A Fatal Case of Drug-Induced Lung Injury Potentially Related to Olanzapine.

Drug-induced lung injury (DILI) occurs when exposure to a drug leads to inflammation and, eventually, fibrosis of the lung interstitium. While DILI is a rare side effect of antipsychotic medication, once it manifests, it requires detailed investigation and prompt treatment. Diagnosing DILI can be challenging at times due to its similarity to conditions such as infectious diseases or interstitial pneumonia induced by other causes. We hereby report a fatal case of suspected DILI associated with olanzapine. A 61-year-old female with a history of delusional disorder was admitted to our hospital due to worsened psychiatric symptoms. Ten milligrams of olanzapine had been initiated a week prior to admission by a psychiatrist at the local clinic to control these symptoms. After admission, although the patient claimed no respiratory symptoms, she developed a slight fever and deterioration of chest radiologic findings. Bronchoalveolar lavage revealed a progressively bloody return of fluid, suggesting pulmonary alveolar hemorrhage. Since no respiratory disorders have been noted, and considering the exclusion of other potential diagnoses, DILI was strongly suspected. Although olanzapine was promptly discontinued, the patient's condition rapidly deteriorated. Despite high-dose steroid therapy, the patient's response to treatment was inadequate, and she finally succumbed to the illness. This case highlights that olanzapine may induce lung injury similar to other psychiatric drugs. Furthermore, early diagnosis and treatment are essential for patients with psychiatric disorders who may sometimes present with fewer symptoms.

Elucidating the role of EPPK1 in lung adenocarcinoma development.

BACKGROUND: We recently found that epiplakin 1 (EPPK1) alterations were present in 12% of lung adenocarcinoma (LUAD) cases and were associated with a poor prognosis in early-stage LUAD when combined with other molecular alterations. This study aimed to identify a probable crucial role for EPPK1 in cancer development. METHODS: EPPK1 mRNA and protein expression was analyzed with clinical variables. Normal bronchial epithelial cell lines were exposed to cigarette smoke for 16 weeks to determine whether EPPK1 protein expression was altered after exposure. Further, we used CRISPR-Cas9 to knock out (KO) EPPK1 in LUAD cell lines and observed how the cancer cells were altered functionally and genetically. RESULTS: EPPK1 protein expression was associated with smoking and poor prognosis in early-stage LUAD. Moreover, a consequential mesenchymal-to-epithelial transition was observed, subsequently resulting in diminished cell proliferation and invasion after EPPK1 KO. RNA sequencing revealed that EPPK1 KO induced downregulation of 11 oncogenes, 75 anti-apoptosis, and 22 angiogenesis genes while upregulating 8 tumor suppressors and 12 anti-cell growth genes. We also observed the downregulation of MYC and upregulation of p53 expression at both protein and RNA levels following EPPK1 KO. Gene ontology enrichment analysis of molecular functions highlighted the correlation of EPPK1 with the regulation of mesenchymal cell proliferation, mesenchymal differentiation, angiogenesis, and cell growth after EPPK1 KO. CONCLUSIONS: Our data suggest that EPPK1 is linked to smoking, epithelial to mesenchymal transition, and the regulation of cancer progression, indicating its potential as a therapeutic target for LUAD.

Serum VEGF-A levels on admission in COVID-19 patients correlate with SP-D and neutrophils, reflecting disease severity: A prospective study.

BACKGROUND AND OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in significant global morbidity and mortality. This study aimed to investigate the clinical significance of serum vascular endothelial growth factor A (VEGF-A) in COVID-19 patients and its association with disease severity and pulmonary injury. METHODS: We prospectively collected data from 71 hospitalized COVID-19 patients between June 2020 and January 2021. Patients were classified as either mild or severe based on their oxygen requirements during hospitalization. Serum VEGF-A levels were measured using an ELISA kit. RESULTS: In comparison to mild cases, significantly elevated serum VEGF-A levels were observed in severe COVID-19 patients. Furthermore, VEGF-A levels exhibited a positive correlation with white blood cell count, neutrophil count, and lymphocyte count. Notably, serum surfactant protein-D (SP-D), an indicator of alveolar epithelial cell damage, was significantly higher in patients with elevated VEGF-A levels. CONCLUSION: These results suggest that elevated serum VEGF-A levels could serve as a prognostic biomarker for COVID-19 as it is indicative of alveolar epithelial cell injury caused by SARS-CoV-2 infection. Additionally, we observed a correlation between VEGF-A and neutrophil activation, which plays a role in the immune response during endothelial cell injury, indicating a potential involvement of angiogenesis in disease progression. Further research is needed to elucidate the underlying mechanisms of VEGF-A elevation in COVID-19.

Nationwide survey in Japan of the causative diseases of bloody sputum and hemoptysis in departments of respiratory medicine at university hospitals and core hospitals.

BACKGROUND: The Guidelines for the Management of Cough and Sputum (2019) of the Japanese Respiratory Society (JRS) were the first internationally published guidelines for the management of sputum. However, the data used to determine the causative diseases of bloody sputum and hemoptysis in these guidelines were not obtained in Japan. METHODS: A retrospective analysis was performed using the clinical information of patients with bloody sputum or hemoptysis who visited the department of respiratory medicine at a university or core hospital in Japan. RESULTS: Included in the study were 556 patients (median age, 73 years; age range, 21-98 years; 302 males (54.3%)). The main causative diseases were bronchiectasis (102 patients (18.3%)), lung cancer (97 patients (17.4%)), and non-tuberculous mycobacterial disease (89 patients (16%)). Sex and age differences were observed in the frequency of causative diseases of bloody sputum and hemoptysis. The most common cause was lung cancer in males (26%), bronchiectasis in females (29%), lung cancer in patients aged <65 years (19%), and bronchiectasis in those aged >65 years (20%). CONCLUSIONS: The present study is the first to investigate the causative diseases of bloody sputum and hemoptysis using data obtained in Japan. When investigating the causative diseases of bloody sputum and hemoptysis, it is important to take the sex and age of the patients into account.

LAG3 is an independent prognostic biomarker and potential target for immune checkpoint inhibitors in malignant pleural mesothelioma: a retrospective study.

BACKGROUND: Lymphocyte-activation gene 3 (LAG3) is an immune checkpoint receptor; novel LAG3 immune checkpoint inhibitors (ICIs) exhibit therapeutic activity in melanoma. The role of LAG3and ICIs of LAG3 are unknown in malignant pleural mesothelioma (MPM). This study aimed to uncover the prognostic landscape of LAG3 in multiple cancers and investigate the potential of using LAG3 as an ICIs target in patients with MPM. METHODS: We used The Cancer Genome Atlas (TCGA) cohort for assessing mRNA expression and our cohort for immunohistochemical expression. TCGA cohort were analyzed using the Wilcoxon rank-sum test to compare mRNA expression between normal and tumor tissues in multiple cancers. We used 86 MPM cases from TCGA and 38 MPM cases from our cohort to analyze the expression of LAG3 in tumor-infiltrating lymphocytes. The mean LAG3 mRNA expression was set as the cut-off and samples were classified as positive/negative for immunohistochemical expression. Overall survival (OS) of patients with MPM was determined using the Kaplan-Meier method based on LAG3 mRNA and immunohistochemical expression. OS analysis was performed using the multivariate Cox proportional hazards model. The correlation of LAG3 expression and mRNA expression of tumor immune infiltration cells (TIICs) gene markers were estimated using Spearman correlation. To identify factors affecting the correlation of LAG3 mRNA expression, a multivariate linear regression model was performed. RESULTS: LAG3 mRNA was associated with prognosis in multiple cancers. Elevated LAG3 mRNA expression was correlated with a better prognosis in MPM. LAG3 expression was detected immunohistochemically in the membrane of infiltrating lymphocytes in MPM. LAG3 immunohistochemical expression was correlated with a better prognosis in MPM. The multivariate Cox proportional hazards model revealed that elevated LAG3 immunohistochemical expression indicated a better prognosis. In addition, LAG3 mRNA expression was correlated with the expression of various gene markers of TIICs, the most relevant to programmed cell death 1 (PD-1) with the multivariate linear regression model in MPM. CONCLUSIONS: LAG3 expression was correlated with prognosis in multiple cancers, particularly MPM; LAG3 is an independent prognostic biomarker of MPM. LAG3 regulates cancer immunity and is a potential target for ICIs therapy. PD-1 and LAG3 inhibitors may contribute to a better prognosis in MPM. TRIAL REGISTRATION: This study was registered with UMIN000049240 (registration day: August 19, 2022) and approved by the Institutional Review Board (approval date: August 22, 2022; approval number: 2022-0048) at Tokyo Women's Medical University.

Mycobacteroides abscessus infection in a patient with tetralogy of Fallot.

A 58-year-old woman with tetralogy of Fallot was referred to our hospital with a 2-month history of hemoptysis and low-grade fever. The sputum smear on admission showed positive results for acid-fast bacilli, and comparative genomic analysis of the cultured sputum confirmed Mycobacteroides abscessus subsp. abscessus infection. Long-term combination antimicrobial therapy gradually improved the patient's symptoms. Although non-tuberculous mycobacteria infection is rarely observed in patients with cyanotic congenital heart disease, a worldwide increase in non-tuberculous mycobacteria infections may increase the incidence of this rare combination.

Higher Prevalence and Severity of Eosinophilic Otitis Media in Patients with Asthma-COPD Overlap Compared with Asthma Alone.

INTRODUCTION: Eosinophilic otitis media (EOM) is well-known to frequently co-exist with adult-onset asthma. Both diseases are similar type 2 inflammation and are considered to have a "one airway, one disease" relationship. Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO), characterized by airway obstruction caused by airway wall thickening (AWT), is a severe condition with a higher incidence of mortality compared to asthma alone or COPD alone. Based on the "one airway, one disease" concept, we hypothesized that the inflammatory pathophysiology of EOM differs depending on its comorbidity with ACO or with asthma alone. METHODS: A total of 77 chronic rhinosinusitis (CRS) patients with asthma were enrolled in this study. The subjects were divided into 2 groups: a group with comorbid asthma alone (asthma group; 46 patients), and a group with comorbid ACO (ACO group; 31 patients). The 2 groups were compared and assessed with regard to various factors, including the patients' clinical characteristics, prevalence rate of EOM, EOM severity, EOMs relationships with smoking and AWT, and the eosinophil and neutrophil cell counts in the middle ear effusion (MEE). RESULTS: The ACO group included significantly more males (p < 0.05), was significantly older (p < 0.05), and showed significantly lower lung function values (FEV1 [L], FEV1 [%pred]) (p < 0.01) compared with the asthma group. The ACO group also had a significant history of smoking as shown by the Brinkman index (p < 0.01) and greater AWT as assessed by high-resolution computed tomography (p < 0.05). The EOM prevalence rate was significantly higher in the ACO group (p < 0.05), especially with increased ACO severity (p < 0.05). The EOM severity was also significantly higher in the ACO group (p < 0.05) and also correlated with the ACO severity (p < 0.05). The pretreatment ear clinical characteristics score and the average air conduction hearing level were significantly higher in the ACO group (p < 0.05). The eosinophil percentage in the MEE/otorrhea was significantly lower in the ACO group (25.3%) than in the asthma group (54.7%) (p < 0.05). Conversely, the neutrophil percentage was significantly higher in the ACO group (75.7% vs. 41.9%) (p < 0.05). CONCLUSIONS: Our findings suggest that, in CRS patients with asthma, comorbidity with ACO may be a clinical factor leading to increased EOM prevalence and severity, as well as a higher neutrophil infiltration percentage in the middle ear. Cessation of smoking and early therapeutic intervention for ACO may mitigate progression of bronchial remodeling (i.e., reduce AWT) and help reduce the prevalence and severity of EOM.

Reduced Asthma Exacerbations in Adult Patients Treated With Bronchial Thermoplasty.

BACKGROUND: Bronchial thermoplasty (BT) has been shown to be effective in randomized controlled trials of patients with severe asthma who failed to achieve disease control with high-dose inhaled corticosteroids combined with bronchodilators. However, the effectiveness of BT in real-world clinical settings, especially among the Asian population, has not been determined. OBJECTIVE: To evaluate the effectiveness of BT using a nationwide database. METHODS: Using the inpatient and outpatient data from the Japanese Diagnosis Procedure Combination database, we applied a self-controlled case series design to evaluate changes in the composite outcome of hospital admissions and emergency department visits, as well as systemic corticosteroid dose, between 1 year before and after BT. We also conducted subgroup analyses based on patients' profiles. RESULTS: Among the 561 patients with asthma who underwent BT treatment between September 2014 and March 2020, 102 patients with at least 1 outcome were analyzed. Bronchial thermoplasty was significantly associated with an improvement in the composite outcome of hospital admission and emergency department visits (incidence rate ratio 0.53; 95% CI 0.44-0.64). Systemic corticosteroid use was reduced after BT sessions (1931.5 mg [1,341.2-3,725.3 mg] to 641.3 mg [134.2-1,691.1 mg] per person-year; P < .001). Although all groups showed a significant improvement in the composite outcome in the subgroup analyses, BT tended to be less effective among people older than 65 years and those with higher body mass index (>25 kg/m2). CONCLUSIONS: The present study using real-world data suggests that BT may improve asthma control; however, the effectiveness of BT can vary depending on patient baseline profiles.

Real-world impact of dupilumab on asthma disease burden in Japan: The CROSSROAD study.

BACKGROUND: Dupilumab, a human monoclonal anti-interleukin (IL)-4Ra antibody blocks the shared receptor component of IL-4 and IL-13, drivers of type 2 inflammation. Dupilumab is approved for severe/refractory asthma inadequately controlled by existing therapies, but knowledge of its effect on real-world disease burden is lacking. This study investigates real-world effects of dupilumab on asthma exacerbation risk and oral corticosteroid (OCS) use in Japanese individuals with asthma. METHODS: This retrospective, cohort study used a Japanese insurance claims database to identify patients who started dupilumab between 26 March 2019-31 May 2020. Patients were followed for ±365 days from dupilumab initiation. The study primarily assessed the annual incidence rate of severe asthma exacerbations occurring simultaneously with hospitalizations or OCS bursts. Secondary and exploratory endpoints assessed OCS dosage and duration, and healthcare resource utilization (HRU), respectively. RESULTS: At dupilumab initiation (N = 215), mean age was 57.2 years, 41.9% of patients were aged ≥65 years, and 59.5% were female. Dupilumab significantly reduced the annual incidence of severe asthma exacerbations from 1.29 to 0.74 (95% confidence interval, 0.44-0.76) per patient per year. Mean OCS dosage decreased from 10.4 to 7.2 mg/day in chronic OCS users; median frequency of OCS bursts decreased from 3 to 0. Both unscheduled outpatient visits (35.8% vs 29.8%) and hospitalizations (21.9% vs 12.1%) decreased. Mean (standard deviation) duration of hospitalization also decreased from 6.7 (27.6) to 2.2 (8.1) days. CONCLUSIONS: Japanese patients with asthma who received dupilumab had reduced incidence rates of severe asthma exacerbations, OCS use, and HRU over 12 months.

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

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

The efficacy of neutralizing monoclonal antibodies in transplant recipients with mild-to-moderate COVID-19.

INTRODUCTION: Transplant recipients (TRs) are at high risk for severe coronavirus disease 2019 (COVID-19). Neutralizing monoclonal antibodies (mAbs) are used for treating mild-to-moderate COVID-19. However, reports comparing the efficacy of COVID-19 treatment without/with mAbs in TRs are limited. We assessed the efficacy of casirivimab/imdevimab against mild-to-moderate COVID-19 in TRs. METHODS: Forty-one patients were retrospectively evaluated. The duration until defervescence, oxygen (O2) requirement ≥5 L, and neutralizing antibody levels were compared in TRs with COVID-19 without/with casirivimab/imdevimab. RESULTS: Casirivimab/imdevimab was correlated with shorter duration until defervescence and non-requirement of O2 ≥ 5 L in TRs with COVID-19 [mean: without/with: 6 vs. 2; P = 0.0002, hazard ratio (HR) = 0.3333, 95% confidence interval (CI) = 0.1763-0.6301; 15 vs. 8; P < 0.0001, HR = 0.5333, 95% CI = 0.2878-0.9883; P = 0.0377, HR = 0.1502, 95% CI = 0.02511-0.8980]. Casirivimab/imdevimab was associated with early defervescence after adjusting for sex and age (P = 0.013, HR = 0.412, 95% CI = 0.205-0.826). The antibody levels between patients without/with casirivimab/imdevimab on the day of hospitalization were not significantly different (P = 0.1055), including 13 TRs with vaccination. Antibody levels were higher in patients with casirivimab/imdevimab at 3-5 days after hospitalization than in those without, at 7-9 days after hospitalization (P < 0.0001, mean, without/with: 414.9/40000 AU/mL). CONCLUSION: Casirivimab/imdevimab was effective and increased the neutralizing antibody in TRs with mild-to-moderate COVID-19, it may contribute toward preventing the progression.

Clinical characteristics and treatment outcomes of severe asthma patients with a history of multiple biologic drugs use.

BACKGROUND: Asthma control has been shown to improve after clinical use of molecular-targeted biologic drugs. Although most patients have shown favorable responses to biologic drugs, some individuals need to switch to another biologic drug. To date, limited data are available regarding patients who received multiple biologic drugs. OBJECTIVE: We aimed to evaluate the characteristics and outcomes of patients treated with multiple biologic drugs. METHODS: We reviewed severe asthma patients who received biologic drugs between May 2009 and September 2019. Clinical characteristics of patients and changes in annualized asthma exacerbation rates, asthma control test (ACT), and oral corticosteroid (OCS) dose, before and after the use of the final biologic drug, were evaluated. RESULTS: Of the 105 patients who received biologic drugs, 20 patients received multiple biologic drugs. Twelve patients received two biologic drugs, six received three, and two received four. Patients who received multiple biologic drugs tended to have a significantly higher number of allergic or eosinophilic airway comorbidities (allergic rhinitis: p = 0.02, chronic rhinosinusitis with nasal polyps: p < 0.001). Approximately half of the patients changed to different treatments due to uncontrolled comorbidities. Annualized exacerbation rates, ACT, and OCS dose significantly improved after the latest biologic drug use (p = 0.035, p < 0.001, and p = 0.038, respectively). CONCLUSIONS: The results of this study indicated that allergic and eosinophilic airway comorbidities should be considered during the selection of biologic drugs. Furthermore, most patients who received multiple biologic drugs achieved disease control after switching to the optimal biologic drug.

Analysis of the diagnosis of Japanese patients with primary ciliary dyskinesia using a conditional reprogramming culture.

BACKGROUND: Primary ciliary dyskinesia (PCD) is diagnosed through multiple methods, including transmission electron microscopy (TEM), a high-speed video microscopy analysis (HSVA), immunofluorescence (IF), and genetic testing. A primary cell culture has been recommended to avoid the misdiagnosis of secondary ciliary dyskinesia derived from infection or inflammation and improve diagnostic accuracy. However, primary cells fail to differentiate into ciliated cells through repeated passages. The conditional reprogramming culture (CRC) method, a combination of a Rho-kinase inhibitor and fibroblast feeder cells, has been applied to cystic fibrosis. The goal of this study was to evaluate the value of CRC in diagnosing PCD in Japanese patients. METHODS: Eleven patients clinically suspected of having PCD were included. Airway epithelial cells were obtained from an endobronchial forceps biopsy and cultured at the air-liquid interface (ALI) combined with CRC. Ciliary movement, ultrastructure, and mutated ciliary protein evaluation were performed using HSVA, TEM, and IF, respectively. Genetic testing was performed on some patients. RESULTS: CRC yielded dense and well-differentiated ciliated cells with a high success rate (∼90%). In patients with PCD, the ciliary ultrastructure phenotype (outer dynein arm defects or normal ultrastructure) and IF findings (absence of the mutated ciliary protein) were confirmed after CRC. In DNAH11-mutant cases with normal ultrastructure by TEM, the HSVA revealed stiff and hyperfrequent ciliary beating with low bending capacity in CRC-expanded cells, thereby supporting the diagnosis. CONCLUSIONS: CRC could be a potential tool for improving diagnostic accuracy and contributing to future clinical and basic research in PCD.

A case of lung intravascular large B cell lymphoma developed with respiratory failure rescued by corticosteroid prior to definite diagnosis.

A 56-year-old man complained progressive dyspnea, fatigue and fever for one month. His chest CT exhibited faint ground-glass opacities, and the levels of serum LDH and soluble interleukin 2 receptor were markedly elevated. Positron emission tomography (PET) showed high uptake of 18-fluoro deoxy glucose (18FDG) only on both lungs. We performed transbronchial lung biopsies (TBLB) for the diagnosis. After bronchoscopy, he had prolonged hypoxemia. Because defects of 99m-Technetium macroaggregated albumin (99mTc-MAA) in pulmonary blood flow scintigraphy were consistent with the distribution of 18FDG uptake in PET, we speculated that the presence of intravascular lymphoma (IVL) cells in the capillaries might have behaved like tumor embolism. We started rescue by prednisolone based on treatment of lymphoma. As a result, his hypoxemia was gradually improved. Histological findings in TBLB specimen showed that CD20+CD79+Bcl-2+c-myc+ lymphoma cells were localized to small vessel lumina in alveoli and bronchioles, and he was definitely diagnosed with lung intravascular large B cell lymphoma (IVLBCL). He was treated with complete cyclophosphamide, doxorubicin, vincristine, and prednisolone with rituximab (R-CHOP) in combination with intrathecal methotrexate injection. After eight cycles of R-CHOP and three times of intrathecal methotrexate, 18FDG uptake of PET on both lungs completely disappeared, achieving complete metabolic remission. We experienced a rare case of lung IVLBCL developed with respiratory failure successfully rescued by prednisolone prior to definite diagnosis.

Direct platelet adhesion potentiates group 2 innate lymphoid cell functions.

BACKGROUND: Platelets are thought to be involved in the pathophysiology of asthma, presumably through direct adhesion to inflammatory cells, including group 2 innate lymphoid cells (ILC2s). Here, we tried to elucidate the effects of platelet adhesion to ILC2s in vitro and in vivo, as well as the mechanisms involved. METHODS: Alternaria-induced ILC2-dependent airway inflammation models using wild-type and c-mpl-/- mice were evaluated. Both purified CD41+ and CD41- ILC2s were cultured with IL-2 and IL-33 to determine in vitro Type 2 (T2) cytokine production and cell proliferation. RNA-seq data of flow-cytometry-sorted CD41+ and CD41- ILC2s were used to isolate ILC2-specific genes. Flow cytometry was performed to determine the expression of CD41 and adhesion-related molecules on ILC2s in both mouse and human tissues. RESULTS: T2 inflammation and T2 cytokine production from ILC2s were significantly reduced in the c-mpl-/- mice compared to wild-type mice. Platelet-adherent ILC2s underwent significant proliferation and showed enhanced T2 cytokine production when exposed to IL-2 and IL-33. The functions of ILC2-specific genes were related to cell development and function. Upstream regulator analysis identified 15 molecules, that are thought to be involved in ILC2 activation. CD41 expression levels were higher in ILC2s from human PBMCs and mouse lung than in those from secondary lymphoid tissues, but they did not correlate with the P-selectin glycoprotein ligand-1 or CD24 expression level. CONCLUSION: Platelets spontaneously adhere to ILC2s, probably in the peripheral blood and airways, thereby potentiating ILC2s to enhance their responses to IL-33.

Tryptase and IL-33 in Bronchoalveolar Lavage Fluid May Predict the Types of Eosinophilic Pneumonia and Disease Recurrence.

INTRODUCTION: Eosinophilic pneumonia (EP) is characterized by a marked accumulation of eosinophils in the lungs and blood. Eosinophils and mast cells play an important role in the pathogenesis of EP via release of biomarkers such as tryptase and interleukin (IL)-33. However, the potential role of these biomarkers is not fully understood. OBJECTIVES: We aimed to evaluate the differences among the levels of tryptase and IL-33 in bronchoalveolar lavage fluid (BALF) from several types of EP. We evaluated the differences between the levels of these biomarkers in the recurrent and nonrecurrent cases. METHOD: We prospectively collected the clinical data of patients with EP, diagnosed between 2006 and 2015 in our institution. Bronchoscopy was performed before steroid treatment; BALF was collected. The clinical characteristics of EP patients and the levels of tryptase and IL-33 in BALF were evaluated. RESULTS: We enrolled 15 patients with chronic EP (CEP), 5 with acute EP (AEP), 10 with drug-induced EP, and 6 with angiitis-related EP. Tryptase levels in the CEP group were significantly higher than that in the drug-induced EP group (p = 0.048), while the AEP group had the highest IL-33 levels. Recurrence of EP was noted in 67% of patients with CEP. The levels of tryptase and IL-33 were notably higher in the recurrent cases than that in the nonrecurrent CEP group (p = 0.004, p = 0.04, respectively). Furthermore, there was a positive correlation between the levels of tryptase and IL-33 in the BALF of patients with CEP (ρ = 0.69, p = 0.004). CONCLUSIONS: Tryptase and IL-33 in BALF are useful biomarkers for the assessment of EP types. These biomarkers could be used to predict disease recurrence.

Mepolizumab decreased the levels of serum galectin-10 and eosinophil cationic protein in asthma.

BACKGROUND: Mepolizumab, a humanized antibody targeting interleukin-5, decreases the number of blood eosinophils and the frequency of exacerbation of severe asthma. Galectin-10 is a protein within the cytoplasm of eosinophils and constitutes Charcot-Leyden crystals, which promotes key features of asthma. However, the relationship between time kinetics and clinical response of eosinophil-derived molecules such as galectin-10 or eosinophil cationic protein (ECP) has not been precisely investigated. OBJECTIVE: This study aimed to clarify the precise time course of the levels of serum galectin-10 and ECP after mepolizumab treatment and to analyze the relationship between the levels of eosinophil-derived molecules and the clinical background or response to mepolizumab treatment. METHODS: This multicenter, prospective open-label study recruited 20 patients with severe eosinophilic asthma. Mepolizumab was administered every 4 weeks for 32 weeks and the levels of various biomarkers were serially analyzed. RESULTS: The serum galectin-10 and ECP significantly and rapidly decreased 4 weeks after initial administration of mepolizumab. In contrast, basophil count, fractional exhaled nitric oxide, and the serum total IgE level were unchanged during treatment. Asthma Control Questionnaire-5, Asthma Health Questionnaire-33, and Lund-Mackay scores significantly improved after mepolizumab treatment. Both high ECP and eosinophil count related to better response in forced expiratory volume in 1 second (FEV1) and measurable ECP level at 4 weeks after administration of mepolizumab related to the further improvement in FEV1 toward week 32. No significant difference in improvement in FEV1 was observed in galectin-10 high group. The level of ECP at baseline was significantly related to the higher prevalence of nasal polyp and Lund-Mackay score. CONCLUSION: This study was the first to show that the levels of serum galectin-10 decreases after initial administration of mepolizumab. The significant relationship between serum ECP and better response in FEV1 suggested the potential role of serum ECP as a predictive biomarker for the efficacy of mepolizumab (UMIN000030466).

Less airway inflammation and goblet cell metaplasia in an IL-33-induced asthma model of leptin-deficient obese mice.

BACKGROUND: Obesity-associated asthma is a phenotype of severe asthma. Late-onset, non-eosinophilic and female-dominant phenotype is highly symptomatic and difficult to treat. Leptin, an adipokine, exerts an immunomodulatory effect. IL-33 associated with innate immunity induces type 2 inflammation and is present in adipose tissue. The purpose of this study was to elucidate the pathogenesis of obesity-associated asthma by focusing on the interaction between leptin and IL-33. METHODS: In leptin-deficient obese (ob/ob) and wild-type mice, IL-33 was instilled intranasally on three consecutive days. In part of the mice, leptin was injected intraperitoneally prior to IL-33 treatment. The mice were challenged with methacholine, and airway hyperresponsiveness (AHR) was assessed by resistance (Rrs) and elastance (Ers) of the respiratory system using the forced oscillation technique. Cell differentiation, IL-5, IL-13, eotaxin, keratinocyte-derived chemokine (KC) in bronchoalveolar lavage fluid (BALF) and histology of the lung were analyzed. For the in vitro study, NCI-H292 cells were stimulated with IL-33 in the presence or absence of leptin. Mucin-5AC (MUC5AC) levels were measured using an enzyme-linked immunosorbent assay. RESULTS: Ob/ob mice showed greater Rrs and Ers than wild-type mice. IL-33 with leptin, but not IL-33 alone, enhanced Ers rather than Rrs challenged with methacholine in ob/ob mice, whereas it enhanced Rrs alone in wild-type mice. IL-33-induced eosinophil numbers, cytokine levels in BALF, eosinophilic infiltration around the bronchi, and goblet cell metaplasia were less in ob/ob mice than in wild-type mice. However, leptin pretreatment attenuated these changes in ob/ob mice. MUC5AC levels were increased by co-stimulation with IL-33 and leptin in vitro. CONCLUSIONS: Ob/ob mice show innate AHR. IL-33 with leptin, but not IL-33 alone, induces airway inflammation and goblet cell metaplasia and enhances AHR involving peripheral airway closure. This is presumably accelerated by mucus in ob/ob mice. These results may explain some aspects of the pathogenesis of obesity-associated asthma.

Recurrent spindle cell carcinoma of the lung successfully treated by chemoimmunotherapy.

There is limited evidence for the treatment of sarcomatoid lung carcinoma, especially spindle cell carcinoma (SpCC) because of the rarity of disease. Although the efficacy of combination of chemotherapy and immunotherapy (i.e. chemoimmunotherapy) for non-small cell lung cancer (NSCLC) is well recognized, the effect for SpCC is not fully elucidated. A 72-year-old woman underwent surgical resection for the treatment of stage IIIA SpCC. Recurrence occurred three months after surgery, and then she received combination of carboplatin, paclitaxel, bevacizumab, and atezolizumab. A clinically favourable response was achieved by four cycles of chemoimmunotherapy and sequential maintenance therapy with bevacizumab and atezolizumab. The prognosis of advanced SpCC is generally poor, but chemoimmunotherapy can be a good therapeutic option for the first-line treatment of SpCC.