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Despite standard treatment with systemic corticosteroids and/or antifungal triazoles, a substantial proportion of patients with allergic bronchopulmonary aspergillosis (ABPA) experience frequent relapses and require long-term treatment despite unfavorable adverse effects. We investigated the efficacy and safety of anti-interleukin (IL)-5/IL-5 receptor α chain (Rα) monoclonal antibodies (mAbs) in patients with ABPA complicated by asthma. ABPA cases treated with anti-IL-5/IL-5Rα mAbs were collected from 132 medical institutes in 2018 and published case reports in Japan. Clinical outcomes, laboratory and physiological data, and radiographic findings during 32 weeks before and after treatment were retrospectively evaluated. We analyzed 29 cases of ABPA: 20 treated with mepolizumab and nine with benralizumab. Treatment with anti-IL-5/IL-5Rα mAbs reduced the frequency of exacerbations (p = 0.03), decreased the dose of oral corticosteroids (p < 0.01), and improved pulmonary function (p = 0.01). Mucus plugs in the bronchi shrank or diminished in 18 patients (82%). Despite the clinical/radiographical improvement, serum levels of total IgE, the key biomarker for the pharmacological response in ABPA, were unchanged. Anti-IL-5/IL-5Rα mAbs that directly target eosinophils are promising candidates for the treatment of patients with ABPA, especially those with mucus plugs in the bronchi. [ABSTRACT FROM AUTHOR]

Background: Few studies on the long-term efficacy of benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, have been conducted for patients with severe eosinophilic asthma (SEA), especially regarding the improvement of pulmonary function and clinical remission in a real-world setting. Objective: To elucidate the long-term efficacy and clinical remission rate (CRR) in patients with SEA. Methods: From July 2018 to July 2022, 23 Japanese patients with SEA received benralizumab for two years or more at Jikei University Hospital. We retrospectively evaluated the patients' characteristics, biomarkers, number of exacerbations, pulmonary function, asthma symptoms, maintenance oral corticosteroid (OCS) dose and CRR. Results: The mean observation period was 38.3 (24– 49) months. Among the 23 patients, 10 patients switched from mepolizumab to benralizumab. After administration of benralizumab, the forced expiratory volume in one second (FEV1) increased and was maintained for two years in the biologic-naïve group and in the switching group (177 ± 404 and 151 ± 236 [mL], respectively, P = 0.80). In all patients, the %FEV1 improved from 76.7 ± 22.9% to 84.3 ± 18.4% (P = 0.016), and the number of annual exacerbations decreased from 2.5 ± 3.3 to 0.74 ± 1.7 (P = 0.014). Furthermore, the Asthma Control Test score significantly improved, and the reduction in OCS dose was maintained for three years. Ultimately, five patients met the clinical remission criteria and exhibited stabilization of pulmonary function, no exacerbation, no OCS use and well-controlled symptoms. The CRR was significantly higher in patients with a blood basophil count (BBC) ≥ 22 than in those with a BBC < 22 (/μL) (38.5% vs 0%, respectively, P = 0.046). Conclusion: Long-term treatment with benralizumab significantly improved pulmonary function, alleviated asthma symptoms and decreased the number of exacerbations at two years in a real-world setting. The CRR may be associated with the BBC at baseline. [ABSTRACT FROM AUTHOR]

Background: Dupilumab, an anti-IL-4α receptor antibody, is a new treatment for severe or refractory asthma. However, real-world evidence on the efficacy of dupilumab in patients with mild to moderate bronchial asthma is lacking.Methods: We retrospectively evaluated the effects of dupilumab in 62 patients who received dupilumab for eosinophilic sinusitis comorbid with asthma at a single centre in Japan. Type 2 inflammatory markers, ACT, respiratory function tests, and forced oscillation technique (FOT) were analysed before, three months after, and one year after dupilumab administration, mainly in patients with mild to moderate asthma.Results: FEV1, %FEV1, %FVC, treatment steps for asthma and ACT improved significantly after three months of dupilumab treatment. FeNO was markedly decreased, whereas IgE and eosinophil counts showed no significant changes. Pre- and post-treatment respiratory resistance (Rrs) and respiratory reactance (Xrs) correlated significantly with FEV1. Improvement in %FEV1 was associated with higher FeNO and higher serum IgE before dupilumab treatment.Conclusion: Dupilumab treatment for sinusitis may improve respiratory functions, asthma symptoms, and asthma treatment reduction, even if the associated bronchial asthma is not severe. [ABSTRACT FROM AUTHOR]

Background: Treatment with dupilumab, an anti-interleukin (IL)-4 receptor α monoclonal antibody that blocks both the IL-4 and IL-13 pathways, has demonstrated efficacy for the treatment of severe asthma (SA) with type 2 inflammation. However, few studies have focused on the efficacy of this biologic for the treatment of SA in a real-world setting. Methods: From April 2019 to December 2021, 26 Japanese patients with SA received dupilumab at Jikei University Hospital. We retrospectively evaluated the number of moderate-to-severe exacerbations, pulmonary function, maintenance dose of corticosteroids, biomarkers, and adverse events. Results: During a mean follow-up period of 12.6 months, 10 patients received dupilumab as the first biologic, and 16 switched to dupilumab from other biologics. Dupilumab treatment significantly reduced the number of annual exacerbations from 3.4 ± 4.1 to 1.6 ± 2.7 (/person-year, p < 0.01) at the last follow-up regardless of previous biologic use. The Asthma Control Test score significantly improved in all patients by six months after administration but tended to worsen by 24 months in patients with previous biologic use. On the other hand, blood eosinophil counts (BECs) transiently increased and peaked three to six months after administration. The peak timing can be affected by previous biologic use. Adverse events included wheezing immediately after injection, hypereosinophilia, mild conjunctivitis, and relapse of chronic eosinophilic pneumonia in the patient switched from benralizumab. Conclusion: Dupilumab treatment was useful for patients with SA in a real-world setting. However, the BEC should be monitored carefully, especially in patients who previously received anti-IL-5/IL-5 receptor antibody. [ABSTRACT FROM AUTHOR]

Objectives: Recently, incidence of Mycobacterium abscessus (Mab) pulmonary disease (Mab-PD) is increasing worldwide. We aimed to identify factors associated with severity of Mycobacterium abscessus (Mab) pulmonary disease (Mab-PD). Methods: All patients diagnosed as Mab-PD based on the official ATS/IDSA statement between 2017 January 1 and 2021 July 31 were included (n = 13). We reviewed medical records, bacteriological and laboratory data of the patients. Severity of lung lesions and esophageal diameters in chest CT were quantitatively evaluated. Gaffky score in the sputum was used as airway mycobacterial burden. We explored the factors associated with high CT score and high Gaffky score. Results: Maximum diameter of esophagus (MDE) in severe disease (CT score≧10) was greater than that in milder disease (CT score<10) (18.0±7.9mm, 9.3±3.1mm, respectively, p = 0.01), and MDE was well correlated with CT score (R = 0.69, p = 0.007). MDE in high mycobacterial burden group (Gaffky score ≧5) tended to be greater than that in low mycobacterial burden group (Gaffky score <5) (16.1±6.8mm, 10.1±5.5mm, respectively, p = 0.12), and MDE was well correlated with Gaffky score (R = 0.68, p = 0.009). Lung lesions were bilateral and predominant in middle or lower lobes. Conclusions: Esophageal dilatation was correlated with severity of Mab-PD and airway mycobacterial burden. Gastroesophageal reflux might be associated with Mab disease progression. [ABSTRACT FROM AUTHOR]

Background: In Japan, biologic therapy was initiated for patients with severe asthma in 2009. In recent years, four biologics with different mechanisms of action have become available in the clinical setting. However, the efficacy of switching between biologics remains uncertain. Methods: To elucidate the efficacy of switching between biologics, 97 patients were enrolled who had received any biologic therapy for severe asthma at Jikei University Hospital, Tokyo, Japan, from July 2009 to December 2020. We retrospectively examined the patient characteristics, biomarkers, pulmonary function test results, selected biologics, and efficacy. Results: Thirty-one males and 66 females received any biologics. The mean age was 53.3 years at the initiation of biologic therapy. Initially, 33, 41, 15 and eight patients received omalizumab, mepolizumab, benralizumab, and dupilumab, respectively. Among three representative indicators for biologics administration, the peripheral blood eosinophil count, serum IgE levels and fractional exhaled nitric oxide, 64% of the patients had two indicators, and 28% had three indicators. Thirty-four patients (35%) switched from the initial biologic to another, and the reasons for switching included persistent asthmatic symptoms (n=22), schedule of hospital visits (n=5), and other reasons. Thus, the treatment was effective in 11 patients after switching. In addition, two patients received combination therapy with different biologics. Eighteen patients (19%) interrupted treatment for various reasons. Regardless of whether the biologic was the initial therapy, the overall efficacy of the four biologics was 60% based on the global evaluation of treatment effectiveness. Conclusion: Switching between biologics can be a promising option for severe asthma patients in whom treatment with an initial biologic is ineffective. [ABSTRACT FROM AUTHOR]

Interleukin (IL)‐17 plays critical roles in the pathogenesis of both psoriasis and interstitial pneumonia (IP). We hypothesized that anti‐IL‐17 biologics might suppress both clinically relevant and latent IP activity and decrease Krebs von den Lungen‐6 (KL‐6) level in psoriasis patients. We aimed to elucidate the effects of anti‐IL‐17 biologics on KL‐6 levels. We retrospectively analyzed the clinical data of psoriasis patients treated with anti‐IL‐17 biologics. KL‐6 levels were measured before treatment (baseline) and at 3 and 6 months after the initiation of the treatment, and ratios of KL‐6 levels at each time point to the baseline levels were calculated. Chest computed tomography (CT) was performed on patients with coexisting IP. The clinical characteristics and radiographic findings were evaluated. A total of 294 psoriasis patients were treated with anti‐IL‐17 biologics. Baseline KL‐6 levels were higher than 401 U/mL in 34 patients (high baseline KL‐6 group). While anti‐IL‐17 biologics did not affect KL‐6 levels and ratios of KL‐6 to the baseline levels at any time point in the overall study population, they decreased both KL‐6 levels and ratios at 6 months after the initiation of the treatment in the high baseline KL‐6 group. A total of 10 patients with coexisting IP showed decreasing ratios of KL‐6 to the baseline levels at 6 months without affecting coexisting IP in CT performed at 3–12 months. Anti‐IL‐17 biologics decreased KL‐6 levels in the high baseline KL‐6 group regardless of recognizable IP. A decrease in KL‐6 levels was not associated with a radiographic improvement of IP, which should be examined in large numbers with long‐term observations in future studies. [ABSTRACT FROM AUTHOR]

Objectives: Anti-IL-17/23 biologics are increasingly used to treat psoriasis. We aimed to elucidate characteristics of drug-induced interstitial pneumonia (DIIP) caused by anti-IL-17/23 biologics. Methods: We retrospectively analyzed the clinical data of psoriasis patients treated with anti-IL-17/23 biologics. Chest CT was performed to evaluate DIIP. Serum KL-6 levels were measured before treatment (baseline) and during treatment. Results: A total of 603 psoriasis patients were treated with anti-IL-17/23 biologics with mean follow-up of 21.1 months. Six patients developed DIIP at mean 14 months after initiation of the therapy. Older age, higher baseline KL-6 value and more frequent pre-existing IPs were associated with development of DIIP by univariate analysis. At the onset of DIIP, elevated serum KL-6 levels with concomitantly increased ground glass opacity (GGO) in Chest CT were demonstrated. DIIP was improved by only cessation of causative agents in five patients but steroid therapy was needed in one patient. Conclusions: DIIP is a plausible complication of anti-IL-17/23 biologics. Age, baseline KL-6 level and underlying IP could be the risk factors for DIIP development. Serum KL-6 levels and chest CT are useful for not only predicting but also detecting DIIP caused by anti-IL-17/23 biologics. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor (ICI)-related pneumonitis is a relatively rare but clinically serious and potentially life-threatening adverse event. The majority of cases can be managed by drug discontinuation, with the administration of corticosteroids added in severe cases. However, worsening of pneumonitis can develop in a subset of patients despite treatment with high doses of corticosteroids. We herein report a case of steroid-refractory ICI-related pneumonitis in a recurrent non-small cell lung cancer (NSCLC) patient treated with pembrolizumab that was successfully improved by triple combination therapy (high-dose corticosteroids, tacrolimus, and cyclophosphamide). After 3 weeks of initial pembrolizumab administration, the patient was diagnosed with ICI-related pneumonitis. Chest computed tomography (CT) showed patchy distributed bilateral consolidation and ground-glass opacities (GGOs) with traction bronchiectasis and bronchiolectasis resembling the diffuse alveolar damage (DAD) radiographic pattern. Although methylprednisolone pulse therapy was initiated, worsening of respiratory failure resulted in the patient being transferred to the intensive care unit. Because of an insufficient therapeutic response to high-dose corticosteroids, tacrolimus and cyclophosphamide pulse therapy were additively performed as triple combination therapy according to the treatment strategy for pulmonary complications of clinically amyopathic dermatomyositis (CADM). In response to this triple combination therapy, the patient's respiratory condition gradually improved, and chest CT showed the marked amelioration of pulmonary opacities. This is the first report suggesting the efficacy of triple combination therapy (high-dose corticosteroids, tacrolimus, and cyclophosphamide) for steroid-refractory ICI-related pneumonitis complicated with respiratory failure. [ABSTRACT FROM AUTHOR]

Background: Benralizumab, an anti-interleukin-5 (IL-5) receptor α monoclonal antibody, significantly reduces the number of annual exacerbations and oral corticosteroid (OCS) maintenance doses for patients with severe eosinophilic asthma (SEA). However, few studies on the efficacy of this biologic in real life are available. The aim was to elucidate the efficacy of benralizumab by evaluating changes in clinical parameters after benralizumab treatment in patients with SEA. Methods: From July 2018 to December 2019, 24 Japanese patients with SEA received benralizumab at Jikei University Hospital. We retrospectively evaluated the patients' characteristics, parameters, numbers of exacerbations and maintenance OCS doses. Results: Among the 24 patients, eleven patients had received mepolizumab treatment and were directly switched to benralizumab. The peripheral blood eosinophil and basophil counts significantly decreased after benralizumab treatment regardless of previous mepolizumab treatment. Pulmonary function, Asthma Control Test scores, the numbers of annual exacerbations and maintenance OCS doses in patients without previous mepolizumab treatment tended to improve without significant differences. Fourteen patients (58%) were responders according to the Global Evaluation of Treatment Effectiveness (GETE) score. The proportion of GETE responders among patients with aspirin-exacerbated respiratory disease (AERD) tended to be lower than that among patients without AERD (p = 0.085). After benralizumab treatment, the change in the forced expiratory volume in 1 s from baseline was 200 ml or greater in eight patients (33%), including three patients who were switched from mepolizumab. Conclusion: Benralizumab treatment improved and controlled asthma symptoms based on the GETE score. [ABSTRACT FROM AUTHOR]

Background: Benralizumab, an anti-interleukin-5 (IL-5) receptor α monoclonal antibody, significantly reduces the number of annual exacerbations and oral corticosteroid (OCS) maintenance doses for patients with severe eosinophilic asthma (SEA). However, few studies on the efficacy of this biologic in real life are available. The aim was to elucidate the efficacy of benralizumab by evaluating changes in clinical parameters after benralizumab treatment in patients with SEA.Methods: From July 2018 to December 2019, 24 Japanese patients with SEA received benralizumab at Jikei University Hospital. We retrospectively evaluated the patients' characteristics, parameters, numbers of exacerbations and maintenance OCS doses.Results: Among the 24 patients, eleven patients had received mepolizumab treatment and were directly switched to benralizumab. The peripheral blood eosinophil and basophil counts significantly decreased after benralizumab treatment regardless of previous mepolizumab treatment. Pulmonary function, Asthma Control Test scores, the numbers of annual exacerbations and maintenance OCS doses in patients without previous mepolizumab treatment tended to improve without significant differences. Fourteen patients (58%) were responders according to the Global Evaluation of Treatment Effectiveness (GETE) score. The proportion of GETE responders among patients with aspirin-exacerbated respiratory disease (AERD) tended to be lower than that among patients without AERD (p = 0.085). After benralizumab treatment, the change in the forced expiratory volume in 1 s from baseline was 200 ml or greater in eight patients (33%), including three patients who were switched from mepolizumab.Conclusion: Benralizumab treatment improved and controlled asthma symptoms based on the GETE score. [ABSTRACT FROM AUTHOR]

Cigarette smoke (CS)-induced accumulation of mitochondrial damage has been widely implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. Mitophagy plays a crucial role in eliminating damaged mitochondria, and is governed by the PINK1 (PTEN induced putative protein kinase 1)-PRKN (parkin RBR E3 ubiquitin protein ligase) pathway. Although both increased PINK1 and reduced PRKN have been implicated in COPD pathogenesis in association with mitophagy, there are conflicting reports for the role of mitophagy in COPD progression. To clarify the involvement of PRKN-regulated mitophagy in COPD pathogenesis, prkn knockout (KO) mouse models were used. To illuminate how PINK1 and PRKN regulate mitophagy in relation to CS-induced mitochondrial damage and cellular senescence, overexpression and knockdown experiments were performed in airway epithelial cells (AEC). In comparison to wild-type mice, prkn KO mice demonstrated enhanced airway wall thickening with emphysematous changes following CS exposure. AEC in CS-exposed prkn KO mice showed accumulation of damaged mitochondria and increased oxidative modifications accompanied by accelerated cellular senescence. In vitro experiments showed PRKN overexpression was sufficient to induce mitophagy during CSE exposure even in the setting of reduced PINK1 protein levels, resulting in attenuation of mitochondrial ROS production and cellular senescence. Conversely PINK1 overexpression failed to recover impaired mitophagy caused by PRKN knockdown, indicating that PRKN protein levels can be the rate-limiting factor in PINK1-PRKN-mediated mitophagy during CSE exposure. These results suggest that PRKN levels may play a pivotal role in COPD pathogenesis by regulating mitophagy, suggesting that PRKN induction could mitigate the progression of COPD. Abbreviations: AD: Alzheimer disease; AEC: airway epithelial cells; BALF: bronchoalveolar lavage fluid; AKT: AKT serine/threonine kinase; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CDKN1A: cyclin dependent kinase inhibitor 1A; CDKN2A: cyclin dependent kinase inhibitor 2A; COPD: chronic obstructive pulmonary disease; CS: cigarette smoke; CSE: CS extract; CXCL1: C-X-C motif chemokine ligand 1; CXCL8: C-X-C motif chemokine ligand 8; HBEC: human bronchial epithelial cells; 4-HNE: 4-hydroxynonenal; IL: interleukin; KO: knockout; LF: lung fibroblasts; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; 8-OHdG: 8-hydroxy-2ʹ-deoxyguanosine; OPTN: optineurin; PRKN: parkin RBR E3 ubiquitin protein ligase; PCD: programmed cell death; PFD: pirfenidone; PIK3C: phosphatidylinositol-4:5-bisphosphate 3-kinase catalytic subunit; PINK1: PTEN induced putative kinase 1; PTEN: phosphatase and tensin homolog; RA: rheumatoid arthritis; ROS: reactive oxygen species; SA-GLB1/β-Gal: senescence-associated-galactosidase, beta 1; SASP: senescence-associated secretory phenotype; SNP: single nucleotide polymorphism; TNF: tumor necrosis factor. [ABSTRACT FROM AUTHOR]

Background: Postoperative pulmonary complications (PPC) in patients with pulmonary diseases remain to be resolved clinical issue. However, most evidence regarding PPC has been established more than 10 years ago. Therefore, it is necessary to evaluate perioperative management using new inhalant drugs in patients with obstructive pulmonary diseases.Methods: April 2014 through March 2015, 346 adult patients with pulmonary diseases (257 asthma, 89 chronic obstructive pulmonary disease (COPD)) underwent non-pulmonary surgery except cataract surgery in our university hospital. To analyze the risk factors for PPC, we retrospectively evaluated physiological backgrounds, surgical factors and perioperative specific treatment for asthma and COPD.Results: Finally, 29 patients with pulmonary diseases (22 asthma, 7 COPD) had PPC. In patients with asthma, smoking index (≥ 20 pack-years), peripheral blood eosinophil count (≥ 200/mm3) and severity (Global INitiative for Asthma(GINA) STEP ≥ 3) were significantly associated with PPC in the multivariate logistic regression analysis [odds ratio (95% confidence interval) = 5.4(1.4-20.8), 0.31 (0.11-0.84) and 3.2 (1.04-9.9), respectively]. In patients with COPD, age, introducing treatment for COPD, upper abdominal surgery and operation time (≥ 5 h) were significantly associated with PPC [1.18 (1.00-1.40), 0.09 (0.01-0.81), 21.2 (1.3-349) and 9.5 (1.2-77.4), respectively].Conclusions: History of smoking or severe asthma is a risk factor of PPC in patients with asthma, and age, upper abdominal surgery, or long operation time is a risk factor of PPC in patients with COPD. Adequate inhaled corticosteroids treatment in patients with eosinophilic asthma and introducing treatment for COPD in patients with COPD could reduce PPCs. [ABSTRACT FROM AUTHOR]

Accumulation of profibrotic myofibroblasts is involved in the process of fibrosis development during idiopathic pulmonary fibrosis (IPF) pathogenesis. TGFB (transforming growth factor β) is one of the major profibrotic cytokines for myofibroblast differentiation and NOX4 (NADPH oxidase 4) has an essential role in TGFB-mediated cell signaling. Azithromycin (AZM), a second-generation antibacterial macrolide, has a pleiotropic effect on cellular processes including proteostasis. Hence, we hypothesized that AZM may regulate NOX4 levels by modulating proteostasis machineries, resulting in inhibition of TGFB-associated lung fibrosis development. Human lung fibroblasts (LF) were used to evaluate TGFB-induced myofibroblast differentiation. With respect to NOX4 regulation via proteostasis, assays for macroautophagy/autophagy, the unfolded protein response (UPR), and proteasome activity were performed. The potential anti-fibrotic property of AZM was examined by using bleomycin (BLM)-induced lung fibrosis mouse models. TGFB-induced NOX4 and myofibroblast differentiation were clearly inhibited by AZM treatment in LF. AZM-mediated NOX4 reduction was restored by treatment with MG132, a proteasome inhibitor. AZM inhibited autophagy and enhanced the UPR. Autophagy inhibition by AZM was linked to ubiquitination of NOX4 via increased protein levels of STUB1 (STIP1 homology and U-box containing protein 1), an E3 ubiquitin ligase. An increased UPR by AZM was associated with enhanced proteasome activity. AZM suppressed lung fibrosis development induced by BLM with concomitantly reduced NOX4 protein levels and enhanced proteasome activation. These results suggest that AZM suppresses NOX4 by promoting proteasomal degradation, resulting in inhibition of TGFB-induced myofibroblast differentiation and lung fibrosis development. AZM may be a candidate for the treatment of the fibrotic lung disease IPF. [ABSTRACT FROM PUBLISHER]

Background:Community-acquired pneumonia (CAP) has high morbidity and mortality. Unfortunately, the pathogen detection rate using conventional culture methods is relatively low. We compared comprehensive real-time polymerase chain reaction (real-time PCR) analysis of nasopharyngeal swab specimens (NPS) and sputum samples against conventional methods for ability to detect causative pathogens of CAP. Methods:We prospectively enrolled adult CAP patients, including those with prior antibiotic use, from December 2012 to May 2014. For each patient, causative pathogens were investigated conventionally and by real-time PCR that can identify 6 bacterial and 11 viral pathogens. Results:Patients numbered 92 (mean age, 63 years; 59 male), including 30 (33%) with prior antibiotic use. Considering all patients, identification of causative pathogens by real-time PCR was significantly more frequent than by conventional methods in all patients (72% vs. 57%,p = 0.018). In patients with prior antibiotic use, identification rates also differed significantly (PCR, 77%; conventional, 50%;p = 0.027). Mixed infections were more frequent according to real-time PCR than conventional methods (26% vs. 4%,p < 0.001). By the real-time PCR,Streptococcus pneumoniaewas most frequently identified (38%) as a causative pathogen, followed byHaemophilus influenzae(37%) andMycoplasma pneumoniae(5%). PCR also identified viral pathogens (21%), with sensitivity enhanced by simultaneous examination of both NPS and sputum samples rather than only NPS samples. Conclusions:Real-time PCR of NPS and sputum samples could better identify bacterial and viral pathogens in CAP than conventional methods, both overall and in patients with prior antibiotic treatment. [ABSTRACT FROM AUTHOR]

Background and objective It is difficult to verify the bacteriological diagnosis of M ycobacterium avium complex ( MAC) infection. The anti-glycopeptidolipid ( GPL)-core IgA antibody test was recently developed as a diagnostic method for MAC pulmonary disease. Only a few studies evaluate its clinical efficacy. We conducted retrospective evaluations of clinical characteristics of patients suspected of MAC infection to explore the usefulness of the anti- GPL-core IgA antibody test. Methods We retrospectively evaluated 296 patients who were suspected to have MAC infection and underwent anti- GPL-core IgA antibody test between March 2013 and July 2014 in Jikei University hospital. Results A total of 29 patients were diagnosed with 'definite MAC' based on the American Thoracic Society ( ATS) criteria with multiple identifications of MAC. On the other hand, 106 patients were diagnosed with other pulmonary diseases than MAC. The sensitivity and specificity of anti- GPL-core IgA antibody test for MAC diagnosis were 58.6% and 98.1%, respectively. The definite MAC group showed no significant differences in strains, treatment history or number of segments involved. The duration of MAC disease in the positive-antibody group was significantly longer than in the negative-antibody group ( P = 0.046). A significant increase in the false-negative rate was observed in patients with malignant disease ( P = 0.029). Conclusions The anti- GPL-core IgA antibody test demonstrated high sensitivity and specificity for the diagnosis of MAC infection especially in patients without malignant diseases. [ABSTRACT FROM AUTHOR]

Mitochondria are dynamic organelles that continuously change their shape through fission and fusion. Disruption of mitochondrial dynamics is involved in disease pathology through excessive reactive oxygen species (ROS) production. Accelerated cellular senescence resulting from cigarette smoke exposure with excessive ROS production has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Hence, we investigated the involvement of mitochondrial dynamics and ROS production in terms of cigarette smoke extract (CSE)- induced cellular senescence in human bronchial epithelial cells (HBEC). Mitochondrial morphology was examined by electron microscopy and fluorescence microscopy. Senescence-associated -galactosidase staining and p21 Western blotting of primary HBEC were performed to evaluate cellular senescence. Mitochondrial-specific superoxide production was measured by MitoSOX staining. Mitochondrial fragmentation was induced by knockdown of mitochondrial fusion proteins (OPA1 or Mitofusins) by small-interfering RNA transfection. N-acetylcysteine and Mito-TEMPO were used as antioxidants. Mitochondria in bronchial epithelial cells were prone to be more fragmented in COPD lung tissues. CSE induced mitochondrial fragmentation and mitochondrial ROS production, which were responsible for acceleration of cellular senescence in HBEC. Mitochondrial fragmentation induced by knockdown of fusion proteins also increased mitochondrial ROS production and percentages of senescent cells. HBEC senescence and mitochondria fragmentation in response to CSE treatment were inhibited in the presence of antioxidants. CSE-induced mitochondrial fragmentation is involved in cellular senescence through the mechanism of mitochondrial ROS production. Hence, disruption of mitochondrial dynamics may be a part of the pathogenic sequence of COPD development [ABSTRACT FROM AUTHOR]

Reepithelialization of remodeled air spaces with bronchial epithelial cells is a prominent pathological finding in idiopathic pulmonary fibrosis (IPF) and is implicated in IPF pathogenesis. Recent studies suggest that epithelial senescence is a risk factor for development of IPF, indicating such reepithelialization may be influenced by the acceleration of cellular senescence. Among the sirtuin (SIRT) family, SIRT6, a class III histone deacetylase, has been demonstrated to antagonize senescence. We evaluated the senescence of bronchiolization in association with SIRT6 expression in IPF lung. Senescence-associated β-galactosidase staining and immunohistochemical detection of p21 were performed to evaluate cellular senescence. As a model for transforming growth factor (TGF)-β-induced senescence of abnormal reepithelialization, we used primary human bronchial epithelial cells (HBEC). The changes of SIRT6, p21, and interleukin (IL)-1β expression levels in HBEC, as well as type I collagen expression levels in fibroblasts, were evaluated. In IPF lung samples, an increase in markers of senescence and SIRT6 expression was found in the bronchial epithelial cells lining cystically remodeled air spaces. We found that TGF-β induced senescence in primary HBEC by increasing p21 expression, and, whereas TGF-β also induced SIRT6, it was not sufficient to inhibit cellular senescence. However, overexpression of SIRT6 efficiently inhibited TGF-β-induced senescence via proteasomal degradation of p21. TGF-β-induced senescent HBEC secreted increased amounts of IL-1β, which was sufficient to induce myofibroblast differentiation in fibroblasts. These findings suggest that accelerated epithelial senescence plays a role in IPF pathogenesis through perpetuating abnormal epithelial-mesenchymal interactions, which can be antagonized by SIRT6. [ABSTRACT FROM AUTHOR]

Background: Several major randomized control studies have demonstrated that mepolizumab, an anti-IL-5 monoclonal antibody, is effective for patients with severe eosinophilic asthma who show exacerbation or require systemic corticosteroid maintenance therapy. However, the predictive factors of the response to mepolizumab other than blood eosinophil count are unclear in clinical practice.Objective: To elucidate the predictive factors of the response to mepolizumab for patients with severe eosinophilic asthma.Methods: From July 2016 to December 2017, 28 patients with severe asthma received mepolizumab in our hospital. To determine the predictive factors, we retrospectively evaluated patient characteristics, comorbidities, biomarkers, pulmonary function, maintenance dose of systemic corticosteroids and number of exacerbations.Results: The response rate to mepolizumab treatment was 70% (19/27; one pregnant woman was excluded from analysis). Compared with 11 patients without eosinophilic chronic rhinosinusitis (ECRS), 16 patients with ECRS showed significantly improved systemic corticosteroid-sparing effects [- 71.3 ± 37.0% vs - 10.7 ± 20.1%, P = 0.006], change from baseline FeNO [- 19 ± 57 (%) vs 30 ± 77 (%), P = 0.023] and symptoms [14 patients (88%) vs five patients (45%), P = 0.033]. ECRS was identified as a predictive factor of the response to mepolizumab in a multivariate logistic regression analysis [odds ratio = 22.5, 95% CI (1.5-336), P = 0.024]. Of the eight patients previously administered omalizumab, five responded to mepolizumab. Staphylococcus aureus enterotoxin B IgE results were negative in 80% of responders (P = 0.14).Conclusion: Both groups showed improved symptom scores and a decreased number of exacerbations. Mepolizumab substantially improved the clinical variables of patients with eosinophilic asthma complicated with ECRS. [ABSTRACT FROM AUTHOR]

Ferroptosis is a necrotic form of regulated cell death (RCD) mediated by phospholipid peroxidation in association with free iron-mediated Fenton reactions. Disrupted iron homeostasis resulting in excessive oxidative stress has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, we demonstrate the involvement of ferroptosis in COPD pathogenesis. Our in vivo and in vitro models show labile iron accumulation and enhanced lipid peroxidation with concomitant non-apoptotic cell death during cigarette smoke (CS) exposure, which are negatively regulated by GPx4 activity. Treatment with deferoxamine and ferrostatin-1, in addition to GPx4 knockdown, illuminate the role of ferroptosis in CS-treated lung epithelial cells. NCOA4-mediated ferritin selective autophagy (ferritinophagy) is initiated during ferritin degradation in response to CS treatment. CS exposure models, using both GPx4-deficient and overexpressing mice, clarify the pivotal role of GPx4-regulated cell death during COPD. These findings support a role for cigarette smoke-induced ferroptosis in the pathogenesis of COPD. Altered iron homeostasis resulting in excessive oxidative stress has been implicated in smoke-induced lung diseases. Here the authors show that ferroptosis of lung epithelial cells, potentially resulting from excessive ferritinophagy, is involved in the pathogenesis of COPD. [ABSTRACT FROM AUTHOR]

Background: Prostaglandin E2 (PGE2) is metabolized to prostaglandin E-major urinary metabolite (PGE-MUM). Enhanced cyclooxygenase-2 (COX-2) expression demonstrated in lung adenocarcinoma indicates increased PGE-MUM levels in patients with lung adenocarcinoma. Objectives: We aimed to elucidate the clinical usefulness of measuring PGE-MUM as an indicator of tumor burden in patients with lung adenocarcinoma. Methods: PGE-MUM was measured by a radioimmunoassay in control healthy volunteers (n = 124) and patients with lung adenocarcinoma (n = 54). Associations between PGE-MUM levels and clinical characteristics of the patients (including lung cancer stage and TNM factors (T: Tumor, N: Node, M: Metastasis) were examined. Results: PGE-MUM levels were significantly elevated in patients with lung adenocarcinoma. A PGE-MUM level of 14.9 μg/g∙Cr showed 70.4% sensitivity and 67.7% specificity for the diagnosis of lung adenocarcinoma. PGE-MUM levels tended to be positively correlated with cancer progression as determined by the TNM staging system. Advanced stage (stage III, stage IV, and recurrence) was significantly associated with high PGE-MUM levels by logistic regression analysis. No apparent correlation was demonstrated between PGE-MUM and carcinoma embryonic antigen (CEA) levels. Conclusions: PGE-MUM can be a promising biomarker reflecting the systemic tumor burden of lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Bronchial thermoplasty (BT) is a bronchoscopic treatment for severe asthma. A 35‐year‐old woman with uncontrolled severe asthma despite maximal pharmacological treatment underwent BT and started coughing after the first procedure. One month later, during the second BT procedure, there were white ulcerous lesions on the right B9 bronchus. Culture of the bronchial brushing specimen showed Aspergillus fumigatus, for which voriconazole was started for treatment. On the third BT procedure, endobronchial mucus sampling demonstrated Nocardia spp., for which trimethoprim‐sulfamethoxazole was given for three months. Seven months after the third BT procedure, no particular endobronchial lesions were found, and no abnormal pathogens were obtained by culture. The resulting bronchial infection in this case may be attributed to the use of systemic steroids, which rendered the patient immunocompromised, and to tissue fragility that was caused by the thermal energy from the BT procedure. Culture of endobronchial mucus should be considered during BT. Bronchial thermoplasty (BT) is a bronchoscopic procedure that uses thermal energy to reduce airway smooth muscle mass for treating uncontrolled severe asthma. Bronchial oedema and radiologic changes are generally known as the major complications of BT, but infections have rarely been reported. We describe a case of fungal and bacterial infections that developed after BT. [ABSTRACT FROM AUTHOR]

Background: Marked accumulation of alveolar macrophages (AM) conferred by apoptosis resistance has been implicated in pathogenesis of chronic obstructive pulmonary disease (COPD). Apoptosis inhibitor of macrophage (AIM), has been shown to be produced by mature tissue macrophages and AIM demonstrates anti-apoptotic property against multiple apoptosis-inducing stimuli. Accordingly, we attempt to determine if AIM is expressed in AM and whether AIM is involved in the regulation of apoptosis in the setting of cigarette smoke extract (CSE) exposure.Methods: Immunohistochemical evaluations of AIM were performed. Immunostaining was assessed by counting total and positively staining AM numbers in each case (n = 5 in control, n = 5 in non-COPD smoker, n = 5 in COPD). AM were isolated from bronchoalveolar lavage fluid (BALF). The changes of AIM expression levels in response to CSE exposure in AM were evaluated. Knock-down of anti-apoptotic Bcl-xL was mediated by siRNA transfection. U937 monocyte-macrophage cell line was used to explore the anti-apoptotic properties of AIM.Results: The numbers of AM and AIM-positive AM were significantly increased in COPD lungs. AIM expression was demonstrated at both mRNA and protein levels in isolated AM, which was enhanced in response to CSE exposure. AIM significantly increased Bcl-xL expression levels in AM and Bcl-xL was involved in a part of anti-apoptotic mechanisms of AIM in U937 cells in the setting of CSE exposure.Conclusions: These results suggest that AIM expression in association with cigarette smoking may be involved in accumulation of AM in COPD. [ABSTRACT FROM AUTHOR]