Publications by authors named "Kazuto Matsunaga"

106 Publications

Significance of alveolar nitric oxide concentration in the airway of patients with organizing pneumonia after allogeneic hematopoietic stem cell transplantation.

Ann Hematol 2022 May 23. Epub 2022 May 23.

Third Department of Internal Medicine, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan.

Organizing pneumonia (OP) is a complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and a manifestation of peripheral airway/alveolar inflammation. Recently, alveolar nitric oxide concentration (Calv) has been revealed as a noninvasive marker of peripheral airway inflammation; however, whether Calv levels are associated with OP and peripheral airway in patients after allo-HSCT remains unclear. Herein, we evaluated whether Calv levels could reflect the presence of OP and structural airway changes in patients after allo-HSCT. We measured the eNO levels of 38 patients (6 with OP and 32 without OP) who underwent allo-HSCT. Three-dimensional computed tomography (CT) analysis of the airway was performed in 19 patients. We found that in patients with OP, Calv levels were significantly higher than in those without OP (10.6 vs. 5.5 ppb, p < 0.01). Receiver-operating characteristic analyses revealed a Calv cut-off value for OP detection of 10.2 ppb. No significant differences in the patient characteristics, except for the presence of OP (p < 0.01), were noted between the two groups stratified by the Calv cut-off value. Three-dimensional CT images of the airway revealed gradually increasing positive correlations between Calv levels and airway wall area of the third-, fourth-, and fifth-generation bronchi (r = 0.20, 0.31, 0.38; p = 0.42, 0.19, 0.038, respectively), indicating that Calv levels are strongly correlated with the wall thickness of the distal bronchi. Our results suggest that the Calv level may be a useful noninvasive detectable marker for OP after an allo-HSCT.
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http://dx.doi.org/10.1007/s00277-022-04868-xDOI Listing
May 2022

Current chronic obstructive pulmonary disease treatment status in Asia: A position statement of the Asian Pacific Society of Respirology.

Tuberc Respir Dis (Seoul) 2022 May 2. Epub 2022 May 2.

Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Ube, Japan.

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http://dx.doi.org/10.4046/trd.2022.0020DOI Listing
May 2022

Sequential Biotherapy Targeting IL-5 and IL-4/13 in Patients with Eosinophilic Asthma with Sinusitis and Otitis Media.

Biomolecules 2022 03 30;12(4). Epub 2022 Mar 30.

Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan.

Type 2 (T2) inflammation plays an important role in the pathogenesis of allergic diseases such as asthma, eosinophilic chronic rhinosinusitis (ECRS), or eosinophilic otitis media (EOM). Currently, in severe asthma with the T2 phenotype, biologics targeting mediators of T2 inflammation dramatically improve the management of severe asthma. While treatment with a single biologic is common, little is known about cases of the sequential use of two biologics. Here, we report a case of severe asthma with refractory ECRS and EOM in which total control of these allergic diseases could not be achieved with a single biologic but could be achieved via the sequential use of the anti-IL-5 receptor antibody and human anti-IL-4/13 receptor monoclonal antibody. It is suggested that it is necessary to control multiple T2 inflammatory pathways to achieve total control of severe allergic diseases. Sequential biotherapy may help solve the clinical challenges associated with single-agent molecular-targeted therapies.
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http://dx.doi.org/10.3390/biom12040522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9025540PMC
March 2022

Measurement of Blood Eosinophils in Asthma and Chronic Obstructive Pulmonary Disease.

Intern Med 2022 Apr 16. Epub 2022 Apr 16.

Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Japan.

Eosinophils are important effector cells in airway inflammation, as pleiotropy and heterogeneity can be linked to various pathophysiologies in asthma and chronic obstructive pulmonary disease (COPD). Sputum eosinophils can reflect the heterogeneity of airway inflammation, and owing to their traits, blood eosinophils can be a surrogate and potential biomarker for managing both conditions. Blood eosinophils are activated via the stimulation of type 2 cytokines, such as interleukin (IL)-5, IL-4/13, granulocyte-macrophage colony-stimulating factor, IL-33, and thymic stromal lymphopoietin. There is sufficient evidence to support the relationship between the blood eosinophil count and clinical outcomes, including pulmonary function decline, exacerbations, all-cause mortality, and treatment response to inhaled corticosteroids and biologics. Thus, there is growing interest in the use of blood eosinophils for the management of these diseases. Compiling recent evidence, we herein review the significance of measuring blood eosinophils in asthma and COPD.
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http://dx.doi.org/10.2169/internalmedicine.9339-22DOI Listing
April 2022

Invasive thymoma extending to the right atrium with superior vena cava syndrome presenting massive intracardiac thrombosis immediately after the start of chemotherapy: an autopsy case report.

Int Cancer Conf J 2022 Apr 28;11(2):158-163. Epub 2022 Feb 28.

Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505 Japan.

Invasive thymomas with intraluminal tumor thrombi are rare. Removal of the thymoma and infiltration of the superior vena cava (SVC) is a curative alternative. We report an autopsy case of invasive thymoma with intraluminal growth into the intracardiac right atrium extension. Furthermore, the patient died of massive intracardiac thrombosis 5 days after the start of chemotherapy. A 66-year-old man with SVC syndrome was referred to our hospital. He had been aware of swelling of the face for 6 months. The patient was diagnosed with invasive thymoma by a CT-guided needle biopsy of the anterior mediastinal mass. Contrast-enhanced chest computed tomography showed a mass in the anterior mediastinum extending to the SVC and right atrium. As a result of discussion with surgeons and radiotherapists, we planned a multidisciplinary treatment in which neoadjuvant chemotherapy would reduce the tumor size, and surgery and postoperative radiotherapy were followed by chemotherapy. He was administered neo-adjuvant chemotherapy with CBDCA + PTX (carboplatin, area under the curve = 6, and paclitaxel, 200 mg/m). On the 4th day of chemotherapy, he suddenly developed obstructive shock due to intracardiac thrombosis in the right ventricle. We believe that chemotherapy may trigger rapid thrombus formation. If an invasive thymoma spreads into a large vessel or the right atrium, surgical treatment should be considered if possible. However, if surgery is impossible, administration of anticoagulants should be considered to prevent thrombus formation before chemotherapy.
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http://dx.doi.org/10.1007/s13691-022-00541-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8938571PMC
April 2022

False-positive Elevation of Beta-D-glucan and Aspergillus Galactomannan Levels Due to Mendelson's Syndrome after Rice Aspiration: A Case Report.

Intern Med 2022 Mar 19. Epub 2022 Mar 19.

Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Japan.

Both 1,3-beta-D-glucan (BDG) and galactomannan (GM) are polysaccharide components of the fungal cell wall. Although elevated levels of serum BDG and Aspergillus GM suggest invasive fungal infection or Pneumocystis pneumonia and aspergillosis, respectively, it is also necessary to consider the possibility of false-positives. We herein report a 68-year-old man with marked elevation in serum BDG and GM levels accompanied by Mendelson's syndrome after rice aspiration. With the improvement of Mendelson's syndrome, his serum BDG and GM levels decreased. The false-positive serum BDG and GM findings may have been due to his aspiration of food containing them. It is important to take a detailed history of aspiration in addition to making a conventional differential diagnosis in patients with pneumonia with elevated serum BDG and GM levels.
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http://dx.doi.org/10.2169/internalmedicine.8805-21DOI Listing
March 2022

Antineutrophil cytoplasmic antibody-negative granulomatosis with polyangiitis localized to the lungs.

Respir Med Case Rep 2022 2;36:101600. Epub 2022 Feb 2.

Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Japan.

Patients with granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis, sometimes exhibit no clinical features. Here, we describe a case of antineutrophil cytoplasmic antibody (ANCA)-negative GPA presenting with only lung granuloma. A 55-year-old woman with a right upper lung mass underwent lobectomy for suspected lung cancer; however, only granuloma was detected, and the etiology was not identified. Serum ANCA results were negative. Four years postoperatively, another pulmonary nodule appeared in the left lung's apex. The kidneys and sinuses were not impaired, but re-examination of the resected specimen revealed necrotizing vasculitis and granulomas around the vessels. Thus, the patient was diagnosed with GPA localized to the lungs. Although this was a non-life-threatening disease, the patient was administered oral prednisolone (PSL) and intravenous cyclophosphamide (IVCY) to prevent fatal complications of GPA as she was non-elderly and had no comorbidities, leading to a decrease in the mass size. Detailed re-examination by expert pulmonary pathologists could aid in GPA diagnosis when clinical features are absent, as in our case. In patients with granulomas of unknown etiology, a careful multidisciplinary approach is pivotal in the diagnosis. If patients tolerate adverse effects, a PSL and IVCY combination may prevent fatal outcomes, even in patients with non-life-threatening disease.
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http://dx.doi.org/10.1016/j.rmcr.2022.101600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8829757PMC
February 2022

The 1-minute sit-to-stand test to detect desaturation during 6-minute walk test in interstitial lung disease.

NPJ Prim Care Respir Med 2022 01 27;32(1). Epub 2022 Jan 27.

Department of Medicine and Clinical Science, Graduate School of Medicine, Yamaguchi University, Ube, Japan.

Although the 6 min walk test (6MWT) is well-established for assessing desaturation in patients with interstitial lung disease (ILD), it cannot be easily performed in primary healthcare settings. This retrospective observational study aimed to evaluate the usefulness of the 1 min sit-to-stand test (1STST) for assessing desaturation during 6MWT in ILD patients with normal resting blood oxygen levels. We included 116 patients, and the pulse oxygen saturation (SpO) for both methods was analyzed. The SpO nadir during the 1STST and 6MWT correlated strongly (ρ = 0.82). The frequency of patients with nadir SpO< 90% was consistent for both tests (κ = 0.82). 1STST was superior to diffusing capacity for carbon monoxide in detecting desaturation during the 6MWT. These findings were similarly stratified according to performance status or dyspnea scale. The 1STST can easily measure exertional desaturation in ILD patients with normal resting blood oxygen levels and is an alternative to the 6MWT.
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http://dx.doi.org/10.1038/s41533-022-00268-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8795411PMC
January 2022

Predicting programmed death-ligand 1 expression level in non-small cell lung cancer using a combination of peritumoral and intratumoral radiomic features on computed tomography.

Biomed Phys Eng Express 2022 02 1;8(2). Epub 2022 Feb 1.

Department of Radiation Oncology, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-8505, Japan.

In this study, we investigated the possibility of predicting expression levels of programmed death-ligand 1 (PD-L1) using radiomic features of intratumoral and peritumoral tumors on computed tomography (CT) images. We retrospectively analyzed 161 patients with non-small cell lung cancer. We extracted radiomic features for intratumoral and peritumoral regions on CT images. The null importance, least absolute shrinkage, and selection operator model were used to select the optimized feature subset to build the prediction models for the PD-L1 expression level. LightGBM with five-fold cross-validation was used to construct the prediction model and evaluate the receiver operating characteristics. The corresponding area under the curve (AUC) was calculated for the training and testing cohorts. The proportion of ambiguously clustered pairs was calculated based on consensus clustering to evaluate the validity of the selected features. In addition, Radscore was calculated for the training and test cohorts. For expression level of PD-L1 above 1%, prediction models that included radiomic features from the intratumoral region and a combination of radiomic features from intratumoral and peritumoral regions yielded an AUC of 0.83 and 0.87 and 0.64 and 0.74 in the training and test cohorts, respectively. In contrast, the models above 50% prediction yielded an AUC of 0.80, 0.97, and 0.74, 0.83, respectively. The selected features were divided into two subgroups based on PD-L1 expression levels≥50% or≥1%. Radscore was statistically higher for subgroup one than subgroup two when radiomic features for intratumoral and peritumoral regions were combined. We constructed a predictive model for PD-L1 expression level using CT images. The model using a combination of intratumoral and peritumoral radiomic features had a higher accuracy than the model with only intratumoral radiomic features.
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http://dx.doi.org/10.1088/2057-1976/ac4d43DOI Listing
February 2022

Feasibility of Discontinuing Biologics in Severe Asthma: An Algorithmic Approach.

J Asthma Allergy 2021 7;14:1463-1471. Epub 2021 Dec 7.

Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi, Japan.

In severe asthma with type 2 (T2) inflammation, biologics targeting key mediators of T2 inflammation, including interleukin (IL)-5, IL-4/IL-13, and immunoglobulin (Ig)E, remarkably improve the management of severe asthma, providing new insights into the clinical course of asthma such as disease modification and broad modulation of T2 inflammation. Once severe asthma has become a "controllable" condition, the question of discontinuation of biologics arises due to cost and side effects. The studies on discontinuing biologics in asthma demonstrate that some of patients successfully discontinue biologics, indicating that it is a feasible option in a subset of patients. Incorporating the evidence of discontinuation, we propose the criteria for the discontinuation of biologics. Our proposed criteria for the discontinuation of biologics consist of an absence of asthma symptoms (asthma control questionnaire [ACQ] score < 1.5 or asthma control test [ACT] score > 19), no asthma exacerbations, no use of oral corticosteroids, normalized spirometry (forced exhaled volume in 1 second [FEV] ≥ 80%), suppressed T2 inflammation (blood eosinophil counts < 300 μL and fractional exhaled nitric oxide [FeNO] < 50 ppb), and control of asthma comorbidities. Real-world evidence verified a subset of patients achieving highly well-controlled conditions after use of biologics, namely super-responders, who are candidates for the discontinuation of biologics. If super-responders meet all of the criteria, they are allowed to discontinue biological therapies. Our proposed algorithm may support physicians' treatment decisions for patients receiving biologics.
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http://dx.doi.org/10.2147/JAA.S340684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8665775PMC
December 2021

Orthogonality-Constrained CNMF-Based Noise Reduction with Reduced Degradation of Biological Sound.

Sensors (Basel) 2021 Nov 29;21(23). Epub 2021 Nov 29.

Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, 1-1-1, Minamikogushi, Ube 755-8505, Japan.

The number of deaths due to cardiovascular and respiratory diseases is increasing annually. Cardiovascular diseases with high mortality rates, such as strokes, are frequently caused by atrial fibrillation without subjective symptoms. Chronic obstructive pulmonary disease is another condition in which early detection is difficult owing to the slow progression of the disease. Hence, a device that enables the early diagnosis of both diseases is necessary. In our previous study, a sensor for monitoring biological sounds such as vascular and respiratory sounds was developed and a noise reduction method based on semi-supervised convolutive non-negative matrix factorization (SCNMF) was proposed for the noisy environments of users. However, SCNMF attenuated part of the biological sound in addition to the noise. Therefore, this paper proposes a novel noise reduction method that achieves less distortion by imposing orthogonality constraints on the SCNMF. The effectiveness of the proposed method was verified experimentally using the biological sounds of 21 subjects. The experimental results showed an average improvement of 1.4 dB in the signal-to-noise ratio and 2.1 dB in the signal-to-distortion ratio over the conventional method. These results demonstrate the capability of the proposed approach to measure biological sounds even in noisy environments.
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http://dx.doi.org/10.3390/s21237981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8659502PMC
November 2021

Anemia is a Prognostic Factor for Overall Survival Rate in Patients with Non-Small Cell Lung Cancer Treated with Stereotactic Body Radiation Therapy.

Cancer Manag Res 2021 27;13:7447-7453. Epub 2021 Sep 27.

Department of Respiratory Medicine and Infectious Disease, Yamaguchi University Graduate School of Medicine, Ube, Japan.

Purpose: Anemia has been associated with poor prognosis in patients with cancer across several cancer types. It has been identified as a prognostic factor in patients with non-small cell lung cancer (NSCLC) who have undergone surgery or chemoradiotherapy. However, there are only a few reports that have evaluated the prognostic significance of anemia in patients with NSCLC undergoing stereotactic body radiation therapy (SBRT).

Patients And Methods: A total of 77 patients were enrolled in this study. The pretreatment hemoglobin (Hb) levels, within 2 weeks before SBRT, were available for all patients. The median age of the participants (56 men, 21 women) was 80 (range, 50-90) years. The median Hb level was 12.8 (range, 7.8-18.3) g/dL. The median follow-up period was 24 (range, 1-87) months.

Results: Local recurrence was observed in 8 (10.4%) cases during the follow-up period. The 1- and 2-year local control (LC) rates were 94.8% and 86.4%, respectively. Seventeen (22.1%) patients died during the follow-up period. The 1- and 2-year overall survival (OS) rates were 93.1% and 85.2%, respectively. Univariate analysis identified anemia and body mass index as significant prognostic factors for predicting OS. On multivariate analysis, anemia was confirmed to be the only significant factor (p = 0.02469).

Conclusion: Our data suggest that anemia is a prognostic factor for predicting the OS rate in patients with early-stage NSCLC treated with SBRT.
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http://dx.doi.org/10.2147/CMAR.S336044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485919PMC
September 2021

Impact of Frailty on Hippocampal Volume in Patients with Chronic Obstructive Pulmonary Disease.

Biomedicines 2021 Aug 28;9(9). Epub 2021 Aug 28.

Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan.

Brain frailty may be related to the pathophysiology of poor clinical outcomes in chronic obstructive pulmonary disease (COPD). This study examines the relationship between hippocampal subfield volumes and frailty and depressive symptoms, and their combined association with quality of life (QOL) in patients with COPD. The study involved 40 patients with COPD. Frailty, depressive symptoms and QOL were assessed using Kihon Checklist (KCL), Hospital Anxiety and Depression Scale (HADS), and World Health Organization Quality of Life Assessment (WHO/QOL-26). Anatomical MRI data were acquired, and volumes of the hippocampal subfields were obtained using FreeSurfer (version 6.0). Statistically, HADS score had significant association with WHO/QOL-26 and KCL scores. KCL scores were significantly associated with volumes of left and right whole hippocampi, presubiculum and subiculum, but HADS score had no significant association with whole hippocampi or hippocampal subfield volumes. Meanwhile, WHO/QOL-26 score was significantly associated with volume of the left CA1. There was a significant association between frailty, depression, and QOL. Hippocampal pathology was related to frailty and, to some extent, with QOL in patients with COPD. Our results suggest the impact of frailty on hippocampal volume and their combined associations with poor QOL in COPD.
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http://dx.doi.org/10.3390/biomedicines9091103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8468719PMC
August 2021

Improved Prognostic Prediction by Combination of Early Initiation of Polymyxin B Hemoperfusion with Modified Gender-Age-Physiology Index in Acute Exacerbation of Idiopathic Pulmonary Fibrosis.

Blood Purif 2021 Sep 9:1-7. Epub 2021 Sep 9.

Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Ube, Japan.

Introduction: Respiratory failure from acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is associated with high mortality. Direct hemoperfusion with polymyxin B-immobilized fiber column (PMX-DHP) has been reported to have beneficial effects on patients with AE-IPF. Whether patient characteristics influence the extent of this benefit remains unclear.

Methods: We retrospectively examined the records of 30 patients with AE-IPF who underwent PMX-DHP. The favorable factors of survival were determined using Cox proportional hazards analyses.

Results: The 1- and 12-month survival rates after PMX-DHP were 70.0% and 50.0%, respectively. The multivariate analysis revealed that low modified Gender-Age-Physiology (GAP) index (≤8 points) (hazard ratio [HR] 0.317, p = 0.015) and PMX-DHP received within 48 h of steroid pulse (HR 0.289, p = 0.012) were favorable factors. Notably, even in the patients with high modified GAP index (>8 points), that is, more advanced IPF, those who received PMX-DHP within 48 h of steroid pulse had a better prognosis than those who did after 48 h of the steroid pulse (p = 0.032).

Conclusions: Early PMX-DHP initiation in patients with AE-IPF, specifically within 48 h after the steroid pulse therapy, may improve prognosis regardless of the severity of chronic phase of IPF before AE-IPF.
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http://dx.doi.org/10.1159/000518705DOI Listing
September 2021

Non-pneumophila species pneumonia with orange-coloured sputum.

Respirol Case Rep 2021 Sep 29;9(9):e0814. Epub 2021 Jul 29.

Department of Respiratory Medicine and Infectious Disease Graduate School of Medicine, Yamaguchi University Ube Japan.

We herein report an immunocompromised patient familiar with gardening admitted to our hospital suffering from severe pneumonia caused by . We suspected non-pneumophila species pneumonia because of gardening habits, the negative urine antigen test and the non-significant Gram staining results of orange-coloured sputum. The pathogen was identified using mass spectrometry analysis of bronchoalveolar lavage fluid. It is important to perform the medical interview carefully, noting the colour of sputum and gardening habits, for diagnosis and targeted therapy of non-pneumophila species pneumonia, even if the urine antigen test is negative.
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http://dx.doi.org/10.1002/rcr2.814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319662PMC
September 2021

Abundant TNF-LIGHT expression in the airways of patients with asthma with persistent airflow limitation: Association with nitrative and inflammatory profiles.

Respir Investig 2021 Sep 7;59(5):651-660. Epub 2021 Jul 7.

Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minami-kogushi, Ube, 755-8505, Japan.

Background: The role of the inflammatory secretory protein TNF-LIGHT (LIGHT) in the molecular mechanisms underlying persistent airflow limitation (PAL) in asthma remains unclear. We hypothesized that high airway LIGHT expression may be a feature of asthma with PAL associated with specific expression patterns of inflammatory molecules.

Methods: This hypothesis was tested in 16 patients with asthma on inhaled corticosteroid treatment. Induced sputum was collected, the expression of LIGHT and 3-nitrotyrosine (NT), which reflects the footprint of reactive nitrogen species content, was measured using immunohistochemical staining, and the inflammatory molecules in the sputum supernatant were analyzed using a magnetic bead array.

Results: LIGHT staining in the cells had a significantly higher intensity in participants with PAL than in participants without PAL (47.9 × 10/ml vs. 5.4 × 10/ml; p < 0.05). The array analysis indicated that IL-8, IL-19, matrix metalloproteinase 2, and osteopontin, were associated with high LIGHT immunoreactivity. The fractionation of 3-NT-positive cells was positively correlated with that of LIGHT-positive cells (r = 0.57, p < 0.05) and the TGF-β1 level (r = 0.61, p < 0.05). LIGHT- and 3-NT-positive cells showed significant positive correlation with the differential cell counts of neutrophils, macrophages, and eosinophils in the induced sputum. Intense immunoreactivities of LIGHT (r = -0.54, p < 0.05) and 3-NT (r = -0.42, p = 0.1) were negatively associated with decreased forced expiratory volume in 1/forced vital capacity ratio.

Conclusions: The findings suggest that LIGHT is a key component in the association between airway inflammation and airflow limitation in patients with asthma, and its expression may be persistently correlated with the abundance of inflammatory cells and inflammatory and profibrogenic radical/molecules.
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http://dx.doi.org/10.1016/j.resinv.2021.05.011DOI Listing
September 2021

[Standardization of Hypnotic Agents for Prevention of Falls: A Pharmacoeconomic Study].

Yakugaku Zasshi 2021 ;141(7):971-978

Pharmacy Department, Yamaguchi University Hospital.

To reduce the number of falls caused by hypnotic agents, the standardization of insomnia treatment was carried out at Yamaguchi University Hospital from April 2019. There were concerns that medical costs would increase due to the selected medicines-suvorexant and eszopiclone-being more expensive than conventional benzodiazepines. In this study, the standardization of insomnia treatment was evaluated by pharmacoeconomics. The costs of the hypnotic agents was considered, as was the cost of examination/treatment following falls. Effectiveness was evaluated as the incidence of falls within 24 hours of taking hypnotic agents. This analysis took the public healthcare payer's perspective. Propensity score matching based on patient background, showed that, per hospitalization the medicine costs of the recommended group increased by 1,020 yen, however, the examination/treatment costs following falls decreased by 487 yen when compared with the non-recommended group. Overall, the recommended group incurred costs of 533 yen more per hospitalization for patients prescribed hypnotic agents compared to the non-recommended group, but the incidence of falls for the recommended group was significantly lower than that in the non-recommended group (1.9% vs. 6.3%; p<0.01). These results suggest that in order to prevent the incidence of falls by 1 case, it is necessary to increase costs by 12,086 yen which is the subthreshold cost for switching to the recommended medicine as standardization. The selection of recommended medicines may be a cost-effectiveness option compared with non-recommended medicines.
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http://dx.doi.org/10.1248/yakushi.21-00020DOI Listing
December 2021

A New Dyspnea Evaluation System Focusing on Patients' Perceptions of Dyspnea and Their Living Disabilities: The Linkage between COPD and Frailty.

J Clin Med 2020 Nov 6;9(11). Epub 2020 Nov 6.

Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan.

Background: As much as there are unmet needs for brief frailty assessment in patients with chronic obstructive pulmonary disease (COPD), the lack of a simplified and comprehensive dyspnea evaluation system that focuses on the patients' perceptions of dyspnea and their COPD living disabilities remains a major challenge. We developed patient-reported outcome measures for dyspnea-related behavior and activity limitation (PROMs-D), which consisted of the Activity-limit Dyspnea Scale (ADS) and Self-Limit Dyspnea Scale (SDS), while investigated the usefulness of PROMs-D in identifying frailty.

Methods: We administered PROMs-D and frailty status evaluations in 128 outpatients.

Results: We classified 30 (23.4%), 50 (39.0%), and 48 (37.5%) patients as robust, prefrail, and frail, respectively. There was a positive correlation between SDS and ADS ( = 0.67, < 0.001), and both ADS and SDS had high accuracies for detecting frailty (AUC, 0.82 and 0.78, respectively). Moreover, a PROMs-D score that consisted of the sum of ADS and SDS was more effective in stratifying frailty (cutoff value, 2; AUC, 0.85; sensitivity, 60%; specificity, 95%).

Conclusions: PROMs-D could be used as the first step for frailty screening in patients with COPD, and we propose the importance of capturing the troublesome nature of living behaviors due to dyspnea in daily clinical practice.
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http://dx.doi.org/10.3390/jcm9113580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694778PMC
November 2020

Comorbid Conditions in Chronic Obstructive Pulmonary Disease: Potential Therapeutic Targets for Unmet Needs.

J Clin Med 2020 Sep 24;9(10). Epub 2020 Sep 24.

Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan.

The management of chronic obstructive pulmonary disease (COPD) has improved significantly due to advances in therapeutic agents, but it has also become apparent that there are issues that remain difficult to solve with the current treatment algorithm. COPD patients face a number of unmet needs concerning symptoms, exacerbations, and physical inactivity. There are various risk factors and triggers for these unmet needs, which can be roughly divided into two categories. One is the usual clinical characteristics for COPD patients, and the other is specific clinical characteristics in patients with comorbid conditions, such as asthma, cardiovascular disease, and bronchiectasis. These comorbidities, which are also associated with the diversity of COPD, can cause unmet needs resistance to usual care. However, treatable conditions that are not recognized as therapeutic targets may be latent in patients with COPD. We again realized that treatable traits should be assessed and treated as early as possible. In this article, we categorize potential therapeutic targets from the viewpoint of pulmonary and systemic comorbid conditions, and address recent data concerning the pathophysiological link with COPD and the impact of intervention on comorbid conditions in order to obtain evidence that could enable us to provide personalized COPD management.
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http://dx.doi.org/10.3390/jcm9103078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598716PMC
September 2020

Cytokine Adsorption to Polymyxin B-Immobilized Fiber: An in vitro Study.

Blood Purif 2021 7;50(2):230-237. Epub 2020 Sep 7.

Department of Clinical Research, National Hospital Organization Yamaguchi Ube Medical Center, Ube, Japan,

Background: Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) are episodes of acute respiratory worsening characterized by diffuse alveolar damage superimposed on usual interstitial pneumonia. Direct hemoperfusion with a polymyxin B-immobilized fiber column (PMX-DHP) is reported to have beneficial effects on the respiratory status and outcome in patients with AE-IPF although its mechanism of action is not fully elucidated.

Objective: To investigate whether and how the PMX-immobilized fiber (PMX-F) adsorbs cytokines because reduction of the serum levels of various cytokines has been noted in AE-IPF patients receiving PMX-DHP.

Methods: The propensity of recombinant cytokines for adsorption onto PMX-F was examined by incubating cytokines with heparin-coated or uncoated PMX-F for 2 h at 37°C. Cytokines were quantitated by multiplex bead array assay or ELISA.

Results: Interleukin (IL)-8, RANTES, platelet-derived growth factor-bb, and transforming growth factor-β were substantially adsorbed onto PMX-F without heparin coating. The adsorbed cytokines could be eluted with PMX sulfate, indicating that the PMX moiety is involved in cytokine adsorption. Importantly, although IL-1β, monocyte chemoattractant protein-1, fibroblast growth factor 2, and vascular endothelial growth factor-A were adsorbed onto PMX-F to lesser extents, the adsorption was enhanced by heparin coating of PMX-F. Furthermore, heparin-coated PMX-F acquired the capability to adsorb IL-6, IL-12, and tumor necrosis factor α. An affinity of heparin to PMX was determined (Kd = 0.061 ± 0.032 mg/mL), which accounts for the enhanced cytokine adsorption onto PMX-F upon heparin coating.

Conclusions: Various cytokines involved in inflammation, fibrosis, and vascular permeability were shown to be adsorbed onto PMX-F. Removal of multiple cytokines may be associated with positive impacts of PMX-DHP in patients with AE-IPF.
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http://dx.doi.org/10.1159/000510290DOI Listing
August 2021

A Novel Role of Growth Differentiation Factor (GDF)-15 in Overlap with Sedentary Lifestyle and Cognitive Risk in COPD.

J Clin Med 2020 Aug 24;9(9). Epub 2020 Aug 24.

Department of Pulmonology and Gerontology Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan.

Sedentary behavior and cognitive impairment have a direct impact on patients' outcomes. An energy metabolic disorder may be involved in the overlap of these comorbid conditions (motoric cognitive risk (MCR)) in patients with chronic obstructive pulmonary disease (COPD). We aimed to explore the linkage between a proapoptotic protein, growth differentiation factor (GDF)-15, and MCR. Physical activity (PA), cognitive function (Japanese version of the Montreal Cognitive Assessment: MOCA-J), and the serum GDF-15 levels were assessed in healthy subjects ( = 14), asthmatics ( = 22), and COPD patients ( = 28). In the entire cohort, serum GDF-15 had negative correlations with exercise (Ex) ( = -0.43, < 0.001) and MoCA-J ( = -0.44, < 0.001), and Ex and MOCA-J showed a positive correlation ( = 0.52, < 0.0001). Compared to healthy subjects and asthmatics, COPD patients showed the highest serum GDF-15 levels and had a significantly higher proportion of subjects with MCR (both sedentary lifestyle (EX < 1.5) and cognitive risk (MoCA-J ≤ 25)). Also, we found that serum GDF-15 has a screening potential (100% sensitivity) greater than aging (67% sensitivity) for detecting MCR in COPD patients. In conclusion, higher serum GDF-15 had interrelationships with a sedentary lifestyle and cognitive risk. This protein was not disease-specific but could be a screening biomarker to detect MCR related to poor health outcomes of COPD patients.
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http://dx.doi.org/10.3390/jcm9092737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565594PMC
August 2020

Role of Type2 Inflammatory Biomarkers in Chronic Obstructive Pulmonary Disease.

J Clin Med 2020 Aug 18;9(8). Epub 2020 Aug 18.

Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, Tokyo 173-8601, Japan.

Airway inflammation in chronic obstructive pulmonary disease (COPD) is typically thought to be driven by Type1 immune responses, while Type2 inflammation appears to be present in definite proportions in the stable state and during exacerbations. In fact, some COPD patients showed gene expression of Type2 inflammation in the airway, and this subset was associated with the inhaled corticosteroid (ICS) response. Interestingly enough, the relationship between COPD and diseases associated with Type2 inflammation from the perspective of impaired lung development is increasingly highlighted by recent epidemiologic studies on the origin of COPD. Therefore, many researchers have shown an interest in the prevalence and the role of existent Type2 biomarkers such as sputum and blood eosinophils, exhaled nitric oxide fraction, and atopy, not only in asthma but also in COPD. Although the evidence about Type2 biomarkers in COPD is inconsistent and less robust, Type2 biomarkers have shown some potential when analyzing various clinical outcomes or therapeutic response to ICS. In this article, we review the existent and emerging Type2 biomarkers with clinically higher applicability in the management of COPD.
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http://dx.doi.org/10.3390/jcm9082670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464674PMC
August 2020

What are key symptoms to be captured for preventing a physician's underestimation of asthma control?

J Allergy Clin Immunol Pract 2021 01 17;9(1):564-566. Epub 2020 Aug 17.

Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Ube, Japan.

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http://dx.doi.org/10.1016/j.jaip.2020.07.053DOI Listing
January 2021

An official JRS statement: The principles of fractional exhaled nitric oxide (FeNO) measurement and interpretation of the results in clinical practice.

Respir Investig 2021 Jan 7;59(1):34-52. Epub 2020 Aug 7.

Department of Respiratory Medicine, Tohoku University, Sendai, Japan.

Nitric oxide (NO) is produced in the body and has been shown to have diverse actions in the abundance of research that has been performed on it since the 1970s, leading to Furchgott, Murad, and Ignarro receiving the Nobel Prize in Physiology or Medicine in 1998. NO is produced by nitric oxide synthase (NOS). NOS is broadly distributed, being found in the nerves, blood vessels, airway epithelium, and inflammatory cells. In asthma, inflammatory cytokines induce NOS activity in the airway epithelium and inflammatory cells, producing large amounts of NO. Measurement of fractional exhaled nitric oxide (FeNO) is a simple, safe, and quantitative method of assessing airway inflammation. The FeNO measurement method has been standardized and, in recent years, this noninvasive test has been broadly used to support the diagnosis of asthma, monitor airway inflammation, and detect asthma overlap in chronic obstructive pulmonary disease (COPD) patients. Since the normal upper limit of FeNO for healthy Japanese adults is 37 ppb, values of 35 ppb or more are likely to be interpreted as a signature of inflammatory condition presenting features with asthma, and this value is used in clinical practice. Research is also underway for clinical application of these measurements in other respiratory diseases such as COPD and interstitial lung disease. Currently, there remains some confusion regarding the significance of these measurements and the interpretation of the results. This statement is designed to provide a simple explanation including the principles of FeNO measurements, the measurement methods, and the interpretation of the measurement results.
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http://dx.doi.org/10.1016/j.resinv.2020.05.006DOI Listing
January 2021

Association of low-dosage systemic corticosteroid use with disease burden in asthma.

NPJ Prim Care Respir Med 2020 08 4;30(1):35. Epub 2020 Aug 4.

Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan.

There is an ongoing debate about the benefit-risk balance of systemic corticosteroids (SCS) in asthma treatment. We investigated the associations between SCS use and disease burden in a database cohort of asthmatics, categorized into SCS and non-SCS prescription at baseline and quartiles (Q) by cumulative SCS dosage. Of the 10,579 patients, the SCS cohort comprised 3103 patients (29.3%). Mean SCS dosages at baseline were 0.08, 0.29, 0.79, and 4.58 mg/day in Q1, Q2, Q3, and Q4, respectively. Similar SCS dosages were used within each quartile throughout the study period. No remarkable changes in asthma severity or control status were observed. All SCS cohorts had a higher risk of intermittent SCS exposure during the observation period. SCS use was associated with osteoporosis, diabetes, anxiety/neurosis, and depression. SCS-dependent treatment does not necessarily lead to the future improvement of asthma control; rather, it may negatively impact systemic health, even at mean dosages <5 mg/day.
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http://dx.doi.org/10.1038/s41533-020-00192-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403577PMC
August 2020

[New Treatment for Patients with Neurosarcoidosis].

Brain Nerve 2020 Aug;72(8):883-890

Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University.

Diagnosis of possible neurosarcoidosis (NS) involves assessment of clinical presentation suggestive of NS and exclusion of other diagnoses, whereas its definitive diagnosis is challenging and it requires positive nervous system histology. Due to an exceptionally low incidence, limited data are available on the optimal therapeutic options for NS. NS is commonly associated with other sarcoidosis forms; however, the patients with NS experience more frequent relapses than with other organs sarcoidosis. While corticosteroid therapy is considered as the first-line of treatment for NS, secondary treatment options with immunosuppressive agents such as methotrexate, azathioprine, mycophenolate mofetil and tumor necrosis factor (TNF)-α inhibitors are considered based on the severity of NS manifestations and the disease status.
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http://dx.doi.org/10.11477/mf.1416201613DOI Listing
August 2020

Impact of sinus surgery on type 2 airway and systemic inflammation in asthma.

J Asthma 2021 06 19;58(6):750-758. Epub 2020 Feb 19.

Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi, Japan.

Asthma is frequently associated with chronic rhinosinusitis with nasal polyps (CRSwNP). Although endoscopic sinus surgery (ESS) improves asthma control in CRSwNP patients with asthma, the mechanism that underlies the response to surgical treatment is still unclear. We evaluated the relevance of changes in asthma control and changes in airway/systemic inflammation in eosinophilic CRSwNP patients with not well controlled asthma who underwent ESS. We prospectively assessed changes in the asthma control questionnaire (ACQ) score, blood eosinophil counts (B-Eos), forced expiratory volume in 1 s (FEV), and fraction of exhaled nitric oxide (FeNO) levels at 1-week before and 8 and 52 weeks after ESS. Twenty-five subjects were analyzed. The ACQ score, B-Eos, and FeNO decreased, and FEV increased significantly after ESS. In the period from baseline to 52 weeks after ESS, changes in ACQ were significantly correlated with the changes in blood eosinophil counts ( = 0.58, <.01) and FeNO ( = 0.45, <.05). Ten subjects (40%) showed consistently improved asthma control at 52-weeks after ESS. In the remaining subjects, although the ACQ score temporarily improved at 8-weeks after ESS, but eventually deteriorated at 52-weeks. Higher levels of total immunoglobulin E were associated with long-term improved asthma control after ESS. In eosinophilic CRSwNP patients with asthma, sinus surgery impacts asthma control through the suppression of airway/systemic type 2 inflammation. The present study reinforced the common pathophysiology of type 2 inflammation between the upper and lower airways.
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http://dx.doi.org/10.1080/02770903.2020.1729380DOI Listing
June 2021

Dupilumab: Basic aspects and applications to allergic diseases.

Allergol Int 2020 Apr 30;69(2):187-196. Epub 2020 Jan 30.

Department of Medicine and Clinical Science, Graduate School of Medicine, Yamaguchi University, Ube, Japan.

Interleukin (IL)-4 and IL-13, signature type 2 cytokines, exert their actions by binding to two types of receptors sharing the IL-4R α chain (IL-4Rα). Since IL-4 and IL-13 play important and redundant roles in the pathogenesis of allergic diseases, blocking both the IL-4 and IL-13 signals would be a powerful and effective strategy for treating allergic diseases. Dupilumab (Dupixent®) is a fully human monoclonal antibody recognizing IL-4Rα and blocking both the IL-4 and IL-13 signals. Dupilumab was first prescribed for atopic dermatitis (AD) patients and has been widely approved for adult patients with moderate to severe AD since 2018. Dupilumab has since been used for asthma, receiving approval for uncontrolled asthma in 2019. A phase 3 study using dupilumab for chronic rhinosinusitis with nasal polyps (CRSwNP) has been just completed, with positive results. Several clinical trials of dupilumab for other diseases in which type 2 inflammation is dominant are now underway. It is hoped that dupilumab will open the door to a new era for treating allergic patients with AD, asthma, and CRSwNP, and for more patients with type 2 inflammations.
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http://dx.doi.org/10.1016/j.alit.2020.01.002DOI Listing
April 2020

Detection of type2 biomarkers for response in COPD.

J Breath Res 2020 02 25;14(2):026007. Epub 2020 Feb 25.

Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi, Japan.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous inflammatory lung disease. It is important to identify patients who would respond to anti-inflammatory treatment. This prospective study aims to determine how inflammatory biomarkers could be used to predict the potential effect of inhaled corticosteroids (ICS) in terms of symptoms and lung function. We evaluated the levels of blood eosinophils, exhaled nitric oxide fraction at a flow rate of 50 ml s (FeNO), alveolar nitric oxide concentration (Calv), immunoglobulin E and atopy in 43 patients with symptomatic COPD and correlated these expression levels with the changes in the COPD Assessment Test (CAT) and lung function by 12 weeks of add-on therapy with ciclesonide 400 μg d on bronchodilators. The mean changes in the CAT score and FEV were -1.4 points and +90 ml, respectively, with significant variation in the levels of change. The area under the receiver's operating characteristic curve (AUC) for FeNO in predicting improvements in both the CAT score and FEV was 0.92. The AUC for Calv and blood eosinophils was 0.82 and 0.65. Two cutoffs were chosen, one corresponding to a high value of FeNO associated with certainty for response inclusion (FeNO = 35 ppb; sensitivity = 0.67, specificity = 0.94; positive predictive value = 0.80) and the other with certainty for response exclusion (FeNO = 20 ppb; sensitivity = 1.00, specificity = 0.58, negative predictive value = 1.00). Baseline FeNO values were significantly correlated with changes in FEV and CAT (all p < 0.0001). FeNO could be a valuable biomarker for identifying individuals who respond to steroid therapy among patients with symptomatic COPD in terms of symptoms and airflow limitation. The study was prospectively registered with the University Hospital Medical Information Network (UMIN) in Japan (protocol ID 000010711).
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http://dx.doi.org/10.1088/1752-7163/ab71a4DOI Listing
February 2020
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