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Nursing and healthcare-associated pneumonia (NHCAP) was proposed by the Japanese Respiratory Society in 2011. However, the clinical characteristics of NHCAP are still unclear. Thus, this study aimed to clarify its clinical characteristics.This multicenter prospective observational study included 596 patients with NHCAP from 73 centers in Japan between May 2014 and February 2016.Patient background was characterized by an older age (81.5 ± 10.1 years), most patients had complications (94.1%), and many patients had a high probability of aspiration pneumonia (68.6%). Among the isolates, Streptococcus pneumoniae was the most common (12.7%), while Pseudomonas aeruginosa was also isolated at 10.8%. The overall 30-day mortality rate for patients was 11.9%, and the factors affecting mortality were non-ambulatory status, high blood urea nitrogen level, impaired consciousness, and low albumin level. Sulbactam/ampicillin was the most commonly administered antibiotic, including in groups with high severity of illness and high risk of multidrug-resistant (MDR) pathogens. Both the A-DROP and I-ROAD scores were useful in predicting the prognosis of NHCAP. Confirmation of intention to provide do not attempt resuscitation (DNAR) instructions was given to 333 patients (55.9%), and 313 patients agreed to DNAR instructions.NHCAP tends to occur in elderly patients with underlying diseases. The risk of MDR pathogens and the mortality rate are intermediate for community-acquired pneumonia and hospital-acquired pneumonia. As NHCAP is considered an important concept in an aging society, such as in Japan, establishing a treatment strategy that considers not only prognosis but also quality of life would be beneficial.

Background The impact of the outbreak of COVID-19 on the work of respiratory physicians in Japan has not yet been evaluated. The study investigates the impact of the outbreak on respiratory physicians’ work over time and identifies problems to be addressed in the future. Methods We conducted a web-based survey of respiratory physicians in 848 institutions. The survey comprised 32 questions and four sections: Survey 1 (April 20, 2020), Survey 2 (May 27, 2020), Survey 3 (August 31, 2020), and Survey 4 (December 4, 2020). Results The mean survey response rate was 24.9%, and 502 facilities (59.2%) participated in at least one survey. The proportion of facilities that could perform PCR tests for diagnosis and more than 20 tests per day gradually increased. The percentage capable of managing extracorporeal membrane oxygenation (ECMO) or more than five ventilators did not increase over time. The proportion that reported work overload of 150% or more, stress associated with lack of personal protective equipment (PPE), and harassment or stigma in the surrounding community did not sufficiently improve. Conclusion While there was an improvement in expanding the examination system and medical cooperation in the community, there was no indication of enhancement of the critical care management system. The overwork of respiratory physicians, lack of PPE, and harassment and stigma related to COVID-19 did not sufficiently improve and need to be addressed urgently.

Background Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive inflammatory disease caused by loss-of-function mutations in both alleles of the ADA2 gene. Most patients with DADA2 exhibit systemic vasculopathy consistent with polyarteritis nodosa, but large phenotypic variability has been reported, and the pathogenesis of DADA2 remains unclear. Objectives This study sought to assess the clinical and genetic characteristics of Japanese patients with DADA2 and to gain insight into the pathogenesis of DADA2 by multi-omics analysis. Methods Clinical and genetic data were collected from 8 Japanese patients with DADA2 diagnosed between 2016 and 2019. ADA2 variants in this cohort were functionally analyzed by in vitro overexpression analysis. PBMCs from 4 patients with DADA2 were subjected to transcriptome and proteome analyses. Patient samples were collected before and after introduction of anti- TNF-α therapies. Transcriptome data were compared with those of normal controls and patients with other autoinflammatory diseases. Results Five novel ADA2 variants were identified in these 8 patients and were confirmed pathogenic by in vitro analysis. Anti-TNF-α therapy controlled inflammation in all 8 patients. Transcriptome and proteome analyses showed that upregulation of type II interferon signaling was characteristic of DADA2. Network analysis identified STAT1 as a key regulator and a hub molecule in DADA2 pathogenesis, a finding supported by the hyperactivation of STAT1 in patients’ monocytes and B cells after IFN-γ stimulation. Conclusions Type II interferon signaling and STAT1 are associated with the pathogenesis of DADA2.

Background Pulmonary hypertension (PH) influences mortality in patients with interstitial lung disease (ILD). Almost all studies on patients with ILD, have focused on the clinical impact of pre-capillary PH on survival. Therefore, little is known about the influence of post-capillary PH. We aimed to assess the prevalence of post-capillary PH and its clinical impact on survival in patients with ILD, followed by comparison with pre-capillary PH. Methods This retrospective study enrolled 1152 patients with ILD who were diagnosed with PH using right heart catheterization between May 2007 and December 2015. We analyzed the demographics and composite outcomes (defined as death from any cause or lung transplantation) of patients with post-capillary PH and compared them with patients with pre-capillary PH. Results Thirty-two (20%) of the 157 patients with ILD-PH were diagnosed with post-capillary PH. Patients with post-capillary PH had significantly lower modified Medical Research Council scores, higher diffusion capacity for carbon monoxide, higher resting PaO2, lower pulmonary vascular resistance (PVR), and higher lowest oxygen saturation during the 6-min walk test compared to those with pre-capillary PH. Cardiovascular diseases were associated with a higher risk of mortality in patients with post-capillary PH. Multivariate Cox proportional hazards analysis demonstrated no significant difference between the composite outcomes in pre-capillary and post-capillary PH, while PVR and the ILD Gender-Age-Physiology Index were significantly associated with the composite outcome. Conclusions We found that approximately one-fifth of patients with ILD-PH were diagnosed with post-capillary PH, and that PVR and not post-capillary PH was associated with mortality.

This manual has been compiled by a joint production committee with the Diffuse Lung Disease Assembly of the Japanese Respiratory Society (JRS) to provide a practical manual for the epidemiology, diagnosis, and treatment of intractable diffuse pulmonary diseases. The contents are based upon the results of research into these diseases by the Diffuse Pulmonary Diseases Study Group (principal researcher: Sakae Homma) supported by the FY2014-FY2016 Health and Labor Sciences Research Grant on Intractable Diseases. This manual focuses on: 1) pulmonary alveolar microlithiasis, 2) bronchiolitis obliterans, and 3) Hermansky-Pudlak Syndrome with interstitial pneumonia. As these are rare/intractable diffuse lung diseases (2 and 3 were first recognized as specified intractable diseases in 2015), there have not been sufficient epidemiological studies made, and there has been little progress in formulating diagnostic criteria and severity scales; however, the results of Japan's first surveys and research into such details are presented herein. In addition, the manual provides treatment guidance and actual cases for each disease, aiming to assist in the establishment of future modalities. The manual was produced with the goal of enabling clinicians specialized in respiratory apparatus to handle these diseases in clinical settings and of further advancing future research and treatment.

Purpose Elastase, produced by Aspergillus fumigatus and A. flavus, is an important pathogenic factor in pulmonary aspergillosis. We investigated the possibility of using A. fumigatus-derived A. fumigatus elastase inhibitor (AFUEI) as a therapeutic agent. As native-AFUEI (N-AFUEI) has an extremely low yield, we generated a synthetic-AFUEI (S-AFUEI) and investigated whether S-AFUEI has a biological activity against A. fumigatus elastase (AFUE) and inhibits cytotoxicity. Methodology A. fumigatus was cultured in Yeast Carbon Base (YCB) -elastin culture medium for 3–7 days, and AFUE was purified by chromatography using DE52 cellulose and Sephadex G-75 column. Elastolytic activity was examined using Glt-Ala-Ala-Pro-Leu-pNA (GAAPLNA) as the substrate. The hydrolytic activity of AFUE was determined using the characteristic substrates, fibrinogen and collagen (Type IV), and human cell cytotoxicity was measured colorimetrically. Furthermore, the inhibitory effect of S-AFUEI on these activities was examined. Results We confirmed that S-AFUEI demonstrated elastase inhibitory activity and heat stability equivalent to that demonstrated by N-AFUEI, and inhibited human collagen hydrolytic activity and human fibrinogen hydrolytic activity. Further, S-AFUEI inhibited cytotoxicity in AFUE human pulmonary artery endothelial cells (HPAEC), human small airway epithelial cells (HSAEC), and human pulmonary alveolar epithelial cells (HPAEpiC). Conclusion As S-AFUEI strongly inhibited cytotoxicity induced by elastase in human-derived cells, it could prove beneficial for the treatment of pulmonary aspergillosis.

We identified a functional SNP in the 3' untranslated region of Pak1 that is responsible for the skin tumor modifier of MSM 1a locus. Candidate SNPs in the 3' untranslated region of Pak1 from resistance strain MSM/Ms were introduced into susceptible strain FVB/N using CRISPR/Cas9. The 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate skin carcinogenesis experiments revealed an SNP (Pak1-3' untranslated region-6

The BK virus (BKV) is a member of the polyomaviridae family of DNA viruses. BKV reactivates under a highly immunosuppressed state and causes renal dysfunction. In renal transplant patients, BKV infection leads to tubular impairment and loss of transplanted kidney grafts. However, few studies have reported on the relationship between BKV and lung transplantation. Adjustment of the dosage of immunosuppressants is needed in some cases, but the treatment method has not been established. Here, we report a case of BKV-associated viruria and viremia in a patient with lymphangioleiomyomatosis (LAM) after lung re-transplantation. A 44-year-old female refractory LAM patient who had undergone lung re-transplantation 3 months earlier was diagnosed with BKV-associated viruria and viremia. Urine cytology indicated decoy cells and the urine and serum polymerase chain reaction test was positive for BKV. As scheduled after re-transplantation surgery, immunosuppressive drugs were progressively reduced. This patient was considered to have experienced spontaneous BKV-associated viremia and viruria. Review of the literature suggested that 17%-42% of BKV-associated viruria cases have been reported after lung transplantation, but cases of BKV-associated nephropathy are rarely reported. Based on the present case, doctors involved in lung transplantation should monitor patients for BKV infection. Decoy cell monitoring by urine cytology is a useful screening method in the follow-up observation after lung transplantation. Early-stage interventions may prevent BKV-associated nephropathy even in patients who have developed BKV viremia, and sirolimus can be administered to patients with histories of BKV infection if they are carefully monitored.

Background Patients with connective tissue disease-associated interstitial lung disease (CTD-ILD) often experience impaired health status. In daily clinical practice, a short and easy instrument for assessing health status would be useful to help better understand the patient's condition. The COPD Assessment Test (CAT) is a simple questionnaire about respiratory symptoms and their impact. We aimed to examine the CAT's performance characteristics and to generate data to support its reliability and validity in patients with CTD-ILD. Methods We used data from 132 CTD-ILD patients evaluated at Tosei General Hospital from July 2011 to July 2016 to assess the cross-sectional and longitudinal validity of the CAT. Results The mean age of the patients was 64.5 years and 87 (66%) were women. There were no significant differences in CAT score between any of the CTD subgroups. Internal consistency (Cronbach's α = 0.881) and repeatability (intraclass correlation coefficient [ICC] = 0.803) for the CAT score were acceptable. At baseline, CAT score was significantly associated with clinically meaningful measures of physiologic function, exercise capacity, and dyspnea. Change in CAT score over 6–12 months was also associated with change in other measures. In the distribution- and anchor-based analyses, the estimated minimal clinically important difference of CAT score was 1–4 points. Conclusion These data support the validity and reliability of CAT as a sensitive measure for assessing health status in patients with CTD-ILD.

Respiratory-related hospitalization, in particular acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF), is common and associated with increasing mortality in patients with IPF. We aimed to evaluate the implications of a newly proposed framework of acute respiratory deterioration (ARD) and AE-IPF in hospitalized patients.Using the data of an IPF cohort consisting of 225 consecutive patients, we retrospectively studied first hospitalizations from January 2008 to December 2017. We analysed the demographics and 90-day mortality of patients with AE-IPF and those with parenchymal cause of ARD other than AE.Among 122 patients with first hospitalization for ARD, 35 patients were diagnosed with AE-IPF, including 11 patients with triggered AE. Parenchymal cause of ARD other than AE was diagnosed in 71 patients, and extra-parenchymal cause in 16 patients. Almost all hospitalized patients (93%) underwent chest CT, and 83% of patients with AE-IPF underwent bronchoalveolar lavage. There was a significant difference in the anti-inflammatory therapy between the AE-IPF group and parenchymal cause of ARD other than AE group (p 0.001). AE-IPF was independently associated with poor survival in multivariate Cox proportional regression analysis.AE-IPF accounted for about 30% of first hospitalizations for ARD, and differentiation between AE-IPF and the other categories in ARD is important from a therapeutic and a prognostic point of view.

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology which accounts for a large proportion of cases of idiopathic interstitial pneumonia. It has a very poor prognosis with a 5-year survival rate of 30% or below, and so far there has been no guideline in Japan offering an established effective therapy based on evidence. In addition to the establishment of basic therapies, there is also an urgent need to establish therapies to deal with complications, as death occurs in many cases due to acute exacerbation or comorbid lung cancer. It was therefore decided to formulate a guideline in order to promote evidence-based clinical practice, to further improve the quality of medical treatment in the clinical setting, and to allow the benefits to be enjoyed by the public.

ファイル公開：2020-01-01

Background There is only limited information on the clinical impact of combined pulmonary fibrosis and emphysema (CPFE) on postoperative and survival outcomes among patients with resected lung cancer. Methods In a retrospective analysis, data were reviewed from 685 patients with resected lung cancer between 2006 and 2011. The clinical impact of thin-section computed tomography (TSCT)–determined emphysema, fibrosis, and CPFE on postoperative and survival outcomes was evaluated. Results The emphysema group comprised 32.4% of the study population, the fibrosis group 2.8%, and the CPFE group 8.3%. The CPFE group had a more advanced pathologic stage and higher prevalence of squamous cell carcinoma as compared with the normal group without emphysema or fibrosis findings on TSCT. The incidence of postoperative complications was significantly higher in the CPFE group. Overall, the 30-day mortality in the CPFE group was 5.3%. Cancer recurrence at pathologic stage I and death due to either cancer or other causes were significantly higher in the CPFE group. Survival curves indicated that a finding of CPFE was associated with worse overall survival for patients with any stage disease. Multivariate analysis suggested that pathologic stage and CPFE were independent factors associated with worse overall survival. The adjusted hazard ratio of overall survival for the CPFE group versus the normal group was 2.990 (95% confidence interval: 1.801 to 4.962). Conclusions Among patients with resected lung cancer, the presence of TSCT-determined CPFE might predict worse postoperative and survival outcomes.

Background Previously, it has been shown that using a fixed ratio of FEV1/FVC of 0.7 to classify airway obstruction could not predict survival outcomes in lung cancer patients undergoing thoracic surgery. We demonstrated that use of the lower limit of normal (LLN) of FEV1/FVC may allow better risk stratification for postoperative outcomes in patients with chronic obstructive pulmonary disease (COPD) patients. Nevertheless, it remained unclear whether survival outcomes in this population could be predicted by LLN-defined airway obstruction. Objective To evaluate the clinical relevance of LLN-defined airway obstruction to survival outcomes. Methods The clinical relevance of LLN-defined airway obstruction was analyzed and compared in 699 subjects, using Kaplan–Meier curves and the log-rank test. A Cox regression model was used to explore prognostic risk factors. Results One hundred-and-seventy-eight subjects were assigned to the below-LLN group, in which airflow obstruction determined by the FEV1/FVC ratio was below the LLN. Five hundred-and-twenty-one subjects were assigned to the above-LLN group. The below-LLN group had a worse overall survival (OS) and disease-free survival (DFS) than the above-LLN group. The diffusing capacity of the lung for carbon monoxide and the ratio of the inspiratory capacity divided to the total lung capacity were independent risk factors for OS and DFS. Conclusions A standardized assessment of LLN-defined airway obstruction may allow risk stratification for survival likelihood in lung cancer patients who undergo thoracic surgery.

BACKGROUND Lung-dominant connective tissue disease (LD-CTD) is a disease concept for interstitial pneumonia; however, it has not been robustly validated. /p study was conducted to elucidate the clinical, radiologic, and histologic features of LD-CTD. METHODS We retrospectively reviewed 44 consecutive patients with serologically defined LD-CTD who underwent surgical lung biopsy. Six were identified as having LD-CTD if they had specific autoantibodies but did not meet the criteria for connective tissue disease. We conducted a multidisciplinary diagnosis and evaluated major histologic patterns according to the current idiopathic interstitial pneumonias (IIPs) classification of 2013. Characteristic histologic features for LD-CTD (eg, prominent plasmacytic infiltration, lymphoid aggregates with germinal centers), high-resolution CT (HRCT) scan patterns, and prognosis were also assessed. METHODS The major histologic patterns were usual interstitial pneumonia (UIP) in 25 patients and nonspecific interstitial pneumonia (NSIP) in 13 patients. Two or more characteristic histologic features for LD-CTD were observed in 15 patients with histologic UIP (h-UIP) and 11 patients with histologic NSIP (h-NSIP). Fifteen patients with h-UIP (60%) showed an inconsistent UIP pattern on HRCT scan multidisciplinary discussion (MDD), 18 patients with h-UIP were labeled as having unclassifiable IIP. The annual change in percent predicted FVC improved significantly in patients with h-NSIP (P = .002), who also had better survival than those with h-UIP (P = .031). In contrast, survival was not associated with HRCT scan pattern (P = .79). CONCLUSIONS The major histologic patterns in LD-CTD were UIP followed by NSIP. Two-thirds of patients had characteristic histologic features for LD-CTD. A majority of patients with h-UIP were considered to have unclassifiable IIP based on MDD. Patients with h-UIP had worse survival than those with h-NSIP. CHEST 2015;148(6):1438-1446

A previously healthy 73-year-old man was hospitalized with left complicated effusion and a consolidation in the left upper lung. He underwent a chest tube insertion and was treated with clindamycin but the consolidation remained after the treatment. We subsequently performed flexible bronchoscopy but it was impossible to make a diagnosis. Three months later, the consolidation had worsened so we performed another bronchoscopy. Finally, we were able to diagnose the consolidation as pulmonary actinomycosis, and to treat the condition appropriately. Pulmonary actinomycosis is a rare and difficult condition to diagnose. There are many conditions with similar clinical features, such as tuberculosis, fungal infections, lung abscesses, and lung malignancy. Respiratory physicians should consider the possibility of pulmonary actinomycosis when investigating patients with persistent pulmonary infiltrations. Early diagnosis and correct treatment may lead to a good prognosis and prevent unnecessary surgery.

Summary Interleukin-34 (IL-34) is an alternative ligand to colony-stimulating factor-1 (CSF-1) for the CSF-1 receptor that acts as a key regulator of monocyte/macrophage lineage. In this study, we show that tumor-derived IL-34 mediates resistance to immune checkpoint blockade regardless of CSF-1 existence in various murine cancer models. Consistent with its immunosuppressive characteristics, the expression of IL-34 in tumors correlates with decreased frequencies of cellular (such as CD8+ and CD4+ T cells and M1-biased macrophages) and molecular (including various cytokines and chemokines) effectors at the tumor microenvironment. Then, a neutralizing antibody against IL-34 improved the therapeutic effects of the immune checkpoint blockade in combinatorial therapeutic models, including a patient-derived xenograft model. Collectively, we revealed that tumor-derived IL-34 inhibits the efficacy of immune checkpoint blockade and proposed the utility of IL-34 blockade as a new strategy for cancer therapy., Graphical Abstract, Highlights • IL-34-expressing tumors are resistant to ICB in several murine models • IL-34 upregulates the ratio of M2-biased to M1-biased macrophage in TME • Blockade of IL-34 with neutralizing antibody (Ab) enhances the efficacy of ICB • Anti-human IL-34 Ab shows the potential to enhance PD-1 blockade efficacy in PDX model, Immunology; Cancer

Background Though the relationship between chronic rhinosinusitis (CRS) and lower airway diseases is well recognized, the impact of CRS on bronchial wall structure has not been elucidated. Here, we evaluated the bronchial wall structure of CRS patients with or without diagnosed airway diseases by three-dimensional computed tomography (3D-CT). Methods Subjects who underwent both chest CT and sinus CT within a year were recruited from consecutive medical records. CRS was defined as a Lund-Mackay score (LMS) of over 5 points. Airway dimensions were measured using validated software. Standard blood tests and pulmonary function tests were performed, and their correlation with airway thickness was examined. Results One-hundred-seventy-two patients were recruited (93 CRS subjects and 79 non-CRS subjects). The bronchial walls of CRS subjects were significantly thicker than those of non-CRS subjects. CRS and asthma were related to bronchial wall thickening by multivariate linear regression analysis adjusted for age, smoking status, and chest symptoms. In addition, LMS was significantly correlated with bronchial wall thickening. Conclusion Airway walls in CRS subjects were thicker than those in non-CRS subjects and associated with the severity of CRS. These data indicate strong relationship between upper and lower airways regardless of chest symptoms or diagnosed airway diseases.

Background: Oncogenic EGFR signaling has been shown to upregulate vascular endothelial growth factor A (VEGFA) expression involved in tumor angiogenesis. However, the clinical benefits of bevacizumab plus cytotoxic chemotherapy for EGFR mutation–positive patients remain unclear. This study aimed to investigate VEGFA messenger RNA expression in patients with EGFR mutation, and to further compare the efficacy of bevacizumab combined with platinum-based chemotherapy between EGFR-mutant and wild-type patients. Patients and Methods: Gene expression of various proangiogenic factors was analyzed in nonsquamous, non–small-cell lung cancer (NSCLC) patients using The Cancer Genome Atlas dataset. Additionally, clinical data of patients receiving carboplatin and pemetrexed (CPem; n = 104) or bevacizumab plus CPem (BevCPem; n = 55) at Nagoya University hospital were retrospectively assessed for progression-free survival and best overall response rate (ORR). Results: Among various proangiogenic factors, only VEGFA expression was significantly higher in patients with advanced nonsquamous NSCLC with EGFR mutation compared to wild-type patients (P = .0476). Progression-free survival in the BevCPem group was significantly longer in patients with EGFR mutation than in wild-type patients (10.5 vs. 6.6 months; Wilcoxon P = .0278), while the difference in the CPem group was not significant (6.6 vs. 4.5 months; Wilcoxon P = .1822). The ORRs in the BevCPem group were 54.5% and 36.4% for EGFR-mutant and wild-type patients, respectively, and the ORRs in the CPem group were 35.5% and 28.8 % in EGFR-mutant and wild-type patients, respectively. Conclusion: VEGFA messenger RNA expression was significantly increased in advanced nonsquamous NSCLC harboring EGFR mutation, and BevCPem provided better clinical benefits to patients with EGFR mutation than wild-type carriers., ファイル公開日: 2021/05/01

Summary Background Appropriate initial antibiotics are essential for the treatment of infectious diseases. However, some patients with pneumonia might develop adverse outcomes, despite receiving appropriate initial antibiotics. We aimed to clarify the risk factors for 30-day mortality in patients who received appropriate initial antibiotics and to identify potential candidates who would benefit from adjunctive therapy. Methods From March 15, to Dec 22, 2010, we did a prospective, observational study at ten medical institutions in hospitalised patients (aged ≥20 years) with pneumonia. We did a multivariable logistic regression analysis to calculate odds ratios (ORs) and 95% CI to assess the risk factors for 30-day mortality. This study was registered with the University Medical Information Network in Japan, number UMIN000003306. Findings The 30-day mortality was 11% (61 of 579 patients) in the appropriate initial antibiotic treatment group and 17% (29 of 168) in the inappropriate initial antibiotic treatment group. Albumin concentration of less than 30 mg/L (adjusted OR 3·39, 95% CI 1·83–6·28), non-ambulatory status (3·34, 1·84–6·05), pH of less than 7·35 (3·13, 1·52–6·42), respiration rate of at least 30 breaths per min (2·33, 1·28–4·24), and blood urea nitrogen of at least 7·14 mmol/L (2·20, 1·13–4·30) were independent risk factors in patients given appropriate initial antibiotic treatment. The 30-day mortality was 1% (one of 126 patients), 1% (two of 168), 17% (23 of 137), 22% (20 of 89), and 44% (14 of 32) for patients with no, one, two, three, and four or five risk factors, respectively. Interpretation Patients with two or more risk factors were at a higher risk of death during the 30 days assessed than were individuals with no or one risk factor, despite appropriate initial antibiotic treatment. Therefore, adjunctive therapy might be important for improving outcomes in patients with two or more risk factors. Funding Central Japan Lung Study Group.

Background Mounting evidence suggests that airway obstruction defined by the lower limit of normal (LLN) of forced expiration volume in 1s (FEV1)/forced vital capacity (FVC) might be an important predictor of mortality in patients with an FEV1/FVC ratio below 0.70. Although better risk stratification for postoperative outcomes in patients with chronic obstructive pulmonary disease (COPD) undergoing thoracic surgery is warranted, whether an FEV1/FVC ratio below 0.70 but above the LLN (i.e., in-between) could identify patients at risk for adverse postoperative outcomes has not been fully evaluated. Methods To determine the clinical impact of this "in-between" group of patients with COPD, we evaluated whether classification of the in-between group and the COPD group with FEV1/FVC ratios below 0.70 and below the LLN could provide more accurate risk stratification for postoperative outcomes in COPD patients undergoing thoracic surgery. Results The criterion of LLN classified 302 patients with an FEV1/FVC ratio below 0.70 into either the in-between group (124 cases) or the COPD group (178 cases). The COPD group showed a 3-fold increase in prolonged oxygen therapy (POT) and a 50% increase in prolonged postoperative stay (PPS), as compared with the in-between group, with an adjusted odds ratio of 3.068 (95% confidence interval: 1.806–5.213) for POT. Conclusions Based on the finding that the in-between group could independently identify patients at risk for adverse postoperative outcomes, LLN assessment of the FEV1/FVC ratio might provide more accurate risk stratification in COPD patients undergoing thoracic surgery.

BACKGROUND Pleuroparenchymal fibroelastosis (PPFE) is a rare form of interstitial pneumonia and sometimes coexists with a histologic usual interstitial pneumonia (UIP) pattern. This study aimed to describe the distinct clinical features of PPFE with UIP pattern compared with idiopathic pulmonary fibrosis (IPF). METHODS We conducted a retrospective review of the medical records of 110 consecutive patients with IPF with a histologic UIP pattern on surgical lung biopsy specimen. Patients meeting radiologic criteria for the diagnosis of PPFE based on high-resolution CT scan and with a histologic UIP pattern were included. RESULTS Nine of eleven patients meeting radiologic criteria for the diagnosis of PPFE were histologically confirmed as having PPFE with UIP pattern. The PPFE with UIP pattern group showed a significantly higher residual volume (1.8 L vs 1.3 L, P 2 (44.6 mm Hg vs 41.7 mm Hg, P = .04), and higher complication rate of pneumothorax and pneumomediastinum than the 99 patients with IPF/UIP. The ratio of anteroposterior to transthoracic diameter in patients with PPFE with UIP pattern was significantly lower than that in patients with IPF/UIP ( P = .04). Survival time tended to be shorter in patients with PPFE with UIP pattern. CONCLUSIONS The results support the view that PPFE with UIP pattern is a disease entity distinct from IPF/UIP and may well be classified as PPFE.

One cause of progressive pulmonary fibrosis is dysregulated wound healing after lung inflammation or damage in patients with idiopathic pulmonary fibrosis and severe acute respiratory distress syndrome. The mechanical forces are considered to regulate pulmonary fibrosis via activation of lung fibroblasts. In this study, the effects of mechanical stretch on the intracellular Ca(2+) concentration ([Ca(2+)]i) and ATP release were investigated in primary human lung fibroblasts. Uniaxial stretch (10-30% in strain) was applied to fibroblasts cultured in a silicone chamber coated with type I collagen using a stretching apparatus. Following stretching and subsequent unloading, [Ca(2+)]i transiently increased in a strain-dependent manner. Hypotonic stress, which causes plasma membrane stretching, also transiently increased the [Ca(2+)]i. The stretch-induced [Ca(2+)]i elevation was attenuated in Ca(2+)-free solution. In contrast, the increase of [Ca(2+)]i by a 20% stretch was not inhibited by the inhibitor of stretch-activated channels GsMTx-4, Gd(3+), ruthenium red, or cytochalasin D. Cyclic stretching induced significant ATP releases from fibroblasts. However, the stretch-induced [Ca(2+)]i elevation was not inhibited by ATP diphosphohydrolase apyrase or a purinergic receptor antagonist suramin. Taken together, mechanical stretch induces Ca(2+) influx independently of conventional stretch-sensitive ion channels, the actin cytoskeleton, and released ATP.

We assessed the efficacy and safety of cefepime monotherapy (1 g intravenously every 8 h) for febrile neutropenia in patients with lung cancer in a multi-institutional phase II study. Patients treated with chemotherapy with or without radiotherapy for lung cancer were eligible for this study. Other eligibility criteria included fever (temperature of ≥38.0 °C) and an absolute neutrophil count of500/mm(3) or1000/mm(3) with an expected decline to500/mm(3) within the next 48 h. Risk assessment was performed using the Multinational Association of Supportive Care in Cancer risk-index score. Cefepime 1 g was given intravenously every 8 h. The primary endpoint was the response rate at the end of cefepime therapy. Co-administration of granulocyte-colony-stimulating factor was permitted. Of 54 patients enrolled, 39 were classified in the low-risk group and 15 in the high-risk group. Overall response rate was 78% (95% CI: 64.4-88.0%). The response rates were 85% (95% CI: 69.5-94.1%) in the low-risk group and 60% (95% CI: 32.3-83.7%) in the high-risk group, respectively. One patient died from septic shock due to Enterobacter cloacae bacteremia. There was no significant adverse event. Cefepime 1 g intravenously every 8 h appears to be effective for febrile neutropenia in patients with lung cancer, especially in those with low-risk febrile neutropenia, and is well tolerated.UMIN Clinical Trials Registry, UMIN000006157.

Background Newer more advanced techniques in bronchoscopy may require longer procedure times, although a standard protocol for sedation during prolonged bronchoscopy has not yet been defined. Methods We designed a prospective, non-randomized, single-arm study (UMIN trial number 000003971) using patient questionnaires and vital sign monitoring to assess the efficacy and safety of a standardized midazolam dosing protocol based on gender and age for use during bronchoscopy. The loading dose of midazolam was 0.075mg/kg for men ≤65 years old and women ≤70 and 0.05mg/kg for men ≥66 years and women ≥71 years, with subsequent doses of one-half the loading dose to be administered every 20min. The primary endpoint was tolerability and secondary endpoints included anxiety and recall of procedure, willingness to undergo repeat procedure, and complications. Safety was evaluated in terms of monitored changes in blood pressures, ECG, oxygen saturation, and CO 2 content in expiration during the procedure. Results A total of 204 patients were included in the study. Overall, 163 patients (79.9%) reported "no distress" during the procedure, 185 patients (90.7%) reported "no anxiety," and 175 (85.8%) replied that they would accept a repeat procedure, if necessary. The mean minimum oxygen saturation was 90.2% and the mean maximum expiratory CO 2 level was 37.7mmHg. There were no serious complications related to the protocol. Conclusions The midazolam dosing protocol examined in this study was safe and effective. It is simple, and it could easily be translated to routine clinical practice.

Introduction Pneumonitis is one of the immune-related adverse events of programmed death 1 (PD-1) inhibitors that sometimes cause lethal outcomes. Although some recent reports have described PD-1 inhibitors as more effective in non–small-cell lung cancer (NSCLC) patients with immune-related adverse events than in those without, few data are available on the prognosis of those treated with PD-1 inhibitors who developed immune-related pneumonitis (IRP). Additionally, the robust risk factors of IRP have not been well elucidated. Patients and Methods A retrospective review of patients with recurrent or advanced NSCLC who took a PD-1 inhibitor (nivolumab or pembrolizumab monotherapy) between January 2016 and March 2018 was undertaken. Radiologic findings such as unilateral infiltration were also defined as IRP as long as they were deemed relevant to PD-1 inhibitors. Results Twenty-seven (16%) of 170 patients developed IRP. Although 22 (81%) of 27 patients with IRP recovered with drug cessation with or without corticosteroid therapy, 8-week landmark analysis showed the overall survival after administration of the PD-1 inhibitor was significantly shorter in patients with IRP than in those without (8.7 vs. 23.0 months, P = .015). Patients with IRP tended to not receive next-line treatment and choose best supportive care after cessation of PD-1 inhibitor therapy. In the multivariate analysis, pembrolizumab (vs. nivolumab) and low serum albumin were independent risk factors for IRP. Conclusion Development of IRP was correlated with poor prognosis in patients with NSCLC. Further study is necessary for establishing the best prediction and management strategies for IRP.

Background The efficacy and safety of immune checkpoint inhibitor (ICI) for advanced or recurrent non-small cell lung cancer (NSCLC) with poor performance status (PS) is unknown. Methods A multicenter retrospective study was conducted for patients with advanced or recurrent NSCLC with PS ≥ 2 who received ICI between January 2016 and September 2018. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and occurrence of immune-related adverse event (irAE) were assessed for all participants. Results A total of 20 patients (median age: 61 years; age range: 44-80 years; male/female ratio: 10/10) were included with the following demographics: PS2/3: 14/6; current or former/never smoker ratio: 15/5; squamous/non-squamous cell carcinoma cases: 2/18; PD-L1 ≥50%/1%-49%/0%/unknown: 6/2/1/11; nivolumab/pembrolizumab/atezolizumab: 11/5/4; 1st/2nd/3rd or subsequent line: 5/4/11. For the overall population, ORR, DCR, median PFS, and median OS were 5%, 20%, 0.8 months [95% confidence interval (CI), 0.5-1.8], and 2.5 months (95% CI, 1.3-4.3), respectively. Even for the population with PD-L1 ≥50%, ORR, DCR, median PFS, and median OS were 0%, 17%, 0.9 months (95% CI, 0.2-NA), and 3.2 months (95% CI, 0.8-NA), respectively. IrAE was recorded in 5 cases; the most common being fever (n = 2) and included pruritus, cholangitis, and pneumonitis (n = 1 each). In the case with cholangitis, ICI was discontinued due to irAE. Conclusion The efficacy of ICI for advanced or recurrent NSCLC patients with PS ≥ 2 was suggested to be poor, including the participant population with PD-L1 ≥ 50%.

Summary Background and objective It has been shown that peripheral muscle dysfunction is a critical factor in determining exercise intolerance in patients with several chronic lung diseases, including idiopathic pulmonary fibrosis. We hypothesized that exercise capacity would be, at least in part, determined by peripheral muscle dysfunction in patients with fibrotic nonspecific interstitial pneumonia (f-NSIP), another major subtype of fibrotic interstitial lung disease. The aim of the current study was to elucidate the relevance of peripheral muscle dysfunction and its contribution to exercise intolerance in f-NSIP. Methods The six-minute walk test was evaluated in 30 consecutive patients with f-NSIP along with potential determinants of exercise capacity, including respiratory muscle force and peripheral muscle force. Results Among 30 patients, the median age was 61 years, and 21 were female. Sixteen patients showed significantly decreased quadriceps force (QF), and 17 had significant decreases in maximum expiratory pressure. Exercise capacity and muscle power were clearly related to sex. Adjusted for sex, QF showed a significant relation to exercise capacity measured by six-minute walk distance (6MWD), whereas pulmonary function parameters such as vital capacity showed marginal correlations. In stepwise multiple regression analysis, only QF was an independent predictor of 6MWD. Conclusions Quadriceps weakness is often observed in patients with f-NSIP. It seems that QF significantly contributes to exercise capacity in this population.

Recent case reports have shown that endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for mediastinal lesions is sometimes accompanied by severe infectious complications. Here, we report 3 cases with refractory febrile complications following EBUS-TBNA for intra-pulmonary large mass lesion of lung cancer (squamous cell carcinoma, n=2; adenocarcinoma, n=1). After the EBUS-TBNA, all cases showed prolonged fever and systemic inflammation despite receiving a sufficient dose of broad-spectrum antibiotics. The presence of a low-density area inside the masses upon CT examination, suggesting necrosis, may be a predictive sign of febrile complications associated with EBUS-TBNA.

The lung is a primary target for oxygen toxicity because of its constant exposure to high oxygen levels and environmental oxidants. Quercetin is one of the most commonly found dietary flavonoids, and it provides cytoprotective actions via activation of specific transcriptional factors and upregulation of endogenous defensive pathways. In the present study, we showed that quercetin increased the levels of heme oxygenase (HO)-1 expression and protected against hydrogen peroxide (H(2)O(2))-induced cytotoxicity in lung epithelial cell lines. Quercetin suppressed H(2)O(2)-induced apoptotic events, including hypodiploid cells, activation of caspase 3 enzyme activity and lactate dehydrogenase release. This cytoprotective effect was attenuated by the addition of the HO inhibitor, tin protoporphyrin IX. In addition, the end products of heme metabolites catalyzed by HO-1, carbon monoxide and bilirubin, protect against H(2)O(2)-induced cytotoxicity in LA-4 cells. Quercetin may well be one of the promising substances to attenuate oxidative epithelial cell injury in lung inflammation.