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Background: Impact of bronchoalveolar lavage (BAL) lymphocytosis >15% on the prognosis of chronic idiopathic interstitial pneumonias other than idiopathic pulmonary fibrosis (non-IPF) has never been evaluated. Methods: Japanese chronic non-IPF patients treated with corticosteroids were identified using the nationwide registry along with multidisciplinary discussion (MDD). We compared the clinical, radiological and pathological features, and outcomes between patients with BAL lymphocytosis >15% and those with BAL lymphocytes ≤15%. Results: Of the 110 patients with chronic non-IPF, 47 (42.7%) had BAL lymphocytosis >15%. The most prevalent MDD diagnosis was unclassifiable IIPs (64.5%), followed by iNSIP (22.7%). Immunosuppressants were administered in 69 (62.7%) patients. There were no significant difference in HRCT and pathological patterns, MDD diagnoses, and treatment regimens between the two groups. One-year changes in KL-6 and FVC % predicted were significantly better in patients with BAL lymphocytosis >15% than those with BAL lymphocytes ≤15%. Patients with BAL lymphocytosis >15% had longer OS than those with BAL lymphocytes ≤15% (Log-rank test, p =0.019). In multivariate analysis, BAL lymphocytosis >15% was a significant prognostic factor for overall survival (HR: 0.37; 95% CI, 0.16-0.87; p =0.022), in addition to FVC % predicted and interstitial pneumonia with autoimmune features. Conclusions: BAL lymphocytosis >15% is associated with favorable outcome in chronic non-IPF. Evaluation of BAL lymphocytes would be helpful to identify corticosteroid-effective patients.

There is limited prospective evidence of the efficacy and safety of ceftriaxone based on the difference in dosage of the drug as empiric therapy for community-acquired pneumonia (CAP). This study aimed to compare initial treatment failure, 30-day mortality and side effects between ceftriaxone doses of 1g twice a day (1g x2) and 2g once a day (2g x1) given intravenously to hospitalized adult CAP patients. We prospectively included patients with CAP who were admitted to our hospital between October 2010 and December 2018. We analyzed patients who were initially treated solely with 1g x2 or 2g x1 of ceftriaxone. The primary outcome was initial treatment failure, and secondary outcomes were 30-day mortality and side effects. Inverse probability of treatment weighting (IPTW) analysis was used to reduce biases. Among 457 CAP patients, there were 186 patients in the 1g x2 group and 271 patients in the 2g x1 group. There were no significant differences in initial treatment failure rate (2.69 % and 4.43 %, p=0.34) and 30-day mortality rate (3.28 and 6.45 %, p=0.17) between the former and latter groups. There was also no significant difference in side effects between the two groups, although there was a marginally significant difference (1.08 % and 4.43 %, p= 0.06). These significant differences and tendency to difference were almost similar to the results after IPTW analysis (p=0.27, 0.13 and 0.08). This study revealed that there are no significant differences between the effects of ceftriaxone administration at doses of 1g x2 and 2g x1 to adult CAP patients, in terms of initial treatment failure, 30-day mortality andoccurrence of side effects.

Immune checkpoint inhibitor-associated interstitial lung disease (ICI-ILD) is a serious immune-related adverse event. We aimed to evaluate the impact of ICI-ILD severity and imaging patterns or post-ILD cancer therapy on prognosis in patients with non-small-cell lung cancer (NSCLC). We retrospectively analysed NSCLC patients who developed ICI-ILD in our institution between January 2016 and March 2019. The primary objective was to report prognosis following onset of ICI-ILD, stratified by severity grade or imaging pattern. The secondary objective was the analysis of cancer therapy after ICI-ILD. Among 222 patients treated with ICI, 27 (12.2%) developed ICI-ILD. No trend for different prognosis depending on severity grade was seen unless ICI-ILD was fatal. Most patients (91.3%) with organising pneumonia (OP) or nonspecific interstitial pneumonia pattern on imaging showed grade 1 or 2, while all patients with a diffuse alveolar damage (DAD) pattern showed grade 3 or higher, and one reached grade 5. Among patients who overcame ICI-ILD, eight patients (30.8%) have been followed up without chemotherapy because of long-term disease control and seven had shown an OP pattern on imaging at onset of ICI-ILD. Three patients underwent ICI rechallenge, but two showed ICI-ILD recurrence and no patient achieved response to rechallenge treatment. The DAD pattern may predict short-term adverse prognosis for ICI-ILD. Once ICI-ILD is overcome, severity grade is not associated with prognosis. Even if initial immunotherapy proves effective, ICI rechallenge requires careful consideration.

Community-acquired pneumonia (CAP) is one of the respiratory infectious diseases caused by not only bacteria, but also viruses. Antibiotic agents are needed to treat only bacterial but not viral CAP. In addition, there are some non-infectious respiratory diseases in the differential diagnosis of CAP, such as malignant diseases, interstitial lung diseases, pulmonary edema, and pulmonary hemorrhage. We usually diagnose patients having CAP by comprehensive evaluation of symptoms, vital signs, laboratory examinations, and radiographic examinations. However, symptoms and vital signs are not specific for the diagnosis of CAP; therefore, we also use inflammatory biomarkers for differentiating bacterial from viral CAP and non-infectious respiratory diseases. We have used the white blood cell count, C-reactive protein (CRP), and erythrocyte sedimentation rate as common inflammatory biomarkers, but they are not specific for bacterial infection because they could be increased by malignant diseases and collagen diseases. Recently, some inflammatory biomarkers such as procalcitonin (PCT), soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), pro-adrenomedullin (proADM), and presepsin have been developed as relatively specific biomarkers for bacterial infection. Many reports have evaluated the usefulness of PCT for diagnosing CAP. In this review, the characteristics of each biomarker are discussed based on previous studies.

Aspiration pneumonia is pneumonia resulting from abnormal entry of food or oral content into the lower airway. Oral streptococci and anaerobes are therefore thought to play an important role in its etiology. Moreover, the common pathogens detected in pneumonia patients without aspiration are also isolated from patients with aspiration pneumonia.

Whether macrolide combination therapy reduces the mortality of patients with severe community-acquired pneumonia (CAP) hospitalized in the non-intensive care unit (ICU) remains unclear. Therefore, we investigated the efficacy of adding azithromycin to β-lactam antibiotics for such patients. This prospective cohort study enrolled consecutive patients with CAP hospitalized in the non-ICU between October 2010 and November 2016. The 30-day mortality between β-lactam and azithromycin combination therapy and β-lactam monotherapy was compared in patients classified as mild to moderate and severe according to the CURB-65, Pneumonia Severity Index (PSI), and Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) criteria. Inverse probability of treatment weighting (IPTW) analysis was used to reduce biases. Based on the CURB-65 and PSI, combination therapy did not significantly reduce the 30-day mortality in either group (179 patients in the combination group, 952 in the monotherapy group). However, based on the IDSA/ATS criteria, combination therapy significantly reduced the 30-day mortality in patients with severe (odds ratio [OR] 0.12, 95% confidence interval [CI] 0.007–0.57), but not non-severe pneumonia (OR 1.85, 95% CI 0.51–5.40); these results were similar after IPTW analysis. Azithromycin combination therapy significantly reduced the mortality of patients with severe CAP who met the IDSA/ATS criteria.

The number of patients with pulmonary nontuberculous mycobacterial disease complicated by chronic pulmonary aspergillosis (CPA) has been increasing. Additionally, CPA is reportedly associated with mortality in patients with Mycobacterium avium complex lung disease (MAC-LD). In the present study, we aimed to identify risk factors for developing CPA and stratify the risk for CPA development in patients with MAC-LD.We retrospectively examined 361 patients newly diagnosed with MAC-LD. Risk factors for CPA development were examined using multivariate Cox proportional hazards regression analyses. A risk stratification system was established using the risk factors and receiver operating characteristic curve analyses.CPA developed in 20 (5.5%) of the 361 patients. Independent risk factors for CPA development included the presence of pulmonary emphysema, baseline steroid use, a serum albumin level3.5 g/dL, and the presence of MAC-LD cavities. A 4-point scoring system was established to stratify patients into low-risk (0-1 point) and high-risk (2-4 points) groups. The 5-year incidence rates of CPA were 2.2% and 31% in the low- and high-risk groups, respectively (P 0.001).We identified independent predictors of CPA development and established a simple risk stratification system for identifying patients with MAC-LD who were at a high risk of developing CPA.

Introduction Nivolumab has been shown to be effective and safe in previously treated patients with advanced non-small cell lung cancer (NSCLC). However, little is known regarding its performance in real-world (i.e., non-trial) settings. Furthermore, nivolumab efficacy is unknown in patients who are ineligible for clinical trials or who are categorized into small subgroups in such trials. Methods We conducted a 15-center, observational, retrospective cohort study of patients with advanced NSCLC who received nivolumab monotherapy between January and December 2016. Results Of 613 patients included in our study, 141 had poor performance status (PS) and 106 were EGFR mutation – or ALK rearrangement-positive. The response and disease control rates were 20% and 44%, respectively; the estimated 1-year progression-free survival (PFS) was 18%. Multivariate analysis identified never smoking, poor PS, and EGFR mutation/ALK rearrangement as independent negative predictors of PFS. The most frequently reported grade ≥3 adverse event was pneumonitis (5% of patients). Severe pneumonitis (grade ≥3) occurred significantly earlier than mild pneumonitis (1.6 vs. 2.3 months, P = 0.031). Patients with pneumonitis achieved higher response rates and longer PFS than those without (37% vs. 18%, and 5.8 vs. 2.1 months, respectively; P = 0.002). Conclusions Smoking status, PS, and EGFR mutation/ALK rearrangement were independent predictors of PFS. Our study elucidated nivolumab's efficacy in previously underreported patient populations; i.e., those with poor PS and/or with driver oncogenes. We also found that pneumonitis is not infrequent, and carries key implications for outcomes. These data should be useful for improving the clinical courses of nivolumab-treated patients with NSCLC.

Slug flow is segmented droplets where internal convection occurs. The internal convection is useful for efficient mixing of their contents when they are used as microreactors. The segmentation is also useful for recording of temporal changes in biological samples such as cells and animals. However, methods to store the droplets separately, which are necessary for precise chemical analysis, are not well developed. Methods with simple structures and controls are required for storing many droplets in the first-come-first-store manner. Passive microvalves allow for prearranged flow without any controls using simple microstructures. To store the droplets one-by-one for precise analysis, we designed an automatic microfluidic device using hydrophobic passive microvalves. The valves are based on capillary forces and have different burst pressures. Using this device, each droplet was automatically stored in a different reservoir.

Background Because of a limited number of reports, we aimed to investigate the clinical characteristics of patients with Legionella pneumonia due to non-Legionella pneumophila serogroup 1 and the diagnostic usefulness of the six-point scoring system for such patients compared with patients with pneumonia caused by L. pneumophila serogroup 1. Methods We retrospectively analysed patients diagnosed with Legionella pneumonia due to non-L. pneumophila serogroup 1 between March 2001 and June 2016. We examined the clinical characteristics, including symptoms, laboratory findings, radiologic findings, pneumonia severity, initial treatment and prognosis. We also calculated scores using the six-point scoring system in these patients. Furthermore, we compared the clinical characteristics and six-point scores between non-L. pneumophila serogroup 1 patients and L. pneumophila serogroup 1 patients among hospitalized community-acquired pneumonia patients enrolled prospectively between October 2010 and July 2016. Results Eleven patients had pneumonia due to non-L. pneumophila serogroup 1; their median age was 66 years and 8 patients (72.7%) were male. The most common pathogen was L. pneumophila serogroup 3 (6/11), followed by L. pneumophila serogroup 9 (3/11), L. pneumophila serogroup 6 (1/11) and L. longbeachae (1/11). Non-specific symptoms, such as fever and cough, were common. Six patients (54.5%) had liver enzyme elevation, but no patient developed hyponatraemia at

The aim of the present study was to investigate the predictors of targeted therapy (TT) for pneumococcal community-acquired pneumonia (PCAP) with a positive urinary antigen test (UAT) and compare the outcomes with those of nontargeted therapy. This prospective cohort study enrolled consecutive PCAP patients with a positive UAT who were hospitalized at Kurashiki Central Hospital from October 2010 to November 2019. A total of 286 patients were included. Of them, 56 patients (19.6%) were included in the TT group. On multivariate analysis, identification of Gram-positive diplococci by Gram stain (OR [95% CI]: 2.46 [1.32-4.63]) was a positive predictor, whereas aspiration pneumonia (0.17 [0.03-0.59]) and CURB-65 score (0.59 [0.42-0.81]) were negative predictors of TT. Initial treatment failure and 30-day mortality were not significantly different. The UAT is not used enough for TT, and TT for PCAP did not have worse outcomes.

Background There have been few data on the chemotherapy in elderly advanced non-small cell lung cancer (NSCLC) patients with poor performance status (PS), and usefulness of chemotherapy for such patients remains unclear. The objective of this study was to identify factors that predicted the survival benefit of chemotherapy. Methods All consecutive elderly patients (≥75 years) with advanced NSCLC, Eastern Cooperative Oncology Group PS ≥2, EGFR mutation wild type/unknown, and newly diagnosed from January 2009 to December 2012 at a tertiary hospital were retrospectively reviewed. Results We enrolled 59 patients, and 31 patients received at least one chemotherapy regimen (chemotherapy group). However, 28 patients received best supportive care (BSC) alone (BSC group). The proportion of PS 2 and serum albumin levels was significantly higher in the chemotherapy group than in the BSC group. In the chemotherapy group, log-rank testing did not show statistically significant differences in overall survival (OS) between the single-agent therapy group and carboplatin-based doublet therapy group; however, the OS of patients receiving chemotherapy for only 1 cycle (early termination) was significantly shorter than patients receiving chemotherapy for ≥2 cycles. Hypoalbuminemia was not only a risk factor for the early termination of chemotherapy but also an independent prognostic factor in the chemotherapy group. A receiver operating characteristic curve analysis showed that the best cut-off value was 3.40 g/dL. In patients with serum albumin levels ≥3.40 g/dL, OS was significantly better in the chemotherapy group than in the BSC group (p = 0.0156), however, patients with serum albumin levels

Background and objective Interstitial lung disease (ILD) is a common pulmonary manifestation of systemic sclerosis (SSc). It is unknown whether radiographic fibrosis score predicts mortality in SSc-associated ILD (SSc-ILD). We retrospectively analysed patients with SSc-ILD to evaluate whether radiographic fibrosis score was a useful predictor of mortality. Methods We identified SSc-ILD patients evaluated at Kurashiki Central Hospital (Japan) from 2006 to 2016, and radiographic fibrosis scores based on the extent of reticulation and honeycombing on high-resolution computed tomography (HRCT) scanning were calculated by manually tracing around each fibrotic area. Independent predictors of overall survival were determined using the Cox proportional hazards model. Results The study included 48 patients, of whom 19 had usual interstitial pneumonia on HRCT. The median follow-up period was 56.6 months, and over the follow-up period 15 patients died. The 5-year survival was 72.4%. In the multivariate analysis, radiographic fibrosis score, age, being male and forced vital capacity were independently associated with an increased risk of death, while HRCT pattern was not. Conclusion A high radiographic fibrosis score was a poor prognostic factor in SSc-ILD. More widespread fibrosis was associated with an increased risk of death, independent of HRCT pattern.

Chronic pulmonary aspergillosis (CPA) is associated with mortality in patients with Mycobacterium avium complex lung disease (MAC-LD). An Aspergillus-positive respiratory specimen often reflects colonization, and thus the clinical significance of Aspergillus isolation in MAC-LD patients is not well understood. The objective of this study was to investigate the clinical characteristics and outcomes of MAC-LD patients in whom Aspergillus was isolated from respiratory specimens. We performed a retrospective review of the medical records of 329 MAC-LD patients. We compared the characteristics and mortality rates between patients with Aspergillus isolation and those without. All Aspergillus species detected from respiratory specimens within the follow-up period were reviewed. Aspergillus was detected in 40 (12.2%) of the 329 patients. There were no significant differences in the clinical characteristics and mortality rates between patients with and without Aspergillus isolation. Among the 40 patients with Aspergillus isolation, 9 (22.5%) developed CPA. CPA was most often caused by A. fumigatus. In the 40 Aspergillus-positive patients, patients with A. fumigatus isolation had a significantly higher mortality rate than those without (P

Background Chronic fibrosing idiopathic interstitial pneumonia (CFIIP) has a potential risk of acute exacerbation (AE). However, the usefulness of cellular analysis of bronchoalveolar lavage fluid (BALF) has never been evaluated. This study aimed to evaluate the impact of the lymphocyte differential count > 15% in BALF on the mortality of patients with AE of CFIIP. Methods We retrospectively analysed 37 patients with AE of CFIIP who underwent BAL on admission. Patients were divided into two groups: one group consisting of those with a lymphocyte differential count > 15% and the other consisting of those with a lymphocyte differential count ≤ 15%. We compared the 90-day mortality between the two groups as the primary outcome, using the two-tailed log-rank test. Results The median follow-up duration was 6.9 months. Twenty-four patients had a lymphocyte differential count > 15%. The 90-day mortality was significantly higher in the group with a lymphocyte differential count ≤ 15% than in the group with a lymphocyte differential count > 15% (long rank test, p = 0.003). In the multivariate analysis a lymphocyte differential count > 15% was shown to be an independent favourable prognostic factor for 90-day mortality (HR: 0.125; 95% CI: 0.0247–0.589; p = 0.009). Conclusions A lymphocyte differential count > 15% in BALF may be associated with favourable outcomes in patients with AE of CFIIP. Electronic supplementary material The online version of this article (doi:10.1186/s12890-017-0412-8) contains supplementary material, which is available to authorized users.

SETTING Practical methods for assessing the radiographic findings of Mycobacterium avium complex lung disease (MAC-LD) have not been established. OBJECTIVE To identify a correlation between the radiological score and semi-quantitative culture results of respiratory samples, and to assess the prognostic impact of this radiological score in MAC-LD patients. DESIGN We retrospectively studied 218 MAC-LD patients. Radiographic findings were classified as nodule (N), infiltration shadow (I), cavity (C) and bronchiectasis (E), scored individually according to the area occupied on six lung field divisions, and added to give the radiological severity score. RESULTS The radiological score positively correlated with the semi-quantitative culture score (P = 0.003). In univariate analysis, the radiological score was a significant negative prognostic factor for overall survival. On multivariate analysis, factors I, C and E were independent negative prognostic factors for overall survival. We compared the prognostic value of the total score of all four factors and the three significant factors (I, C and E) using receiver operating characteristic curve analysis; the corresponding areas under the curves were respectively 0.628 and 0.763 (P < 0.001). CONCLUSIONS The radiological score correlates with prognosis. The combined score of factors I, C and E may more accurately predict prognosis in MAC-LD patients.

This study aimed to investigate the usefulness of procalcitonin-guided therapy in hospitalized community-acquired pneumonia patients to reduce antibiotic duration and costs without worsening prognosis.352 hospitalized community-acquired pneumonia patients in an observational cohort study in which procalcitonin was measured three times serially, on admission (Day 1) and 2-3 days (Day 3) and 6-8 days (Day 7) after admission, between October 2010 and February 2016 were reviewed retrospectively. Antibiotics could be stopped if Day 7 procalcitonin was0.25 ng mLUsing theoretical procalcitonin guidance, antibiotic duration could be reduced from 12.6 to 8.6 days (P 0.001), while costs could be reduced from 45,833 to 38,952 yen (P = 0.005). Among the patients in whom theoretical procalcitonin guidance could be adopted, recurrence rates (5.6% vs. 8.1%, P = 0.15) and mortality rates (0% vs. 5.1%, P = 0.07) did not worsen between the group having the same antibiotic durations as with theoretical procalcitonin guidance in actual practice (N = 71) and the group having durations more than 2 days longer in actual practice than in theoretical procalcitonin guidance (N = 198). There was no significant difference in pneumonia severity using A-DROP, CURB-65, and PSI between two groups.Procalcitonin-guided therapy may be useful in hospitalized community-acquired pneumonia patients to reduce antibiotic duration and costs without worsening the prognosis.

Introduction: Nontuberculous mycobacterial (NTM) pleuritis, pleural effusion combined with NTM lung disease (NTM-LD), has not been previously described as a common manifestation of NTM infections. Aims: This study aimed to investigate the clinical features and prognosis of NTM pleuritis. Methods: A retrospective observational study was performed including patients with NTM pleuritis fromJanuary 2001 to December 2017 at 8 hospitals. NTM pleuritis was defined as a positive culture of NTM from pleural effusion. Furthermore, we matched patients with NTM-LD but without pleuritis by sex and age (within a 10-year range) to obtain comparative data for individuals. We investigated the association between clinical parameters and prognosis. Results: We identified 58 patients with NTM pleuritis (median age, 72 years; 35 females; Mycobacterium avium complex [MAC], 48 patients). The median follow-up period was 16 months and 26 patients died. Patients with NTM pleuritis had significantly worse survival than sex- and age-matched patients presenting NTM-LD without pleuritis (P Conclusions: Our results suggest that prognosis of NTM pleuritis is worse than NTM-LD without pleuritis. Moreover, lower BMI, UPD, and no treatment history after pleuritis are associated with poor prognosis in patients with NTM pleuritis.

Introduction Previous studies have described an association between immune-related adverse events (irAEs) and better outcomes in patients administered nivolumab for advanced non–small-cell lung cancer. However, the patients in previous studies were not stratified by potential predictive factors, such as programmed cell death ligand 1 status and treatment lines. Additionally, little is known of whether the timing and type of irAEs can inform the prediction of outcomes. Patients and Methods We prospectively investigated the association between irAEs and outcomes in the single-center cohort that included patients administered nivolumab in the second or later line of therapy. Subsequently, we confirmed these findings in a retrospective multicenter cohort that included patients with programmed cell death ligand 1 tumor proportion score of ≥ 50% who had received first-line pembrolizumab. The primary outcome was progression-free survival (PFS). Results In the prospective cohort (n = 76), the median PFS was significantly longer for the patients experiencing irAEs within 2 weeks of beginning nivolumab compared with the PFS for those who did not (median, 5.0 months [95% confidence interval (CI), 2.1-8.6 months] vs. median, 2.0 months [95% CI, 1.9-2.5 months]; P = .046). The association was stronger with earlier (within 2 weeks) than with later (within 6 weeks) irAEs. In the retrospective cohort (n = 148), the median PFS was significantly longer for the patients with early irAEs (within 3 weeks) than for those without (median, not reached [95% CI, 5.9 months to not reached] vs. median, 6.9 months [95% CI, 4.2-9.7 months]; P = .04). Rash was common and a better predictor of outcomes in both cohorts. Conclusion Our results have provided firmer evidence of the association between the occurrence of irAEs and outcomes and suggest that early irAEs (especially rash) might better predict outcomes.

The usefulness of existing pneumonia severity indices for predicting mortality in nursing and healthcare-associated pneumonia (NHCAP) is unclear. This study compared the usefulness of existing pneumonia severity indices for predicting mortality in NHCAP and community-acquired pneumonia (CAP). Consecutive hospitalized pneumonia patients including NHCAP and CAP patients were prospectively enrolled between October 2010 and November 2017. Admission pneumonia severity was assessed using CURB-65, Pneumonia Severity Index (PSI), A-DROP, Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) severe pneumonia criteria, and I-ROAD. The primary outcome was 30-day mortality. The discriminatory ability of each severity index was evaluated by receiver operating characteristic curve analysis. Overall, 828 patients had NHCAP, and 1330 patients had CAP. Thirty-day mortality was 12.8% and 5.6% in NHCAP and CAP patients, respectively. The area under the curve of PSI (0.717, 95% confidence interval 0.673–0.761) was the highest among all pneumonia severity indices, with significant differences compared with CURB-65 (0.651, 95% confidence interval 0.598–0.705, P = 0.02) and IDSA/ATS severe pneumonia criteria (0.659, 95% confidence interval 0.612–0.707, P = 0.03). The predictive abilities for 30-day mortality of the pneumonia severity indices, excluding PSI and I-ROAD, were significantly inferior for NHCAP than for CAP. PSI may be the most useful pneumonia severity score for predicting mortality in NHCAP. However, the predictive ability for mortality of each pneumonia severity score was worse for NHCAP than for CAP; therefore, the prognostic factors in NHCAP need to be identified for better management of NHCAP patients.

The impact of EGFR tyrosine kinase inhibitors (TKI) on the tumor immune microenvironment (TME) in non-small cell lung cancer (NSCLC) is unclear.We retrospectively identified 138 patients withThe proportion of patients with a PD-L1 expression level of ≥50% (high) increased from 14% before to 28% after EGFR-TKI (EGFR-TKI treatment was associated with changes in the TME of

Pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA) is associated with poor clinical outcomes. We surveyed clinical outcomes of MRSA pneumonia in daily practice to identify risk factors for the clinical failure and mortality in patients with MRSA pneumonia. This multicenter prospective observational study was performed across 48 Japanese medical institutions. Adult patients with culture-positive MRSA pneumonia were recruited and treated with anti-MRSA antibiotics. The relationships between clinical and microbiological characteristics and clinical outcomes at test of cure (TOC) or 30-day all-cause mortality were analyzed. In total, 199 eligible patients, including nursing and healthcare-associated pneumonia (n = 95), hospital-acquired pneumonia (n = 76), and community-acquired pneumonia (n = 25), received initial treatment with anti-MRSA agents such as vancomycin (n = 135), linezolid (n = 36), or teicoplanin (n = 22). Overall clinical failure rate at TOC and the 30-day mortality rate were 51.1% (48/94 patients) and 33.7% (66/196 patients), respectively. Multivariable logistic regression analyses for vancomycin-treated populations revealed that abnormal white blood cell count (odds ratio [OR] 4.34, 95% confidence interval [CI] 1.31–14.39) was a risk factor for clinical failure and that no therapeutic drug monitoring (OR 3.10, 95% CI 1.35–7.12) and abnormally high C-reactive protein level (OR 3.54, 95% CI 1.26–9.92) were risk factors for mortality. In conclusion, this study provides evidence that majority of MRSA pneumonia patients are initially treated with vancomycin in Japan, and the absence of therapeutic drug monitoring for vancomycin is significantly associated with the mortality in patients with MRSA pneumonia.

We developed the microfluidic liquid cell which has the 80-nm-thick electron transparent membrane with the temperature and humidity control inside a microchannel, and in-situ observed the microscaled water drop condensation on the membrane at different temperatures. The droplets condensed by growth and coalescence. As the temperature around the microfluidic liquid cell increased, the enlargement rate of water droplets increased due to the increase of coalescences.

Background Empyema is an important and serious disease with high morbidity and mortality worldwide. However, the bacteriology and prognostic factors of empyema remain poorly understood, and data on the relationships among these parameters are scant. Methods We retrospectively analyzed a prospectively collected database of patients with empyema admitted to Kurashiki Central Hospital, Japan, between May 2007 and September 2015. Only patients who had positive results on pleural fluid bacterial culture were included. We collected patient characteristics, bacteriology findings, treatments, and outcomes, and we assessed the prognostic factors for in-hospital mortality. Results We included 71 patients in this study. The most commonly isolated bacteria were members of the Streptococcus anginosus group (37%), followed by anaerobes (30%). In-hospital mortality was 11%. On multivariate analysis, polymicrobial empyema (odds ratio [OR], 8.25; 95% confidence interval [CI], 1.08–62.90) and RAPID (renal, age, purulence, infection source, and dietary factors) score (OR, 6.89; 95% CI, 1.73–27.40) were significant risk factors for in-hospital mortality. The most common etiology of polymicrobial empyema was a combination of the members of the S. anginosus group and anaerobes, but no relationship was observed between the combination of microorganisms and outcomes. Although no significant difference was observed in treatment between the survivor and non-survivor groups, all patients who underwent surgery survived. Conclusions Members of the S. anginosus group and anaerobes were frequent pathogens in empyema, and polymicrobial etiology was independently associated with mortality in addition to the RAPID score. Surgery may be one option for preventing mortality.

Objectives Afatinib is an effective treatment in patients who have epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC), but its toxicities often require dose adjustment. Exploratory analyses of previous trials have suggested that reducing the dose of afatinib can decrease treatment-related adverse events without negatively affecting effectiveness. The aim of this study was to assess the efficacy and safety of low starting dose of afatinib with dose modification according to its toxicity in patients with EGFR mutation-positive NSCLC. Materials and methods This study was a multicenter, single-arm, open-label phase II trial. Treatment-naive patients with advanced NSCLC positive for common EGFR mutations received afatinib starting in a dose of 20 mg/day. If tolerated, the dose was increased in 10-mg increments up to 50 mg/day. The primary endpoint was progression-free survival (PFS). Results From February 2015 through March 2016, 46 patients were enrolled. The median age was 73 years (range, 43–86), and 35 patients (72%) were women.EGFR mutation subtypes included exon 19 deletion (54%) and Leu858Arg point mutation (46%). Most patients had a performance status of 0 or 1 (91%) and a histological diagnosis of adenocarcinoma (98%). As of the data cut-off date of June 2017, the median follow-up was 18.9 months. The median PFS was 15.2 months (95% CI: 13.2–not estimable). The 1-year overall survival rate was 95.6% (95% CI: 89.7%–100%). The objective response rate was 81.8% (95% CI, 81.3%–98.6%). Adverse events of grade 3 or higher occurred in 14 patients (30.4%) and included rash/acne in 4 patients (8.7%), paronychia in 4 patients (8.7%), diarrhea in 2 patients (4.3%). There was no treatment-related death. Conclusions Low starting dose of afatinib therapy showed promising clinical efficacy and good tolerability. Further investigations are warranted.

A 40-year-old Japanese man was diagnosed with systemic lupus erythematosus. Chest computed tomography showed patchy consolidation in both lungs. A cryobiopsy and bronchoalveolar lavage showed organizing pneumonia, not acute lupus pneumonia or diffuse alveolar hemorrhage. This case demonstrates the usefulness of cryobiopsy for the management of systemic lupus erythematosus interstitial lung disease.

Background and objectives It can be difficult to treat respiratory tract infections caused by Mycobacterium abscessus ( M. abscessus ) as there is no established treatment strategy. Complications involving other nontuberculous mycobacterial infections such as Mycobacterium avium complex (MAC) are also commonly observed. Methods We investigated the clinical background and course of 18 cases of pulmonary M. abscessus infection treated over 8 years at Kurashiki Central Hospital. Radiological evaluation was performed using NICE scoring system, a method of semi-quantitative evaluation of imaging findings of pulmonary MAC infection. Results The mean age of the 18 patients (males, 6; females, 12) was 74.7 years. The median follow-up period was 1316 days (95% confidence interval; 720–1675 days), and 11 patients were concomitantly infected with pulmonary MAC. Among the patients that underwent antibacterial treatment for M. abscessus , there was one MAC-complication case and one non-MAC-complication case. All MAC-complication cases underwent antibacterial treatment including clarithromycin. Chest X-ray NICE scores for all cases were 8.50 ± 5.45 and 10.94 ± 6.03 at baseline and follow-up, respectively ( p = 0.0063). For MAC-complication cases, scores were 8.36 ± 4.74 and 12.00 ± 6.02 at baseline and follow-up, respectively ( p = 0.00818), and for non-MAC-complication cases, scores were 8.71 ± 6.82 and 9.29 ± 6.13 at baseline and follow-up, respectively ( p = 0.356). MAC-complication cases were significantly further exacerbated than non-MAC-complication cases ( p = 0.027). Conclusions Some cases of pulmonary M. abscessus infection progressed well without undergoing antibacterial treatment. In particular, results suggested that the clinical course of MAC-complication and non-MAC-complication cases differs.

SETTING Community-acquired pneumonia (CAP) is a common cause of morbidity and mortality worldwide. While interactions among bacterial pathogens in the respiratory tract have been studied, the impact of polybacterial aetiology on mortality has not been fully elucidated. OBJECTIVE To investigate the impact of polybacterial aetiology on mortality, prevalence, microbial patterns and clinical characteristics among CAP patients. DESIGN Retrospective data analysis. RESULTS Bacterial aetiology was established in 711 (46.0%) of 1544 enrolled hospitalised CAP patients. Of these, polybacterial aetiology was identified in 89 (12.5%): Streptococcus pneumoniae was the most frequently identified pathogen (n = 55, 61.8%). The most prevalent microbial combination was S. pneumoniae and Haemophilus influenzae (n = 19, 21.3%). Alcoholism and lack of previous antibiotic therapy were independent predictors of polybacterial aetiology. The proportion of patients with severe pneumonia was significantly higher in the polybacterial aetiology group than in the monobacterial group. Multivariate analysis showed that polybacterial aetiology was a predictor of 30-day mortality (OR 2.14, 95%CI 1.07-4.24, P = 0.030), independently of severe pneumonia status, pneumonia severity index, chronic obstructive pulmonary disease and inappropriate empirical therapy. CONCLUSION Polybacterial CAP tends to advance in severity, and indicates adverse outcomes.

Legionella species are important causative pathogens for severe community-acquired pneumonia (CAP). Most cases of Legionella pneumonia are due to Legionella pneumophila serogroup 1, and CAP due to L. pneumophila serogroup 9 is rare. A fourth case of CAP due to L. pneumophila serogroup 9 has been reported, and initial treatment using single-dose oral azithromycin appeared useful. Azithromycin or fluoroquinolone injection is usually recommended for the treatment of Legionella pneumonia, and no previous reports have shown the effectiveness of single-dose oral azithromycin. This case report is therefore valuable from the perspective of possible treatment for mild to moderate Legionella pneumonia using single-dose oral azithromycin.

Microfluidic devices utilizing spheroids play important roles in in vitro experimental systems to closely simulate morphological and biochemical characteristics of the in vivo tumor microenvironment. For the observation and analysis of the inner structure of spheroids, sectioning is an efficient approach. However, conventional microfluidic devices are difficult for sectioning, and therefore, spheroids inside the microfluidic channels have not been sliced well. We proposed a microfluidic device created from embedding resin for sectioning. Spheroids were cultured, embedded by resin, and sectioned in the microfluidic device. Slices of the sectioned spheroids yielded clear images at the cellular level. According to morphological and immunohistochemical analyses of the slices of the spheroid, specific protein distribution was observed.

Background Baloxavir marboxil (baloxavir) is an antiviral drug that inhibits the viral "cap-snatching" step in virus RNA transcription initiation. In Phase 2 study, baloxavir significantly shortend the time to alleviation of symptoms (TTAS) and showed significantly greater reduction in influenza virus titer compared with placebo. This provides additional outcomes including efficacy against virus types/subtypes and pharmacokinetic/pharmacodynamic (PK/PD) analysis. Methods Subgroup analyses by virus types/subtype were conducted for the primary and key secondary endpoints. Blood samples were collected totally at 2 to 5 points including Day 2 after baloxavir dosing. PK/PD analyses were conducted for TTAS and change in virus titer using the liner model and the Emax model, respectively. Results The median TTAS in each baloxavir dose group was significantly shorter than in the placebo group for patients with A/H1N1pdm virus, and was numerically shorter than the placebo group for patients with A/H3N2 and type B virus. Baloxavir significantly reduced virus titer within 1 day after treatment: for A/H1N1pdm, A/H3N2, and B virus, all 3 doses of baloxavir marboxil reduced virus titer on Day 2 to a greater extent than placebo. No clear PK/PD relationships were found for the TTAS, but the larger reduction in virus titer was observed in increasing C24. Conclusion These results support that baloxavir marboxil will be effective against a range of virus types/subtypes.

Nivolumab is effective in the treatment of previously treated patients with advanced NSCLC. However, its radiological evaluation is challenging because of atypical patterns of response such as pseudoprogression. We examined the characteristics and outcomes of previously treated patients with NSCLC who were treated with nivolumab and experienced development of pseudoprogression.We conducted a 15-center retrospective cohort study of previously treated patients with advanced NSCLC who received nivolumab monotherapy. For the patients who showed pseudoprogression, we defined progression-free survival 1 (PFS1) as the time to Response Evaluation Criteria in Solid Tumors-defined first progressive disease and progression-free survival 2 (PFS2) as the time to Response Evaluation Criteria in Solid Tumors-defined second progressive disease or death.Among the 542 patients included, 20% and 53% showed a typical response and progression, respectively. Of the 14 (3%) patients who showed pseudoprogression, most (n = 10) showed a response within 3 months of nivolumab treatment. The median PFS1 and PFS2 were 1.0 and 7.3 months, respectively. The median PFS2 was significantly shorter in the patients who showed pseudoprogression than the PFS of the patients with a typical response (p 0.001). In contrast, patients showing pseudoprogression had significantly longer overall survival than did patients showing typical progression (p = 0.001).Pseudoprogression was uncommon, and the duration of response in patients who showed pseudoprogression was shorter than that in patients who showed a typical response. However, the survival benefit of pseudoprogression was markedly better than that of typical progression. Further research is required to elucidate the characteristics of and mechanisms underlying pseudoprogression.

Background Quick Sepsis-related Organ Failure Assessment (qSOFA) is a new screening system for sepsis. The prognostic performance of qSOFA for patients with suspected infections outside the intensive care unit (ICU) is similar to that of full SOFA; however, its performance for community-acquired pneumonia (CAP) has not yet been evaluated in detail. The objectives of the present study were to compare the prognostic performance of qSOFA with existing pneumonia severity scores, such as CURB-65 (confusion, blood urea nitrogen > 19 mg/dL, respiratory rate ≥ 30/min, systolic blood pressure

Background Most patients with acute eosinophilic pneumonia (AEP) show rapid improvement. However, some cases of AEP prove fatal. The aims of this study were to determine the clinical, radiographic, and pathologic characteristics of patients in whom AEP has a fatal outcome and to identify predictors of a poor prognosis. Methods We retrospectively identified the medical records of all patients diagnosed with AEP at our institution in Japan from July 2005 to July 2013. Results There were four deaths among 41 patients diagnosed to have AEP during the study period. All the patients who died were male; three cases were idiopathic and one was medication-related. The median bronchoalveolar lavage eosinophil differential count was 59%. An autopsy was performed on the patient with medication-related AEP who died and the pathologic finding was diffuse alveolar damage with eosinophilic infiltration. Diffuse ground-glass attenuation and traction bronchiectasis (TBE) were identified on high-resolution computed tomography in the four patients with fatal AEP. TBE was observed in six patients (five with idiopathic AEP, one with medication-related AEP), and 67% of these patients died. None of the patients with smoking-related AEP had TBE; all these patients had better responses to treatment and survived. Conclusions We observed the characteristics of patients with fatal AEP who did not respond to treatment. TBE was observed in all fatal cases and may be associated with a poor prognosis.

Real-time observation of the actual contact area between surface interfaces at the nanoscale enables more precise examination of what happens during friction. We have combined micro electro mechanical system actuators and transmission electron microscopy (TEM) observation, to both apply and measure forces across nanoscale junctions and contacts. This custom-designed experimental system can measure the true surface area of a contact site from a lateral viewpoint, while simultaneously measuring the friction force. We scratched surfaces coated with diamond like carbon, a classical solid lubricant, and observed the formation of wear particles that slipped and rolled between the interface. TEM images showed that the shape of the surface at the nanoscale underwent permanent deformation when acted upon with forces as low as several tens of nano newtons. The results demonstrated the limitations of friction analyses relying on friction force measurements without real-time surface profiling.

BACKGROUND Empiric therapy of pneumonia is currently based on the site of acquisition (community or hospital), but could be chosen, based on risk factors for multidrug-resistant (MDR) pathogens, independent of site of acquisition. METHODS We prospectively applied a therapeutic algorithm based on MDR risks, in a multicenter cohort study of 1089 patients with 656 community-acquired pneumonia (CAP), 238 healthcare-associated pneumonia (HCAP), 140 hospital-acquired pneumonia (HAP), or 55 ventilator-associated pneumonia (VAP). RESULTS Approximately 83% of patients were treated according to the algorithm, with 4.3% receiving inappropriate therapy. The frequency of MDR pathogens varied, respectively, with VAP (50.9%), HAP (27.9%), HCAP (10.9%), and CAP (5.2%). Those with ≥2 MDR risks had MDR pathogens more often than those with 0-1 MDR risk (25.8% vs 5.3%, P < .001). The 30-day mortality rates were as follows: VAP (18.2%), HAP (13.6%), HCAP (6.7%), and CAP (4.7%), and were lower in patients with 0-1 MDR risks than in those with ≥2 MDR risks (4.5% vs 12.5%, P < .001). In multivariate logistic regression analysis, 5 risk factors (advanced age, hematocrit

High-resolution computed tomography (HRCT) parenchymal patterns have been used to predict prognosis in patients with interstitial lung disease (ILD). In idiopathic pulmonary fibrosis, the fibrosis score (i.e. the combined extent of reticulation and honeycombing) has been associated with worse survival. This study aimed to identify HRCT patterns and patient characteristics that can predict poor prognosis in rheumatoid arthritis-related ILD (RA-ILD).We retrospectively analysed 65 patients with newly diagnosed RA-ILD from 2007 to 2016 at Kurashiki Central hospital. Using univariate and bivariate Cox regression analysis, associations with mortality, were identified.During a median follow-up of 56.5 months, 16/65 (24.6%) patients died. Univariate analysis identified six significant poor prognostic factors: lower baseline % predicted forced vital capacity, total interstitial disease score, reticulation score, traction bronchiectasis score, fibrosis score, and definite UIP pattern. Fibrosis score remained to be an independently significant poor prognostic factor of survival on bivariate analysis. Patients with a fibrosis score20% had higher mortality (HR, 9.019; 95% CI, 2.87-28.35; p .05).This study showed that fibrosis score is strongly associated with worse survival in RA-ILD, and patients with fibrosis score20% had a 9.019-fold increased risk of mortality.

Background Pneumococcal pneumonia causes high morbidity and mortality among adults. This study aimed to identify risk factors for bacteremic pneumococcal pneumonia, and to construct a prediction model for the development of bacteremia in patients with community-acquired pneumococcal pneumonia. Methods We retrospectively analyzed data from patients hospitalized with community-acquired pneumococcal pneumonia between April 2007 and August 2015. Logistic regression models were applied to detect risk factors for pneumococcal bacteremia, and a receiver operating characteristic curve was used to devise a prediction model. Results Based on the results of sputum cultures, urine antigen tests, and/or blood cultures, 389 patients were diagnosed with pneumococcal pneumonia, 46 of whom had bacteremia. In the multivariate analysis, age 20 mg/dL were identified as independent risk factors for the development of pneumococcal bacteremia. The bacteremia prediction score based on receiver operating characteristic curve analysis had a sensitivity of 0.74 and a specificity of 0.78 in patients with two risk factors. The area under the receiver operating characteristic curve was 0.77 (95% confidence interval (CI), 0.70–0.85). Conclusions Age

BACKGROUND Baloxavir marboxil is a selective inhibitor of influenza cap-dependent endonuclease. It has shown therapeutic activity in preclinical models of influenza A and B virus infections, including strains resistant to current antiviral agents. METHODS We conducted two randomized, double-blind, controlled trials involving otherwise healthy outpatients with acute uncomplicated influenza. After a dose-ranging (10 to 40 mg) placebo-controlled trial, we undertook a placebo- and oseltamivir-controlled trial of single, weight-based doses of baloxavir (40 or 80 mg) in patients 12 to 64 years of age during the 2016-2017 season. The dose of oseltamivir was 75 mg twice daily for 5 days. The primary efficacy end point was the time to alleviation of influenza symptoms in the intention-to-treat infected population. RESULTS In the phase 2 trial, the median time to alleviation of influenza symptoms was 23.4 to 28.2 hours shorter in the baloxavir groups than in the placebo group (P

Introduction Epidermal growth factor receptor (EGFR) mutation T790M accounts for approximately half of acquired resistances to EGFR-tyrosine kinase inhibitor (TKI). Because T790M is mediated by TKI exposure, its penetration and "on–off" may affect T790M status. Methods We retrospectively reviewed T790M status and clinical course of patients who had undergone multiple rebiopsies after acquired resistance to EGFR-TKI. Results Of 145 patients with EGFR-mutant NSCLC receiving rebiopsy after acquired resistance, 30 underwent multiple site rebiopsies, and 24 received repeated rebiopsies at the same lesion. In 22 patients who underwent rebiopsies from both central nervous system (CNS; 20 cerebrospinal fluids [CSF] and 2 brain tumoral tissues) and thoracic lesions (7 lung tissues, 14 pleural effusions, and 1 lymph node), 12 were thoracic-T790M-positive. Of these 12 patients, 10 were CNS-T790M-negative, despite exhibiting thoracic-T790M-positive. All 10 thoracic-T790M-negatives were CNS-T790M-negative. Three patients revealed a spatial heterogeneous T790M status among their thoracic lesions. In 24 patients receiving repeated rebiopsies at the same lesion (12 lung tissues, 6 CSFs, and 6 pleural effusions), T790M status of lung lesions varied in five patients after TKI-free interval. In all five patients whose T790M status changed from positive to negative, EGFR-TKI rechallenge was effective. In three of these five patients, after further TKI exposure, T790M status changed from negative to positive again. There was also a patient whose CSF T790M status changed from negative to positive after high-dose erlotinib therapy. Conclusions T790M status in an individual patient can be spatiotemporally heterogeneous because of selective pressure from EGFR-TKI.

Background The aim of the study was to describe the epidemiology, clinical features, antimicrobial treatment, and outcomes of bedridden pneumonia patients receiving home healthcare. Methods A 3-year prospective observational study of poor performance status (PS) 3–4 patients receiving long-term home healthcare and hospitalized at a single center with pneumonia between October 2010 and September 2013 was conducted, and their clinical characteristics were compared with non-bedridden community-acquired pneumonia (CAP) patients. Results A total of 131 CAP patients with PS 3-4, and 400 CAP patients with PS 0-2 were evaluated. The PS 3–4 patients were older, and exhibited a higher frequency of underlying diseases. Aspiration was thought to be associated with pneumonia in 77.1% of the PS 3–4 patients. Streptococcus pneumoniae was the leading pathogen in both groups, whereas the frequency of streptococci and polymicrobial infections was higher in the PS 3-4 group. The incidence of multidrug-resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa was lower than in previous healthcare-associated pneumonia reports. The in-hospital mortality and recurrence rates were significantly higher in the PS 3-4 group than in the good PS group (17.6% vs. 6.0%, p Conclusions The clinical characteristics of pneumonia in poor PS patients were similar to healthcare-associated pneumonia (HCAP), except for the frequency of drug-resistant pathogens. Hence, it might be beneficial to categorize pneumonia in home residents with poor PS separately from pneumonia in CAP patients who were previously healthy or experienced mild comorbidities.

The uniform dispersion of cells in a microchamber is important to reproduce results in cellular research. However, achieving this is difficult owing to the laminar flow caused by the small dimensions of such a chamber. In this study, we propose a technique to achieve a uniform distribution of cells using a micropillar array inside a microchamber. The cells deform when they pass through a gap between the micropillars. The deformation causes a repetitive clog-and-release process of cells at the gaps between the micropillars. The micropillar array generates random flow inside the microchamber, resulting in the uniform distribution of the cells via cell accumulation. In the experiment, the distribution of cells in the microchamber with the micropillar array is uniform from end to end, whereas that in the microchamber without the micropillar array is centered. The deviation of the cell distribution from the ideally uniform distribution in the microchamber with the micropillar array is suppressed by 63% compared with that in the microchamber without the micropillar array. The doubling time of the cells passed through the micropillar array did not change relative to that of normal N87 cells. This technique will be helpful for reproducing results in cellular research at the micro scale or for those using microfluidic devices.