aimed to elucidate the efficacy of mepolizumab in a patient with ABPA who showed improvement in AHR. METHODS: Case report. RESULTS: A 63-year-old Asian woman with ABPA showed improvement in asthmatic symptoms and AHR following mepolizumab therapy. CONCLUSIONS: Our results suggest that IL-5 may serve in the pathogenesis of ABPA.

Characteristics of and reasons for patients with chronic obstructive pulmonary disease to continue smoking, quit smoking, and switch to heated tobacco products.

INTRODUCTION: Smoking is the leading cause of chronic obstructive pulmonary disease (COPD), and smoking cessation is the most effective treatment for patients with COPD. However, few studies have investigated the continuation/cessation of smoking and heated tobacco products (HTP) in patients with COPD. The objective of this study was to examine the characteristics of patients with COPD, those who are current smokers and those who switched from cigarettes to HTP, and to examine the reason for the continuation or cessation of smoking. METHODS: This multicenter, cross-sectional study included 411 outpatients with COPD. Data for this study were part of a study conducted for a comprehensive evaluation of the smoking status and clinical factors in patients with COPD and their families. RESULTS: Logistic regression analysis revealed that a younger age, longer duration of smoking, fewer daily cigarettes, and lower modified Medical Research Council (mMRC) dyspnea score, and a lower Simplified Nutritional Appetite Questionnaire (SNAQ) score for appetite, were characteristics of current smokers (age OR=0.94; duration of smoking OR=1.07; number of cigarettes per day OR=0.94; mMRC OR=0.68; SNAQ OR=0.83; p<0.05). The logistic regression analysis model showed that a younger age and higher education level were associated with the use of HTP (age OR=0.83; higher education level OR=4.63; p<0.05). Many of the current smokers displayed smoking behaviors that are not guaranteed to be safe, such as reducing smoking or switching to lighter cigarettes or HTP. CONCLUSIONS: Patients with COPD who continue smoking tended to have low appetite as well as smoking behaviors that are not guaranteed to be safe. Physicians should provide appropriate guidance to these patients on smoking cessation.

Extracorporeal Membrane Oxygenation for Secondary Organizing Pneumonia after Severe SARS-CoV-2 Infection: A Case Report.

(Background) COVID-19 is caused by SARS-CoV-2 infection and may result in unfavorable outcomes. A recent large-scale study showed that treatment with dexamethasone leads to favorable outcomes in patients with severe COVID-19, and the use of extracorporeal membrane oxygenation (ECMO) has also been shown to improve outcomes. Recently, secondary organizing pneumonia (SOP) has been reported after SARS-CoV-2 infection, but the diagnostic and treatment strategies are still unclear. (Case presentation) Here, we report a patient with severe COVID-19 who developed SOP even after the use of dexamethasone, for whom the introduction of ECMO on the 19th day after hospitalization led to a favorable outcome. (Conclusions) Life-threatening SOP may evolve even after the use of dexamethasone, and the late-phase introduction of ECMO may save such patients with COVID-19.

Investigating Patient and Family Satisfaction with the Respiratory Status in Patients with Chronic Obstructive Pulmonary Disease.

The current chronic obstructive pulmonary disease (COPD) management aims to improve the patients' quality of life and healthy life expectancy; however, few studies have evaluated the level of satisfaction with the patients' current respiratory status in COPD patients and their families. This study aimed to examine the level of patient and family satisfaction with the patients' current respiratory status and to identify the clinical factors closely linked to dissatisfaction.This multicenter, cross-sectional study included 454 outpatients with COPD and 296 family members. Patients and families were allocated to the satisfied and dissatisfied groups based on their satisfaction with the patients' current respiratory status. Patients' health status, dyspnoea, appetite, respiratory function, and mood disorders were assessed.Among the participants of this study, 67% of patients and 60% of their families were dissatisfied with the patients' current respiratory status. The COPD assessment test (CAT) was the most sensitive marker of dissatisfaction compared to other clinical factors (p < 0.01). The statistical cut-off value of CAT for predicting patient dissatisfaction was 11. CAT reflected patient dissatisfaction independent of age, sex, dyspnoea, appetite, mood disorders, body mass index, and respiratory function (odds ratio: CAT; 1.12 (1.07-1.19): p < 0.01).Many patients and families are dissatisfied with the patients' respiratory status, and the patients' CAT score is useful to predict dissatisfaction. Our findings are consistent with the Global Initiative for Chronic Obstructive Lung Disease indicating that treatment should be enhanced in patients with a CAT score ≥10. Furthermore, treatment strategies targeting CAT may contribute to an improved patient satisfaction.

Utility of Basophil Activation Test in a Case of Daisaikoto- and Yokukansan-induced Lung Injury.

Drug-induced lung injury is defined as a respiratory disorder. The usefulness of the basophil activation test (BAT) for drug allergy-related cases was recently reported. The patient was an 82-year-old woman who had been taking Daisaikoto and Yokukansan (herbal medicines) 3 months before developing dry cough. She was admitted to our hospital with an initial diagnosis of pneumonia with elevated serum LDH, KL-6, and IgE. Chest CT showed bilateral ground-glass opacities. Her bronchoalveolar lavage fluid showed increased eosinophils. Finally, a BAT was positive for both medications. Based on the findings, the patient was diagnosed with Daisaikoto- and Yokukansan-induced lung injury. The current case suggests that the BAT may be useful for the diagnosis of drug-induced lung injury.

The Relationship Between the "Adherence Starts with Knowledge-20" Questionnaire and Clinical Factors in Patients with COPD: A Multi-Center, Cross-Sectional Study.

Purpose: Inhaler therapy is the mainstay of chronic obstructive pulmonary disease (COPD) management. Poor adherence causes disease exacerbation and affects patient mortality. Although the Adherence Starts with Knowledge-20 (ASK-20) questionnaire is a reliable tool for assessing medication adherence, the relationship between the ASK-20 and clinical factors in patients with COPD remains unknown. We investigated the relationship between the ASK-20 and clinical factors, and assessed real-world inhaler therapy use. Patients and Methods: A multicenter, cross-sectional study of outpatients with COPD undergoing inhaler treatment who completed the ASK-20 questionnaire was performed. We investigated COPD-related health status using the COPD Assessment Test (CAT), psychological status using the Hospital Anxiety and Depression Scale (HADS-anxiety and HADS-depression), respiratory function, patient satisfaction levels, and real-world inhaler therapy use. Results: Of the total 319 patients, 87% were male with a median age of 74 years. Most patients had mild or moderate COPD, according to Global Initiative for Chronic Obstructive Lung Disease stage. The total ASK-20 scores correlated significantly with the CAT, HADS-anxiety, and HADS-depression scores (r = 0.27, 0.33, and 0.29, respectively, p < 0.01). Multivariable analysis showed that CAT and HADS-anxiety scores had an independent and significant impact on the ASK-20 scores [ß, standardized regression coefficient: 0.18 (95% CI, 0.03-0.35; p = 0.02), and 0.29 (95% CI, 0.17-0.42; p < 0.01), respectively]; however, the ASK-20 scores were not correlated with age, sex, body mass index, cohabitation, modified Medical Research Council Dyspnea Scale score, pulmonary function, disease duration, number of COPD exacerbations per year, comorbidities, inhaler numbers, nor inhaler components. Conclusion: The ASK-20 scores in patients with COPD were significantly associated with CAT and HADS scores. In Japan, Respimat was prescribed to younger patients and patients with lower CAT scores. The ASK-20, a simple evaluation method, is useful for identifying clinical factors affecting adherence in patients with COPD.

Correlation of Arterial CO2 and Respiratory Impedance Values among Subjects with COPD.

Chronic obstructive pulmonary disease (COPD) is a respiratory illness characterized by airflow limitation and chronic respiratory symptoms with a global prevalence estimated to be more than 10% in 2010 and still on the rise. Furthermore, hypercapnic subject COPD leads to an increased risk of mortality, morbidity, and poor QoL (quality of life) than normocapnic subjects. Series of studies showed the usefulness of the forced oscillation technique (FOT) to measure small airway closure. Traditional findings suggested that hypercapnia may not be the main treating targets, but recent findings suggested that blood stream CO2 may lead to a worse outcome. This study aimed to seek the relationship between CO2 and small airway closure by using FOT. Subjects with COPD (n = 124; hypercapnia 22 and normocapnia 102) were analyzed for all pulmonary function values, FOT values, and arterial blood gas analysis. Student's t-test, Spearman rank correlation, and multi linear regression analysis were used to analyze the data. COPD subjects with hypercapnia showed a significant increase in R5, R20, Fres, and ALX values, and a greater decrease in X5 value than normocapnic patients. Also, multiple linear regression analysis showed R5 was associated with hypercapnia. Hypercapnia may account for airway closure among subjects with COPD and this result suggests treating hypercapnia may lead to better outcomes for such a subject group.

Combination treatment of short-course systemic corticosteroid and favipiravir in a successfully treated case of critically ill COVID-19 pneumonia with COPD.

Use of systemic corticosteroids for the treatment for coronavirus disease 2019 (COVID-19) among chronic obstructive pulmonary disease (COPD) patients is not well described. A 58-year-old man with fever and progressive dyspnea was admitted to the Showa University Hospital, and showed severe respiratory failure which needed mechanical ventilation. His chest computed tomography scanning showed emphysema and bilateral ground-glass opacity caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. He received 30 mg prednisolone for five days with antiviral drug of favipiravir, and was successfully extubated on day five. A SARS-CoV-2 polymerase chain reaction (PCR) test became negative on day 15. He was discharged on day 21. Serum IgM and IgG antibodies against SARS-CoV-2 converted to positive on day 7 and they kept positive on day 54 for both IgM and IgG. Combination treatment of short-course systemic corticosteroid and favipiravir might improve the prognosis for critically ill COVID-19 pneumonia with COPD without negative influence on viral clearance or antibody production.

Oral meal intake as a prognostic predictor of community-acquired pneumonia: A retrospective cohort study.

INTRODUCTION: The association between oral intake volume and prognosis has not been studied in hospitalized patients with community-acquired pneumonia (CAP). METHODS: We retrospectively examined 503 hospitalized CAP patients to evaluate whether early-phase meal intake (EMI) (within the first 24 h after hospitalization) and maximum meal intake (MMI) (on the day during hospitalization) are useful prognostic predictors. RESULTS: Of the 503 patients, 40 (8.0%) died within 30 days. Area under the curve (AUC) for prognosis was comparable between EMI, A-DROP, and serum albumin [EMI: 0.80, 95% confidence interval (CI) 0.75-0.84; A-DROP: 0.77, 95% CI 0.71-0.83; Serum albumin: 0.72, 95% CI 0.64-0.79]. Mortality rate was <1% in patients with EMI ≥ 50%. Univariate analysis showed that patients with EMI < 50% showed poor prognosis [odds ratio 53.4, 95% CI 7.2-392.2]. Multivariate analysis showed that EMI was an independent prognostic predictor [odds ratio 23.6, 95% CI 3.11-179.7]. AUC of MMI for prognosis was 0.94 (95% CI 0.91-0.96); mortality rate was <1% for patients who ingested ≥50% of meals on any day during hospitalization. We defined ingesting ≥50% of meals on any day during hospitalization as oral intake stability. Multivariate analyses revealed an association between oral intake stability and prognosis. Odds ratio of oral intake stability for prognosis was higher than that of conventional evaluations (vital sign and CRP level stability). Fewer days were required to reach oral intake stability than to reach vital sign and CRP level stability. CONCLUSIONS: Oral intake is a simple, non-invasive, cost-free, and powerful prognostic predictor for patients with CAP.

Beneficial Effect of Early Intervention with Garenoxacin for Bacterial Infection-Induced Acute Exacerbation of Bronchial Asthma and Chronic Obstructive Pulmonary Disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and asthma have similar clinical features and are both exacerbated by airway infection. OBJECTIVE: To determine whether garenoxacin mesylate hydrate (GRNX) added to the standard care for bacterial infection-induced acute exacerbation of asthma or COPD in adults has clinical benefits. METHOD: This single-arm clinical trial was conducted from January 2015 to March 2016. Adults with a history of asthma or COPD for more than 12 months were recruited within 48 h of presentation with fever and acute deterioration of asthma or COPD requiring additional intervention. Participants were administered 400 mg GRNX daily for 7 days without additional systemic corticosteroids or other antibiotics. The primary outcome was efficacy of GRNX based on clinical symptoms and blood test results after 7 days of treatment. Secondary outcomes were: (1) comparison of the blood test results, radiograph findings, and bacterial culture surveillance before and after treatment; (2) effectiveness of GRNX after 3 days of administration; (3) analyzation of patient symptoms based on patient diary; and (4) continued effectiveness of GRNX on 14th day after the treatment (visit 3). RESULTS: The study included 44 febrile patients (34 asthma and 10 COPD). Frequently isolated bacteria included Moraxella catarrhalis (n = 6) and Klebsiella pneumoniae (n = 4). On visit 2, 40 patients responded, and no severe adverse events were observed. All secondary outcomes showed favorable results. CONCLUSION: GRNX effectively treated asthma and COPD patients with acute bacterial infection without severe adverse events. Further research with a larger study population is needed.

Association between respiratory impedance measured by forced oscillation technique and exacerbations in patients with COPD.

Background: It is well known that increased airflow limitation as measured by spirometry is associated with the risk of exacerbation in patients with COPD. The forced oscillation technique (FOT) is a noninvasive method used to assess respiratory impedance (resistance and reactance) with minimal patient cooperation required. The clinical utility of the FOT in assessing the risk of exacerbations of COPD is yet to be determined. We examined the relationship between respiratory impedance as measured by FOT and exacerbations in patients with COPD. Materials and methods: Among 310 patients with COPD (Global Initiative for Chronic Obstructive Lung Disease stages I-IV) who presented at the outpatient clinic of the Showa University Hospital from September 2014 through January 2015, 119 were collected and assigned into 2 groups according to their history of exacerbation: exacerbators and nonexacerbators. Respiratory resistance components and respiratory reactance components, as measured by FOT, were compared between the two groups. Results: Exacerbators were significantly older and had a higher white blood cell count than nonexacerbators. Resistance at 20 Hz, reactance at 5 Hz (X5), resonant frequency (Fres), and area of low reactance (ALX) differed significantly between the two groups. In addition, among patients with stage II COPD, there were significant differences in X5, Fres, and ALX between the two groups despite no significant differences in respiratory function as assessed by spirometry. Finally, receiver operating characteristic curve analysis revealed that the reactance components rather than the resistance components were associated with the risk of exacerbation. Conclusion: There were significant differences in respiratory impedance between exacerbators and nonexacerbators in patients with moderate COPD. FOT is a promising tool for assessing future exacerbations in patients with COPD.

Nattokinase-promoted tissue plasminogen activator release from human cells.

When heated to a temperature of 70 degrees C or higher, the strong fibrinolytic activity of nattokinase in a solution was deactivated. Similar results were observed in the case of using Suc-Ala-Ala-Pro-Phe-pNA and H-D-Val-Leu-Lys-pNA, which are synthetic substrates of nattokinase. In the current study, tests were conducted on the indirect fibrinolytic effects of the substances containing nattokinase that had been deactivated through heating at 121 degrees C for 15 min. Bacillus subtilis natto culture solutions made from three types of bacteria strain were heat-treated and deactivated, and it was found that these culture solutions had the ability to generate tissue plasminogen activators (tPA) from vascular endothelial cells and HeLa cells at certain concentration levels. For example, it was found that the addition of heat-treated culture solution of the Naruse strain (undiluted solution) raises the tPA activity of HeLa cells to about 20 times that of the control. Under the same conditions, tPA activity was raised to a level about 5 times higher for human vascular endothelial cells (HUVEC), and to a level about 24 times higher for nattokinase sold on the market. No change in cell count was observed for HeLa cells and HUVEC in the culture solution at these concentrations, and the level of activity was found to vary with concentration.

Molecular cytogenetic identification of nullisomy 5B induced homoeologous recombination between wheat chromosome 5D and barley chromosome 5H.

Chromosome 5H of Hordeum vulgare 'New Golden' (NG) carries a gene(s) that accelerates heading in a wheat background. To introduce the early heading gene(s) of NG barley into the wheat genome, we attempted to induce homoeologous recombination between wheat and NG 5H chromosomes by 5B nullisomy. A nullisomic 5B, trisomic 5A, monosomic 5H plant (2n = 42) was produced from systematic crosses between aneuploid stocks of wheat group 5 chromosomes. A total of 656 F2 plants produced by self-fertilization were screened for recombinants by a PCR assay with 3 5H-specific amplicon markers. Twelve plants (1.8%) were selected as putative wheat-barley 5H recombinants. Five of them were inviable or sterile and the remaining 7 were fertile and subjected to the progeny test. Cytological analyses using fluorescence in situ hybridization and C-banding revealed that 6 of the 7 progeny lines are true homoeologous recombinants between the long arms of chromosomes 5D and 5H, but that the other one was not a recombinant having an aberrant barley telosome. The 6 cytologically confirmed recombinant lines included only 2 types (3 lines each), which were reciprocal products derived from exchanges at the same distal interval defined by two flanking markers. One type had a small 5HL segment translocated to the 5DL terminal, and the other type had a small terminal 5DL segment translocated to the 5HL terminal. In the latter type, the physical length of translocated barley segments slightly differed among lines. Homoeologous recombinants obtained in this study should be useful for further chromosome manipulation to introgress a small interstitial 5HL chromosome segment with the early heading gene(s) to wheat. Preferential occurrence of restricted types of recombinants is discussed in relation to homoeologous relationships between wheat and barley chromosomes.

Differential effects of cultivated and wild barley 5H chromosomes on heading characters in wheat-barley chromosome addition lines.

Wheat (Triticum aestivum L.)-barley (Hordeum vulgare L.) chromosome addition lines are possible vehicles for transferring barley genes into wheat. The barley 5H chromosome has genetic effects on the heading characters in wheat-barley addition lines: accelerating narrow-sense earliness, decreasing vernalization requirement and/or increasing photoperiodic sensitivity. To elucidate the effects of different 5H chromosomes under an identical wheat genetic background, two wheat-barley addition lines, i.e. cultivated barley 'New Golden' 5H chromosome added to 'Shinchunaga' wheat (Shi-NG5H) and wild barley H. vulgare ssp. spontaneum 5H chromosome added to 'Shinchunaga' wheat (Shi-Spn5H), were examined for their heading characters. The addition line Shi-NG5H showed a significantly lower vernalization requirement in comparison with 'Shinchunaga' wheat, whereas Shi-Spn5H did not. Furthermore, both NG5H and Spn5H chromosomes shortened narrow-sense earliness and increased photoperiodic sensitivity in wheat, but the effects of Spn5H were weaker than those of NG5H. The fact that NG5H and Spn5H showed differential effects on heading characters in wheat demonstrated that the heading characters were altered by the function of the barley genes located on 5H chromosomes, not merely by the aneuploid effect alone.