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.

Acute Exacerbation of Idiopathic Interstitial Pneumonia Triggered by Cardiac Ablation: The First Case Report.

Acute exacerbation of idiopathic interstitial pneumonia (AE-IIP) is associated with invasive procedures and respiratory infections. However, there have been no reports of AE-IIP triggered by catheter ablation. We herein report a case of AE-IIP after catheter ablation for atrial fibrillation in an 82-year-old man who was diagnosed with IIP. Cardiac ablation has become an increasingly common procedure for managing patients with arrhythmias. Considering that catheter ablation causes AE-IIP, a detailed clinical interview, physical examination, and chest radiography are necessary before catheter ablation. We should additionally consider AE-IIP as a differential diagnosis of respiratory failure after catheter ablation.

Spontaneous sputum discriminates inflammatory phenotypes in patients with asthma.

BACKGROUND: Eosinophils in induced sputum are not only a useful biomarker for diagnosing asthma but are also associated with severe asthma. However, little is known about the association between eosinophils in spontaneous sputum and asthma severity. OBJECTIVE: To investigate whether spontaneous sputum eosinophils are related to severe asthma in adult patients with asthma. METHODS: We conducted a retrospective cross-sectional study on 86 people with asthma whose spontaneous sputa were successfully collected. Patients were classified into 4 phenotypes according to the eosinophil and neutrophil levels in spontaneous sputum. We determined the association between inflammatory phenotypes and severe asthma. Moreover, we also compared asthma severity among the phenotypes classified according to blood eosinophils and spontaneous sputum eosinophils. RESULTS: Asthma phenotypes were as follows: paucigranulocytic, 30.2%; neutrophilic, 18.6%; eosinophilic, 32.6%; and mixed, 18.6%. People with eosinophilic asthma had the highest blood eosinophils, total immunoglobulin E (IgE), and fractional exhaled nitric oxide among the 4 phenotypes. Significant differences were observed in asthma severity between the phenotypes (P = .019). In particular, 57.2% and 56.2% of patients had severe eosinophilic asthma and mixed asthma, respectively. The logistic regression analysis revealed that spontaneous sputum eosinophilia represented the strongest association with severe asthma among the inflammatory variables. Finally, more patients with severe asthma were included in the phenotype with spontaneous sputum eosinophils greater than 3% and blood eosinophils less than or equal to 300/µL and in the phenotype with spontaneous sputum eosinophils greater than 3% and blood eosinophils greater than 300/µL. CONCLUSION: Spontaneous sputum can provide helpful information on airway inflammatory phenotyping in patients with asthma.

Serum creatinine/cystatin C ratio as a surrogate marker for sarcopenia in patients with chronic obstructive pulmonary disease.

BACKGROUND & AIMS: Sarcopenia is common in patients with chronic obstructive pulmonary disease (COPD). Serum creatinine/cystatin C (Cr/CysC) ratio has attracted attention as a surrogate marker for sarcopenia but has not been adequately studied in patients with COPD. Thus, the purpose of this study was to investigate the validity of serum Cr/CysC ratio as a predictor of sarcopenia, evaluate a statistical cut-off value, and assess the relationship between Cr/CysC ratio and clinical factors. METHODS: In this prospective observational study, we enrolled 234 male outpatients with COPD. We determined the relevance of serum Cr/CysC ratio as a surrogate maker for sarcopenia by comparing it with various biomarkers and prospectively investigated the relationship of Cr/CysC ratio with the annual exacerbation rate. RESULTS: Serum Cr/CysC was significantly correlated with handgrip strength (r = 0.53, P < 0.01) and muscle mass (r = 0.44, P < 0.01). The area under the curve for sarcopenia was significantly larger for serum Cr/CysC ratio than for other biomarkers (Cr/CysC: 0.87, CysC: 0.63, Cr: 0.61, albumin: 0.57). Multivariate analysis showed no significant difference in the frequency of acute exacerbations between patients in the low- and high-Cr/CysC group, defined by the cutoff value 0.71; however, the frequency of severe acute exacerbations was significantly higher in the low-Cr/CysC group. CONCLUSION: Serum Cr/CysC ratio can be used accurately, inexpensively, and easily to evaluate sarcopenia in male patients with COPD. Our study shows that patients with Cr/CysC below 0.71 have poor physical clinical factors and are at high risk of severe acute COPD exacerbations.

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.

Airway Epithelial Dysfunction in Asthma: Relevant to Epidermal Growth Factor Receptors and Airway Epithelial Cells.

Airway epithelium plays an important role as the first barrier from external pathogens, including bacteria, viruses, chemical substances, and allergic components. Airway epithelial cells also have pivotal roles as immunological coordinators of defense mechanisms to transfer signals to immunologic cells to eliminate external pathogens from airways. Impaired airway epithelium allows the pathogens to remain in the airway epithelium, which induces aberrant immunological reactions. Dysregulated functions of asthmatic airway epithelium have been reported in terms of impaired wound repair, fragile tight junctions, and excessive proliferation, leading to airway remodeling, which contributes to aberrant airway responses caused by external pathogens. To maintain airway epithelium integrity, a family of epidermal growth factor receptors (EGFR) have pivotal roles in mechanisms of cell growth, proliferation, and differentiation. There are extensive studies focusing on the relation between EGFR and asthma pathophysiology, which describe airway remodeling, airway hypermucus secretion, as well as immunological responses of airway inflammation. Furthermore, the second EGFR family member, erythroblastosis oncogene B2 (ErbB2), has been recognized to be involved with impaired wound recovery and epithelial differentiation in asthmatic airway epithelium. In this review, the roles of the EGFR family in asthmatic airway epithelium are focused on to elucidate the pathogenesis of airway epithelial dysfunction in asthma.

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.

[A CASE OF ANAPHYLAXIS DUE TO STINGING OF A Brachyponera chinensis].

The case involved a man in his forties. While working at the restaurant that the patient runs, the patient experienced a stab-like pain on the left shoulder and developed systemic pruritic eruptions. He was diagnosed with anaphylaxis upon visiting our emergency department. Conjunctival hyperemia, lip swelling, cold sweats, and nausea presented later. A cap fluorescence enzyme immunoassay using the serum of the patient showed specific immunoglobulin E (IgE) positivity for wasps; therefore, we hypothesized that he had anaphylaxis caused by the insect's sting. Insects of the same species as that by which the patient had been stung were collected and finally identified as the Asian needle ant (Brachyponera chinensis). The freeze-dried insects' bodies were sonicated into powders and stored for following examinations. Next, a basophil activation test was performed using the patient's whole blood treated with the reagent above, which showed positivity. Furthermore, a skin prick test using the same reagent showed a positive result, and the reaction increased in a concentrationdependent manner. Based on these results, the patient was diagnosed with anaphylaxis after a sting by the ant. Based on the results of the allergen component specific IgE test, we speculated that the pathogens in this case was group5 allergen of the Asian needle ant. Anaphylaxis following insect stings by this ant has been reported frequently in South Korea. However, it is quite rare in Japan, although the ant is native to Japan. Clinicians should consider that this allergy can occur indoors, unlike allergies to other types of venom.

Virus-Induced Asthma Exacerbations: SIRT1 Targeted Approach.

The prevalence of asthma has increased worldwide. Asthma exacerbations triggered by upper respiratory tract viral infections remain a major clinical problem and account for hospital admissions and time lost from work. Virus-induced asthma exacerbations cause airway inflammation, resulting in worsening asthma and deterioration in the patients' quality of life, which may require systemic corticosteroid therapy. Despite recent advances in understanding the cellular and molecular mechanisms underlying asthma exacerbations, current therapeutic modalities are inadequate for complete prevention and treatment of these episodes. The pathological role of cellular senescence, especially that involving the silent information regulator 2 homolog sirtuin (SIRT) protein family, has recently been demonstrated in stable and exacerbated chronic respiratory disease states. This review discusses the role of SIRT1 in the pathogenesis of bronchial asthma. It also discusses the role of SIRT1 in inflammatory cells that play an important role in virus-induced asthma exacerbations. Recent studies have hypothesized that SIRT1 is one of major contributors to cellular senescence. SIRT1 levels decrease in Th2 and non-Th2-related airway inflammation, indicating the role of SIRT1 in several endotypes and phenotypes of asthma. Moreover, several models have demonstrated relationships between viral infection and SIRT1. Therefore, targeting SIRT1 is a novel strategy that may be effective for treating virus-induced asthma exacerbations in the future.

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.

Usefulness of Ninjin'yoeito for Chronic Obstructive Pulmonary Disease Patients with Frailty.

Objectives: Frail patients with chronic obstructive pulmonary disease (COPD) have a higher risk of mortality, mood disorder, and poor quality of life (QOL). There are few intervention studies in frail patients with COPD, and there is a need for an effective therapy. Ninjin'yoeito (NYT) is a Kampo medicine that has been reported to improve fatigue, psychosomatic vulnerability, and respiratory symptoms. We examined the efficacy of NYT in frailty or prefrailty patients with COPD. Design: Prospective, single-center, open-label, randomized controlled trial. Location: Showa University Hospital, Tokyo, Japan. Subjects: Sixty-two patients (53 males and 9 females) with a mean age of 76 ± 6 years were included in the analysis. Interventions: The patients were divided into two groups: the NYT group (n = 31) and the control (standard treatment) group (n = 31). Outcome measures: The primary outcome was changes in Kihon checklist (KCL) scores at week 24, which reflect changes in frailty. The secondary outcomes were changes in the following assessment scores at week 24: Simplified Nutritional Appetite Questionnaire (SNAQ) scores, which reflect changes in appetite; COPD Assessment Test (CAT) scores, which reflect changes in QOL in patients with COPD; Hospital Anxiety and Depression Scale (HADS)-Anxiety scores, which reflect changes in anxiety; and HADS-Depression scores, which reflect changes in depression. Results: There was a slight but not significant difference in changes in KCL scores between the NYT and control groups (p = 0.09). However, there were statistically significant differences in changes in SNAQ (p = 0.03), CAT (p = 0.03), HADS-Anxiety (p < 0.01), and HADS-Depression (p = 0.02) scores between the two groups. Conclusions: Our results suggest that NYT is an effective and promising drug with various effects in patients with COPD who are frail, despite conventional treatment.

Brigatinib and Alectinib for ALK Rearrangement-Positive Advanced Non-Small Cell Lung Cancer With or Without Central Nervous System Metastasis: A Systematic Review and Network Meta-Analysis.

To date, no head-to-head trials have compared the efficacy of brigatinib and alectinib against anaplastic lymphoma kinase (ALK) rearrangement-positive (ALK-p), ALK-inhibitor-naïve, advanced non-small cell lung cancer (NSCLC) with central nervous system (CNS) metastasis. We conducted an indirect treatment comparison (ITC) between brigatinib and alectinib, with crizotinib as a common comparator, using a Bayesian model with non-informative prior distribution and assessed the between-study heterogeneity of the studies. The primary efficacy endpoint was progression-free survival (PFS), and efficacy was ranked using the surface under the cumulative ranking (SUCRA) curve values. ITC analysis showed that there were no significant differences in PFS between the brigatinib and alectinib arms. However, the SUCRA values revealed that alectinib ranked the highest by efficacy in the overall patient population, whereas brigatinib ranked the highest by efficacy in the CNS metastasis sub-group. Although there were no significant differences in the incidence of G3-5 adverse events between the brigatinib and alectinib arms in the overall patient population, the data were deemed insufficient for the CNS metastasis sub-group analysis. This study provides critical information to clinicians regarding the efficacy of brigatinib for ALK-p, ALK-inhibitor-naïve, advanced NSCLC patients, with and without CNS metastasis. Larger randomized, controlled trials are warranted to confirm our results.

Inhibition of Virus-Induced Cytokine Production from Airway Epithelial Cells by the Late Addition of Budesonide.

BACKGROUND: Viral infection is the main cause of asthma and COPD (chronic obstructive pulmonary disease) exacerbation and accumulate inflammatory cells to airway tissue. We have reported poly I:C, a mimic product of the virus and ligand of toll-like receptor 3 (TLR3), induced inflammatory chemokines from airway epithelial cells and found prior incubation with corticosteroids diminishes the effect of TLR3 activation. In clinical practice, mild asthma is recommended as-needed budesonide (BUD) when symptoms occur following a viral infection, etc. However, many questions still surround BUD's usefulness if taken after a virus has already infected airway tissue. OBJECTIVE: The aim of this study was to investigate the inhibitory effects of BUD on inflammatory cytokines induced by viral infection. Methods: Normal human bronchial epithelial (NHBE) cells were stimulated with poly I:C or infected with human rhinovirus-16 (HRV16) and BUD was added after the initial stimulation. Expression of both thymic stromal lymphopoietin (TSLP) and CCL26/eotaxin-3 was quantified by real-time RT-PCR and enzyme-linked immunosorbent assay (ELISA), respectively. Knockdown study was performed. Results: Pre-or post-incubation with BUD inhibited both poly I:C- and HRV16-induced mRNAs and proteins of both thymic stromal lymphopoietin (TSLP) and CCL26 with significance. Knockdown of the glucocorticoid receptor diminished these effects of BUD. Under the same conditions of BUD's experiment, post-incubation with neither fluticasone propionate nor dexamethasone suppressed expression of both TSLP and CCL26, which induced by poly I:C. CONCLUSION: Post-addition of BUD inhibited the virus-induced TSLP and CCL26 from the airway epithelial cells. These results suggest that inhalation of BUD after viral infection has beneficial effects on asthma. CONCLUSION: Late addition of BUD may benefit among patient with viral infection and type 2 allergic airway disease such as asthma.