Language：English  

DOI： 10.1007/s00535-023-02071-x

PubMed

Language：English   Publisher：Metabolism: Clinical and Experimental  

Background: Computed tomography (CT) imaging is widely used for diagnosing and determining the severity of coronavirus disease 2019 (COVID-19). Chest CT imaging can be used to calculate the epicardial adipose tissue (EAT) and upper abdominal visceral adipose tissue (Abd-VAT) areas. The EAT is the main source of inflammatory cytokines involved in chest inflammatory diseases; thus, the EAT area might be a more useful severity predictor than the Abd-VAT area for COVID-19. However, to the best of our knowledge, there are no large-scale reports that sufficiently consider this issue. In addition, there are no reports on the characteristics of patients with normal body mass index (BMI) and high adipose tissue. Aim: The purpose of this study was to analyze whether the EAT area, among various adipose tissues, was the most associated factor with COVID-19 severity. Using a multicenter COVID-19 patient database, we analyzed the associations of chest subcutaneous, chest visceral, abdominal subcutaneous, and Abd-VAT areas with COVID-19 outcomes. In addition, the clinical significance of central obesity, commonly disregarded by BMI, was examined. Methods: This retrospective cohort study evaluated patients with COVID-19 aged ≥18 years In Japan. Data including from chest CT images collected between February 2020 and October 2022 in four hospitals of the Japan COVID-19 Task Force were analyzed. Patient characteristics and COVID-19 severity were compared according to the adipose tissue areas (chest and abdominal subcutaneous adipose tissue [Chest-SAT and Abd-SAT], EAT, and Abd-VAT) calculated from chest CT images. Results: We included 1077 patients in the analysis. Patients with risk factors of severe COVID-19 such as old age, male sex, and comorbidities had significantly higher areas of EAT and Abd-VAT. High EAT area but not high Abd-VAT area was significantly associated with COVID-19 severity (adjusted odds ratio (aOR): 2.66, 95 % confidence interval [CI]: 1.19–5.93). There was no strong correlation between BMI and VAT. Patients with high VAT area accounted for 40.7 % of the non-obesity population (BMI < 25 kg/m2). High EAT area was also significantly associated with COVID-19 severity in the non-obesity population (aOR: 2.50, 95 % CI: 1.17–5.34). Conclusions: Our study indicated that VAT is significantly associated with COVID-19 severity and that EAT is the best potential predictor for risk stratification in COVID-19 among adipose tissue areas. Body composition assessment using EAT is an appropriate marker for identifying obesity patients overlooked by BMI. Considering the next pandemic of the global health crisis, our findings open new avenues for implementing appropriate body composition assessments based on CT imaging.

DOI： 10.1016/j.metabol.2023.155715

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

Objective

This study aimed to investigate the clinical features of long COVID cases presenting with upper respiratory symptoms, a topic not yet fully elucidated.

Study Design

Prospective cohort study.

Setting

A multicenter study involving 26 medical facilities in Japan.

Methods

Inclusion criteria were patients aged ≥18 years old with a confirmed COVID‐19 diagnosis via severe acute respiratory syndrome coronavirus 2 polymerase chain reaction or antigen testing, who were hospitalized at the participating medical facilities. Analyzing clinical information and patient‐reported outcomes from 1009 patients were analyzed. The outcome measured the degree of initial symptoms for taste or olfactory disorders and assessed the likelihood of these symptoms persisting as long COVID, as well as the impact on quality of life if the upper respiratory symptoms persisted as long COVID.

Results

Patients with high albumin, low C‐reactive protein, and low lactate dehydrogenase in laboratory tests tended to experience taste or olfactory disorders as part of long COVID. Those with severe initial symptoms had a higher risk of experiencing residual symptoms at 3 months, with an odds ratio of 2.933 (95% confidence interval [CI], 1.282‐6.526) for taste disorders and 3.534 (95% CI, 1.382‐9.009) for olfactory disorders. Presence of upper respiratory symptoms consistently resulted in lower quality of life scores.

Conclusion

The findings from this cohort study suggest that severe taste or olfactory disorders as early COVID‐19 symptoms correlate with an increased likelihood of persistent symptoms in those disorders as long COVID.

DOI： 10.1002/oto2.120

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PubMed

Language：English   Publisher：Thorax  

Background: Pulmonary hypertension (PH) is defined by elevated mean pulmonary arterial pressure (MPAP), and elevated pulmonary vascular resistance (PVR) reflects pulmonary vascular abnormalities. The clinical significance of non-severe PH in patients with various interstitial lung diseases (ILDs) has not been fully elucidated. We aimed to investigate the clinical significance of MPAP and PVR for mortality in patients with newly diagnosed ILD. Methods: We retrospectively analysed consecutive patients with ILD at initial evaluations that included right heart catheterisation from 2007 to 2018. These patients were classified by MPAP and PVR using the 2022 the European Society of Cardiology (ESC)/the European Respiratory Society (ERS) guidelines for PH. The clinical significance of MPAP and PVR for mortality was analysed. Results: Among 854 patients, 167 (19.6%) had MPAP>20 mm Hg. The proportion of patients with PVR>2 Wood units (WU) among those with MPAP≤20 mm Hg, 20<MPAP<25 mm Hg, and ≥25 mm Hg were 26.2%, 60.4% and 86.4%, respectively. In Cox proportional hazards analyses with adjustment for ILD-Gender, Age and Physiology Index, PVR but not MPAP was associated with a higher mortality rate (HR 1.37, 95% CI 1.23 to 1.52, p<0.0001; HR 0.98, 95% CI 0.96 to 1.01, p=0.1671, respectively). PVR>2 WU was associated with a higher mortality rate (HR 1.61, 95% CI 1.28 to 2.02, p<0.0001) even in a group with MPAP≤20 mm Hg. Conclusions: Mild elevation of PVR was associated with a higher mortality rate in patients with newly diagnosed ILD, even in those with MPAP≤20 mm Hg.

DOI： 10.1136/thorax-2023-220179

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

The severity of chest X-ray (CXR) findings is a prognostic factor in patients with coronavirus disease 2019 (COVID-19). We investigated the clinical and genetic characteristics and prognosis of patients with worsening CXR findings during early hospitalization. We retrospectively included 1656 consecutive Japanese patients with COVID-19 recruited through the Japan COVID-19 Task Force. Rapid deterioration of CXR findings was defined as increased pulmonary infiltrates in ≥ 50% of the lung fields within 48 h of admission. Rapid deterioration of CXR findings was an independent risk factor for death, most severe illness, tracheal intubation, and intensive care unit admission. The presence of consolidation on CXR, comorbid cardiovascular and chronic obstructive pulmonary diseases, high body temperature, and increased serum aspartate aminotransferase, potassium, and C-reactive protein levels were independent risk factors for rapid deterioration of CXR findings. Risk variant at the ABO locus (rs529565-C) was associated with rapid deterioration of CXR findings in all patients. This study revealed the clinical features, genetic features, and risk factors associated with rapid deterioration of CXR findings, a poor prognostic factor in patients with COVID-19.

DOI： 10.1038/s41598-023-49340-6

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PubMed

Language：English   Publisher：Scientific Reports  

Various liquid biopsy methods have been developed for the non-invasive and early detection of diseases. In particular, the detection of circulating tumor cells (CTCs) and cancer-associated fibroblasts (CAFs) in blood has been receiving a great deal of attention. We have been developing systems and materials to facilitate such liquid biopsies. In this study, we further developed glass filters (with various patterns of holes, pitches, and non-adhesive coating) that can capture CTCs, but not white blood cells. We optimized the glass filters to capture CTCs, and demonstrated that they could be used to detect CTCs from lung cancer patients. We also used the optimized glass filters for detecting CAFs. Additionally, we further developed a system for visualizing the captured cells on the glass filters. Finally, we demonstrated that we could directly culture the captured cells on the glass filters. Based on these results, our high-performance glass filters appear to be useful for capturing and culturing CTCs and CAFs for further examinations.

DOI： 10.1038/s41598-023-31265-9

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PubMed

Language：English  

DOI： 10.1016/j.jvacx.2023.100381

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Gastrointestinal (GI) long-COVID symptoms, including diarrhea and abdominal pain, have been reported in patients with long-COVID. However, the clinical features of patients with GI long-COVID symptoms remain unclear. We conducted a large-scale prospective cohort study focusing on the clinical characteristics of patients with GI long-COVID symptoms in Japan. Among 943 COVID-19 patients, 58 patients (6.2%) had GI long-COVID symptoms. The health-related quality of life (QOL) parameters (the Short Form-8 [SF-8] and Euro Quality of Life 5 Dimensions 5 level [EQ-5D-5L]) at 12 months after diagnosis in patients with GI long-COVID symptoms were significantly lower than in those without GI long-COVID symptoms (P < 0.0001). Moreover, patients with GI long-COVID symptoms had more varied long-COVID symptoms compared to patients without GI long-COVID symptoms.

DOI： 10.1002/jgh3.13006

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Statistical fine-mapping prioritizes putative causal variants from a large number of candidate variants, and is widely used in expression quantitative loci (eQTLs) studies. In eQTL fine-mapping, the existence of causal variants for gene expression is not guaranteed, since the genetic heritability of gene expression explained by nearby (cis-) variants is limited. Here we introduce a refined fine-mapping algorithm, named Knockoff-Finemap combination (KFc). KFc estimates the probability that the causal variant(s) exist in the cis-window of a gene through construction of knockoff genotypes (i.e. a set of synthetic genotypes that resembles the original genotypes), and uses it to adjust the posterior inclusion probabilities (PIPs). Utilizing simulated gene expression data, we show that KFc results in calibrated PIP distribution with improved precision. When applied to gene expression data of 465 genotyped samples from the Japan COVID-19 Task Force (JCTF), KFc resulted in significant enrichment of a functional score as well as reporter assay hits in the top PIP bins. When combined with functional priors derived from an external fine-mapping study (GTEx), KFc resulted in a significantly higher proportion of hematopoietic trait putative causal variants in the top PIP bins. Our work presents improvements in the precision of a major fine-mapping algorithm.

DOI： 10.1093/nargab/lqad090

Scopus

PubMed

Language：English   Publisher：eClinicalMedicine  

Background: Immune checkpoint inhibitors (ICI) plus platinum-based chemotherapy has been recognized as a standard first-line therapy in non-small cell lung cancer (NSCLC); however, no prospective clinical trials of docetaxel (DTX) plus ramucirumab (RAM) following first-line ICI plus platinum-based chemotherapy has been reported. Methods: In this multicentre, open-label, single-arm, phase 2 trial, we enrolled patients with NSCLC from eight centres in Japan. Patients with metastatic NSCLC with disease progression after platinum-based chemotherapy plus ICI were eligible for the study. Patients were intravenously treated with 60 mg/m2 of DTX and 10 mg/kg of RAM on day 1 with a strong recommendation of pegfilgrastim administration on day 2 every 3 weeks. The primary end point was objective response rate (ORR) in efficacy analysis population. Safety was assessed in all patients treated at least one dose. The ORR of the null and alternative hypotheses were 10% and 30%, with α error of 0.1 and β error of 0.1. This trial is registered with the Japan Registry for Clinical Trials, jCRTs041190077. Findings: Between 16 January, 2020, and 24 August, 2021, 33 patients (median age 66 [range 42–79] years) were enrolled. Thirteen patients (41%) had Eastern Cooperative Oncology Group performance status of 1. Twenty-five patients (78%) had an interval of <60 days after the last administration of ICI. In the efficacy analysis population (n = 32), the primary endpoint was met as 11 patients achieved partial response (PR), with ORR of 34.4% (80% CI, 23.1–47.2). Grade ≥3 anaemia and febrile neutropenia were observed in 2 (6%) and 3 (9%) patients, respectively. No treatment-related deaths and no new safety signals were observed. Interpretation: DTX plus RAM demonstrated encouraging antitumor activity with a manageable safety profile in patients who have progressed on front-line ICIs plus platinum-based chemotherapy. The results of this trial can be a helpful reference in conducting further phase III trials of new second-line treatment options. Funding: Eli Lilly Japan K.K.

DOI： 10.1016/j.eclinm.2023.102303

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Multiple prolonged symptoms are observed in patients who recover from an acute COVID-19 infection, which is defined as long COVID. General fatigue is frequently observed in patients with long COVID during acute and post-acute phases. This study aimed to identify the specific risk factors for general fatigue in long COVID. METHODS: Hospitalized patients with COVID-19 aged over 18 years were enrolled in a multicenter cohort study at 26 medical institutions. Clinical data during hospitalization and patient-reported outcomes after discharge were collected from medical records, paper-based questionnaires, and smartphone apps. RESULTS: Among prolonged symptoms through 1-year follow-ups, general fatigue was the most interfering symptom in daily life. Patients with protracted fatigue at all follow-up periods had lower quality of life scores at the 12-month follow-up. Univariate logistic regression analysis of the presence or absence of general fatigue at the 3-month, 6-month, and 12-month follow-ups identified asthma, younger age, and female sex as risk factors for prolonged fatigue. Multivariable logistic regression analysis revealed that asthma was an independent risk factor for persistent fatigue during the 12-month follow-up period. Longitudinal changes in the symptoms of patients with or without asthma demonstrated that general fatigue, not cough and dyspnea, was significantly prolonged in patients with asthma. CONCLUSIONS: In a Japanese population with long COVID, prolonged general fatigue was closely linked to asthma. A preventive approach against COVID-19 is necessary to avoid sustained fatigue and minimize social and economic losses in patients with asthma.

DOI： 10.1016/j.alit.2023.11.003

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

With the rising numbers of patients infected with severe acute respiratory syndrome coronavirus 2, long coronavirus disease 2019 (COVID-19)-a sequelae of COVID-19-has become a major problem. Different sexes and age groups develop different long COVID symptoms, and the risk factors for long COVID remain unclear. Therefore, we performed subgroup analyses of patients with COVID-19, classifying them into different groups. In this multicenter cohort study, using an original questionnaire, we examined patients (≥18 years old) diagnosed with COVID-19 from November 2020 to March 2022 and hospitalized at participating medical facilities. In total, 1066 patients were registered (361 female, 620 male). Hypertension was the most common comorbidity (n = 344; 32.5%). Females with hypertension were significantly less likely to develop long COVID symptoms than those without hypertension (odds ratio [OR] 0.51, 95% confidence interval [CI] 0.27-0.98; p = 0.043). In females, Ca channel blocker administration, rather than having hypertension, was significantly associated with reductions in the frequency of alopecia (OR 0.14, 95% CI 0.03-0.67, p = 0.015), memory impairment (OR 0.14, 95% CI 0.02-0.82, p = 0.029), sleeping disorders (OR 0.17, 95% CI 0.04-0.67, p = 0.012), tinnitus (OR 0.23, 95% CI 0.05-0.98, p = 0.047), sputum (OR 0.31, 95% CI 0.10-0.92, p = 0.035), and fever (OR 0.33, 95% CI 0.12-0.93, p = 0.036). Several long COVID symptoms, including alopecia, were significantly negatively associated with Ca channel-blocker administration in female patients with long COVID. Calcium channel blockers may reduce the development of long COVID in females.

DOI： 10.1038/s41440-023-01501-w

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Multiple prolonged symptoms are observed in patients who recover from acute coronavirus disease 2019 (COVID-19), defined as long COVID. Cough and sputum are presented by patients with long COVID during the acute and post-acute phases. This study aimed to identify specific risk factors for cough and sputum in patients with long COVID. METHODS: Hospitalized patients with COVID-19 aged 18 years were enrolled in a multicenter cohort study at 26 medical institutions. Clinical data during hospitalization and patient-reported outcomes after discharge were collected from medical records, paper-based questionnaires, and smartphone apps. RESULTS: At the 3-, 6-, and 12-month follow-ups, there were no differences in the incidence rates of wet and dry coughs. In contrast, the proportion of patients presenting sputum without coughing increased over time compared to those with sputum and coughing. Univariate analyses of cough and sputum at all follow-up visits identified intermittent mandatory ventilation (IMV), smoking, and older age as risk factors for prolonged symptoms. At the 12-month follow-up, persistent cough and sputum were associated with the characteristics of severe COVID-19 based on imaging findings, renal and liver dysfunction, pulmonary thromboembolism, and higher serum levels of LDH, KL-6, and HbA1C. The Kaplan-Meier curves showed that the severity of acute COVID-19 infection was correlated with prolonged cough and sputum production. Multivariable logistic regression analysis showed that IMV ventilator management were independent risk factors for prolonged cough and sputum at 12 months. CONCLUSIONS: In a Japanese population with long COVID, prolonged cough and sputum production were closely associated with severe COVID-19. These findings emphasize that a preventive approach including appropriate vaccination and contact precaution and further development of therapeutic drugs for COVID-19 are highly recommended for patients with risk factors for severe infection to avoid persistent respiratory symptoms.

DOI： 10.1186/s12931-023-02591-3

Scopus

PubMed

Publisher：株式会社　医学書院  

DOI： 10.11477/mf.1437200680

CiNii Research

Language：English  

DOI： 10.1186/s12931-023-02530-2

PubMed

Language：Japanese   Publisher：The Japan Society for Respiratory Endoscopy  

<p><b><i>Background.</i></b> Few studies have investigated whether endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) can be conducted without a balloon for a definitive diagnosis of mediastinal lymphadenopathy. <b><i>Case 1.</i></b> A woman in her 70s with an allergy to rubber gloves. During an examination for uveitis, CT showed multiple enlarged lymph nodes in #4R and #7. <b><i>Case 2.</i></b> A man in his 40s presented with an allergy to rubber gloves. Follow-up CT after the surgical treatment of lung adenocarcinoma revealed an enlarged lymph node (#7). <b><i>Results.</i></b> EBUS-TBNA was performed in these two cases to definitively diagnose enlarged mediastinal lymph nodes without a balloon. In Case 1, #7 and #4R had short diameters of 10 mm and 15 mm, respectively, while in Case 2, #7 had a short diameter of 17 mm. The lesion was delineated and punctured without a balloon. Case 1 was diagnosed with sarcoidosis, and case 2 was diagnosed with recurrent lung adenocarcinoma. <b><i>Conclusions.</i></b> It is crucial to carefully assess whether the target lesion is puncturable before the examination when performing EBUS-TBNA without a balloon.</p>

DOI： 10.18907/jjsre.45.5_339

CiNii Research

Publisher：Nature  

DOI： 10.1038/s41586-023-06355-3

Scopus

Publisher：Nature  

DOI： 10.1093/1476-4687

Scopus

Language：English  

DOI： 10.1007/s00277-023-05407-y

PubMed

Language：English  

DOI： 10.1016/j.ijid.2023.07.030

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The long-term exercise tolerance changes in patients with nontuberculous mycobacterial pulmonary disease (NTM-PD) are of great interest because of its chronic course. This study aimed to characterize the associations between changes over time in six-minute walking test (6MWT) parameters and clinical parameters in patients with NTM-PD. METHODS: Overall, 188 patients with NTM-PD, visiting outpatient clinics at Keio University Hospital from April 2012 to March 2020 were included in the study. Data were collected using the St. George's Respiratory Questionnaire (SGRQ), pulmonary function test (PFT), blood tests, and the 6MWT at registration and at least once after that. The association of the anchors and clinical indicators with the 6MWT parameters was assessed. RESULTS: The median age [interquartile range] of the patients was 67 [63-74] years. The median baseline six-minute walk distance (6MWD) and final Borg scale (FBS) were 413 [361-470] m and 1 [0-2], respectively. In the correlation analysis, ΔSGRQ total/year (yr), Δforced vital capacity (FVC, % predicted)/yr, Δforced expiratory volume in 1 s (FEV1, % predicted)/yr, and Δdiffusing capacity for carbon monoxide (DLCO, % predicted)/yr correlated with both Δ6MWD/yr and ΔFBS/yr in the longitudinal analysis (|Rho| > 0.20). When stratified into three quantiles of changes in each anchor, the 6MWT parameters worsened over time in the bottom 25% group by mixed-effects model. Specifically, Δ6MWD was affected by SGRQ activity, SGRQ impacts, PFT (FVC, FEV1, and DLCO), and C-reactive protein (CRP). ΔFBS was affected by all SGRQ components, total score, and PFT. Anchor scores and variables at baseline that worsened Δ6MWD were higher SGRQ scores, lower FVC (% predicted), lower DLCO (% predicted), higher Krebs von den Lungen-6, old age, and undergoing treatment at registration. Similarly, these clinical parameters and elevated CRP, excluding undergoing treatment at registration, worsened ΔFBS. CONCLUSIONS: The decreased walking distance and exacerbation of dyspnea on exertion over time in patients with NTM-PD may reflect a deterioration of health-related quality of life and pulmonary function. Thus, the change in 6MWT over time can be used as an indicator to accurately assess the patient's condition and tailor their healthcare environment.

DOI： 10.1186/s12890-023-02528-y

Web of Science

Scopus

PubMed

Language：English  

DOI： 10.1093/ofid/ofad311

PubMed

Language：English  

DOI： 10.1007/s13691-023-00620-y

Web of Science

PubMed

Language：English   Publisher：iScience  

Several antibody therapeutics have been developed against SARS-CoV-2; however, they have attenuated neutralizing ability against variants. In this study, we generated multiple broadly neutralizing antibodies from B cells of convalescents, by using two types of receptor-binding domains, Wuhan strain and the Gamma variant as bait. From 172 antibodies generated, six antibodies neutralized all strains prior to the Omicron variant, and the five antibodies were able to neutralize some of the Omicron sub-strains. Structural analysis showed that these antibodies have a variety of characteristic binding modes, such as ACE2 mimicry. We subjected a representative antibody to the hamster infection model after introduction of the N297A modification, and observed a dose-dependent reduction of the lung viral titer, even at a dose of 2 mg/kg. These results demonstrated that our antibodies have certain antiviral activity as therapeutics, and highlighted the importance of initial cell-screening strategy for the efficient development of therapeutic antibodies.

DOI： 10.1016/j.isci.2023.106955

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PubMed

Language：English   Publisher：Investigational New Drugs  

Immune-related sclerosing cholangitis (irSC) is relatively rare and its clinical characteristics are not well known. In this study, we aimed to summarize the clinical features of irSC. Clinical data were collected retrospectively from 1,393 patients with advanced malignancy treated with immune-checkpoint inhibitors (ICIs) between August 2014 and October 2021. We analyzed patients with immune-related adverse events of liver injury (liver-irAEs) and compared irSC and non-irSC groups. Sixty-seven patients (4.8%) had a liver-irAE (≥ grade 3) during the follow-up period (median, 262 days). Among these, irSC was observed in eight patients (11.9%). All patients in the irSC group were treated with anti-PD-1/PD-L1 antibodies. Compared with the non-irSC group, the irSC group showed mainly non-hepatocellular liver injury (87.5 % vs 50.8 %, P = 0.065), and had elevated serum inflammatory markers (e.g., CRP and NLR) and biliary enzymes (e.g., GGTP and ALP) at the onset of liver-irAEs. Furthermore, most patients with irSC had abdominal pain. In the non-irSC group, the liver injury of 23 patients improved only with the discontinuation of ICIs, and 22 patients improved with medication including prednisolone (PSL). Conversely, almost all patients (n=7) in the irSC group were treated with PSL, but only two patients experienced an improvement in liver injury. We found that irSC is characterized by a non-hepatocellular type of liver injury with abdominal pain and a high inflammatory response and is refractory to treatment. Further examination by imaging is recommended to detect intractable irSC in cases with these characteristics.

DOI： 10.1007/s10637-023-01366-3

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Scopus

PubMed

Language：English  

DOI： 10.1016/j.resinv.2023.04.005

PubMed

Language：English  

DOI： 10.1080/02770903.2023.2209173

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Krebs von den Lungen-6 (KL-6) is a known biomarker for diagnosis and monitoring of interstitial lung diseases. However, the role of serum KL-6 and the mucin 1 (MUC1) variant (rs4072037) in COVID-19 outcomes remains to be elucidated. We aimed to evaluate the relationships among serum KL-6 levels, critical outcomes and the MUC1 variant in Japanese patients with COVID-19. METHODS: This is a secondary analysis of a multicentre retrospective study using data from the Japan COVID-19 Task Force collected from February 2020 to November 2021, including 2226 patients with COVID-19 whose serum KL-6 levels were measured. An optimal serum KL-6 level cut-off to predict critical outcomes was determined and used for multivariable logistic regression analysis. Furthermore, the relationship among the allele dosage of the MUC1 variant, calculated from single nucleotide polymorphism typing data of genome-wide association studies using the imputation method, serum KL-6 levels and COVID-19 critical outcomes was evaluated. RESULTS: Serum KL-6 levels were significantly higher in patients with COVID-19 with critical outcomes (511±442 U/mL) than those without (279±204 U/mL) (p<0.001). Serum KL-6 levels ≥304 U/mL independently predicted critical outcomes (adjusted OR (aOR) 3.47, 95% CI 2.44 to 4.95). Moreover, multivariable logistic regression analysis with age and sex indicated that the MUC1 variant was independently associated with increased serum KL-6 levels (aOR 0.24, 95% CI 0.28 to 0.32) but not significantly associated with critical outcomes (aOR 1.11, 95% CI 0.80 to 1.54). CONCLUSION: Serum KL-6 levels predicted critical outcomes in Japanese patients with COVID-19 and were associated with the MUC1 variant. Therefore, serum KL-6 level is a potentially useful biomarker of critical COVID-19 outcomes.

DOI： 10.1136/bmjresp-2023-001625

Web of Science

Scopus

PubMed

Publisher：Nature Genetics  

Mechanisms underpinning the dysfunctional immune response in severe acute respiratory syndrome coronavirus 2 infection are elusive. We analyzed single-cell transcriptomes and T and B cell receptors (BCR) of >895,000 peripheral blood mononuclear cells from 73 coronavirus disease 2019 (COVID-19) patients and 75 healthy controls of Japanese ancestry with host genetic data. COVID-19 patients showed a low fraction of nonclassical monocytes (ncMono). We report downregulated cell transitions from classical monocytes to ncMono in COVID-19 with reduced CXCL10 expression in ncMono in severe disease. Cell–cell communication analysis inferred decreased cellular interactions involving ncMono in severe COVID-19. Clonal expansions of BCR were evident in the plasmablasts of patients. Putative disease genes identified by COVID-19 genome-wide association study showed cell type-specific expressions in monocytes and dendritic cells. A COVID-19-associated risk variant at the IFNAR2 locus (rs13050728) had context-specific and monocyte-specific expression quantitative trait loci effects. Our study highlights biological and host genetic involvement of innate immune cells in COVID-19 severity.

DOI： 10.1038/s41588-023-01375-1

Web of Science

Scopus

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Although cases of respiratory bacterial infections associated with coronavirus disease 2019 (COVID-19) have often been reported, their impact on the clinical course remains unclear. Herein, we evaluated and analyzed the complication rates of bacterial infections, causative organisms, patient backgrounds, and clinical outcome in Japanese patients with COVID-19. METHODS: We performed a retrospective cohort study that included inpatients with COVID-19 from multiple centers participating in the Japan COVID-19 Taskforce (April 2020 to May 2021) and obtained demographic, epidemiological, and microbiological results and the clinical course and analyzed the cases of COVID-19 complicated by respiratory bacterial infections. RESULTS: Of the 1,863 patients with COVID-19 included in the analysis, 140 (7.5%) had respiratory bacterial infections. Community-acquired co-infection at COVID-19 diagnosis was uncommon (55/1,863, 3.0%) and was mainly caused by Staphylococcus aureus, Klebsiella pneumoniae and Streptococcus pneumoniae. Hospital-acquired bacterial secondary infections, mostly caused by Staphylococcus aureus, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia, were diagnosed in 86 patients (4.6%). Severity-associated comorbidities were frequently observed in hospital-acquired secondary infection cases, including hypertension, diabetes, and chronic kidney disease. The study results suggest that the neutrophil-lymphocyte ratio (> 5.28) may be useful in diagnosing complications of respiratory bacterial infections. COVID-19 patients with community-acquired or hospital-acquired secondary infections had significantly increased mortality. CONCLUSIONS: Respiratory bacterial co-infections and secondary infections are uncommon in patients with COVID-19 but may worsen outcomes. Assessment of bacterial complications is important in hospitalized patients with COVID-19, and the study findings are meaningful for the appropriate use of antimicrobial agents and management strategies.

DOI： 10.1186/s12890-023-02418-3

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: Coronavirus disease (COVID-19) was severe in the Delta variant-dominated epidemic wave (fifth wave) in Japan. The clinical characteristics and effectiveness of COVID-19 vaccination are not fully understood in the Omicron variant-dominated wave (sixth and seventh waves), especially in hospitalized patients. We investigated the relationship between vaccination and disease severity in the Omicron-dominated wave and compared these variant-dominated waves. METHODS: The nationwide COVID-19 database (Japan COVID-19 Task Force) was used to compare clinical characteristics and critical outcome in patients hospitalized from Delta (5th, N=735) vs Omicron-dominated waves (6th, N=495; 7th, N=128). RESULTS: Patients in the sixth and seventh waves had a lower incidence of critical outcomes and respiratory outcomes, and a higher incidence of bacterial infection, although the mortality rate did not differ significantly between waves. In the sixth and seventh waves, 138 (27.9%) and 29 (22.7%) COVID-19 patients were unvaccinated, respectively. Multivariable analysis adjusted with previously reported factors revealed that the proportion of 1) critical outcomes and 2) respiratory outcomes decreased in a frequency-dependent manner; 1) (the number of vaccinations): 1-2 times, aOR 0.37 (95% CI; 0.20-0.69); 3-4 times: aOR 0.25 (95% CI; 0.11-0.58), 2) 1-2 times, aOR 0.43 (95% CI; 0.27-0.66); 3-4 times: aOR 0.36 (95% CI; 0.21-0.60). CONCLUSIONS: COVID-19 hospitalized patients with Omicron infections showed a lower incidence of critical outcomes than those with Delta infections, and COVID-19 vaccination may contribute to preventing respiratory failure.

DOI： 10.1016/j.ijid.2023.04.399

PubMed

Language：English  

DOI： 10.1021/acsmeasuresciau.2c00057

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

We investigated the association between complete blood count, including neutrophil-to-lymphocyte ratio (NLR) in combination with patient characteristics, and coronavirus disease (COVID-19) outcomes to identify the best prognostic indicator. We analyzed data of patients with confirmed COVID-19 from the nationwide database of the Japan COVID-19 Task Force between February 2020 and November 2021. A composite outcome was defined as the most severe condition, including noninvasive positive-pressure ventilation, high-flow nasal cannula, invasive mechanical ventilation, extracorporeal membrane oxygenation, or death. Of 2425 patients in the analysis, 472 (19.5%) experienced a composite outcome. NLR was the best predictor of composite outcomes, with an area under the curve (AUC) of 0.81, and a sensitivity and specificity of 72.3% and 75.7%, respectively, using a cut-off value of 5.04. The combination of NLR and an oxygen requirement on admission had the highest AUC (0.88). This simple combination may help identify patients at risk of progression to severe disease.

DOI： 10.1016/j.resinv.2023.03.007

PubMed

Language：English   Publisher：Journal of Infection and Chemotherapy  

Objectives: We investigated the occurrence of non-respiratory bacterial and fungal secondary infections, causative organisms, impact on clinical outcomes, and association between the secondary pathogens and mortality in hospitalized patients with coronavirus disease 2019 (COVID-19). Methods: This was a retrospective cohort study that included data from inpatients with COVID-19 from multiple centers participating in the Japan COVID-19 Taskforce (April 2020 to May 2021). We obtained demographic, epidemiological, and microbiological data throughout the course of hospitalization and analyzed the cases of COVID-19 complicated by non-respiratory bacterial infections. Results: Of the 1914 patients included, non-respiratory bacterial infections with COVID-19 were diagnosed in 81 patients (4.2%). Of these, 59 (3.1%) were secondary infections. Bacteremia was the most frequent bacterial infection, occurring in 33 cases (55.9%), followed by urinary tract infections in 16 cases (27.1%). Staphylococcus epidermidis was the most common causative organism of bacteremia. Patients with COVID-19 with non-respiratory secondary bacterial infections had significantly higher mortality, and a multivariate logistic regression analysis demonstrated that those with bacteremia (aOdds Ratio = 15.3 [5.97–39.1]) were at higher risk of death. Multivariate logistic regression analysis showed that age, male sex, use of steroids to treat COVID-19, and intensive care unit admission increased the risk for nosocomial bacteremia. Conclusions: Secondary bacteremia is an important complication that may lead to poor prognosis in cases with COVID-19. An appropriate medical management strategy must be established, especially for patients with concomitant predisposing factors.

DOI： 10.1016/j.jiac.2023.01.006

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DOI： 10.1016/j.celrep.2023.112212

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Language：English  

DOI： 10.1016/j.jaci.2023.03.014

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Authorship：Last author   Publisher：Surgical Innovation  

DOI： 10.1177/15533506231160201

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：English  

DOI： 10.1016/j.ijid.2022.12.019

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Authorship：Last author   Language：Japanese   Publisher：The Japan Society for Respiratory Endoscopy  

<p><b><i>Background.</i></b> Endobronchial ultrasonography with a guide sheath transbronchial biopsy (EBUS-GS TBB) was shown to be unsatisfactory for the diagnosis of pulmonary actinomycosis. The definitive diagnosis of pulmonary actinomycosis using EBUS-GS often necessitates penetration of the lesion to obtain samples. <b><i>Case.</i></b> A 52-year-old woman was referred to our hospital for the evaluation of an increase in nodules observed on chest computed tomography over 2 years prior to presentation. <b><i>Results.</i></b> A histopathological evaluation of specimens retrieved using EBUS-GS TBB revealed nonspecific findings, such as inflammatory cells. However, specimens retrieved via transbronchial needle aspiration through a guide sheath (GS-TBNA) using the PeriView FLEX device in addition to those obtained via EBUS-GS TBB showed necrotic tissue. Culture of tissue obtained using EBUS-GS TBB yielded <i>Actinomyces odontolyticus</i>. Based on these results, we diagnosed the lesion as pulmonary actinomycosis, and the patient was administered antibiotics, which led to the improvement of the lesion. <b><i>Conclusion.</i></b> GS-TBNA performed in addition to EBUS-GS TBB facilitated direct penetration of the lesion to obtain samples for an accurate diagnosis of pulmonary actinomycosis.</p>

DOI： 10.18907/jjsre.45.1_37

CiNii Research

Language：English  

DOI： 10.1371/journal.pone.0284806

PubMed

Language：English   Publisher：Cancer Medicine  

Background: The Cockcroft–Gault formula is commonly used as a substitute for glomerular filtration rate (GFR) in Calvert's formula for carboplatin dosing, where adjusting serum creatinine measured using the enzymatic method with 0.2 mg/dL has been suggested in Japan. However, the effects of these adjustments on efficacy in patients with non-small-cell lung cancer remain unknown. Methods: We conducted a post hoc analysis of the PREDICT1 study (CJLSG1201), a multicenter prospective observational trial of carboplatin–pemetrexed. Glomerular filtration rate values in Calvert's formula were back-calculated from the administered dosages of carboplatin and the reported value of the target area under the curve. We estimated the serum creatinine adjustments and divided the patients into crude and adjusted groups. Results: Patients in the crude group (N = 169) demonstrated similar efficacy to those in the adjusted group (N = 104) in progression-free survival (PFS) and overall survival (OS) (hazard ratio [HR], 1.02; 95% confidence interval [CI], 0.76–1.35; p = 0.916 vs. HR, 0.87; 95% CI, 0.65–1.17; p = 0.363), with higher grade 3–4 hematologic toxicity. Among patients aged ≥75 years, the crude group (N = 47) showed superior efficacy compared with the adjusted group (N = 17) in PFS and OS (HR, 0.37; 95% CI, 0.20–0.69; p = 0.002 vs. HR, 0.43; 95% CI, 0.23–0.82; p = 0.010). Conclusions: Serum creatinine adjustment may be associated with similar efficacy compared to the crude serum creatinine value. In older patients, the adjustment should be cautiously applied owing to the potential for reduced efficacy.

DOI： 10.1002/cam4.6235

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Language：English   Publisher：Respiratory Medicine Case Reports  

We present a case of 79-year-old female with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) developed an acute exacerbation (AE) triggered by coronavirus disease 2019 (COVID-19). The patient was unresponsive to a combination therapy of remdesivir, dexamethasone, and tocilizumab. Given that a recent multicenter cohort study reported ILD as a poor prognostic contributor in patients with RA and COVID-19, there may be potentially a certain number of patients with AE of RA-ILD triggered by COVID-19. This case highlights the need for a discussion how to treat these patients in a daily clinical practice.

DOI： 10.1016/j.rmcr.2023.101857

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Language：English   Publisher：Hypertension Research  

The effect of preexisting hypertension on coronavirus disease 2019 (COVID-19) prognosis remains controversial. Additionally, no studies have compared the association between blood pressure (BP) indices on admission and COVID-19 outcomes using preexisting hypertension status. Therefore, this study aimed to investigate the association between preexisting hypertension and COVID-19 outcomes in Japanese patients with COVID-19 and assess the impact of BP indices on admission on clinical outcomes in patients with and without preexisting hypertension. Preexisting hypertension presence was confirmed based on the patient’s clinical history. Critical outcomes were defined as high-flow oxygen use, non-invasive and invasive positive-pressure ventilation, extracorporeal membrane oxygenation, or death during hospitalization. Preexisting hypertension was observed in 64.6% of the patients. Multivariable logistic regression analysis of severe COVID-19 risk factors indicated that preexisting hypertension was independently associated with critical outcomes [adjusted odds ratio (OR): 1.35; 95% confidence interval (CI): 1.05–1.73]. Low or high BP and high pulse pressure on admission were associated with critical outcomes in patients without preexisting hypertension [OR for systolic BP < 100 mmHg: 2.13, 95% CI: 1.21–3.75; OR for high BP stage 2 (160–179 systolic and/or 100–109 mmHg diastolic BP): 2.13, 95% CI: 1.27–3.58; OR for pulse pressure ≥60 mmHg: 1.68, 95% CI: 1.14–2.48]. Preexisting hypertension is a risk factor for critical outcomes in Japanese patients with COVID-19. BP indices are useful biomarkers for predicting COVID-19 outcomes, particularly in patients without preexisting hypertension. Thus, hypertension history, systolic BP, and pulse pressure should be assessed to predict severe COVID-19 outcomes. [Figure not available: see fulltext.]

DOI： 10.1038/s41440-023-01490-w

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Language：English   Publisher：Journal of Chemotherapy  

Remdesivir is an antiviral drug for the treatment of coronavirus disease 2019 (COVID-19), and the sustained antiviral activity against Omicron variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been reported. In this single-center retrospective study, we first compared the clinical effectiveness of remdesivir-based therapy between Omicron and other variant phases of moderate COVID-19 in a real-world setting. Between Dec 2020 and July 2022, a total of 406 patients with COVID-19 pneumonia were treated with remdesivir-based therapy on admission. The oxygen deterioration rate after initiation of treatment significantly decreased in the Omicron variant phase compared to the alpha and delta variant phases. In an adjusted multivariate Cox proportional hazards model, Omicron variant phase was significantly associated with delayed oxygen deterioration and early recovery from hypoxia. These favorable outcomes during the Omicron variant phase, compared to previous variant phases, might be due to the attenuation and the popularization of vaccination.

DOI： 10.1080/1120009X.2023.2289268

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Language：English  

DOI： 10.1016/j.isci.2022.105596

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Language：English   Publisher：BMC infectious diseases  

BACKGROUND: We aimed to elucidate differences in the characteristics of patients with coronavirus disease 2019 (COVID-19) requiring hospitalization in Japan, by COVID-19 waves, from conventional strains to the Delta variant. METHODS: We used secondary data from a database and performed a retrospective cohort study that included 3261 patients aged ≥ 18 years enrolled from 78 hospitals that participated in the Japan COVID-19 Task Force between February 2020 and September 2021. RESULTS: Patients hospitalized during the second (mean age, 53.2 years [standard deviation {SD}, ± 18.9]) and fifth (mean age, 50.7 years [SD ± 13.9]) COVID-19 waves had a lower mean age than those hospitalized during the other COVID-19 waves. Patients hospitalized during the first COVID-19 wave had a longer hospital stay (mean, 30.3 days [SD ± 21.5], p < 0.0001), and post-hospitalization complications, such as bacterial infections (21.3%, p < 0.0001), were also noticeable. In addition, there was an increase in the use of drugs such as remdesivir/baricitinib/tocilizumab/steroids during the latter COVID-19 waves. In the fifth COVID-19 wave, patients exhibited a greater number of presenting symptoms, and a higher percentage of patients required oxygen therapy at the time of admission. However, the percentage of patients requiring invasive mechanical ventilation was the highest in the first COVID-19 wave and the mortality rate was the highest in the third COVID-19 wave. CONCLUSIONS: We identified differences in clinical characteristics of hospitalized patients with COVID-19 in each COVID-19 wave up to the fifth COVID-19 wave in Japan. The fifth COVID-19 wave was associated with greater disease severity on admission, the third COVID-19 wave had the highest mortality rate, and the first COVID-19 wave had the highest percentage of patients requiring mechanical ventilation.

DOI： 10.1186/s12879-022-07927-w

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Language：Japanese   Publisher：(株)北隆館  

新型コロナウイルス感染症(COVID-19)のパンデミック下で臨床研究を推進することは,最前線で診療にあたる臨床医や患者にとって負担が大きく,容易なことではない。筆者は,COVID-19の流行初期よりCOVID-19診療チームのサブリーダーとして診療に携わる一方で,このパンデミック下において,多くの臨床医や基礎研究者のサポートを得ながら,チームとしてCOVID-19の各種の多施設共同臨床研究にたずさわってきた。本稿では,筆者が関わってきたこれらの研究に関して紹介したい。(著者抄録)

Language：English   Publisher：Respiratory Research  

Background: Respiratory symptoms are associated with coronavirus disease 2019 (COVID-19) outcomes. However, the impacts of upper and lower respiratory symptoms on COVID-19 outcomes in the same population have not been compared. The objective of this study was to characterize upper and lower respiratory symptoms and compare their impacts on outcomes of hospitalized COVID-19 patients. Methods: This was a multicenter, retrospective cohort study; the database from the Japan COVID-19 Task Force was used. A total of 3314 COVID-19 patients were included in the study, and the data on respiratory symptoms were collected. The participants were classified according to their respiratory symptoms (Group 1: no respiratory symptoms, Group 2: only upper respiratory symptoms, Group 3: only lower respiratory symptoms, and Group 4: both upper and lower respiratory symptoms). The impacts of upper and lower respiratory symptoms on the clinical outcomes were compared. The primary outcome was the percentage of patients with poor clinical outcomes, including the need for oxygen supplementation via high-flow oxygen therapy, mechanical ventilation, and extracorporeal membrane oxygenation or death. Results: Of the 3314 COVID-19 patients, 605, 1331, 1229, and 1149 were classified as Group 1, Group 2, Group 3, and Group 4, respectively. In univariate analysis, patients in Group 2 had the best clinical outcomes among all groups (odds ratio [OR]: 0.21, 95% confidence interval [CI]: 0.11–0.39), while patients in Group 3 had the worst outcomes (OR: 3.27, 95% CI: 2.43–4.40). Group 3 patients had the highest incidence of pneumonia, other complications due to secondary infections, and thrombosis during the clinical course. Conclusions: Upper and lower respiratory tract symptoms had vastly different impacts on the clinical outcomes of COVID-19.

DOI： 10.1186/s12931-022-02222-3

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Language：English  

DOI： 10.1038/s41598-022-24157-x

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Language：Japanese   Publisher：(株)ライフメディコム  

Language：English   Publisher：Nature  

Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.

DOI： 10.1038/s41586-022-05163-5

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Language：English   Publisher：BMC Infectious Diseases  

Background: The clinical course of coronavirus disease (COVID-19) is diverse, and the usefulness of phenotyping in predicting the severity or prognosis of the disease has been demonstrated overseas. This study aimed to investigate clinically meaningful phenotypes in Japanese COVID-19 patients using cluster analysis. Methods: From April 2020 to May 2021, data from inpatients aged ≥ 18 years diagnosed with COVID-19 and who agreed to participate in the study were collected. A total of 1322 Japanese patients were included. Hierarchical cluster analysis was performed using variables reported to be associated with COVID-19 severity or prognosis, namely, age, sex, obesity, smoking history, hypertension, diabetes mellitus, malignancy, chronic obstructive pulmonary disease, hyperuricemia, cardiovascular disease, chronic liver disease, and chronic kidney disease. Results: Participants were divided into four clusters: Cluster 1, young healthy (n = 266, 20.1%); Cluster 2, middle-aged (n = 245, 18.5%); Cluster 3, middle-aged obese (n = 435, 32.9%); and Cluster 4, elderly (n = 376, 28.4%). In Clusters 3 and 4, sore throat, dysosmia, and dysgeusia tended to be less frequent, while shortness of breath was more frequent. Serum lactate dehydrogenase, ferritin, KL-6, d-dimer, and C-reactive protein levels tended to be higher in Clusters 3 and 4. Although Cluster 3 had a similar age as Cluster 2, it tended to have poorer outcomes. Both Clusters 3 and 4 tended to exhibit higher rates of oxygen supplementation, intensive care unit admission, and mechanical ventilation, but the mortality rate tended to be lower in Cluster 3. Conclusions: We have successfully performed the first phenotyping of COVID-19 patients in Japan, which is clinically useful in predicting important outcomes, despite the simplicity of the cluster analysis method that does not use complex variables.

DOI： 10.1186/s12879-022-07701-y

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Language：English   Publisher：International Journal of Infectious Diseases  

Objectives: This study aimed to identify the relationship between abnormal serum uric acid levels or a history of hyperuricemia and COVID-19 severity in the Japanese population. Methods: We included 1523 patients enrolled in the Japan COVID-19 Task Force cohort between February 2020 and May 2021. We compared the clinical characteristics, including co-morbidities, laboratory findings, and outcomes, particularly invasive mechanical ventilation (IMV), among patients with and without abnormal uric acid levels or a history of hyperuricemia. Results: Patients with high serum uric acid levels were older and had higher body weight and body mass index than those without. In addition, the multiple logistic regression analysis revealed a significant association between high serum uric acid levels or a history of hyperuricemia and an increased risk of IMV (odds ratio [OR] = 1.77; P = 0.03/OR = 1.56; P = 0.04). Moreover, patients with low uric acid levels on admission were also associated significantly with the requirement of IMV (OR = 5.09; P <0.0001). Conclusion: Abnormal serum uric acid levels or a history of hyperuricemia were significantly associated with COVID-19 severity in the Japanese cohort.

DOI： 10.1016/j.ijid.2022.07.014

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Language：Japanese   Publisher：日本VR医学会  

DOI： 10.24764/jsmvr.2022.0_27

CiNii Research

Language：English   Publisher：Journal of Cancer Research and Clinical Oncology  

Purpose: We determined the clinical relevance of early C-reactive protein (CRP) and neutrophil–lymphocyte ratio (NLR) change in blood as surrogate markers of pro-tumor inflammation (PTI) for predicting clinical outcome of programmed cell death (PD)-1/programmed cell death ligand (PD-L) 1 inhibitor treatment in non-small-cell lung carcinoma (NSCLC). Methods: We retrospectively reviewed NSCLC patients treated with anti-PD-1 or PD-L1 inhibitors. Early CRP change was defined as the ratio of 6 weeks CRP to baseline CRP, and early NLR change was defined as that of the 6 weeks NLR to baseline NLR. PTI index was determined by combinatorial evaluation of early CRP change and early NLR change, PTI index low: both of these were low, intermediate: either of these was low, high; both of these were high. Results: The study included 217 patients. Early CRP change and early NLR change were both associated with PFS and OS. The combinatorial evaluation using these two markers enabled the clear stratification of PFS and OS. The median PFS in patient with PTI index low was 13.9 months, while the median PFS in those with PTI index high was 2.5 months (p < 0.01, log-rank test). The median OS in patients with PTI index low was not reached; the median OS in those with PTI index high was only 15.4 months (p < 0.01, log-rank test). Conclusions: The combinatorial early CRP change and early NLR change as PTI biomarkers have clinical potential in identifying NSCLC patients who can achieve a durable response and long-term survival using PD-1/PD-L1 inhibitors.

DOI： 10.1007/s00432-022-04300-x

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Language：English   Publisher：Nature Communications  

Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection.

DOI： 10.1038/s41467-022-32276-2

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Language：English   Publisher：Nutrition and Diabetes  

Background: Obesity is reported to be a risk factor for severe disease in patients with coronavirus disease 2019 (COVID-19). However, there are no specific reports on the risk of severe disease according to body mass index (BMI) in Japan. Thus, this study aimed to investigate the effect of obesity stratified by BMI on the severity of COVID-19 in the general Japanese population. Methods: From February 2020 to May 2021, 1 837 patients aged ≥18 years were enrolled in the Japan COVID-19 Task Force. Patients with known BMI and disease severity were analyzed. Severity was defined as critical if the patient was treated in the intensive care unit, required invasive mechanical ventilation, or died. Results: Class 1 obesity (25.0 ≤ BMI < 30.0 kg/m2), class 2 obesity (30.0 ≤ BMI < 35.0 kg/m2), and class 3 or 4 obesity (BMI ≥ 35 kg/m2) were present in 29%, 8%, and 3% of the cases, respectively. Multiple logistic regression analysis with known risk factors for critical illness indicated that class 2 obesity was an independent risk factor for oxygenation (adjusted odds ratio, 4.75) and critical cases (adjusted odds ratio, 1.81). Class 1 obesity and class 3 or 4 obesity were independent risk factors for oxygen administration (adjusted odds ratios 2.01 and 3.12, respectively), but not for critical cases. However, no differences in the mortality rates were observed between the BMI classes (P = 0.5104). Conclusion: Obesity is a risk factor for respiratory failure in Japanese patients with COVID-19, regardless of the degree of obesity. However, it may not cause severe COVID-19 in a dose–response relationship with BMI. COVID-19 patients with mild obesity may benefit from aggressive intensive care.

DOI： 10.1038/s41387-022-00217-z

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Publisher：株式会社　医学書院  

DOI： 10.11477/mf.1437200567

CiNii Research

Language：Japanese   Publisher：(一社)日本結核・非結核性抗酸菌症学会  

Language：English   Publisher：BMC Pulmonary Medicine  

Background: Since nontuberculous mycobacterial pulmonary disease (NTM-PD) is common in middle-aged/elderly slender women at risk of osteoporosis, we hypothesized that NTM-PD could be associated with osteoporosis. The study aimed to evaluate the prevalence of osteoporosis in patients with NTM-PD compared with that in the general population and determine the factors associated with osteoporosis in the subjects, including the serum estradiol (E2) and 25-hydroxyvitamin D (25OHD) levels. Methods: We have recruited 228 consecutive adult patients with NTM-PD from a prospective cohort study at the Keio University Hospital, who had no history of osteoporosis or osteoporosis-associated bone fracture but underwent dual-energy X-ray absorptiometry-based bone mineral density (BMD) evaluation from August 2017–September 2019. The E2 and 25OHD levels were measured in 165 patients with available stored serum samples. We performed multivariable logistic regression analyses for osteopenia and osteoporosis. Results: Osteoporosis (T-score ≤ − 2.5) and osteopenia (T-score − 1 to − 2.5) were diagnosed in 35.1% and 36.8% of patients with NTM-PD, respectively. Compared with the general population, the proportion of osteoporosis was significantly higher in 50–59-, 60–69-, and 70–79-year-old women with NTM-PD. Multivariable analysis revealed that older age (adjusted odds ratio [aOR] for 1-year increase = 1.12; 95% confidence interval [CI] = 1.07–1.18), female sex (aOR = 36.3; 95% CI = 7.57–174), lower BMI (aOR for 1 kg/m2 decrease = 1.37; 95% CI = 1.14–1.65), and chronic Pseudomonas aeruginosa (PA) infection (aOR = 6.70; 95% CI = 1.07–41.8) were independently associated with osteoporosis. Additionally, multivariable analysis in 165 patients whose serum E2 and 25OHD levels were measured showed that both low E2 levels (< 10 pg/mL) and lower 25OHD levels were independently associated with osteoporosis. Conclusions: Middle-aged/elderly women with NTM-PD have a higher prevalence of osteoporosis than the general population. BMD screening should be considered in NTM-PD, especially in older females with severe diseases such as chronic PA infection and lower BMI, and low serum E2 and 25OHD levels.

DOI： 10.1186/s12890-022-01991-3

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：English   Publisher：Respiratory Research  

Background: Cigarette smoke (CS) is associated with chronic obstructive pulmonary disease (COPD) and cancer. However, the underlying pathological mechanisms are not well understood. We recently reported that mice exposed to long-term intermittent CS for 3 months developed more severe emphysema and higher incidence of adenocarcinoma than mice exposed to long-term continuous CS for 3 months and long-term continuous CS exposure activated alveolar stem cell proliferation. However, the influence of variations in the CS exposure pattern in alveolar stem cell in unknown. Here, we exposed mice to 3 weeks of continuous or intermittent CS to identify whether different CS exposure patterns would result in differential effects on stem cells and the mechanisms underlying these potential differences. Methods: Female mice expressing GFP in alveolar type 2 (AT2) cells, which are stem cells of the alveolar compartment, were exposed to mainstream CS via nasal inhalation. AT2 cells were collected based on their GFP expression by flow cytometry and co-cultured with fibroblasts in stem cell 3D organoid/colony-forming assays. We compared gene expression profiles of continuous and intermittent CS-exposed AT2 cells using microarray analysis and performed a functional assessment of a differentially expressed gene to confirm its involvement in the process using activator and inhibitor studies. Results: AT2 cells sorted from intermittent CS-exposed mice formed significantly more colonies compared to those from continuous CS-exposed mice, and both CS-exposed groups formed significantly more colonies when compared to air-exposed cells. Comparative microarray analysis revealed the upregulation of genes related to fatty acid oxidation (FAO) pathways in AT2 cells from intermittent CS-exposed mice. Treatment of intermittent CS-exposed mice with etomoxir, an inhibitor of the FAO regulator Cpt1a, for 5 weeks resulted in a significant suppression of the efficiency of AT2 cell colony formation. In vitro treatment of naïve AT2 cells with a FAO activator and inhibitor further confirmed the relationship between FAO and AT2 stem cell function. Conclusions: Alveolar stem cell function was more strongly activated by intermittent CS exposure than by continuous CS exposure. We provide evidence that AT2 stem cells respond to intermittent CS exposure by activating stem cell proliferation via the activation of FAO.

DOI： 10.1186/s12931-022-01948-4

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Language：Japanese   Publisher：(公財)大和証券ヘルス財団  

当院および関連病院14施設で確定診断したCOVID-19患者234例を対象として、次元の異なる生体情報(年齢・性別等の基本情報、症状、採血所見、画像情報など)を網羅的に集積した。また、回復者の症状の推移に関して患者へのアンケートを行った。得られた情報に関してデータクレンジングを行い、COVID-19の重症化例と非重症化例を比較した。多次元特徴解析を行って重症化の予測式を構築し、各患者の総合的な重症化リスクを発症初期の段階で提示することを目指した。その結果、ロジスティック回帰解析において精度89%で重症化と非重症化を予測できる式が得られた。重症化を早期に予測することにより、医療資源の最適化、早期治療介入が行え、死亡率低下につながると考えられた。

Language：English   Publisher：Scientific Reports  

Recently, an international randomized controlled clinical trial showed that patients with SARS-CoV-2 infection treated orally with the 3-chymotrypsin-like protease (3CLpro) inhibitor PF-07321332 within three days of symptom onset showed an 89% lower risk of COVID-19-related hospital admission/ death from any cause as compared with the patients who received placebo. Lending support to this critically important result of the aforementioned trial, we demonstrated in our study that patients infected with a SARS-Cov-2 sub-lineage (B.1.1.284) carrying the Pro108Ser mutation in 3CLpro tended to have a comparatively milder clinical course (i.e., a smaller proportion of patients required oxygen supplementation during the clinical course) than patients infected with the same sub-lineage of virus not carrying the mutation. Characterization of the mutant 3CLpro revealed that the Kcat/Km of the 3CLpro enzyme containing Ser108 was 58% lower than that of Pro108 3CLpro. Hydrogen/deuterium-exchange mass spectrometry (HDX-MS) revealed that the reduced activity was associated with structural perturbation surrounding the substrate-binding region of the enzyme, which is positioned behind and distant from the 108th amino acid residue. Our findings of the attenuated clinical course of COVID-19 in patients infected with SARS-CoV-2 strains with reduced 3CLpro enzymatic activity greatly endorses the promising result of the aforementioned clinical trial of the 3CLpro inhibitor.

DOI： 10.1038/s41598-022-05424-3

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Language：English   Publisher：Infection and Drug Resistance  

Background: Nontuberculous mycobacterial pulmonary disease (NTM-PD) often develops in patients with rheumatoid arthritis (RA), especially during immunosuppressive treatment, including biological disease-modifying antirheumatic drugs. NTM-PD is associated with airway lesions such as bronchiectasis, which is frequently seen in RA patients. Distinguishing which diseases cause the pulmonary lesion is difficult. However, there are limited reports of the development of RA during the follow-up of NTM-PD and how biological agents should be administered in these conditions, especially with cavitary lesions. Case Presentation: A 62-year-old woman with hemosputum was referred to our hospital, where she was diagnosed with Mycobacterium avium pulmonary disease. She began treatment with several antibiotics, including clarithromycin, ethambutol, rifampicin, and amikacin. In the course of treatment, M. avium became macrolide-resistant. Five years after beginning antibiotic treatment, she felt arthralgia in the fingers and wrists and had a high titer of rheumatoid factor and anticitrullinated peptide antibody, with which we diagnosed RA. Methotrexate, prednisolone, and iguratimod were subsequently admi-nistered, but the activity of RA gradually worsened. Meanwhile, M. avium changed to a macrolide-susceptible strain, her sputum smear results remained almost negative, and the NTM-PD disease was well controlled with antimicrobial therapy, despite her having cavitary lesions. Therefore, we started using CTLA4-Ig (abatacept). RA symptoms were substantially ameliorated. The pulmonary lesions and NTM-PD worsened mildly, but her pulmonary symptoms were stable. Conclusion: Physicians should be mindful of the etiologies of bronchiectasis, including RA, even in patients with a long-term history of treatment for bronchiectasis and NTM-PD. When NTM-PD is well controlled, even with remaining cavitary lesions, abatacept may be an option for patients with RA based on a comprehensive assessment of disease progression using NTM sputum smear/culture, computed tomography findings, and treatment response.

DOI： 10.2147/IDR.S343763

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Language：English   Publisher：Infection and Drug Resistance  

Purpose: Amikacin liposome inhalation suspension (ALIS), which efficiently allows amikacin to reach the pulmonary periphery for effect while minimising systemic adverse effects, was recently approved for treating Mycobacterium avium complex (MAC) infections. The international Phase 3 open-label clinical trials showed promising results, contributing to sputum culture conversion, but few studies have examined the efficacy and adverse effects of ALIS using real-world data. We identified the clinical outcome and adverse effects of ALIS in the early phase of treatment, for more effective and safe use in clinical practice. Patients and Methods: The study population consisted of patients with MAC lung disease (MAC-LD), introduced to ALIS therapy after July 2021 at Keio University Hospital due to poor response to multidrug therapy. The sputum smear/culture results, symptoms, adverse effects, and the serum amikacin concentrations of the early phase of ALIS inhalation therapy were examined. Results: A total of 11 patients (9 women; median age 64.6 years) were included in this study. The median disease duration of MAC-LD was 13.7 years, and all patients exhibited a positive culture at the beginning of ALIS inhalation. Three of the six patients (50.0%) who were initially sputum-smear-positive were confirmed to have become sputum-smear-negative within one month, including one culture conversion. ALIS inhalation therapy caused some adverse effects in nine patients (81.8%); however, no serious systemic adverse effects were observed. The most common adverse effect was hoarseness (72.7%), which mostly occurred around 1 week after initiation. The medians of peak serum amikacin concentrations were 1.4 and 2.3 μg/mL for the first and third inhalations, respectively. Trough serum concentrations just before the third inhalation were <1.2 μg/mL in all patients. Conclusion: ALIS therapy might be a treatment option for patients with refractory MAC infection with long disease duration and a poor response to guideline-based therapy.

DOI： 10.2147/IDR.S373783

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Authorship：Corresponding author   Language：English   Publisher：The Keio Journal of Medicine  

<p>Coronavirus disease 2019 (COVID-19) was first reported in Wuhan, China, in December 2019 as an outbreak of pneumonia of unknown origin. Previous studies have suggested the utility of chest computed tomography (CT) in the diagnosis of COVID-19 because of its high sensitivity (93%–97%), relatively simple procedure, and rapid test results. This study, performed in Japan early in the epidemic when COVID-19 prevalence was low, evaluated the diagnostic accuracy of chest CT in a population presenting with lung diseases having CT findings similar to those of COVID-19. We retrospectively included all consecutive patients (≥18 years old) presenting to the outpatient department of Keio University Hospital between March 1 and May 31, 2020, with fever and respiratory symptoms. We evaluated the performance of diagnostic CT for COVID-19 by using polymerase chain reaction (PCR) results as the reference standard. We determined the numbers of false-positive (FP) results and assessed the clinical utility using decision curve analysis. Of the 175 patients, 22 were PCR-positive. CT had a sensitivity of 68% and a specificity of 57%. Patients with FP results on CT diagnosis were mainly diagnosed with diseases mimicking COVID-19, e.g., interstitial lung disease. Decision curve analysis indicated that the clinical utility of CT imaging was limited. The diagnostic performance of CT for COVID-19 was inadequate in an area with low COVID-19 prevalence and a high prevalence of other lung diseases with chest CT findings similar to those of COVID-19. Considering this insufficient diagnostic performance, CT findings should be evaluated in the context of additional medical information to diagnose COVID-19.</p>

DOI： 10.2302/kjm.2021-0012-oa

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.2139/ssrn.4272351

Publisher：Nature  

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

DOI： 10.1038/s41586-021-03767-x

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Language：English   Publisher：International Journal of Infectious Diseases  

Background and design:: The coronavirus disease (COVID-19) pandemic is having a devastating effect worldwide. Host genome differences between populations may influence the severity of COVID-19. The Japan COVID-19 Task Force is conducting host genome analysis of hospitalized patients with COVID-19 from more than 70 institutions nationwide in Japan. This report describes the clinical characteristics of patients enrolled to date. Results:: The median (interquartile range) age of the 1674 patients included in the analysis was 59 (45–71) years, and more than half of the patients (66.2%) were male. Less than half of the patients (41.2%) had severe disease. The case fatality rate was 3.2%. Conclusions:: Since this is a hospital-based study, the number of severe cases was relatively high, but the case fatality rate was relatively low, when compared to that of other countries. In the future, we will continue to enroll patients and conduct genome analyses of patients with COVID-19.

DOI： 10.1016/j.ijid.2021.09.070

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Language：English   Publisher：(一社)日本臨床腎移植学会  

56歳男性。紫斑病性腎炎による慢性腎不全にてX-19年血液透析導入、同年血液型適合生体腎移植施行。維持免疫抑制剤はシクロスポリン(CyA)、ミコフェノール酸モフェチル(MMF)、プレドニゾロン(PSL)であった。X年に頭重感と微熱を主訴に来院、CTにて肺一部にすりガラス影を認め、鼻咽頭PCRにてSARS-CoV-2陽性となり緊急入院。MMF減量しファビピラビル、セフトリアキソン投与開始した。さらに抗生剤をタゾバクタム/ピペラシリンに、PSLをデキサメタゾンとしMMFを中止した。肺炎増悪したためメチルプレドニゾロン(mPSL)90mg/day投与、抗凝固療法開始しCyA減量した。呼吸状態増悪のため人工呼吸器管理としCyA中止、レムデシビル投与開始、腹臥位療法を施行した。一時血液透析を3回施行。徐々に酸素化は改善しmPSLは漸減とした。細菌性肺炎合併を疑い抗生剤をバンコマイシンとメロペネムとし、肺炎は改善した。下気道PCRにてSARS-CoV-2陰性を2回確認後CyA、MMFを再開し退院となった。(著者抄録)

Language：English   Publisher：American Journal of Physiology - Lung Cellular and Molecular Physiology  

The influenza virus infection poses a serious health threat worldwide. Myeloid cells play pivotal roles in regulating innate and adaptive immune defense. A disintegrin and metalloproteinase (ADAM) family of proteins contributes to various immune responses; however, the role of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) in influenza virus infection remains largely unknown. Herein, we investigated its role, focusing on myeloid cells, during influenza virus infection in mice. ADAM10 gene (Adam10)flox/flox/Lyz2-Cre (Adam10DLyz2) and control Adam10flox/flox mice were intranasally infected with 200 plaque-forming units of influenza virus A/H1N1/PR8/34. Adam10DLyz2 mice exhibited a significantly higher mortality rate, stronger lung inflammation, and a higher virus titer in the lungs than control mice. Macrophages and inflammatory cytokines, such as TNF-a, IL-1b, and CCL2, were increased in bronchoalveolar lavage fluid from Adam10DLyz2 mice following infection. CD11b+Ly6G-F4/80+ myeloid cells, which had an inflammatory monocyte/macrophage-like phenotype, were significantly increased in the lungs of Adam10DLyz2 mice. Adoptive transfer experiments suggested that these cells likely contributed to the poorer prognosis in Adam10DLyz2 mice. Seven days after infection, CD11b+Ly6G-F4/80+ lung cells exhibited significantly higher arginase-1 expression levels in Adam10DLyz2 mice than in control mice, whereas an arginase-1 inhibitor improved the prognosis of Adam10DLyz2 mice. Enhanced granulocyte-macrophage colony-stimulating factor (GM-CSF)/GM-CSF receptor signaling likely contributed to this process. Collectively, these results indicate that myeloid ADAM10 protects against influenza virus pneumonia and may be a promising therapeutic target.

DOI： 10.1152/ajplung.00619.2020

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Language：English   Publisher：BMJ Open Respiratory Research  

Introduction The rapid spread of COVID-19 posed a global burden. Substantial number of people died of the disease in the acute phase of infection. In addition, a significant proportion of patients have been reported to suffer from post-acute phase symptoms, sequelae of COVID-19, which may negatively influence the quality of daily living and/or socioeconomic circumstances of the patients. However, no previous study has comprehensively and objectively assessed the quality of life of patients by using existing international scales. Further, evidence of socioeconomic consequences among patients with COVID-19 is scarce. To address the multidimensional issues from sequelae of COVID-19, evidence from comprehensive surveys beyond clinical perspectives is critical that investigates health, and social determinants of disease progression as well as socioeconomic consequences at a large scale. Methods and analysis In this study, we plan to conduct a nationwide and comprehensive survey for the sequelae of COVID-19 in a total of 1000 patients diagnosed at 27 hospitals throughout Japan. This study will evaluate not only the health-related status of patients from clinical perspectives but also the Health-related Quality of Life (HRQoL) scores, socioeconomic status and consequences to discuss the sequelae of the disease and the related risk factors. The primary endpoint is the frequency of long-term complications of COVID-19 infection. The secondary endpoints are risk factors for progression to sequelae of COVID-19 infection. The study will provide robust and important evidence as a resource to tackle the issues from the sequelae of COVID-19 from the multi-dimensional perspectives. Ethics and dissemination This trial was approved by the Keio University School of Medicine Ethics Committee (20200243, UMIN000042299). The results of this study will be reported at a society meeting or published in a peer-reviewed journal.

DOI： 10.1136/bmjresp-2021-001015

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Publisher：南江堂  

DOI： 10.15106/j_naika128_828

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Language：English   Publisher：Annals of the American Thoracic Society  

Rationale: The clinical features and prognosis of nontuberculous mycobacterial (NTM) pleuritis and pleural effusion combined with NTM lung disease remain unclear. Objectives: To investigate the clinical features and prognosis of NTM pleuritis. Methods: This retrospective observational study included patients with NTM pleuritis from January 2001 to June 2018 across eight hospitals in Japan. NTM pleuritis was defined by a positive NTM culture of pleural effusion samples. We matched patients with Mycobacterium avium complex (MAC) lung disease (MAC-LD) without pleuritis by sex and age to obtain comparative data and investigated the association between clinical parameters and the prognosis. Results: We identified 64 patients with NTM pleuritis (median age, 73 yr; 37 female patients). The median follow-up duration was 11 months, and 27 patients died. Patients with MAC pleuritis had a significantly lower survival rate than matched patients with MAC-LD without pleuritis. Multivariate analysis revealed that pleuritis (adjusted hazard ratio, 6.99; 95% confidence interval [CI], 2.58–19.00) and underlying pulmonary diseases (adjusted hazard ratio, 3.01; 95% CI, 1.44–6.28) were independently associated with all-cause mortality in patients with MAC-LD. Conclusions: The prognosis of MAC pleuritis is poorer than that of MAC-LD without pleuritis. Pleuritis is an independent prognostic factor in patients with MAC-LD.

DOI： 10.1513/AnnalsATS.202008-938OC

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Language：English   Publisher：European Respiratory Journal  

Rationale Nontuberculous mycobacteria (NTM) are environmental mycobacteria that can cause a chronic progressive lung disease. Although epidemiological data indicate potential genetic predisposition, its nature remains unclear. Objectives We aimed to identify host susceptibility loci for Mycobacterium avium complex (MAC), the most common NTM pathogen. Methods This genome-wide association study (GWAS) was conducted in Japanese patients with pulmonary MAC and healthy controls, followed by genotyping of candidate single-nucleotide polymorphisms (SNPs) in another Japanese cohort. For verification by Korean and European ancestry, we performed SNP genotyping. Results The GWAS discovery set included 475 pulmonary MAC cases and 417 controls. Both GWAS and replication analysis of 591 pulmonary MAC cases and 718 controls revealed the strongest association with chromosome 16p21, particularly with rs109592 (p=1.64×10−13, OR 0.54), which is in an intronic region of the calcineurin-like EF-hand protein 2 (CHP2). Expression quantitative trait loci analysis demonstrated an association with lung CHP2 expression. CHP2 was expressed in the lung tissue in pulmonary MAC disease. This SNP was associated with the nodular bronchiectasis subtype. Additionally, this SNP was significantly associated with the disease in patients of Korean (p=2.18×10−12, OR 0.54) and European (p=5.12×10−03, OR 0.63) ancestry. Conclusions We identified rs109592 in the CHP2 locus as a susceptibility marker for pulmonary MAC disease.

DOI： 10.1183/13993003.02269-2019

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Publishing type：Research paper (scientific journal)   Publisher：Cold Spring Harbor Laboratory  

<jats:p>To elucidate the host genetic loci affecting severity of SARS-CoV-2 infection, or Coronavirus disease 2019 (COVID-19), is an emerging issue in the face of the current devastating pandemic. Here, we report a genome-wide association study (GWAS) of COVID-19 in a Japanese population led by the Japan COVID-19 Task Force, as one of the initial discovery GWAS studies performed on a non-European population. Enrolling a total of 2,393 cases and 3,289 controls, we not only replicated previously reported COVID-19 risk variants (e.g., <jats:italic>LZTFL1</jats:italic>, <jats:italic>FOXP4</jats:italic>, <jats:italic>ABO</jats:italic>, and <jats:italic>IFNAR2</jats:italic>), but also found a variant on 5p35 (rs60200309-A at <jats:italic>DOCK2</jats:italic>) that was significantly associated with severe COVID-19 in younger (&lt;65 years of age) patients with a genome-wide significant p-value of 1.2 × 10<jats:sup>-8</jats:sup> (odds ratio = 2.01, 95% confidence interval = 1.58-2.55). This risk allele was prevalent in East Asians, including Japanese (minor allele frequency [MAF] = 0.097), but rarely found in Europeans. Cross-population Mendelian randomization analysis made a causal inference of a number of complex human traits on COVID-19. In particular, obesity had a significant impact on severe COVID-19. The presence of the population-specific risk allele underscores the need of non-European studies of COVID-19 host genetics.</jats:p>

DOI： 10.1101/2021.05.17.21256513

Language：English   Publisher：Annals of the Rheumatic Diseases  

DOI： 10.1136/annrheumdis-2020-218157

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Language：English   Publisher：Respiratory Investigation  

The clinical course of coronavirus disease 2019 (COVID-19) varies from mild to critical. We retrospectively examined whether clinical and laboratory findings on admission could predict COVID-19 prognosis. Among various factors associated with COVID-19 severity, our results indicated that the real-time reverse transcription-polymerase chain reaction (RT-PCR) threshold cycle (Ct) values for severe acute respiratory syndrome coronavirus 2 were the most useful predictor of COVID-19 prognosis.

DOI： 10.1016/j.resinv.2020.12.011

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

当院の新型コロナウイルス感染症の診療状況について4月前後の第1波と6月以降の第2波で比較検討し、第2波で致死率が低下し重症化が抑制されていた。重症化マーカーである白血球数、CRP、フェリチン、LDH、D-dimerは酸素吸入を要する中等症・重症群で有意な上昇を認め、第2波では一部は有意な低下を呈したが、第1波と同等に高値である群が存在した。第2波では軽症から中等症への悪化は抑制されていないが、中等症から重症への悪化が抑制されており、レムデシビル(remdesivir)やデキサメタゾン(dexamethasone)などの治療の早期介入が寄与している可能性が考えられた。(著者抄録)

Language：English   Publisher：Arthritis and Rheumatology  

Objective: To identify immunologic factors in the lungs of patients with rheumatoid arthritis–associated interstitial lung disease (RA-ILD) and patients with idiopathic inflammatory myopathy–associated ILD (IIM-ILD) and to examine their pathologic mechanisms. Methods: Eleven patients with RA-ILD, 16 with IIM-ILD, 6 with drug-induced ILD (DI-ILD), and 8 healthy controls were enrolled. Peripheral blood (PB) and bronchoalveolar lavage (BAL) fluid were immunophenotyped by flow cytometry. Alveolar macrophages (AMs) were analyzed by coculture assay with PB naive CD4+ T cells from healthy individuals and RNA sequencing. Results: Several coinhibitory molecules were coexpressed on BAL fluid T cells (CTLA-4, programmed death 1 [PD-1], T cell immunoglobulin and mucin domain–containing protein 3 [TIM-3], and lymphocyte activation gene 3 protein, from most to least), whereas only PD-1 was expressed on PB T cells. CTLA-4+PD-1+CD4+ T cells were characteristic of RA-ILD, whereas CTLA-4+PD-1+TIM-3+CD8+ T cells were characteristic of IIM-ILD. BAL fluid PD-1+CD4+ T cells rarely expressed CXCR5, but their levels correlated with levels of plasmablasts and plasma cells (ρ = 0.57, P = 0.006), indicating that most of them would be considered peripheral helper T cells. In coculture experiments, AMs from patients with RA-ILD and IIM-ILD induced more PD-1 and TIM-3 on T cells (P < 0.05), suggesting that coinhibitory molecule expression on BAL fluid T cells was partly due to AMs. RNA sequencing showed significant down-regulation of PD ligand 1/2 genes in AMs from patients with RA-ILD compared to those with DI-ILD. Conclusion: We have identified differences in coinhibitory molecule expression between patients with RA-ILD and those with IIM-ILD. PD-1 on T cells in RA-ILD and TIM-3 on CD8+ T cells in IIM-ILD might be key factors in the disease process. Evaluation of coinhibitory molecules on BAL fluid T cells could be clinically useful.

DOI： 10.1002/art.41554

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Language：English   Publisher：Virology  

The pandemic of COVID-19 is still ongoing, and many studies on serum antibodies have been reported, however, there are few studies about asymptomatic and mild patients. In this study, we enrolled 44 COVID-19 patients with relatively mild disease and 48 pre-pandemic controls. We measured serum antibodies against extracellular domain, S1 domain, and receptor-binding domain of Spike and N protein, examined neutralization titers by authentic virus neutralization assay and newly-developed bead/cell-based Spike-ACE2 inhibition assay, and compared them with clinical features. Most of these antibodies, including neutralizing titers, were mutually correlated, and the production of antibodies were associated with low Ct values of PCR test, disease severity, symptoms especially pneumonia, lymphopenia, and serological test including CRP, LD, D-dimer, and procalcitonin. Notably, 87.5% of asymptomatic and 23.5% of mild patients did not have antibody against SARS-CoV-2. Our results revealed the inadequate acquisition of humoral immunity in patients with asymptomatic and mild COVID-19 patients.

DOI： 10.1016/j.virol.2020.12.020

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Language：English   Publisher：Journal of Clinical Pathology  

DOI： 10.1136/jclinpath-2020-206972

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Language：English   Publisher：CJC Open  

Thrombosis, especially venous thromboembolism, is a complication often associated with coronavirus disease 2019 (COVID-19). However, there have been relatively few reports of arterial thrombosis. Here, we describe a case of non-severe COVID-19 in a patient with dilated cardiomyopathy. After admission, symptoms, laboratory data, and imaging findings improved, but D-dimer levels gradually increased. Contrast computed tomography and echocardiography revealed a left ventricular thrombus. Anticoagulant treatment diminished the thrombus, and the patient recovered and was discharged. Although a left ventricular thrombus is a rare COVID-19 complication, performing appropriate diagnostic tests could improve COVID-19 mortality in patients with dilated cardiomyopathy.

DOI： 10.1016/j.cjco.2020.09.014

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Language：English   Publisher：Respirology  

Background and objective: The lack of useful biomarkers reflecting the disease state limits the management of Mycobacterium avium complex lung disease (MAC-LD). We clarified the associations between serum KL-6 level, disease progression and treatment response. Methods: Resected lung tissues from MAC-LD patients were immunostained for KL-6. We compared serum KL-6 levels between MAC-LD and healthy control or bronchiectasis patients without nontuberculous mycobacterial lung disease (NTM-LD). Serum KL-6 level was assessed in a prospective observational study at Keio University Hospital between May 2012 and May 2016. We investigated associations between serum KL-6 level and disease progression and treatment response in patients untreated for MAC-LD on registration (n = 187). Results: The KL-6+ alveolar type 2 cell population in the lung and serum KL-6 level were significantly higher in MAC-LD patients than in controls. Serum KL-6 level in bronchiectasis patients without NTM-LD showed no significant increase. Of the 187 patients who did not receive treatment on registration, 53 experienced disease progression requiring treatment. Multivariable Cox analysis revealed that the serum KL-6 level (aHR: 1.18, P = 0.005), positive acid-fast bacilli smear (aHR: 2.64, P = 0.001) and cavitary lesions (aHR: 3.01, P < 0.001) were significantly associated with disease progression. The change in serum KL-6 (ΔKL-6) was significantly higher in the disease progression group; it decreased post-treatment, reflecting the negative sputum culture conversion. Conclusion: Serum KL-6 level is associated with disease progression and treatment response. Longitudinal assessment combined with AFB smear status and presence of cavitary lesions may aid MAC-LD management.

DOI： 10.1111/resp.13886

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Language：English   Publisher：Respiratory Medicine  

Background: Although previous cross-sectional studies showed the feasibility and clinical association of the St. George's Respiratory Questionnaire (SGRQ) in Mycobacterium avium complex pulmonary disease (MAC-PD), its longitudinal validity is poorly understood. We aimed to determine the longitudinal validity and prognostic significance of SGRQ. Methods: In this prospective observational study conducted between May 2012 and August 2018, we evaluated 269 enrolled patients with MAC-PD and examined associations between baseline SGRQ total scores and mortality or clinical variables (anchors), including serum C-reactive protein levels and pulmonary function test results. Results: Age- and sex-matched SGRQ scores indicated significantly greater impairment in patients with MAC-PD than in the general population (P < 0.001). On multivariable Cox proportional hazards regression analysis, the SGRQ total score ≥25 was an independent risk factor for mortality (adjusted hazard ratio, 5.90; 95% confidence interval, 1.65–37.7) as well as age, body mass index, and forced vital capacity (FVC). Mixed-effect model results showed a significant association between SGRQ symptom/total scores and forced expiratory volume in 1 s (FEV1), FVC, and diffusing carbon monoxide capacity. Older age, a positive smear, non-nodular/bronchiectatic form, and cavity regions were associated with SGRQ total score deterioration. Patients with a greater decline from baseline FEV1 (% predicted) exhibited significantly worse impairment in the SGRQ total score (mean ± SE, 4.69 ± 10.9 points, P = 0.001). Conclusions: SGRQ showed longitudinal validity in assessing disease severity and was sensitive to changes in patients with MAC-PD, especially changes in %FEV1. The SGRQ total score may be an important prognostic factor.

DOI： 10.1016/j.rmed.2021.106515

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Language：English   Publisher：Respiratory Medicine Case Reports  

Acquired immunodeficiency in thymoma (Good's syndrome) without hypogammaglobulinemia is a rare condition. Here we describe the case of a 29-year-old Japanese woman with thymoma-associated T cell immunodeficiency after radiation therapy. She was admitted to the hospital with refractory pneumonia, which resulted from as T cell immunodeficiency, as revealed through low peripheral lymphocytes and oral candidiasis triggered through radiotherapy and required long-term antimicrobial therapy. Although radiotherapy is commonly administered for thymoma, our findings suggest that physicians should consider carrying out lymphocyte counts during thymoma treatment.

DOI： 10.1016/j.rmcr.2021.101408

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Publisher：Cold Spring Harbor Laboratory  

SARS-CoV-2 genome accumulates point mutations constantly. However, whether non-synonymous mutations affect COVID-19 severity through altering viral protein function remains unknown. SARS-CoV-2 genome sequencing revealed that the number of non-synonymous mutations correlated inversely with COVID-19 severity in Tokyo Metropolitan area. Phylogenic tree analyses identified two predominant groups which were differentiated by a set of six-point mutations (four non-synonymous amino acid mutations). Among them, Pro108Ser in 3 chymotrypsin-like protease (3CLpro) and Pro151Leu in nucleocapsid protein occurred at conserved locations among β-coronaviruses. Patients with these mutations (N = 48) indicated significantly lower odds ratio for developing hypoxia which required supplemental oxygen (odds ratio 0.24 [95% CI 0.07-0.88, p-value = 0.032]) after adjustments for age and sex, versus those lacking this haplotype in the canonical Clade 20B (N = 37). The Pro108Ser 3CLpro enzyme in vitro decreases in the activity by 58%, and the hydrogen/deuterium exchange mass spectrometry reveals that mechanisms for reduced activities involve structural perturbation at the substrate-binding region which is positioned behind and distant from the 108th amino acid residue of the enzyme. This mutant strain rapidly outcompeted pre-existing variants to become predominant in Japan. Our results may benefit the efforts underway to design small molecular compounds or antibodies targeting 3CLpro.

DOI： 10.1101/2020.11.24.20235952

Language：English   Publisher：Journal of Infection  

DOI： 10.1016/j.jinf.2020.08.052

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Language：English   Publisher：Respirology Case Reports  

Novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 is rapidly spreading worldwide. A typical clinical manifestation of COVID-19 is pneumonia, which can progress to acute respiratory distress syndrome and respiratory failure. Recent studies have reported that COVID-19 is often accompanied by coagulopathy, and a significant number of patients with severe or critical COVID-19 develop concomitant thrombosis, including pulmonary embolism (PE). However, there are limited reports of the incidence of PE in non-severe COVID-19 patients. Here, we report a case of non-severe COVID-19 complicated by PE, which indicates that the possibility of PE should consistently be considered, even in non-severe cases of COVID-19 without any risk of thrombosis.

DOI： 10.1002/rcr2.622

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Language：English   Publisher：International Journal of Infectious Diseases  

This study investigated, using cycle threshold (Ct) qPCR values, the association between symptoms and viral clearance in 57 patients with asymptomatic/mild SARS-CoV-2 infection. Patients with olfactory/taste disorders (OTDs) exhibited lower qPCR Ct values and longer time to negative qPCR than those without OTDs, suggesting an association between OTDs and high viral burden.

DOI： 10.1016/j.ijid.2020.07.034

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Language：English   Publisher：Respiratory Medicine  

Background: Although recent studies have identified anti-glycopeptidolipid (GPL)-core IgA antibodies as a serodiagnostic test for Mycobacterium avium complex lung disease (MAC-LD), this test shows insufficient sensitivity. This study aimed to determine the clinical utility of these antibodies in assessing disease progression and the clinical characteristics of MAC-LD patients with negative antibody results. Methods: We retrospectively reviewed the medical records of consecutive newly diagnosed, untreated MAC-LD patients in two referral hospitals. We evaluated the association of anti-GPL-core IgA antibody results with disease progression requiring treatment and the factors associated with negative antibody results. Results: In total, 229 patients (161 females; median age, 71 years; 185 with nodular/bronchiectatic disease phenotype; 69 with cavitary lesions) were enrolled; 146 patients (64%) were anti-GPL-core IgA antibody-positive. Radiological severity scores were associated with anti-GPL-core IgA antibody titers. During the median 364-day follow-up, 114 patients (49.8%) required treatment. Multivariate Cox proportional hazards analysis showed that positive anti-GPL-core IgA antibody results, a younger age, the absence of malignancy, and the presence of cavitary lesions were associated with disease progression requiring treatment. Multivariate logistic analysis revealed that significant factors related to the negative antibody results included underlying pulmonary disease, lower radiological scores, chronic sinusitis, and macrolide monotherapy. Conclusion: In addition to cavitary lesions, anti-GPL-core IgA antibody positivity was associated with disease progression requiring treatment. Physicians should carefully use anti-GPL-core IgA antibody results for the diagnosis of patients with underlying pulmonary disease, chronic sinusitis, macrolide monotherapy, and lower radiological severity.

DOI： 10.1016/j.rmed.2020.106086

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PubMed

Language：English   Publisher：American Journal of Respiratory Cell and Molecular Biology  

Chronic exposure to cigarette smoke (CS) causes chronic inflammation, oxidative stress, and apoptosis of epithelial cells, which results in destruction of the lung matrix. However, the mechanism by which the lung fails to repair the CS-induced damage, thereby succumbing to emphysema, remains unclear. Alveolar type 2 (AT2) cells comprise the stem cells of the alveolar compartments and are responsible for repairing and maintaining lung tissues. In this study, we examined the effect of chronic CS on AT2 stem cells. Adult mice expressing GFP in their AT2 cells were exposed to CS for > 3 months. Histological assessment showed that CS not only induced emphysematous changes but also increased the number of AT2 cells compared with that of air-exposed lungs. Assessment of sorted GFP1/AT2 cells via the stem cell three-dimensional organoid/colony-forming assay revealed that the number and size of the colonies formed by the CS-exposed AT2 stem cells were significantly higher than those of air-exposed control AT2 cells. Although CS-exposed lungs had more apoptotic cells, examination of the surviving AT2 stem cells in two-dimensional in vitro culture revealed that they developed a higher ability to resist apoptosis. Microarray analysis of CS-exposed AT2 stem cells revealed the upregulation of genes related to circadian rhythm and inflammatory pathways. In conclusion, we provide evidence that AT2 stem cells respond to chronic CS exposure by activating their stem cell function, thereby proliferating and differentiating faster and becoming more resistant to apoptosis. Disturbances in expression levels of several circadian rhythm-related genes might be involved in these changes.

DOI： 10.1165/rcmb.2019-0188OC

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PubMed

Language：Japanese   Publisher：(一社)日本結核・非結核性抗酸菌症学会  

Language：English   Publisher：Medicine  

INTRODUCTION: Pneumonia is one of the most important characteristics of coronavirus disease 2019 (COVID-19) and imaging findings of COVID-19 pneumonia are diverse and change over disease course. However, the detailed clinical course of organizing pneumonia (OP) caused by COVID-19 has not been clarified. PATIENT CONCERNS: A 60-year-old man and a 61-year-old woman diagnosed with mild COVID-19 were admitted to our hospital. Their respiratory symptoms were deteriorating even after initiating treatment with antiviral drugs. DIAGNOSIS: Chest X-rays and computed tomography scan showed a rapid progression of linear consolidation with reversed halo sign, distributed in subpleural and peri-bronchial regions. They also presented with pulmonary fibrosis findings, including traction bronchiectasis and marked lung volume reduction. They were diagnosed with rapidly progressing OP. INTERVENTIONS: They were treated with systemic corticosteroids. OUTCOMES: The patients' imaging findings and respiratory conditions improved rapidly without any adverse effects. CONCLUSION: Physicians should carefully monitor patients with COVID-19, as they can develop rapidly progressive and fibrotic OP, which respond to corticosteroids.

DOI： 10.1097/MD.0000000000021804

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PubMed

Language：English   Publisher：American Journal of Physiology - Lung Cellular and Molecular Physiology  

Pulmonary emphysema is a major manifestation of chronic obstructive pulmonary disease and is associated with chronic pulmonary inflammation caused by cigarette smoking, with contributions from immune cells such as neutrophils, macrophages, and lymphocytes. Although matrix metalloproteinases are well known to contribute to emphysema progression, the role of a disintegrin and metalloproteinase (ADAM) family proteins, other major metalloproteinases, in disease pathogenesis is largely unknown. ADAM17 is a major sheddase that cleaves various cell surface proteins, including CD62L, an adhesion molecule that plays a critical role in promoting the migration of immune cells to the site of inflammation. In the present study, we aimed to investigate the potential role of ADAM17 and CD62L in the development of elastase-induced emphysema. Control and Adam17flox/flox/Mx1-Cre(Adam17ΔMx1) mice (8-10 wk old) were intratracheally injected with 5 units of porcine pancreas elastase and monitored for 35 days after injection. Lung alveolar destruction was evaluated by analyzing the mean linear intercepts of lung tissue specimens and by histopathological examination. Mean linear intercepts data indicated that the degree of elastase-induced emphysema was significantly more severe in Adam17ΔMx1 mice. Furthermore, flow cytometry showed that CD62L+ neutrophil, CD62L+ macrophage, and CD62L+ B lymphocyte numbers were significantly increased in Adam17ΔMx1 mice. Moreover, the pharmacological depletion of CD62L+ cells with a CD62L-neutralizing antibody ameliorated the extent of emphysema in Adam17ΔMx1 mice. Collectively, these results suggest that ADAM17 possibly suppresses the progression of emphysema by proteolytically processing CD62L in immune cells and that ADAM17 and CD62L could be novel therapeutic targets for treating pulmonary emphysema.

DOI： 10.1152/ajplung.00214.2019

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DOI： 10.1136/annrheumdis-2020-eular.4542

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Language：English   Publisher：BMC Infectious Diseases  

After publication of the original article [1], we were notified that units of testosterone in main text and abstract and units of DHEA-S in Fig. 1 and Table 4 are incorrect. 1. In the Abstract: 'testosterone (0.230 ng/L vs. 0.250 ng/L, p = 0.005)' should be replaced with 'testosterone (0.230 ng/mL vs. 0.250 ng/mL, p = 0.005)' 2. In the section 'Serum levels of sex hormones': 'testosterone (0.23 ng/L vs. 0.25 ng/L, p = 0.005)' should be replaced with 'testosterone (0.23 ng/mL vs. 0.25 ng/mL, p = 0.005)' 3. The unit of serum DHEA-S, in Fig. 1 (3rd column): 'μg/mL' should be replaced with 'μg/dL' 4. unit of DHEA-S in Table 4 (4th row): 'μg/mL' should be replaced with 'μg/dL'.

DOI： 10.1186/s12879-020-4868-4

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Language：English   Publisher：Journal of Stem Cells and Regenerative Medicine  

The use of in vitro 3D organoid/colony forming assay (CFA); which mimics the in vivo environment have provided insight into the mechanisms by which lung stem cells maintain and repair the lung. In recent years, the use of CFA has markedly expanded. However, variations among laboratories in lung cell isolation methods, media used, type, origin, and processing methods of mesenchymal cells used as feeders for the epithelial colonies, and terms utilized to describe and quantify the growing colonies, have caused difficulty in reproducing results among different labs. In this study, we compared several previously described methods for lung cell isolation and culture media, to identify their influence on retrieved cells and growing colonies. We also characterized the effect of freeze/thaw, and propagation of fibroblasts on their ability to support epithelial colonies. Importantly, we suggested markers to identify fibroblast subtypes that offer the best support to alveolar stem cell proliferation. Then, we used our optimized assay to confirm the in vitro identity of recently described epithelial progenitors. We also tested the effect of hyperoxia on lung stem cells, and examined the expression of the receptors for the SARS-COV-2 virus entry into epithelial cells, on our organoids. In summary, our findings facilitate CFA standardization, help understand how niche cell variations influence growing colonies, and confirm some of the recently described lung stem cells.

DOI： 10.46582/jsrm.1602009

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Language：English   Publisher：BMC Infectious Diseases  

Background: The risk factors for Mycobacterium avium complex lung disease (MAC-LD) are not well known. We hypothesized that low serum estradiol (E2) levels are related to MAC-LD as most patients with MAC-LD are postmenopausal women. Methods: This cross-sectional study compared patients with MAC-LD and healthy controls. Study subjects were postmenopausal women aged 65 years or younger. Serum testosterone, dehydroepiandrosterone sulfate (DHEA-S), and E2 levels were measured and categorized as high or low based on median levels. We performed multivariate analysis, receiver operating characteristic (ROC) curve analysis, and age-and body mass index (BMI)-matched subgroup analysis to evaluate the association between low serum E2 levels and MAC-LD. Additionally, using blood samples obtained for other clinical studies, the levels of sex steroid hormones were compared between age-and BMI-matched MAC-LD and bronchiectasis female patients without non-tuberculosis mycobacterial infections (non-NTM BE). Results: Forty-two patients with MAC-LD and 91 healthy controls were included. The median E2 (2.20 pg/mL vs. 15.0 pg/mL, p < 0.001), testosterone (0.230 ng/L vs. 0.250 ng/L, p = 0.005), and DHEA-S (82.5 μg/dL vs. 114.0 μg/dL, p < 0.001) levels were lower in the MAC-LD group than in the control group. Multivariate analysis revealed that low serum E2 (adjusted odds ratio = 34.62, 95% confidence interval = 6.02-199.14) was independently related to MAC-LD, whereas low DHEA-S and testosterone were not. ROC analysis illustrated a strong relationship between low serum E2 levels and MAC-LD (area under the curve = 0.947, 95% confidence interval = 0.899-0.995). Even the age-and BMI-matched subgroup analysis of 17 MAC-LD patients and 17 healthy controls showed lower serum E2 in MAC-LD patients than in healthy controls. Additionally, serum E2 levels of 20 MAC-LD patients were lower than plasma E2 levels of 11 matched non-NTM BE patients (1.79 pg/mL vs. 11.0 pg/mL, p < 0.001). Conclusions: Low serum E2 levels were strongly related to MAC-LD in postmenopausal women.

DOI： 10.1186/s12879-019-4668-x

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DOI： 10.1183/13993003.congress-2019.PA3841

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Language：English   Publisher：Frontiers in Immunology  

Microfold (M) cells residing in the follicle-associated epithelium of mucosa-associated lymphoid tissues are specialized for sampling luminal antigens to initiate mucosal immune responses. In the past decade, glycoprotein 2 (GP2) and Tnfaip2 were identified as reliable markers for M cells in the Peyer's patches of the intestine. Furthermore, RANKL-RANK signaling, as well as the canonical and non-canonical NFκB pathways downstream, is essential for M-cell differentiation from the intestinal stem cells. However, the molecular characterization and differentiation mechanisms of M cells in the lower respiratory tract, where organized lymphoid tissues exist rarely, remain to be fully elucidated. Therefore, this study aimed to explore M cells in the lower respiratory tract in terms of their specific molecular markers, differentiation mechanism, and functions. Immunofluorescence analysis revealed a small number of M cells expressing GP2, Tnfaip2, and RANK is present in the lower respiratory tract of healthy mice. The intraperitoneal administration of RANKL in mice effectively induced M cells, which have a high capacity to take up luminal substrates, in the lower respiratory epithelium. The airway M cells associated with lymphoid follicles were frequently detected in the pathologically induced bronchus-associated lymphoid tissue (iBALT) in the murine models of autoimmune disease as well as pulmonary emphysema. These findings demonstrate that RANKL is a common inducer of M cells in the airway and digestive tracts and that M cells are associated with the respiratory disease. We also established a two-dimensional culture method for airway M cells from the tracheal epithelium in the presence of RANKL successfully. This model may be useful for functional studies of M cells in the sampling of antigens at airway mucosal surfaces.

DOI： 10.3389/fimmu.2019.01323

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Language：English   Publisher：Biochemical and Biophysical Research Communications  

Increasing evidence indicates that obesity is a risk factor for increased severity of influenza virus infection. However, its precise immunological mechanism is not fully understood. To investigate this, diet-induced obese (DIO)mice were established by feeding C57BL/6 male mice a high-fat diet for 16 weeks. DIO and lean control mice were infected intranasally with 3000 pfu of influenza A virus (IAV)(PR8/H1N1). Interestingly, we found adipose tissue located along the bronchus in naïve DIO mice. In addition, the Nos2 level was significantly higher and Arg1 level was significantly lower in lung macrophages of naïve DIO mice, consistent with an M1-skewed phenotype. The survival rate and body weight of DIO mice infected with IAV were significantly lower than those of lean control mice and associated with higher viral load in the lungs of DIO mice. Histopathological analysis demonstrated higher numbers of inflammatory cells in the lungs of DIO mice after IAV infection. Levels of cytokines, including TNF-α, IL-6, IL-10, and type I IFN (IFN-α and IFN-β), in bronchoalveolar lavage fluid (BALF)were altered after IAV infection; in particular, IFN-α and IFN-β levels were significantly suppressed in the BALF of DIO mice. In vitro, bone marrow-derived macrophages were stimulated with ligands of toll-like receptor (TLR)7/8, a pattern recognition receptor for single-stranded RNA, and levels of TNF-α, IL-6, and IL-10 were similarly altered. In addition, levels of IFN-α and IFN-β were significantly lower in culture supernatants of alveolar macrophages sorted from naïve DIO mice and infected with IAV, compared to those in macrophages sorted from lean control mice. Collectively, these results suggest that macrophages may be the main contributors to poor outcomes of influenza virus infection in obesity.

DOI： 10.1016/j.bbrc.2019.03.211

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Language：English   Publisher：PLoS ONE  

Background There is no proven management for mild cases of Mycobacterium avium complex (MAC) pulmonary disease, who do not immediately receive treatment and are managed with observation alone, because its long term-natural course, factors predictive of deterioration, and the effect of treating the disease remain unclear. Thus, we sought to investigate the natural course of mild cases of MAC pulmonary disease. Methods We conducted a multicenter retrospective study. Sixty-five patients with mild MAC pulmonary disease in whom treatment was withheld for at least 6 months after diagnosis were retrospectively recruited after a review of 747 medical records. Longitudinal changes in clinical features were evaluated by using a mixed effects model. Results Mean follow-up was 6.9 ± 5.7 years. During the follow-up period, 15 patients (23%) required treatment and 50 (77%) were managed with observation alone. At diagnosis, 65 patients had nodular bronchiectatic disease without fibrocavitary lesions. Among clinical features, mean body mass index (BMI), forced expiratory volume in 1 second as percent of forced vital capacity (%FEV 1 ), nodular lung lesions, and bronchiectasis worsened significantly in the observation group during follow-up. In the treatment group, BMI, and % FEV 1 were stable, but bronchiectasis significantly worsened. At diagnosis, the polyclonal MAC infection rate in the treatment group was higher than that in the observation group. Other microbiological factors, such as insertion sequences, did not differ significantly between the groups. Conclusions Mild MAC pulmonary disease progresses slowly but substantially without treatment. Treatment prevents the deterioration of the disease but not the progression of bronchiectasis. Polyclonal MAC infection is a predictor of disease progression.

DOI： 10.1371/journal.pone.0216034

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Language：English   Publisher：Open Forum Infectious Diseases  

Background. Sitafloxacin (STFX) exhibits potent activity against Mycobacterium avium complex (MAC) in both in vitro and in vivo experiments. However, limited data are available for the clinical efficacy and adverse effects of STFX and the susceptibility of refractory MAC lung disease (MAC-LD) to the drug. Therefore, this study was aimed at evaluating the clinical efficacy and safety of an STFX-containing regimen for the treatment of refractory MAC-LD. Methods. We retrospectively evaluated treatment outcomes of 31 patients with refractory MAC-LD, who received an STFXcontaining regimen for ≥4 weeks between January 2010 and July 2017. Refractory MAC-LD was defined as persistent positive sputum cultures for >6 months of macrolide-based standard therapy. Results. Clarithromycin resistance (minimum inhibitory concentration [MIC] ≥32 μg/mL) was identified in 15 patients (48%). Twelve months after receiving the STFX-containing regimen, 26% and 19% of patients showed symptomatic and radiological responses, respectively. Although STFX-associated adverse effects were noted in 9 patients, their severity was grade 1 (National Cancer Institute Common Terminology Criteria); only 1 patient discontinued STFX because of suspected gastrointestinal disturbance. Negative sputum culture conversion was achieved in 7 patients (23%). Both univariate and multivariate logistic regression analyses revealed that surgery, low STFX MIC (≤1 μg/mL), and macrolide resistance were significant predictors of negative sputum culture conversion. Conclusions. Our results demonstrate that STFX may be effective in one-fourth of patients with refractory MAC-LD. Prospective larger studies that include the analyses of MAC are needed to determine the clinical efficacy of STFX against refractory MAC-LD.

DOI： 10.1093/ofid/ofz108

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Language：English   Publisher：American Journal of Respiratory Cell and Molecular Biology  

Chemoattractant receptor homologous with T-helper cell type 2 cells (CRTH2), a receptor for prostaglandin D 2 , is preferentially expressed on T-helper cell type 2 lymphocytes, group 2 innate lymphoid cells, eosinophils, and basophils, and elicits the production of type 2 cytokines, including profibrotic IL-13. We hypothesized that lack of CRTH2 might protect against fibrotic lung disease, and we tested this hypothesis using a bleomycin-induced lung inflammation and fibrosis model in CRTH2-deficient (CRTH2 – / – ) or wild-type BALB/c mice. Compared with wild-type mice, CRTH2 – / – mice treated with bleomycin exhibited significantly higher mortality, enhanced accumulation of inflammatory cells 14–21 days after bleomycin injection, reduced pulmonary compliance, and increased levels of collagen and total protein in the lungs. These phenotypes were associated with decreased levels of IFN-g, IL-6, IL-10, and IL-17A in BAL fluid. Adoptive transfer of splenocytes from wild-type, but not CRTH2 – / – , mice 2 days before injection of bleomycin resolved the sustained inflammation as well as the increased collagen and protein accumulation in the lungs of CRTH2 – / – mice. We consider that the disease model is driven by gdT cells that express CRTH2; thus, the adoptive transfer of gdT cells could ameliorate bleomycin-induced alveolar inflammation and fibrosis.

DOI： 10.1165/rcmb.2017-0397OC

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PubMed

Language：English   Publisher：Journal of Infection and Chemotherapy  

Background: The optimal duration of antimicrobial therapy for Mycobacterium avium complex lung disease (MAC-LD) is unknown, and recurrence rates are high after treatment discontinuation. Intermittent therapy is recommended for the initial treatment of non-cavitary nodular/bronchiectatic MAC-LD. We hypothesized that intermittent maintenance therapy (IMT) could effectively prevent recurrence after successful treatment of MAC-LD. Methods: Adult patients diagnosed with MAC-LD who received IMT after successful daily therapy (DT) between January 1, 2006 and December 31, 2016 were identified from clinical databases at three institutions in Japan. Treatment outcomes were evaluated for all patients. Results: Of 38 patients (median age, 66 years; 29 women; nodular/bronchiectatic form, 29 patients) who received IMT after successful treatment, one was excluded due to death from an unknown cause, 1 month after IMT initiation. Finally, treatment outcomes were evaluated for 37 patients. Twenty-eight (76%) patients had sustained negative culture results over a median follow-up duration of 2.7 (interquartile range [IQR], 1.9–6.0) years, while six (16%) required switching to DT because of clinical deterioration over a median follow-up duration of 2.7 (IQR, 1.6–4.1) years. Favorable clinical outcomes were achieved for all patients who exhibited clinical deterioration. All patients tolerated the antimicrobials without discontinuation, and follow-up drug susceptibility testing showed negative results for clarithromycin-resistant MAC in the patients who experienced clinical deterioration. Conclusions: IMT after successful treatment may be a feasible option for patients with MAC-LD. Further studies should determine the population that would benefit from this strategy.

DOI： 10.1016/j.jiac.2018.07.021

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Language：English   Publisher：Respiratory Investigation  

Background: As lung cancer development in patients with nontuberculous mycobacterial lung disease (NTM-LD) has never been reported, we investigated its incidence and clinical characteristics. Methods: Prospective observational cohort registry (from June 2012 to June 2017), and retrospective identification by the International Classification of Diseases, tenth revision (between March 2010 and March 2018), were used to identify NTM-LD patients aged ≥20 years who developed lung cancer. Results: Eight patients (two men and six women, one with smoking history), having Mycobacterium avium complex lung disease (MAC-LD) were identified. Four were identified from retrospective chart reviews and four from the prospective observational cohort registry (n = 361, 289 women; 311 never-smokers). All patients underwent chest computed tomography (CT) at least once a year. The incidence rate of lung cancer developing in NTM-LD patients was 124.6 per 100,000 patient-years, which was higher than the lung cancer rate in Japan. The mean age at diagnosis of MAC-LD and lung cancer was 63.6 and 74.4 years, respectively. The most common lung cancer types were adenocarcinoma (six patients) followed by squamous cell carcinoma (two patients). Lung cancer was diagnosed at early and advanced clinical stages in seven and one patients, respectively. Outcomes were favorable, except in two patients: one with advanced stage disease, and another with poor performance status. Conclusions: We identified the clinical characteristics of eight MAC-LD patients who developed lung cancer. NTM-LD may be a risk factor for lung cancer development. Periodic follow-up with chest CT might contribute to early diagnosis and curative therapy for lung cancer.

DOI： 10.1016/j.resinv.2018.11.004

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Language：Japanese   Publisher：(一社)日本感染症学会  

Language：English   Publisher：BMC Pulmonary Medicine  

Background: In the Berlin definition, acute respiratory distress syndrome (ARDS) is stratified into three stages according to oxygenation severity at the onset. The relevance between ARDS severity and prognosis varies among published reports and has not been verified, especially in Asian patients. Methods: In this study, we examined the associations between the Berlin definition criteria and prognosis and clinical parameters, including high-resolution computed tomography (HRCT) scores of fibroproliferative changes of the lungs. One hundred fifty-three patients (45 females; mean age, 67 y/o), who met the Berlin definition and received treatment in our intensive care unit between January 2012 and December 2015, were enrolled. Results: The severity of ARDS was mild in 42 patients, moderate in 71, and severe in 40. The underlying diseases included pneumonia in 56 patients and aspiration in 43. Forty-two (27.5%) patients were deceased within 30 days, and the 30-day mortality was 10% in mild ARDS, 23% in moderate, and 55% in severe, which were significantly different (P < 0.05). In the non-survivors, APACHE II, SOFA, and SAPS II scores were higher than in the survivors (P < 0.001). Multivariate analyses revealed that elevated blood lactate level (≥ 2.0 mmol/L) and increased HRCT scores were significantly associated with weaning failure and 30-day mortality of the patients with ARDS. Conclusions: These results suggested that the severity criteria in the Berlin definition might be associated with the prognosis of the patients. Blood lactate levels and HRCT score might be predictive of the outcome of patients with ARDS.

DOI： 10.1186/s12890-019-0803-0

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Language：English   Publisher：Clinical Case Reports  

The images show the path of pancreatic pleural effusion from the pancreatic pseudocyst in a patient with alcoholic pancreatitis who presented with black pleural effusion, however, without symptoms. Pancreatic pseudocyst rupture rarely causes pleural effusion; however, it should be considered in patients with chronic pancreatitis with black pleural effusion.

DOI： 10.1002/ccr3.1994

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Language：English   Publisher：Journal of Tissue Engineering and Regenerative Medicine  

Ageing is associated with decreased lung function and an increased incidence of lung infections. Several studies have suggested that long-term calorie restriction (CR) promotes health and longevity and results in the reduced risk of several diseases. The effect of CR is thought to be through improving the function of tissue stem cells. Stem cell function is known to decline with ageing. In this study, we examined the effects of ageing on lung epithelial and stem cells and the effect of CR on young and old lungs. We found that ageing results in a decrease in tracheal basal stem cells. CR induced an increase in basal stem cells in both young and old mice. In addition, ageing induced lung inflammation, and CR tended to reduce baseline lung inflammatory cell infiltration in young mice and significantly reduced ageing-induced lung inflammation. Furthermore, ageing reduced the number and function of mitochondria in lung and increased the level of mitochondrial reactive oxygen species. CR increased the number and function of mitochondria both in young and old mice. Moreover, ageing reduced lung stem cell colony-forming efficiency (CFE), and CR increased the CFE in both young and old mice. Finally, CR improved epithelial cell survival in injured lungs of young mice. In conclusion, ageing causes several structural and functional changes/impairments in lung epithelial cells. CR induces several potentially beneficial changes in lung epithelial cells, even when it is initiated at an older age, including reversal of some ageing-induced changes.

DOI： 10.1002/term.2792

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Language：English   Publisher：New Microbes and New Infections  

This study describes a patient who experienced hepatobiliary Mycobacterium avium infection associated with neutralizing anti–interferon gamma (IFN-γ) autoantibodies during treatment for disseminated M. avium disease. Hepatobiliary M. avium infection should be considered in jaundiced patients with neutralizing anti–IFN-γ autoantibodies, including those receiving antimycobacterial therapy for disseminated M. avium disease.

DOI： 10.1016/j.nmni.2018.10.001

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Language：English   Publisher：Stem Cell Research  

High fat diet (HFD) decreases the lifespan of mice, and is a risk factor for several human diseases. Here, we investigated the effects of a HFD on lung epithelial and stem cells and its interaction with aging. Young and old mice were fed with either a standard diet (SD) or a HFD then their trachea and lung were examined for histological changes, inflammation, and mitochondrial function. Their stem cell function was examined using the in vitro organoid/colony forming efficiency (CFE) assay. Aging reduced the number of tracheal basal and alveolar type-2 (AT2) cells. HFD significantly increased the number of AT2 cells. Aging also caused a significant increase in lung inflammation, and HFD caused a similar increase, in young mice. Aging reduced mitochondrial mass and function, and increased reactive oxygen species. In young mice, HFD caused mitochondrial changes similar to the aging-induced changes. Organoid culture of tracheal and lung epithelial cells collected from both young and old HFD-fed mice showed higher CFE compared to SD-fed mice. Switching the HFD to low calorie/fat diet (LCD) efficiently reversed several of the HFD-induced effects. Thus, HFD induces several histological, inflammatory, and functional changes in the lung, and exacerbates the aging-induced lung inflammation and mitochondrial deterioration. LCD can reverse many of the HFD-induced effects.

DOI： 10.1016/j.scr.2018.10.006

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Language：English   Publisher：Respiratory Medicine  

Background and objective: No reports exist regarding skeletal muscle involvement in patients with Mycobacterium avium complex lung disease (MAC-LD). The cross-sectional area of the erector spinae muscles (ESMCSA) reflects physical activity and can be assessed by computed tomography (CT). We investigated the relationship between ESMCSA and physiological parameters and prognosis in MAC-LD patients. Material and methods: In this prospective observational study, the ESMCSA was measured on single-slice axial CT images. MAC-LD patients and sex- and age-matched controls (non-MAC-LD participants) were evaluated. We evaluated the relationship between the ESMCSA and physiological parameters and prognosis. Results: A total of 260 patients (209 female; median age, 69 years; 190 with nodular/bronchiectatic disease; 74 with cavitary lesions) were enrolled. The ESMCSA was not different between MAC-LD patients and controls. In MAC-LD patients, the ESMCSA was significantly associated with age, body mass index (BMI), pulmonary function, CT severity, and health-related quality of life (HRQL). Multivariate Cox proportional hazards analyses revealed that an ESMCSA < −1 standard derivation (hazards ratio [HR], 2.76; P = 0.047) was significantly associated with all-cause mortality, along with BMI < 18.5 kg/m2 (HR, 3.67; P = 0.02) and presence of cavitary lesions (HR, 5.84; P = 0.001). However, the ESMCSA was not significantly associated with all-cause mortality when current treatment status, % predicted functional vital capacity, and forced expiratory volume in 1 s were added to the analyses. Conclusions: Although the prognostic impact was limited, ESMCSA was significantly associated with HRQL and prognostic physiological parameters, such as BMI and pulmonary function.

DOI： 10.1016/j.rmed.2018.10.023

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PubMed

Language：English   Publisher：Mucosal Immunology  

Sphingolipids play a pivotal role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, little is known about the precise roles of sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite, and its receptor modulation in COPD. In this study, we demonstrated that the S1P receptor modulator ONO-4641 induced the expansion of lung CD11b+Gr-1+ cells and lymphocytopenia in naive mice. ONO-4641-expanded CD11b+Gr-1+ cells showed higher arginase-1 activity, decreased T cell proliferation, and lower IFN-γ production in CD3+ T cells, similar to the features of myeloid-derived suppressor cells. ONO-4641 treatment decreased airspace enlargement in elastase-induced and cigarette smoke-induced emphysema models and attenuated emphysema exacerbation induced by post-elastase pneumococcal infection, which was also associated with an increased number of lung CD11b+Gr-1+ cells. Adoptive transfer of ONO-4641-expanded CD11b+Gr-1+ cells protected against elastase-induced emphysema. Lymphocytopenia observed in these models likely contributed to beneficial ONO-4641 effects. Thus, ONO-4641 attenuated murine pulmonary emphysema by expanding lung CD11b+Gr-1+ cell populations and inducing lymphocytopenia. The S1P receptor might be a promising target for strategies aimed at ameliorating pulmonary emphysema progression.

DOI： 10.1038/s41385-018-0077-5

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DOI： 10.1183/13993003.congress-2018.PA4267

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DOI： 10.1183/13993003.congress-2018.PA355

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Language：English   Publisher：American Journal of Respiratory and Critical Care Medicine  

DOI： 10.1164/rccm.201801-0173IM

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PubMed

Publisher：(株)ヴァンメディカル  

DOI： 10.34426/j03177.2019012928

CiNii Research

Language：English   Publisher：BMC Pulmonary Medicine  

Background: Pulmonary nocardiosis frequently develops as an opportunistic infection in cell-mediated immunosuppressive patients, and sometimes requires differentiation from pulmonary malignancy. Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is a neoplastic disorder which leads to impaired cell-mediated immunity, and is commonly associated with small cell lung cancer (SCLC). Because pulmonary infection and causative malignancy can appear as pulmonary lesions with EAS, differentiation of these diseases remains a critical issue for physicians. Case presentation: A 52-year-old woman with progressive lower limb paralysis and general fatigue was referred to us. She had been diagnosed with olfactory neuroblastoma (ONB) and treated with surgery and radiation therapy 10 years before the referral and had required stereotactic radiosurgery and chemotherapy 4 years later for a relapse of the ONB. On referral, she presented with Cushing's syndrome with elevated cortisol and ACTH levels. Potassium supplement improved her symptoms; however, a month later, she was urgently hospitalized due to acute pleuritic chest pain on inspiration. Chest computed tomography revealed left lower lobular consolidations and a contralateral nodule in the right middle lobe. The clinical history and laboratory work-up suggested that her Cushing's syndrome had most likely arisen from EAS. Additionally, the lungs were suspected as the ACTH source due to high levels of progastrin-releasing peptide and progressive pulmonary consolidation with a contralateral nodule, suggesting SCLC. However, histological examination from bronchoscopy revealed no evidence of malignancy, and Nocardia cyriacigeorgica was isolated from bronchoalveolar lavage fluid. Sulfamethoxazole/trimethoprim improved her pulmonary lesions. Somatostatin receptor scintigraphy revealed strong tracer uptake in the ONB lesions, indicating that the origin of the EAS was the olfactory tumor. However, histological examination of ONB specimens resected 10 years earlier showed no intracytoplasmic immunopositivity for ACTH. Conclusions: We highlight a rare case of pulmonary nocardiosis, which was associated with EAS mimicking SCLC, and was related to ONB transformation. Nocardiosis has to be considered even though anamnestic, clinical, and radiological aspects suggest the presence of metastasis. Additionally, physicians should carefully monitor patients with ONB for the development of Cushing's symptoms because the tumor can transform into an ACTH-producing form, even after long-term follow-up.

DOI： 10.1186/s12890-018-0710-9

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Language：English   Publisher：BMC Pulmonary Medicine  

Background: Pulmonary Mycobacterium avium complex (pMAC) disease is a chronic, slowly progressive disease. The aim of the present study was to determine the association of six-minute walk test (6MWT) parameters with pulmonary function and the health-related quality of life (HRQL) in patients with pMAC disease. Methods: This cross-sectional study included adult patients with pMAC and was conducted at Keio University Hospital. We investigated the relationship of 6MWT parameters with clinical parameters, including pulmonary function, and HRQL, which was assessed using the 36-Item Short Form Health Survey (SF-36) and St. George's Respiratory Questionnaire (SGRQ). Results: In total, 103 consecutive patients with pMAC participated in 6MWT (median age, 64 years; 80 women) and completed SF-36 and SGRQ. The six-minute walk distance (6MWD) showed significant negative and positive correlations with all SGRQ domain scores [ρ = (- 0.54)-(- 0.32)] and the physical component summary (PCS) score (ρ = 0.39) in SF-36, respectively; the opposite was observed for the final Borg scale (FBS) score (all SGRQ scores, ρ = 0.34-0.58; PCS score, ρ = - 0.50). The distance-saturation product showed significant negative and positive correlations with all SGRQ scores [ρ = (- 0.29)-(- 0.55)] and the PCS score (ρ = 0.40), respectively. Multivariate analysis revealed that 6MWD and the FBS score were significant predictors of HRQL. Conclusions: Our findings suggest that 6MWD and the FBS score are useful parameters for evaluating HRQL in patients with pMAC. Further studies should investigate the impact of 6WMT parameters on disease progression, treatment responses, and prognosis.

DOI： 10.1186/s12890-018-0686-5

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Language：English   Publisher：QJM  

DOI： 10.1093/qjmed/hcy008

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PubMed

Language：English   Publisher：International Journal of Tuberculosis and Lung Disease  

Background: Little is known about the clinical characteristics and health-related quality of life (HQOL) of elderly patients with pulmonary Mycobacterium avium complex (pMAC) disease. Objectives : To evaluate HQOL using the 36-Item Short-Form Health Survey and St George's Respiratory Questionnaire (SGRQ) and to investigate the predictors of HQOL changes among elderly patients with pMAC disease. Methods : This prospective cohort registry was conducted at Keio University Hospital, Tokyo, Japan, between May 2012 and July 2015 and included 84 patients with pMAC disease aged ≥75 years who had completed the HQOL questionnaire and 48 patients with pMAC disease who had been followed up and completed the HQOL questionnaire in cross-sectional and longitudinal analyses, respectively. Results : In cross-sectional analyses, elderly patients with pMAC disease had significantly lower rolephysical, general health, vitality, social functioning, role-emotional and role/social component scores than the general Japanese elderly population. Analysis of covariance revealed that patients with cavitary lesions had significantly worse physical functioning and SGRQ scores (P < 0.05). Longitudinal analysis showed that under-treatment, short duration of disease and positive sputum smear at baseline were predictors of worse HQOL at 12 months. Conclusions : Elderly patients with pMAC disease have reduced HQOL. Further large studies on HQOL are required to refine the use of this parameter in the treatment of these patients.

DOI： 10.5588/ijtld.17.0433

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Language：English   Publisher：Clinical Microbiology and Infection  

DOI： 10.1016/j.cmi.2017.12.018

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Language：English   Publisher：Respiratory Medicine  

Rationale: Little is known about the role of Aspergillus precipitating antibody (APAb) in patients with Mycobacterium avium complex lung disease (MAC-LD). Objectives: We investigated the clinical characteristics of patients with MAC-LD positive for APAb. Methods: We conducted a cross-sectional study targeting patients with MAC-LD. APAb was checked in all participants. Clinical variables included laboratory data, pulmonary function, high-resolution computed tomography findings, and health-related quality of life. Results: We analyzed 109 consecutive patients. Their median age was 68 years, and the median duration of MAC-LD was 4.8 years. Twenty (18.3%) patients tested positive for APAb. APAb-positive patients had significantly longer duration of MAC-LD (9.4 vs. 4.0 years, P = 0.017), more severe bronchiectasis evaluated by modified Reiff score (6.5 vs. 4, P = 0.0049), and lower forced expiratory volume in 1 s (%FEV1) (75.1% vs. 86.2%, P = 0.013) than APAb-negative patients. Analysis of covariance adjusted for background factors and underlying pulmonary disease revealed that %FEV1 was also significantly lower in patients with APAb (P = 0.045). Ten patients were newly diagnosed with chronic pulmonary aspergillosis (N = 5) or allergic bronchopulmonary aspergillosis (N = 5). Conclusions: APAb is associated with lower pulmonary function, and observed especially in patients with longer duration of MAC-LD and severe bronchiectasis, even in the absence of cavitary lesions.

DOI： 10.1016/j.rmed.2018.03.013

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Language：English   Publisher：QJM  

DOI： 10.1093/qjmed/hcx233

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Language：English   Publisher：PLoS Pathogens  

Macrolides are used to treat various inflammatory diseases owing to their immunomodulatory properties; however, little is known about their precise mechanism of action. In this study, we investigated the functional significance of the expansion of myeloid-derived suppressor cell (MDSC)-like CD11b+Gr-1+cells in response to the macrolide antibiotic clarithromycin (CAM) in mouse models of shock and post-influenza pneumococcal pneumonia as well as in humans. Intraperitoneal administration of CAM markedly expanded splenic and lung CD11b+Gr-1+cell populations in naïve mice. Notably, CAM pretreatment enhanced survival in a mouse model of lipopolysaccharide (LPS)-induced shock. In addition, adoptive transfer of CAM-treated CD11b+Gr-1+cells protected mice against LPS-induced lethality via increased IL-10 expression. CAM also improved survival in post-influenza, CAM-resistant pneumococcal pneumonia, with improved lung pathology as well as decreased interferon (IFN)-γ and increased IL-10 levels. Adoptive transfer of CAM-treated CD11b+Gr-1+cells protected mice from post-influenza pneumococcal pneumonia. Further analysis revealed that the CAM-induced CD11b+Gr-1+cell expansion was dependent on STAT3-mediated Bv8 production and may be facilitated by the presence of gut commensal microbiota. Lastly, an analysis of peripheral blood obtained from healthy volunteers following oral CAM administration showed a trend toward the expansion of human MDSC-like cells (Lineage−HLA-DR−CD11b+CD33+) with increased arginase 1 mRNA expression. Thus, CAM promoted the expansion of a unique population of immunosuppressive CD11b+Gr-1+cells essential for the immunomodulatory properties of macrolides.

DOI： 10.1371/journal.ppat.1006955

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Language：English   Publisher：Cytotherapy  

Background: Pneumonia is the fourth leading cause of death worldwide, and Streptococcus pneumoniae is the most commonly associated pathogen. Increasing evidence suggests that mesenchymal stromal cells (MSCs) have anti-inflammatory roles during innate immune responses such as sepsis. However, little is known about the effect of MSCs on pneumococcal pneumonia. Methods: Bone marrow–derived macrophages (BMDMs) were stimulated with various ligands in the presence or absence of MSC-conditioned medium. For in vivo studies, mice intranasally-inoculated with S. pneumoniae were intravenously treated with MSCs or vehicle, and various parameters were assessed. Results: After stimulation with toll-like receptor (TLR) 2, TLR9 or TLR4 ligands, or live S. pneumoniae, TNF-α and interleukin (IL)–6 levels were significantly decreased, whereas IL-10 was significantly increased in BMDMs cultured in MSC-conditioned medium. In mice, MSC treatment decreased the number of neutrophils in bronchoalveolar lavage fluid (BALF) after pneumococcal infection, and this was associated with a decrease in myeloperoxidase activity in the lungs. Levels of proinflammatory cytokines, including TNF-α IL-6, GM-CSF and IFN-γ were significantly lower in MSC-treated mice, and the bacterial load in the lung after pneumococcal infection was significantly reduced. In addition, histopathologic analysis confirmed a decrease in the number of cells recruited to the lungs; however, lung edema, protein leakage into the BALF and levels of the antibacterial protein lipocalin 2 in the BALF were comparable between the groups. Conclusions: These results indicate that MSCs could represent a potential therapeutic application for the treatment of pneumonia caused by S. pneumoniae.

DOI： 10.1016/j.jcyt.2018.01.003

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Language：English   Publisher：International Journal of Infectious Diseases  

Background Mycobacterium lentiflavum is a slow-growing non-tuberculous Mycobacterium that is often associated with an immunocompromised state and cervical lymphadenitis in young children. However, little is known about the clinical importance of pulmonary infection with M. lentiflavum in adults. Methods The medical records of all adults who met the diagnostic criteria of pulmonary M. lentiflavum disease at Keio University Hospital and Fukujuji Hospital from 2001 to 2015 were reviewed. In addition, the PubMed database was searched to identify further reported cases in non-HIV adults. Results Five cases of pulmonary M. lentiflavum disease were identified in the medical records search and 11 additional cases were identified in the literature review. Eleven of the total 16 cases were female, and 15 of 16 cases showed a nodular/bronchiectatic pattern on chest computed tomography imaging. No cases showed an aggressive clinical course of pulmonary M. lentiflavum disease, although one patient died of an exacerbation of underlying vasculitis and bacterial pneumonia. Conclusions The clinical characteristics of pulmonary M. lentiflavum disease in adult patients were identified. This disease mainly affects females, displays a nodular/bronchiectatic pattern on chest computed tomography imaging, and does not demonstrate an aggressive clinical course. Further larger studies are needed to reveal detailed clinical features.

DOI： 10.1016/j.ijid.2017.12.001

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Language：English   Publisher：BMC Infectious Diseases  

Background: Presence of Mycobacterium fortuitum in respiratory tracts usually indicates mere colonization or transient infection, whereas true pulmonary infection occurs in patients with gastroesophageal disease. However, little is known about the diagnostic indications for true M. fortuitum pulmonary infection and the natural history of the disease. Case presentation: A 59-year-old man was referred to our hospital for treatment against M. fortuitum pulmonary infection. Fifteen years before the referral, he underwent total gastrectomy, after which he experienced esophageal reflux symptoms. After the referral, the patient was closely monitored without antimicrobial therapy because of mild symptoms and no pathological evidence of M. fortuitum pulmonary infection. During the observation, chest imaging showed migratory infiltrates. Two years after the referral, his lung biopsy specimen revealed foamy macrophages and multinucleated giant cells, indicating lipoid pneumonia. However, he was continually monitored without any treatment because there was no evidence of nontuberculous mycobacterial infection. Four years after the referral, he developed refractory pneumonia despite receiving adequate antibiotic therapy. After confirmation of granulomatous lesions, multiple antimicrobial therapy for M. fortuitum resulted in a remarkable improvement with no exacerbation for over 5 years. Random amplified polymorphic DNA polymerase chain reaction analysis revealed identical M. fortuitum strains in seven isolates from six sputum and one intestinal fluid specimens obtained during the course of the disease. Conclusions: We have described a patient with M. fortuitum pulmonary infection who presented with migratory infiltrates. The pathological evidence and microbiological analysis suggested that M. fortuitum pulmonary infection was associated with lipoid pneumonia and chronic exposure to gastrointestinal fluid. Therefore, physicians should carefully monitor patients with M. fortuitum detected from lower respiratory tract specimens and consider antimicrobial therapy for M. fortuitum infection when the patient does not respond to adequate antibiotic therapy against common pneumonia pathogens.

DOI： 10.1186/s12879-017-2892-9

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Language：English   Publisher：BMC Pulmonary Medicine  

Background: In bronchiectasis patients, chronic Pseudomonas aeruginosa (PA) infection has been associated with worse health-related quality of life (HRQL), but little is known about Mycobacterium avium complex lung disease (MACLD) patients in this context. This study aimed to evaluate HRQL and investigate the impact of chronic PA infection in MACLD patients. Methods: This cross-sectional study was conducted using the Registry of Prospective Cohort Study including MACLD patients. The 36-item Short-Form health survey (SF-36) and St. George's Respiratory Questionnaire (SGRQ) were administered to assess clinical outcomes. Clinical variables included treatment and sputum culture status, pulmonary function tests, cavitary lesions, and modified Reiff scores on high-resolution computed tomography. Results: The study included 244 MACLD patients (median age, 68 years; 196 women), 19 of whom had chronic PA infection. Modified Reiff score was higher in patients with chronic infection than in those without (P=0.028). Regarding SF-36 scores, physical functioning subscale scores were significantly lower in patients with chronic infection (P=0.029). Additionally, SGRQ symptoms, impact, and total scores were significantly higher in patients with chronic infection. During analysis of covariance comparisons, SGRQ symptoms and impact scores were significantly higher for patients with chronic infection (P=0.043 and 0.021, respectively). Conclusions: MACLD patients with chronic PA infection exhibited significantly higher SGRQ scores, indicating impaired HRQL. Chronic PA infection was significantly associated with the severity of bronchiectasis.

DOI： 10.1186/s12890-017-0544-x

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Language：English   Publisher：Medicine (United States)  

Rational: The efficacy of nintedanib, a multitarget receptor tyrosine kinase inhibitor, has been demonstrated in recent randomized controlled trials involving patients with idiopathic pulmonary fibrosis (IPF). However, accelerated disease progression after nintedanib discontinuation has never been reported. Patient concerns: We report 2 cases involving patients with a history of IPF who presented with respiratory deterioration at 3 weeks after the discontinuation of nintedanib therapy for IPF. Neither patient fulfilled the definition of "acute exacerbation of IPF" on unilateral computed tomography. Diagnoses: Accelerated disease progression after the discontinuation of nintedanib therapy for IPF. Interventions: One patient received steroid therapy. The other patient refused to undergo steroid therapy. Outcomes: The first patient showed that the affected lobe exhibited volume loss with traction bronchiectasis after receiving steroid therapy, and succumbed to pneumothorax after 3 months. The other patient was transferred to another hospital because of a decline in his general condition. Lessons: To our knowledge, this report is the first to document accelerated disease progression after the discontinuation of nintedanib therapy for IPF. Although the accurate mechanism remains unclear, the effects of nintedanib against vascular endothelial growth factor and platelet-derived growth factor receptor may play a role. Our findings suggest that physicians should carefully monitor patients with IPF after nintedanib discontinuation.

DOI： 10.1097/MD.0000000000009081

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Language：English   Publisher：BMC Pulmonary Medicine  

Background: Late-onset noninfectious pulmonary complications (LONIPCs), which occur more than 3months after allogeneic hematopoietic stem cell transplantation (HSCT), are major causes of morbidity and mortality after transplantation. Among LONIPCs, we occasionally treat patients with late-onset severe restrictive lung defect after HSCT; however, its clinical features have not been fully elucidated. Methods: A retrospective chart review of a single center on cases of late-onset severe restrictive lung defect after HSCT was performed. Among 453 patients who survived longer than 100days after allogeneic HSCT with evaluable spirometry data, 12 patients (2.6%) developed late-onset severe restrictive lung defect (i.e., vital capacity percent of predicted less than 60%). Results: Median duration from transplantation to diagnosis of late-onset severe restrictive lung defect cases was 44.5months. Major computed tomography (CT) finding was pleuroparenchymal thickening with volume loss, an evidence of fibrosis, predominantly in upper lobes (n=7), which was consistent with pleuroparenchymal fibroelastosis. The remaining patients showed unclassifiable interstitial pneumonia pattern (n=2) and airway-predominant pattern (n=3). The diffusing capacity for carbon oxide tended to decrease, while the residual volume/total lung capacity ratio tended to increase after HSCT. Of 12 patients, 8 patients died and the median month from diagnosis to death was 33.5months. Seven patients died of pulmonary or systemic infection, and one patient died due to relapse of the primary disease. Conclusion: Severe restrictive lung defect could develop in selected cases in the late-phase after HSCT and could be a unique clinical entity with specific radiographical findings.

DOI： 10.1186/s12890-017-0466-7

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Language：English   Publisher：BMC Infectious Diseases  

Background: In multidrug regimens, including an intravenous aminoglycoside (e.g. amikacin [AMK]) is recommended for difficult-to-treat non-tuberculous mycobacterial (NTM) lung diseases. We aimed to evaluate the efficacy, safety, and feasibility of inhaled AMK therapy in patients with difficult-to-treat NTM lung diseases in a retrospective chart review. Methods: The study population consisted of patients with NTM lung diseases who received combination therapy, including inhaled AMK therapy, at Keio University Hospital (Tokyo, Japan), from January 2014 through May 2016. A total of 26 cases, consisting of 23 Mycobacterium avium complex (MAC) and three Mycobacterium abscessus complex (MABC) infections cases, were included in this study. The efficacy, safety, and feasibility of inhaled AMK therapy were retrospectively investigated. The Research Ethics Committee of Keio University Hospital approved this study, and informed consent was obtained from all patients. Results: All 26 patients were culture-positive at enrolment. Twenty-three of the 26 patients (88.5%), including 21/23 MAC patients (91.3%) and 2/3 MABC patients (66.7%), were administered inhaled AMK therapy for >3months. The proportion of patients who had clinical symptoms, including, cough and sputum, declined after inhalation AMK therapy. Ten of the 23 patients (43.5%) who received AMK inhalation, including 8/21 MAC (38.1%) and 2/2 MABC patients (100%), showed sputum conversion, defined as at least three consecutive negative sputum cultures. Seven of the 23 patients, including, 5/21 MAC and 2/2 MABC patients, showed improvements in high-resolution computed tomography imaging of the chest. In addition, the serum AMK trough levels before the second inhalation were <1.2μg/mL in all 26 patients, with no occurrence of severe adverse events, such as renal toxicity. One patient (3.8%) experienced auditory toxicity, in the form of tinnitus. However, this symptom was reversible, after temporary interruption of AMK, the patient was able to safely resume the therapy. Conclusions: Inhaled AMK therapy is an effective and feasible therapy for difficult-to-treat NTM lung disease.

DOI： 10.1186/s12879-017-2665-5

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Language：English   Publisher：Clinical Infectious Diseases  

Background. Pulmonary resection along with multiple antimicrobial therapy has produced favorable outcomes at a few centers. However, little is known regarding the risk factors for long-term survival and microbiological recurrence after pulmonary resection for nontuberculous mycobacterial pulmonary disease (NTMPD). We evaluated the long-term outcomes of pulmonary resection, including microbiological recurrence and survival. Methods. This retrospective cohort study included 125 patients (median age, 60 years) with NTMPD treated by pulmonary resection at two referral centers between January 1994 and August 2015. Results. Postoperative complications occurred in 27 patients (22%). The complication rate after pneumonectomy was significantly higher than those after other types of pulmonary resection (odds ratio, 4.1; 95% confidence interval [CI], 1.6-10.3; P =.005). The median follow-up period was 7.1 years. While 19 patients experienced microbiological recurrence, 26 died. Multivariate analysis revealed pneumonectomy (adjusted hazard ratio [aHR], 0.12; 95% CI,.007-.66; P =.0098) and cavitary lesions after surgery (aHR, 6.73; 95% CI, 1.68-22.7; P =.0095) to be predictors of microbiological recurrence and old age (aHR, 1.06; 95% CI, 1.01-1.13; P =.016), low body mass index (BMI; aHR for every 1-kg/m 2 increase, 0.72; 95% CI,.60-.85; P <.0001), pneumonectomy (aHR, 4.38; 95% CI, 1.78-11.3; P =.014), and remnant cavitary lesions (aHR, 3.53; 95% CI, 1.35-9.57; P =.011) to be predictors of poor prognosis. Conclusions. Patients who could benefit from pulmonary resection should be carefully selected considering age, BMI, remnant lesions after surgery, and type of pulmonary resection.

DOI： 10.1093/cid/cix274

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Language：English   Publisher：Respiratory Medicine  

Background and objectives Pulmonary Mycobacterium avium complex (pMAC) disease manifests as various types of lesions, such as infiltrates, nodules, cavities, and bronchiectasis. However, the important determinants for clinical parameters in lung involvement are poorly understood. The objective of this study was to obtain quantitative parameters by 3-dimensional CT, and investigate the relationship between these parameters and the pulmonary function tests (PFTs) and health-related quality of life. Material and methods Quantitative analysis using CT was performed in 67 pMAC patients. The relationship between new quantitative parameters for evaluating lung involvement using 3-dimensional CT and PFTs or St George's Respiratory Questionnaire (SGRQ) was evaluated. Results The ratio of infiltration to total lung volume showed significant correlation with the PFT results, especially the percent-predicted forced vital capacity (%FVC; ρ = −0.52), residual volume (ρ = −0.51), and total lung capacity (ρ = −0.59). The cavity volume was strongly correlated with the %FVC (ρ = −0.78) in the cavity group, while the ratio of infiltration to total lung volume was strongly correlated with the %FVC (ρ = −0.53) in the non-cavity group. The ratio of infiltration to total lung volume was significantly correlated with all SGRQ parameters (ρ = 0.41–0.52) in the non-cavity group. Conclusions Infiltration was an important parameter for the PFTs and SGRQ in pMAC patients according to the 3-dimensional CT analysis. Moreover, cavity volume was an important parameter of the PFTs in the cavity group. Therefore, infiltration and cavity volume are key features for the management of pMAC disease.

DOI： 10.1016/j.rmed.2017.03.010

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Language：English   Publisher：Respiratory Research  

Background: Aldehyde dehydrogenases (ALDHs) play a major role in detoxification of aldehydes. High expression of ALDHs is a marker for stem cells of many organs including the lungs. A common polymorphism in ALDH2 gene (ALDH2*2) results in inactivation of the enzyme and is associated with alcohol flushing syndrome and increased risk for cardiovascular and Alzheimer's diseases and some cancers. The effect of this ALDH2 polymorphism on the lung and its stem cells has not been thoroughly examined. Methods: We examined the association between the ALDH2*2 allele and lung function parameters in a population of healthy individuals. We also examined its association with the incidence of asthma and COPD in patient cohorts. We used the in vitro colony forming assay to detect the effect of the polymorphism on lung epithelial stem cells from both primary human surgical samples and Aldh2*2 transgenic (Tg) and Aldh2 -/- mice. Response to acute and chronic lung injuries was compared between wild type (WT), Aldh2*2 Tg and Aldh2 -/- mice. Results: In humans, the ALDH2*2 allele was associated with lower FEV1/FVC in the general population, but not with the development of asthma or COPD. Both the bronchial and lung epithelium carrying the ALDH2*2 allele showed a tendency for lower colony forming efficiency (CFE) compared to ALDH2 allele. In mice, the tracheal epithelial thickness, nuclear density, and number of basal stem cells were significantly lower in Aldh2 -/- and Aldh2*2 Tg adult mice than in WT. Electron microscopy showed significantly increased number of morphologically abnormal mitochondria in the trachea of Aldh2 -/- mice. Aldh2 -/- tracheal and lung cells showed higher ROS levels and fewer functional mitochondria than those from WT mice. No significant differences were detected when tracheal and lung epithelial stem cells were examined for their in vitro CFE. When exposed to chronic cigarette smoke, Aldh2*2 Tg mice were resistant to emphysema development, whereas influenza infection caused more epithelial damage in Aldh2 -/- mice than in WT mice. Conclusions:ALDH2 polymorphism has several subtle effects on the lungs, some of which are similar to changes observed during normal aging, suggesting a "premature lung aging" effect.

DOI： 10.1186/s12931-017-0554-5

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Language：English   Publisher：Annals of the American Thoracic Society  

DOI： 10.1513/AnnalsATS.201612-952LE

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Language：Japanese   Publishing type：Research paper (other academic)  

CiNii Books

Language：Japanese   Publishing type：Research paper (other academic)  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese  

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Language：English   Publisher：IDCases  

DOI： 10.1016/j.idcr.2017.04.005

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Language：English   Publisher：Annals of the American Thoracic Society  

Rationale: The management of macrolide-resistant Mycobacterium aviumcomplex (MR-MAC)pulmonary disease is difficult and is thought to be analogous to that of multidrug-resistant tuberculosis (MDR-TB). Objectives: This study aimed to clarify the cause of MR-MAC, to see how its management affected outcome, and to compare its prognosis with that of MDR-TB. Methods: The medical records of 102 consecutive cases with MR-MACpulmonary disease at three tertiary hospitals for mycobacteriosis in metropolitan Tokyo and one in Aichi prefecture from 2005 to 2014were reviewed.The data of 311 consecutive caseswith MDR-TB were extracted from the medical data at Fukujuji Hospital. Measurements and Main Results: Of the 90 patients who met the criteria, 53 (58.9%) received inappropriate first-line treatment, and 28 (31.1%) deviated from the standard treatment because of the adverse effects of ethambutol. The survival rates for MR-MAC disease and MDR-TB were not significantly different (P = 0.6). Multivariate analysis showed that the combination of aminoglycoside and surgery resulted in the best treatment outcome (P = 0.02), although neither of the two factors reached significance by themselves. The continuation of clarithromycin and the addition of fluoroquinolones did not improve the outcome for the treatment of disease caused by MR-MAC. Conclusions: Inappropriate prescription patterns and deviations from the standard treatment because of adverse drug reactions appeared to be the main causes of macrolide resistance in this patient series. Drug sensitivity testing should be performed at diagnosis to identify macrolide resistance and patients who may benefit from other therapy.

DOI： 10.1513/AnnalsATS.201604-246OC

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Language：English   Publisher：Critical Care Medicine  

Objectives: Secondary bacterial pneumonia following influenza virus infection is associated with high mortality, but the mechanism is largely unknown. Epigenetic gene regulation appears to play key roles in innate and adaptive immunity. We hypothesized that histone acetylation, a major epigenetic mechanism associated with transcriptionally active chromatin, might contribute to the poor outcome of postinfluenza pneumonia. Design: Prospective experimental study. Setting: University research laboratory. Subjects: C57BL/6 male mice. Interventions: Mice were infected intranasally with 1.0 × 10 4 colony-forming units of Streptococcus pneumoniae, 7 days after intranasal inoculation with five plaque-forming units of influenza virus A/H1N1/PR8/34. The mice were intraperitoneally injected with the histone deacetylase inhibitor trichostatin A (1 mg/kg) or vehicle once a day from 1 hour after pneumococcal infection throughout the course of the experiment. The primary outcome was survival rate. Measurements and Main Results: Trichostatin A significantly suppressed histone deacetylase activity and significantly improved the survival rate of mice (56.3%) after postinfluenza pneumococcal infection when compared with vehicle-treated mice (20.0%), which was associated with a significant decrease in the total cell count of the bronchoalveolar lavage fluid. The interleukin-1β level in the serum and the number of natural killer cells in the lungs were significantly lower in the trichostatin A-treated group. Conclusions: The histone deacetylase inhibitor trichostatin A protects mice against postinfluenza pneumonia possibly through multiple factors, including decreasing local cell recruitment into the lungs and suppressing systemic inflammation.

DOI： 10.1097/CCM.0000000000001821

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DOI： 10.3892/mco.2016.981

PubMed

Language：English   Publisher：BMC Infectious Diseases  

Background: Mycobacterium abscessus (M. abscessus) pulmonary disease is a refractory chronic infectious disease. Options for treating M. abscessus pulmonary disease are limited, especially in outpatient settings. Among parenteral antibiotics against M. abscessus, intravenous amikacin (AMK) is expected to be an effective outpatient antimicrobial therapy. This study evaluated the clinical efficacy and safety of intravenous AMK therapy in outpatients with M. abscessus pulmonary disease. Methods: This retrospective chart review of cases of M. abscessus pulmonary disease evaluated patient background data, AMK dosage and duration, sputum conversion, clinical symptoms radiological findings, and adverse events. M. massiliense was excluded on the basis of multiplex PCR assay. Results: Thirteen patients (2 men and 11 women) with M. abscessus pulmonary disease were enrolled at 2 hospitals. The median age at the initiation of intravenous AMK treatment was 65 years (range: 50-86 years). Patients received a median AMK dose of 12.5 mg/kg (range: 8.3-16.2 mg/kg) for a median duration of 4 months (range: 3-9 months). The addition of intravenous AMK led to sputum conversion in 10 of 13 patients, and 8 patients continued to have negative sputum status 1 year after treatment. Approximately half of the patients showed improvement on chest high-resolution computed tomography. There were no severe adverse events such as ototoxicity, vestibular toxicity, and renal toxicity. Conclusions: Thrice weekly intravenous AMK administration in outpatient settings is effective and safe for patients with M. abscessus pulmonary disease.

DOI： 10.1186/s12879-016-1689-6

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PubMed

Language：English   Publisher：Medicine (United States)  

The incidence of nontuberculous mycobacterial pulmonary disease (NTMPD) is increasing worldwide. Secondary spontaneous pneumothorax occurs as a complication of underlying lung disease and is associated with higher morbidity, mortality, and recurrence than primary spontaneous pneumothorax. We here investigated the clinical features and long-term outcomes of pneumothorax associated with NTMPD. We conducted a retrospective study on consecutive adult patients with pneumothorax associated with NTMPD at Fukujuji Hospital and Keio University Hospital from January 1992 to December 2013. We reviewed the medical records of 69 such patients to obtain clinical characteristics, radiological findings, and long-term outcomes, including pneumothorax recurrence and mortality. The median age of the patients was 68 years; 34 patients were women. The median body mass index was 16.8kg/m2. Underlying pulmonary diseases mainly included chronic obstructive pulmonary disease and pulmonary tuberculosis. On computed tomography, nodules and bronchiectasis were observed in 46 (98%) and 45 (96%) patients, respectively. Consolidation, pleural thickening, interlobular septal thickening, and cavities were most common, and observed in 40 (85%), 40 (85%), 37 (79%), and 36 (77%) patients, respectively. Regarding pneumothorax treatment outcomes, complete and incomplete lung expansion were observed in 49 patients (71%) and 15 patients (22%), respectively. The survival rate after pneumothorax was 48% at 5 years. By the end of the follow-up, 33 patients had died, and the median survival was 4.4 years with a median follow-up period of 1.7 years. The rate of absence of recurrence after the first pneumothorax was 59% at 3 years. By the end of the follow-up, 18 patients had experienced pneumothorax recurrence. Furthermore, 12/18 patients (66%) with recurrent pneumothorax died during the study period. Twentythree patients (70%) died because of NTMPD progression. Low body mass index (BMI) was a negative prognostic factor for pneumothorax associated with NTMPD in multivariate analysis (HR 0.79, 95% CI 0.64-0.96; P=0.018) Patients with pneumothorax associated with NTMPD have advanced disease, a high rate of pneumothorax recurrence, and poor prognosis, regardless of the pneumothorax treatment used. Further improvements in early diagnosis of NTMPD and appropriate management in both NTMPD and NTMPD-associated pneumothorax are needed.

DOI： 10.1097/MD.0000000000004246

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Language：English  

DOI： 10.1002/ccr3.555

PubMed

Publisher：Clinical Medicine Insights: Circulatory, Respiratory and Pulmonary Medicine  

Receptor for advanced glycation end products (RAGE) is a multiligand receptor of S100/calgranulins, high-mobility group box 1, and others, and it is associated with the pathogenesis of various inflammatory and circulatory diseases. The soluble form of RAGE (sRAGE) is a decoy receptor and competitively inhibits membrane-bound RAGE activation. In this study, we measured sRAGE levels in bronchoalveolar lavage fluid (BALF) of 78 patients, including 41 with interstitial pneumonia, 11 with sarcoidosis, 9 with respiratory infection, 7 with ARDS, 5 with lung cancer, and 5 with vasculitis. Among them, sRAGE was detectable in BALF of 73 patients (94%). In patients with ARDS and vasculitis, the sRAGE levels were significantly higher than in the control subjects and those with interstitial pneumonia. The sRAGE levels were positively correlated with total cell counts in BALF and serum levels of surfactant protein-D, lactate dehydrogenase, and C-reactive protein. There was an inverse correlation between PaO2/FIO2 ratio and sRAGE levels. These results indicate that sRAGE in BALF might be considered as a biomarker of lung inflammatory disorders, especially ARDS and vasculitis.

DOI： 10.4137/CCRPRPM.S23326

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Language：English   Publisher：Journal of Infectious Diseases  

Background. Acute exacerbation of chronic obstructive pulmonary disease (COPD) - typically caused by bacterial or viral infection - is associated with poor prognosis and emphysema progression through unknown mechanisms. We aimed to elucidate the mechanisms responsible for the poor prognosis and emphysema progression associated with COPD exacerbation. Methods. We established a mouse model mimicking acute human COPD exacerbation, wherein mice with elastase-induced emphysema were intranasally infected with Streptococcus pneumoniae. Results. In mice with elastase-induced emphysema, infection with S. pneumoniae resulted in increased mortality, an increased number of inflammatory cells in bronchoalveolar lavage fluid (BALF), and increased matrix metalloproteinase 12 (MMP-12) production in the lungs, as well as enhanced emphysema progression. The increased MMP-12 production was mostly due to alveolar type II cells, alveolar macrophages, and lymphocytes that aggregated around vessels and bronchioles. Dexamethasone treatment suppressed the mortality rate and number of inflammatory cells in BALF but not emphysema progression, possibly owing to the failure of MMP-12 suppression in the lungs, whereas treatment with the MMP inhibitor ONO-4817 dramatically suppressed both mortality rate and emphysema progression. Conclusions. These results suggest that MMP-12 production during COPD exacerbation results in increased mortality and emphysema progression. Our study identifies MMP-12 as a target to prevent further aggravation of COPD.

DOI： 10.1093/infdis/jiv527

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PubMed

Language：English   Publisher：Medicine (United States)  

Mycobacterium marinum is a ubiquitous waterborne organism that mainly causes skin infection in immunocompetent patients, and its disseminated infection is rare. Extranodal NK/T cell lymphoma, nasal type (ENKL) usually localizes at the nasal and/or paranasal area, but occasionally disseminates into the skin/soft tissue and gastrointestinal tract. Compromised immunity is a risk factor for developing nontuberculous mycobacterial (NTM) infection and malignant lymphoma, and the 2 diseases may share similar clinical presentation; however, only a few reports have described NTM infection mimicking malignant lymphoma. A 43-year-old Japanese man presented to our hospital complaining of multiple progressive skin nodules and purulent nasal discharge for 3 weeks. He was diagnosed with Crohn disease with refractory enteropathic arthritis and has been treated with anti-tumor necrosis factor alpha agents for 25 years. Fiberoptic nasal examination revealed septal perforation with hemorrhagic mucus and purulent rhinorrhea. Histological examination of the nasal septum revealed the infiltration of atypical medium-to-large-sized cells with erosion. The cells were positive for cytoplasmic CD3, granzyme B, and Epstein-Barr virusencoded small RNA. Histological examination of the skin nodules and auricle also showed infiltration of atypical lymphocytes. The patient was tentatively diagnosed with ENKL, and chemotherapy was considered. However, the skin lesions decreased in size after discontinuation of immunosuppressive agents and minocycline administration. Two weeks later, nasal septum and lavage fluid and left leg skin cultures were positive for M marinum, and minocycline was discontinued. The skin and the nasal lesions improved after 2 months. To the best of our knowledge, this is the first case of disseminated M marinum infection with a destructive nasal lesion mimicking ENKL. The differentiation between M marinum infection and ENKL is clinically important because misdirected treatment leads to a poor prognosis. NTM infections including M marinum should be considered in differential diagnosis of ENKL. Bacterial cultures, pathological analysis, and close monitoring are required for the differentiation of ENKL and disseminated M marinum infection; both are serious diseases and early diagnostic distinction between them and immediate appropriate treatment will improve the patient's prognosis.

DOI： 10.1097/MD.0000000000003131

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Language：Japanese  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

DOI： 10.11477/mf.1404205896

CiNii Research

Language：English   Publisher：American Journal of Respiratory and Critical Care Medicine  

DOI： 10.1164/rccm.201508-1527IM

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PubMed

Language：English   Publisher：Human Vaccines and Immunotherapeutics  

Pneumonia is the fourth-leading cause of death globally, and Streptococcus pneumoniae is the most important causative pathogen. Because the incidence of pneumococcal diseases is likely to increase with the aging society, we should determine an optimal strategy for pneumococcal vaccination. While consensus indicates that 23-valent pneumococcal polysaccharide vaccine prevents invasive pneumococcal diseases (IPD), its effects on community-acquired pneumonia (CAP) remain controversial. Recently, a 13-valent pneumococcal conjugate vaccine (PCV13) was released. The latest clinical study (CAPiTA study) showed that PCV13 reduced vaccine-type CAP and IPD. Based on these results, the Advisory Committee on Immunization Practices recommended initial vaccination with PCV13 for the elderly. Scientific evidence regarding immunosenescence is needed to determine a more ideal vaccination strategy for the elderly with impaired innate and adaptive immunity. Continuing research on the cost effectiveness of new vaccine strategies considering constantly changing epidemiology is also warranted.

DOI： 10.1080/21645515.2015.1075678

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Language：English   Publisher：Infection  

DOI： 10.1007/s15010-015-0816-4

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PubMed

Publisher：Respiration and Circulation  

Scopus

Language：English   Publisher：Journal of Infection and Chemotherapy  

Background Mycobacterium scrofulaceum is a well-known pathogen associated with cervical lymphadenitis in children. However, pulmonary M. scrofulaceum disease is a rare condition with unknown clinical features. The present study aimed to clarify the clinical features of pulmonary M. scrofulaceum disease described in recent cases and reports. Methods We reviewed the medical records of all adult patients with pulmonary M. scrofulaceum disease at Keio University Hospital and the National Center for Global Health and Medicine Center Hospital between 2001 and 2011. We also conducted a review of the PubMed database to identify additional cases of pulmonary M. scrofulaceum disease in adults. Results Our study identified 8 cases of pulmonary M. scrofulaceum disease at the 2 identified institutions during our study period. Most cases were diagnosed in middle-aged and elderly men with underlying pulmonary diseases such as chronic obstructive pulmonary disease and Mycobacterium avium complex lung disease, as well as those with a history of pulmonary tuberculosis. In contrast, most previously reported cases identified through our literature review had a history of dust inhalation or underlying silicosis. Three of 8 cases at our institutions and 20 of 23 cases from the literature were treated with combination therapies. Conclusions We conclude that in the recent histories of our institutions, pulmonary M. scrofulaceum disease has mainly occurred in patients with chronic pulmonary diseases. We further conclude that combination therapies that include clarithromycin might yield better patient outcomes.

DOI： 10.1016/j.jiac.2016.06.006

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Language：English   Publisher：Antiviral Therapy  

Background: Some subtypes of influenza virus, such as H5N1 and H7N9, cause severe viral pneumonia, for which the intraluminal concentration of the anti-influenza agent in the airway is critical. However, the pharmacokinetics of peramivir, the only available injectable neuraminidase inhibitor formulation, in the airway epithelial lining fluid (ELF) remains unclear. In this study, we aimed to determine the time course of peramivir in the pharyngeal ELF, bronchial ELF and plasma of healthy volunteers using bronchoscopic microsampling technique. Methods: Six healthy volunteers were studied. After baseline plasma sampling, 0.3 g peramivir was intravenously injected over 0.5 h. ELF was obtained from the upper and lower airways using bronchoscopic microsampling at the end of the infusion (0.5 h) and after 1.0, 1.5, 2.0, 2.5, 3.0, 4.0 and 5.0 h. The concentrations of peramivir in the ELFs and in the plasma were quantified by LC/MS/MS analysis. Results: The mean maximum concentration (Cmax) in pharyngeal ELF, bronchial ELF and plasma was 1.20 ±0.42, 9.60 ±2.30 and 50.52 ±17.51 ng/ml, respectively. The penetration ratio at Cmax in pharyngeal and bronchial ELFs was 2.4 and 19.0, respectively. The ratio of the area under the curve from 0 to infinity in pharyngeal and bronchial ELFs was 4.8 and 39.1 mg•min/l, respectively. Conclusions: The time course of peramivir concentration in the ELFs revealed that concentrations above the 50% inhibitory concentration value of influenza were achieved in the upper and lower airways. Therefore, peramivir could be an important treatment option for influenza viral pneumonia.

DOI： 10.3851/IMP3096

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PubMed

Language：Japanese   Publisher：日本臨床免疫学会  

<p>  【背景】近年，既知の免疫不全を有さず，播種性NTM症を発症した患者の一部から抗IFNγ中和自己抗体の検出が報告されているが，その臨床的特徴は十分に明らかではない．【症例1】70代女性．喀痰・胸水・気管支肺胞洗浄液・肺組織・尿・肝臓・骨髄からMACを認め，播種性MAC症の診断となる．化学療法により病勢の改善を認め，2年間で治療終了とした．その後，微熱・全身倦怠感を認め，精査の結果，骨髄からMACの検出を認めた．【症例2】60代男性．腋窩リンパ節膿瘍を契機に，播種性MAC症の診断となる．化学療法を開始し改善を認めた．経過中に皮膚掻痒・肝機能障害を新規に認め，ERCPを施行した所，胆汁培養からMACの検出を認めた．【症例3】70代男性．頸部リンパ節・腹腔内リンパ節腫脹を認め，悪性リンパ腫疑いで紹介．頚部リンパ節の培養検査でDDH法では同定不能の抗酸菌を認めた．16S rRNAによる解析で<i>M. genavense</i>を同定した．【考察】抗IFNγ中和自己抗体が陽性の播種性NTM症の3例を経験した．長期間に及ぶ化学療法を施行しても，骨髄や肝臓内にNTMを認めた．</p>

DOI： 10.2177/jsci.39.402a

PubMed

CiNii Research

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Language：English   Publisher：Respiratory Research  

Background: Mycobacterium avium complex (MAC) lung diseases generally cause chronic disease in immunocompetent hosts. Although a few studies have examined health-related quality of life (HRQL) in patients with MAC lung disease, there have been no large studies. This study aimed to evaluate HRQL and its correlation with clinical outcomes in MAC lung disease. Methods: A cross-sectional study was conducted at Keio University Hospital to investigate the factors associated with HRQL in pulmonary nontuberculous mycobacterial diseases. MAC lung diseases were diagnosed according to the 2007 ATS/IDSA guidelines for nontuberculous mycobacterial diseases. The 36-item short form health survey (SF-36) was administered to assess clinical outcomes. Clinical variables included treatment status, latest haematological data, and bacterial smear and culture results. Results: The SF-36 scores for the 235 patients (median age, 69years; 45 men and 190 women) with MAC lung disease, except for the bodily pain and mental health subscale scores, were significantly lower than the Japanese population norms. In the multivariable analyses, current treatment for MAC and a positive sputum smear or culture within the past year were significantly associated with lower SF-36 scores. C-reactive protein (CRP) and age showed stronger inverse correlations with SF-36 scores. Conclusions: HRQL, especially the physical component, was impaired in patients with MAC lung diseases; this appears to be related with current treatment status, positive sputum smear or culture within the previous year, and particularly CRP and age. Further studies including qualitative assessments are needed to investigate the efficacy of CRP as a marker for progression or treatment response in MAC lung disease. Trial registration: Clinical trial registered with UMIN (UMIN000007964 ).

DOI： 10.1186/s12931-015-0304-5

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Language：Japanese  

エピジェネティクスとは、DNA配列の変化をともなわない遺伝子発現・情報を調節する機構を言う。発生学や腫瘍学などの分野でのエピジェネティクスの重要性は確立されているが、近年では感染症学でもエピジェネティクスの重要性が報告され、研究が進みつつある。本稿では、筆者らが検討を行ってきた敗血症やインフルエンザウイルス感染症を中心に、エピジェネティクスの関与に関して概説する。呼吸器感染症におけるエピジェネティクスの関与の詳細が明らかになれば、抗菌薬に加え、将来的にはエピジェネティクスをターゲットとした創薬により、エピジェネティクスの調整による治療の可能性が広がると考えられる。(著者抄録)

Language：English  

BACKGROUND: Acute exacerbation of chronic obstructive pulmonary disease (COPD)-typically caused by bacterial or viral infection-is associated with poor prognosis and emphysema progression through unknown mechanisms. We aimed to elucidate the mechanisms responsible for the poor prognosis and emphysema progression associated with COPD exacerbation. METHODS: We established a mouse model mimicking acute human COPD exacerbation, wherein mice with elastase-induced emphysema were intranasally infected with Streptococcus pneumoniae. RESULTS: In mice with elastase-induced emphysema, infection with S. pneumoniae resulted in increased mortality, number of inflammatory cells in bronchoalveolar lavage fluid (BALF), and matrix metalloproteinase (MMP)-12 production in the lungs, as well as enhanced emphysema progression. The increased MMP-12 production was mostly due to alveolar type II cells, alveolar macrophages, and lymphocytes that aggregated around vessels and bronchioles. Dexamethasone treatment suppressed the mortality rate and number of inflammatory cells in BALF but not emphysema progression, possibly due to the failure of MMP-12 suppression in the lungs, whereas treatment with the MMP inhibitor ONO-4817 dramatically suppressed both mortality rate and disease progression. CONCLUSION: These results suggest that MMP-12 production during COPD exacerbation results in increased mortality and emphysema progression. Our study identifies MMP-12 as a target to prevent further aggravation of COPD.

Language：English   Publisher：Journal of Medical Case Reports  

Introduction: Mycobacterium avium complex (MAC) lung disease presenting as a solitary pulmonary nodule (MAC-SPN) is often asymptomatic, is more common in middle to old age, and mimics lung cancer or tuberculoma. We report herein a case of MAC-SPN in an immunocompetent young adult patient, presenting with persistent chest pain and a subacutely progressive nodule with high intense 18F-fluorodeoxyglucose uptake. Histological examination of resected specimens revealed pleurisy, which is a rare finding of MAC-SPN. Case presentation: A 36-year-old Japanese male presented with chest pain and a subacutely progressive pulmonary nodule. Positron emission tomography-computed tomography showed high intense 18F-fluorodeoxyglucose uptake in the nodule. Owing to his continuous chest pain and subacutely progressive nodules, wedge resection was performed using video-assisted thoracoscopic surgery. Histological examination revealed an epithelioid granuloma and pleurisy, and the lung tissue culture was positive for mycobacteria identified as M. avium. Conclusion: This is the first report of MAC-SPN occurring with persistent chest pain, suggesting that MAC should be considered in the differential diagnosis of a solitary pulmonary nodule, even for patients who experience persistent chest pain. As in the present case, surgical resection with video-assisted thoracoscopic surgery is a reasonable approach to the diagnosis and treatment of MAC-SPN with possible malignancy, especially as MAC can be diagnosed using resected lung tissue culture with histological confirmation.

DOI： 10.1186/s13256-015-0723-4

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PubMed

Language：English   Publisher：BMC Pulmonary Medicine  

Background: Biological agents inhibiting TNF-aα and other molecules involved in inflammatory cascade have been increasingly used to treat rheumatoid arthritis (RA). However, it remains controversial whether biological agents can be used safely in a patient with an underlying chronic infectious disease. Case presentation: A 63-year-old woman who had been treated with tocilizumab (TCZ), anti-interleukin-6 receptor antibody, for RA presented to our outpatient clinic due to hemoptysis. She was diagnosed with pulmonary Mycobacterium avium complex (MAC) infection, and high-resolution computed tomography (HRCT) showed a single cavitary lesion in the right upper lobe. After diagnosis of pulmonary MAC disease, TCZ was discontinued and combination chemotherapy with clarithromycin, rifampicin, ethambutol and amikacin was started for MAC pulmonary disease. Since the lesion was limited in the right upper lobe as a single cavity formation, she underwent right upper lobectomy. As her RA symptoms were deteriorated around the operation, TCZ was resumed. After resumption of TCZ, her RA symptoms improved and a recurrence of pulmonary MAC infection has not been observed for more than 1 year. Conclusion: This case suggested that TCZ could be safely reintroduced after the resection of a pulmonary MAC lesion. Although the use of biological agents is generally contraindicated in patients with pulmonary MAC disease, especially in those with a fibrocavitary lesion, a multimodality intervention for MAC including both medical and surgical approaches may enable introduction or resumption of biological agents.

DOI： 10.1186/s12890-015-0130-z

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PubMed

Language：English   Publisher：BMC Medical Imaging  

Background: In human immunodeficiency virus (HIV)-infected patients, immune reconstitution inflammatory syndrome (IRIS) due to nontuberculous mycobacteria (NTM) infection is one of the most difficult types of IRIS to manage. 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (18 F-FDG PET/CT) has been suggested as a useful tool for evaluating the inflammatory status of HIV-infected patients. We present the first case of Mycobacterium avium complex (MAC)-associated IRIS (MAC-IRIS) that was successfully followed up using 18 F-FDG PET/CT. Case presentation: A 44-year-old homosexual Japanese man was referred to our hospital with fever and dyspnea. He was diagnosed with Pneumocystis jiroveci pneumonia and found to be HIV positive. After the initiation of combined antiretroviral therapy (cART), the patient's mediastinal and bilateral hilar lymphadenopathy gradually enlarged, and bilateral infiltrates appeared in the upper lung fields. 18 F-FDG PET/CT was performed five months after the initiation of cART and showed intense accumulation of fluorodeoxyglucose (FDG) corresponding to the lesions of infiltration as well as the mediastinal and bilateral hilar lymphadenopathy. A bronchial wash culture and pathology findings led to a diagnosis of MAC-IRIS. Anti-mycobacterial chemotherapy with rifampicin, ethambutol, clarithromycin, and levofloxacin was started. One year after the chemotherapy was initiated, there was a significant reduction in FDG uptake in the area of the lesions except in the mediastinal lymph node. This implied incomplete resolution of the MAC-IRIS-related inflammation. Anti-mycobacterial chemotherapy was continued because of the residual lesion. To date, the patient has not experienced a recurrence of MAC-IRIS, a period of nine months. Conclusion: We present a case of MAC-IRIS in an HIV-infected patient whose disease FDG PET/CT is useful for evaluating the disease activity of NTM-IRIS and assessing the appropriate duration of anti-mycobacterial chemotherapy for NTM-IRIS in HIV-infected patients.

DOI： 10.1186/s12880-015-0063-2

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Language：English   Publisher：American Journal of Case Reports  

Objective: Rare disease Background: Increasing evidence has indicated that Staphylococcus aureus pneumonia complicated with influenza virus infection is often fatal. In these cases, disease severity is typically determined by susceptibility to antimicrobial agents and the presence of high-virulence factors that are produced by Staphylococcus aureus, such as Panton- Valentine leukocidin (PVL). Case Report: We describe a rare case of fatal community-acquired pneumonia caused by methicillin-sensitive Staphylococcus aureus (MSSA), which did not secrete major high-virulence factors and coexisted with influenza type B infection. The 32-year-old previously healthy male patient presented with dyspnea, high fever, and cough. His roommate had been diagnosed with influenza B virus infection 3 days earlier. Gram-positive clusters of cocci were detected in the patient’s sputum; therefore, he was diagnosed with severe pneumonia and septic shock, and was admitted to the intensive care unit. Despite intensive antibiotic and antiviral treatment, he died of multiple organ failure 5 days after admission. His blood culture from the admission was positive for MSSA, and further analysis revealed that the strain was negative for major high-virulence factors, including PVL and enterotoxins, although influenza B virus RNA was detected by PCR. Conclusions: Physicians should pay special attention to patients with pneumonia following influenza and Staphylococcus aureus infection, as it may be fatal, even if the Staphylococcus aureus strain is PVL-negative and sensitive to antimicrobial agents.

DOI： 10.12659/AJCR.894022

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PubMed

Language：English   Publisher：Stem Cell Research  

The niche surrounding stem cells regulate their fate during homeostasis and after injury or infection. The 3D organoid assay has been widely used to study stem cells behavior based on its capacity to evaluate self-renewal, differentiation and the effect of various medium supplements, drugs and co-culture with supportive cells. We established an assay to study both lung and trachea stem cells in vitro. We characterized their proliferation and differentiation spectrum at baseline then evaluated the effect of co-culturing with fibroblasts and endothelial cells and/or treating with several biologically relevant substances as possible contributors to their niche. We found that lung epithelial (but not tracheal basal) stem cells require co-culture with stromal cells to undergo clonal proliferation and differentiation. Fibroblasts were more efficient than endothelial cells in offering this support and the pattern of support varied based on the tissue origin of the stromal cells. Treating distal lung epithelial or basal stem cells with FGF2, FGF9, FGF10, LIF as well as ALK5 and ROCK inhibitors increased their colony formation efficiency and resulted in variable effects on colonies number, size and differentiation spectrum. This model and findings pave the way for better understanding of lung stem cell niche components and factors that can manipulate lung stem cell behavior.

DOI： 10.1016/j.scr.2015.05.005

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J00298&link_issn=&doc_id=20150521230417&doc_link_id=%2Fcf0brond%2F2015%2F0037s1%2F417%2F5292-5292%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcf0brond%2F2015%2F0037s1%2F417%2F5292-5292%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：English   Publisher：BMJ Case Reports  

DOI： 10.1136/bcr-2015-209394

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PubMed

Language：Japanese  

過去20年間で造血幹細胞移植後に肺機能検査を行った453例のうち晩発性の高度拘束性肺換気障害を呈した特発性肺炎症候群(IPS)症例12例(男女各6例:発症率2.6%)を対象に、臨床的特徴について後ろ向きに検討した。その結果、移植時年齢は30代、40代で各5例、原疾患は急性リンパ性白血病5例、急性骨髄性白血病3例であった。経過観察中の死亡は8例、IPS発症後の生存中央値は33.5ヵ月であり、呼吸器感染症による呼吸不全での死亡や気胸合併の割合が高かった。画像所見では上葉優位の胸膜直下線維化/容積減少7例、気胸6例、気管支拡張・Air Trapping 5例を認め、肺機能は感染や気胸を契機に増悪する傾向を認めた。

Language：Japanese  

呼吸器感染症や敗血症は重篤な致死的疾患であり、わが国でもこれらの感染症は全死因の上位を占めている。また、慢性閉塞性肺疾患(chronic obstructive lung disease:COPD)も死因の上位を占め、なかでも感染を契機としたCOPD増悪により致死的となることが多い。我々はおもに、これらの重症呼吸器感染症やCOPDにおける免疫制御機構の検討をマウスモデルを用いて行っている。本稿では、特に、(1)Lipopolysaccharide(LPS)ショックにおけるマクロライド系抗菌薬の免疫調整作用、(2)間葉系幹細胞のインフルエンザ感染における免疫調整作用、(3)インフルエンザなどの重症感染症におけるエピジェネティクスの関与、(4)COPD増悪モデルの作成と同モデルを用いた病態の解析の4つの研究に関して紹介したい。(著者抄録)

Language：Japanese   Publisher：(一社)日本結核・非結核性抗酸菌症学会  

Language：English   Publisher：Vaccine  

An open-labeled randomized study was conducted to compare the immunogenicity and safety of polysaccharide (PPV23) or protein-conjugated pneumococcal vaccine (PCV7) among the elderly aged 80 years or older. A total of 105 nursing home residents were enrolled in this study. We analyzed the geometric mean concentration (GMC) of serotype-specific immunoglobulin G (IgG) and the geometric mean titer (GMT) of the opsonization index (OI) for serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F. The GMCs of serotype-specific IgG and the GMTs of the OI significantly increased one month after vaccination in both groups for all seven serotypes evaluated. In the PCV7 group, study subjects with serotypes 4, 9V, 18C, and 23F exhibited statistically significant elevations in both serotype-specific IgGs and OIs compared to those of the PPV23 group. Both vaccines were tolerated without any severe adverse events, and no differences in systemic adverse events were observed between the two groups, although adverse reactions such as redness and localized swelling were more common in the PCV7 group. Our data demonstrated that the GMCs of serotype-specific IgG and the GMTs of the OI were higher in the PCV7 group compared to those in the PPV23 group. Our study also confirmed the safety of both the PCV7 and PPV23 vaccines in elderly people aged 80 years or older.

DOI： 10.1016/j.vaccine.2014.11.023

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Language：Japanese   Publisher：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.37.special_s292_2

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Language：English   Publisher：International Journal of COPD  

Background: Triple combination therapy involving long-acting muscarinic antagonists long-acting β2 agonists, and inhaled corticosteroids has recently become an option for maintenance treatment of COPD. Some add-on clinical trials have reported the benefits of these combinations. However, the process to step up to triple therapy varies for individual cases. Methods: Keio University and affiliated hospitals conducted an observational COPD cohort study, recruiting patients diagnosed as having COPD by pulmonary physicians and those referred for investigation of possible COPD. Their prescription history and clinical course were retrospectively analyzed based on the physicians’ medical records and patient questionnaires. This study was registered with UMIN (UMIN000003470, April 10, 2010). Results: A total of 95 of the 445 COPD patients (21%) were treated with inhaled corticosteroids/long-acting β2 agonists/long-acting muscarinic antagonists as maintenance therapy, including 12 in COPD Grade I, 31 in Grade II, 38 in Grade III, and 14 in Grade IV, based on the Global Initiative for Chronic Obstructive Lung Disease spirometric grading. For more than half of the patients on triple therapy, the treatment had been intensified due to unsatisfactory improvement of symptoms, and 32% were treated with triple therapy due to comorbid asthma. In contrast, there were COPD patients whose therapy was maintained after starting with triple therapy because of their serious conditions or concurrent exacerbation at diagnosis (8%). Conclusion: Triple therapy was often prescribed in the real-life management of COPD, even in patients whose airflow limitation was not severe. To better control symptoms was the major reason for choosing triple therapy, regardless of the severity of COPD, in Japan.

DOI： 10.2147/COPD.S79864

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Language：English   Publisher：BMC Infectious Diseases  

Pulmonary nocardiosis frequently occurs in immunocompromised hosts and in some immunocompetent hosts with chronic lung disease; however, few reports have described pulmonary nocardiosis with nontuberculous mycobacterial lung infection. Here we report for the first time two cases of pulmonary nocardiosis caused by Nocardia cyriacigeorgica associated with Mycobacterium avium complex (MAC) lung disease caused by M. avium. Case presentation: Case 1 is that of a 72-year-old Japanese man with untreated MAC lung disease, who was diagnosed with rheumatoid arthritis and initiated on methotrexate. After 3 years of methotrexate therapy, the patient remained smear-negative and culture-positive for MAC, but also became smear-positive for Nocardia species. He received trimethoprim/sulfamethoxazole, and his symptoms and lung infiltrates improved. Case 2 is that of an immunocompetent 53-year-old Japanese woman with MAC lung disease, who was treated with a combined therapy of clarithromycin, rifampicin, ethambutol, and levofloxacin. MAC sputum culture was negative after 1 year of combined treatment, which was maintained for 2 years. After four treatment-free years, Nocardia species were occasionally isolated from her sputum, although MAC was rarely isolated from sputum cultures over the same period. In both cases, the Nocardia species were identified as the recently defined N. cyriacigeorgica by 16S ribosomal RNA gene sequencing. Conclusion: We report two cases of pulmonary nocardiosis caused by N. cyriacigeorgica associated with MAC lung disease caused by M. avium and suggest that N. cyriacigeorgica may be a major infective agent associated with MAC lung disease.

DOI： 10.1186/s12879-014-0684-z

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Language：English   Publisher：Journal of Infection and Chemotherapy  

Polymerase chain reaction (PCR) technique is being increasingly used for the microbiological diagnosis of Pneumocystis pneumonia (PCP). As PCR is highly sensitive, it can be positive even in a patient with Pneumocystis colonization. In this study, we evaluated whether the β-d-glucan assay could be used to differentiate between PCP and Pneumocystis jirovecii colonization in immunocompromised patients with pulmonary infiltrates. We retrospectively evaluated data from 166 consecutive patients who underwent bronchoalveolar lavage for the diagnosis of PCP. Serum levels of β-d-glucan in the negative, colonization, probable PCP, and definite PCP groups were 20.2 ± 6.3, 48.8 ± 15.9, 89.9 ± 20.2, 224.9 ± 25.9 pg/mL, respectively. The β-d-glucan levels in the definite PCP group were significantly higher than those in the other 3 groups (p < 0.001). Serum β-d-glucan levels in patients with either definite or probable PCP (173.1 ± 18.8 pg/mL) were significantly greater than those in patients with colonization who had positive PCR results but improved without anti-PCP treatment (p < 0.002). The cut-off level for discrimination was estimated to be 33.5 pg/mL, with which the positive predictive value was 0.925. These results indicate that β-d-glucan is a useful marker to differentiate between PCP and Pneumocystis colonization. A positive β-D-glucan assay result might be a good indication to begin anti-PCP treatment.

DOI： 10.1016/j.jiac.2014.07.001

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クラリスロマイシン(CAM)はCD11b(+)Gr-1(+)細胞を誘導し、LPS腹腔内投与ショックモデルの予後を改善させるか検討した。CAM投与により肺・脾臓にそれぞれ、CD11b(+)Gr-1(+)細胞が有意に増加した。in vitroにおいて、CAMによって誘導されるCD11b(+)Gr-1(+)細胞は免疫抑制性に作用することが示された。CAMはCD11b(+)Gr-1(+)細胞を介して、LPS腹腔内投与ショックモデルの予後を改善させることが示された。CAMにより誘導されるCD11b(+)Gr-1(+)cellsからのIL-10産生が、LPS腹腔内投与ショックモデルに対する保護的効果に必須であることが示された。CAMは抗炎症作用を有するCD11b(+)Gr-1(+)cellsを誘導し、LPS腹腔内投与ショックモデルの予後を改善させることが示唆された。

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Language：Japanese   Publisher：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.36.special_s245_2

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Language：English   Publisher：Journal of Infection and Chemotherapy  

Arbekacin is a unique aminoglycoside antibiotic with anti-methicillin-resistant Staphylococcus aureus activity. The efficacy of aminoglycosides is related to their serum maximum concentration. Local concentration of antibiotics in pulmonary epithelial lining fluid, rather than its serum concentration, can help determine its clinical efficacy more precisely for treatment of respiratory infectious disease. The objective of this study was to sequentially measure arbekacin concentration in epithelial lining fluid after infusion of a single clinically available dose.

DOI： 10.1016/j.jiac.2014.05.007

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Language：English   Publisher：Journal of Infection and Chemotherapy  

Biapenem has been widely used to treat bacterial pneumonia; however, there is little information concerning its efficacy and safety in elderly patients. Based on pharmacokinetic-pharmacodynamic theory, administration of biapenem thrice rather than twice daily would be expected to be more effective because of longer time above the minimum inhibitory concentration. In this study, we aimed to evaluate the efficacy, safety, and pharmacokinetics of biapenem (300 mg) administered thrice daily in pneumonic patients aged 65 years or older. Biapenem was effective in 22 of 25 patients, as assessed by the improvement in clinical symptoms and/or the eradication of the causative organisms, and caused no serious adverse events. The pharmacokinetic profile was established based on simulations using a modeling program. Among 17 patients whose causative organisms were detected, time above the minimum inhibitory concentration was estimated to be 100% in 16 patients, all of whom showed clinical improvement. The results of this study confirmed the efficacy and safety of 300 mg of biapenem administered thrice daily for the treatment of pneumonia in elderly patients. © 2014, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jiac.2013.12.010

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Language：English   Publisher：BMC Medical Imaging  

Background: Psoas abscess complicating tuberculous spondylitis is a rare morbidity in extrapulmonary tuberculosis. There are no established guidelines for evaluating the clinical response of psoas abscess. Although several studies have shown that positron emission tomography-computed tomography with 18 F-fluorodeoxyglucose can play a potential role in diagnosing multifocal tuberculosis and monitoring the clinical response of pulmonary tuberculosis, to our knowledge, this is the first report demonstrating that positron emission tomography-computed tomography is useful for evaluating local inflammation and disease activity of a tuberculous psoas abscess. Case presentation: We report a case of multifocal bone and lymph node tuberculosis with concomitant lumbar psoas abscess in a 77-year-old man, along with a literature review. An initial positron emission tomography-computed tomography scan showed intense 18 F-fluorodeoxyglucose accumulation in the sternum, ribs, vertebrae, and lymph nodes. The patient was successfully treated with antitubercular agents and computed tomography-guided drainage therapy. A follow-up positron emission tomography-computed tomography after abscess drainage and 9 months of antitubercular drug treatment revealed that the majority of lesions improved; however, protracted inflammation surrounding the psoas abscess was still observed. These results indicate that disease activity of psoas abscess can remain, even after successful drainage and antitubercular medication regime of appropriate duration.Conclusion: We have successfully followed up the extent of skeletal tuberculosis complicated with psoas abscess by positron emission tomography-computed tomography. In this patient, positron emission tomography-computed tomography is useful for evaluating the disease activity of tuberculous psoas abscess and for assessing the appropriate duration of antitubercular drug therapy in psoas abscess. © 2013 Kimizuka et al.; licensee BioMed Central Ltd.

DOI： 10.1186/1471-2342-13-37

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Language：Japanese   Publisher：(一社)日本Shock学会  

Language：Japanese  

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Language：Japanese   Publisher：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.35.4_464_1

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Language：Japanese   Publisher：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.35.3_352_1

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Language：Japanese   Publisher：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.35.special_s196_3

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Language：Japanese   Publisher：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.35.special_s194_1

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Language：English   Publisher：Mediators of Inflammation  

Increasing evidence suggests that mesenchymal stem cells (MSCs) play anti-inflammatory roles during innate immune responses. However, little is known about the effect of MSCs or their secretions on the ligand response of Toll-like receptor (TLR) 7 and TLR8, receptors that recognize viral single-stranded RNA (ssRNA). Macrophages play a critical role in the innate immune response to ssRNA virus infection; therefore, we investigated the effect of MSC-conditioned medium on cytokine expression in macrophages following stimulation with TLR7/8 ligands. After stimulation with TLR7/8 ligand, bone marrow-derived macrophages cultured with MSCs or in MSC-conditioned medium expressed lower levels of tumor necrosis factor (TNF) α and interleukin (IL) 6 and higher levels of IL-10 compared to macrophages cultured without MSCs or in control medium, respectively. The modulations of cytokine expression were associated with prostaglandin E(PGE secreted by the MSCs. PGEenhanced extracellular signal-related kinase (ERK) signaling and suppressed nuclear factor-B (NF-B) signaling. Enhanced ERK signaling contributed to enhanced IL-10 production, and suppression of NF-B signaling contributed to the low production of TNF-α. Collectively, these results indicate that MSCs and MSC-conditioned medium modulate the cytokine expression profile in macrophages following TLR7/8-mediated stimulation, which suggests that MSCs play an immunomodulatory role during ssRNA virus infection. © 2013 Takahiro Asami et al.

DOI： 10.1155/2013/264260

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Language：English   Publisher：Journal of Medical Case Reports  

Introduction. The majority of multifocal micronodular pneumocyte hyperplasia associated with tuberous sclerosis complex is diagnosed with the classical clinical triad of seizures, mental retardation, and skin lesions. We report a rare case of tuberous sclerosis complex with no classical clinical findings, which was diagnosed through incidental computed tomography findings of multiple nodular lesions of multifocal micronodular pneumocyte hyperplasia. Case presentation. A chest computed tomography scan of a 51-year-old Japanese woman showed multiple nodular ground-glass opacities that were not seen on chest X-ray. Video-assisted thoracoscopic surgery was performed. A histological examination demonstrated type II pneumocyte hyperplasia with thickened fibrotic alveolar septa, which was consistent with multifocal micronodular pneumocyte hyperplasia. Brain magnetic resonance imaging displayed multiple cortical tubers, and abdominal computed tomography showed bilateral renal angiomyolipoma. Our patient was finally diagnosed as having tuberous sclerosis complex with multifocal micronodular pneumocyte hyperplasia, although she had no episodes of epilepsy, no skin lesions, and no family history. Conclusions: Multifocal micronodular pneumocyte hyperplasia with latent tuberous sclerosis complex should be considered in the differential diagnosis of multiple ground-glass opacities. © 2012 Ishii et al.; licensee BioMed Central Ltd.

DOI： 10.1186/1752-1947-6-352

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Language：English   Publisher：Respirology  

Background and objective: Combined pulmonary fibrosis and emphysema (CPFE) is characterized by upper lobe emphysema together with lower lobe fibrosis. The aim of this study was to examine whether cytokine levels in the alveolar space are associated with emphysematous changes superimposed on pulmonary fibrosis. Methods: Consecutive patients (n = 102), diagnosed with pulmonary fibrosis were retrospectively evaluated. Cytokine levels and differential cell counts in bronchoalveolar lavage (BAL) fluid, pulmonary function, computed tomography (CT) scores and levels of serum markers were compared between patients with or without emphysema. Results: Among the 102 patients (14 females, mean age 68 years), 38 (37%) had evidence of upper lobe emphysema on computed tomography (CT). Levels of epithelial neutrophil activating peptide 78 (ENA-78/CXCL5) and interleukin (IL)-8/CXCL8 in BAL fluid were significantly higher in patients with emphysema. Vital capacity (VC, % predicted) was greater, and ratio of forced expiratory volume in 1 s/forced vital capacity and diffusing capacity of carbon monoxide (DLCO)/alveolar volume (VA) were lower in patients with emphysema. CXCL8 and CXCL5 levels were associated with percentage or absolute numbers of neutrophils in BAL fluid. In addition, CXCL8 levels were inversely correlated with VC and DLCO/VA, and positively correlated with composite physiological index (CPI) and the extent of areas of low attenuation on CT. Conclusions: Increased CXC chemokine levels in the airspaces may be associated with emphysematous lung changes in patients with pulmonary fibrosis. The levels of various inflammatory mediators in bronchoalveolar lavage fluid were measured in patients with combined pulmonary fibrosis and emphysema. In patients with pulmonary fibrosis, elevated concentrations of CXC chemokines (CXCL5 and CXCL8) were associated with the development of emphysematous changes, neutrophil accumulation in the alveolar space, and impaired diffusing capacity. © 2012 Asian Pacific Society of Respirology.

DOI： 10.1111/j.1440-1843.2012.02182.x

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Language：English   Publisher：Journal of Immunology  

Although arachidonic acid cascade has been shown to be involved in sepsis, little is known about the role of PGD2 and its newly found receptor, chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), on the septic response. Severe sepsis is associated with the failure of neutrophil migration. To investigate whether CRTH2 influences neutrophil recruitment and the lethality during sepsis, sepsis was induced by cecal ligation and puncture (CLP) surgery in mice. CRTH2 knockout (CRTH2 -/-) mice were highly resistant to CLP-induced sepsis, which was associated with lower bacterial load and lower production of TNF-α, IL-6, and CCL3. IL-10, an anti-inflammatory cytokine, was higher in CRTH2 -/- mice, blunting CLP-induced lethality in CRTH2 -/- mice. Neutrophil accumulation in the peritoneum was more pronounced after CLP in CRTH22/2 mice, which was associated with higher CXCR2 levels in circulating neutrophils. Furthermore, sepsis caused a decrease in the level of acetylation of histone H3, an activation mark, at the CXCR2 promoter in wild-type neutrophils, suggesting that CXCR2 expression levels are epigenetically regulated. Finally, both pharmacological depletion of neutrophils and inhibition of CXCR2 abrogated the survival benefit in CRTH2 -/- mice. These results demonstrate that genetic ablation of CRTH2 improved impaired neutrophil migration and survival during severe sepsis, which was mechanistically associated with epigenetic-mediated CXCR2 expression. Thus, CRTH2 is a potential therapeutic target for polymicrobial sepsis. Copyright©2012 by The American Association of Immunologists, Inc.

DOI： 10.4049/jimmunol.1102330

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Language：Japanese  

Publisher：Infection and Immunity  

Interleukin-17 (IL-17) is a key factor in T helper type 17 (Th17) lineage host responses and plays critical roles in immunological control of a variety of infectious diseases. Although Legionella pneumophila, an intracellular bacterium found widely in the environment, often causes a serious and life-threatening pneumonia in humans, the contribution of IL-17 to immune function during Legionella pneumonia is unknown. In the present study, we used an experimental Legionella pneumonia infection to clarify the role of IL-17 in the resulting immune response. We observed robust production of pulmonary IL-17A and IL-17F (IL-17A/ F), peaking on day 1 and declining thereafter. Upregulated production of tumor necrosis factor alpha (TNF-α), IL-6, and IL-1β, but not monocyte chemotactic protein 1 (MCP-1), was observed in Legionella-infected bone marrow-derived macrophages from BALB/c mice that had been stimulated with IL-17A or IL-17F. A significant decrease in the production of proinflammatory cytokines IL-6 and TNF-α was observed in IL-17A/F-deficient mice (BALB/c background) infected with L. pneumophila. Moreover, we found impaired neutrophil migration and lower numbers of chemokines (KC, LIX, and MIP-2) in IL-17A/F-deficient mice. IL-17A/F-deficient mice also eliminated L. pneumophila more slowly and were less likely to survive a lethal challenge. These results demonstrate that IL-17A/F plays a critical role in L. pneumophila pneumonia, probably through induction of proinflammatory cytokines and accumulation of neutrophils at the infection site. © 2012, American Society for Microbiology.

DOI： 10.1128/IAI.05544-11

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インフルエンザウイルス肺炎惹起マウスを用いて、ヒストン脱アセチル化酵素(HDAC)阻害薬であるトリコスタチンA(TSA)投与の及ぼす効果について検討した。その結果、1)TSA連日投与群はコントロール群に比べ、インフルエンザウイルス感染後の体重減少が有意に抑制され、TSAの保護的効果が示唆された。2)感染3日後と6日後の肺内のサイトカインmRNA発現は両群間で有意差を認められなかった。3)マウスマクロファージのインフルエンザウイルス感染やTLR7/8リガンド刺激において、TSA投与はサイトカイン発現の抑制効果を示した。特にHDAC1やHDAC6のmRNAはTSA投与により上昇しており、TSAの作用はHDAC1やHDAC6が関与する可能性が示唆された。

Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：English   Publisher：Experimental Biology and Medicine  

With the recent increasing use of nanoparticles, there is concern that they may become an environmental risk factor as airborne particles. However, the impact of these particles on susceptible subjects with predisposing lung disease have not been sufficiently elucidated. In the present study, we investigated the effects of nanoparticles on pulmonary inflammatory and fibrotic changes induced by intratracheal bleomycin (BLM) challenge in mice. Mice were intratracheally administered either vehicle, 14-nm carbon black nanoparticles (CBNPs), BLM or BLM plus CBNP. First, we assessed lung collagen content, lung compliance and fibrotic changes in histopathology on day 21 after instillation. Then, to elucidate how CBNP contributes to the development of BLM-induced fibrosis, we collected bronchoalveolar lavage (BAL) fluid on days 2, 7, 14 and 21 and determined the total and differential cell counts and concentrations of two proinflammatory cytokines (keratinocyte chemoattractant [KC] and interleukin [IL]-6) and two fibrogenic mediators (CC chemokine ligand 2 [CCL2] and transforming growth factor-β 1 [TGF-β 1]). Expression of nitrotyrosine, an indicator of oxidant injury, was also evaluated on days 7 and 21. CBNP, when combined with BLM, significantly enhanced BLM-induced increase in lung collagen content, decrease in lung compliance, and fibrotic changes in histopathology. CBNP significantly augmented BLM-induced increase in the numbers of inflammatory cells in BAL fluid on days 2 and 7 and levels of KC and IL-6 on day 2. In addition, CBNP administered in combination with BLM significantly elevated the levels of CCL2 on days 2, 7 and 14, and TGF-β 1 on day 14 in BAL fluid as compared with BLM alone. Nitrotyrosine expression was also increased by BLM plus CBNP compared with BLM alone. In contrast, CBNP did not exert any significant effect on these parameters by itself. These results indicate that CBNP can exaggerate BLM-induced inflammatory and fibrotic changes in the lung, suggesting the potential impact of nanoparticles on lung inflammation and fibrosis. Copyright © 2011 by the Society for Experimental Biology and Medicine.

DOI： 10.1258/ebm.2011.010180

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Language：Japanese   Publisher：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.33.special_s270_1

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ヒトゲノムの全塩基配列解読の完了が2003年に宣言され、現在ではその意味を解読するという機能解析に焦点が当てられ、genome-wide association study(GWAS)などゲノムワイドでの関連解析も行われるようになった。ARDSにおいてもその病態を遺伝子レベルで再検討することが積極的に行われつつある。ARDSはさまざまな環境因子と遺伝的因子が関与して病態を形成する多因子疾患と考えられ、ある複数個の遺伝子変異の存在によりARDSの易発症性あるいは易重症化が規定される可能性が指摘されている。これらの遺伝子はARDS疾患特異的感受性遺伝子と定義される。さらにDNA配列の変化を伴わない遺伝子発現制御としてヒストン修飾等のエピジェネティックな遺伝子制御機構の存在の可能性も示唆されており、これらの解析がさらに進めば、ARDSの病態が遺伝子レベルで詳細に解明され、その関与分子を標的とした新規治療薬の開発、さらには各患者の遺伝子変異の相違に応じた個別化医療も近い将来可能となり、ARDSに対する治療法の質が大幅に変化するものと期待される。(著者抄録)

Language：English   Publisher：Microbiology and Immunology  

The clinical features of PCP differ according to the factors responsible for the predisposing immunosuppression. Although the diagnosis of PCP often requires BAL, the profiles of the inflammatory mediators in the BAL fluid are not thoroughly documented. The aim of the current study was to characterize the profiles of inflammatory mediators in BAL fluid during PCP in patients with underlying autoimmune diseases, malignancies, or AIDS. The medical records of 14 patients with autoimmune diseases, 10 with malignancies, and 8 with AIDS, all of whom had been diagnosed with PCP by microscopic examination of BAL fluid, were reviewed. The concentrations of TNF-α, MCP-1, HMGB1, IL-8, IL-6, IL-10, and IFN-γ in the BAL fluid that had been obtained for the diagnosis of PCP were measured. The concentrations of MCP-1, IL-8, and IL-6 differed according to the underlying disease, tending to be higher in patients with autoimmune diseases and lower in those with AIDS. The concentrations of HMGB1, IL-8, and IL-6 were positively correlated with the proportion of neutrophils in BAL fluid and inversely with the oxygenation index. Although the serum concentrations of CRP and LDH were positively correlated with those of IL-8 and MCP-1, none of the mediators in BAL fluid was correlated with the serum β-D-glucan concentration. The production of inflammatory mediators in the lung differed between the patient groups with different underlying disorders. The modest upregulation of IL-8 and IL-6 might be associated with the milder clinical manifestations of PCP in AIDS patients. © 2010 The Societies and Blackwell Publishing Asia Pty Ltd.

DOI： 10.1111/j.1348-0421.2010.00229.x

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Publisher：Blood  

One of the more insidious outcomes of patients who survive severe sepsis is profound immunosuppression. In this study, we addressed the hypothesis that post septic immune defects were due, in part, to the presence and/or expansion of regulatory T cells (Tregs). After recovery from severe sepsis, mice exhibited significantly higher numbers of Tregs, which exerted greater in vitro suppressive activity compared with controls. The expansion of Tregs was not limited to CD25+ cells, because Foxp3 expression was also detected in CD25- cells from post septic mice. This latter group exhibited a significant increase of chromatin remodeling at the Foxp3 promoter, because a marked increase in acetylation at H3K9 was associated with an increase in Foxp3 transcription. Post septic splenic dendritic cells promoted Treg conversion in vitro. Using a solid tumor model to explore the function of Tregs in an in vivo setting, we found post septic mice showed an increase in tumor growth compared with sham-treated mice with a syngeneic tumor model. This observation could mechanistically be related to the ability of post septic Tregs to impair the antitumor response mediated by CD8+ T cells. Together, these data show that the post septic immune system obstructs tumor immunosurveillance, in part, by augmented Treg expansion and function. © 2010 by The American Society of Hematology.

DOI： 10.1182/blood-2009-09-241083

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Publisher：European Journal of Immunology  

Immunosuppression following severe sepsis remains a significant human health concern, as long-term morbidity and mortality rates of patients who have recovered from life-threatening septic shock remain poor. Mouse models of severe sepsis indicate this immunosuppression may be partly due to alterations in myeloid cell function; however, the effect of severe sepsis on subsequent CD4+ T-cell responses remains unclear. In the present study, CD4 + T cells from mice subjected to an experimental model of severe sepsis (cecal ligation and puncture (CLP)) were analyzed in vitro. CD4 +CD62L+ T cells from CLP mice exhibited reduced proliferative capacity and altered gene expression. Additionally, CD4 +CD62L+ T cells from CLP mice exhibit dysregulated cytokine production after in vitro skewing with exogenous cytokines, indicating a decreased capability of these cells to commit to either the TH1 or TH2 lineage. Repressive histone methylation marks were also evident at promoter regions for the TH1 cytokine IFN-γ and the T H2 transcription factor GATA-3 in naïve CD4+ T cells from CLP mice. These results provide evidence that CD4+ T-cell subsets from post-septic mice exhibit defects in activation and effector function, possibly due to chromatin remodeling proximal to genes involved in cytokine production or gene transcription. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.

DOI： 10.1002/eji.200939739

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Language：Japanese   Publisher：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.32.special_s217_2

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Publisher：Blood  

Alternatively activated (M2) macrophages play critical roles in diverse chronic diseases, including parasite infections, cancer, and allergic responses. However, little is known about the acquisition and maintenance of their phenotype. We report that M2-macrophage marker genes are epigenetically regulated by reciprocal changes in histone H3 lysine-4 (H3K4) and histone H3 lysine-27 (H3K27) methylation; and the latter methylation marks are removed by the H3K27 demethylase Jumonji domain containing 3 (Jmjd3). We found that continuous interleukin-4 (IL-4) treatment leads to decreased H3K27 methylation, at the promoter of M2 marker genes, and a concomitant increase in Jmjd3 expression. Furthermore, we demonstrate that IL-4-dependent Jmjd3 expression is mediated by STAT6, a major transcription factor of IL-4-mediated signaling. After IL-4 stimulation, activated STAT6 is increased and binds to consensus sites at the Jmjd3 promoter. Increased Jmjd3 contributes to the decrease of H3K27 dimethylation and trimethylation (H3K27me2/3) marks as well as the transcriptional activation of specific M2 marker genes. The decrease in H3K27me2/3 and increase in Jmjd3 recruitment were confirmed by in vivo studies using a Schistosoma mansoni egg-challenged mouse model, a wellstudied system known to support an M2 phenotype. Collectively, these data indicate that chromatin remodeling is mechanistically important in the acquisition of the M2-macrophage phenotype. © 2009 by The American Society of Hematology.

DOI： 10.1182/blood-2009-04-217620

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Publisher：Journal of Experimental Medicine  

Ligands from dying cells are a source of Toll-like receptor (TLR) activating agents. Although TLR3 is known to respond to RNA from necrotic cells, the relative importance of this response in vivo during acute inflammatory processes has not been fully explored. We observed the involvement of TLR3 activation during experimental polymicrobial septic peritonitis and ischemic gut injury in the absence of an exogenous viral stimulus. In TLR3-deficient mice, increased chemokine/cytokine levels and neutrophil recruitment characterized the initial inflammatory responses in both injury models. However, the levels of inflammatory chemo- kines and tumor necrosis factor α; quickly returned to baseline in tlr3 -/- mice, and these mice were protected from the lethal effects of sustained inflammation. Macrophages from tlr3 -/- mice responded normally to other TLR ligands but did not respond to RNA from necrotic neutrophils. Importantly, an immunoneutralizing antibody directed against TLR3 attenuated the generation of inflammatory chemokines evoked by byproducts from necrotic neutrophils cultured with wild-type macrophages. In vivo, anti-TLR3 antibody attenuated the tissue injury associated with gut ischemia and significantly decreased sepsis-induced mortality. Collectively, these data show that TLR3 is a regulator of the amplification of immune response and serves an endogenous sensor of necrosis, independent of viral activation.

DOI： 10.1084/jem.20081370

Scopus

Publisher：European Journal of Immunology  

The present study addressed the modulatory role of CC chemokine receptor 4 (CCR4) in Toll-like receptor (TLR) 9-mediated innate immunity and explored the underlying molecular mechanisms. Our results demonstrated that CCR4-deficient mice were resistant to both septic peritonitis induced by cecal ligation and puncture (CLP) and CpG DNA/ D-galactosamine-induced shock. In bone marrow-derived macrophages (BMMΦ) from CLP-treated CCR4-deficient mice, TLR9-mediated pathways of MAPK/AP-1, PI3K/Akt, and IκB kinase (IKK)/NF-κB were impaired compared to wild-type (WT) cells. While TLR9 expression was not altered, the intensity of internalized CpG DNA was increased in CCR4-deficient macrophages when compared to WT macrophages. Pharmacological inhibitor studies revealed that impaired activation of JNK, PI3K/Akt, and/or IKK/NF-κB could be responsible for decreased proinflammatory cytokine expression in CCR4-deficient macrophages. Interestingly, the CCR4-deficient BMMΦ exhibited an alternatively activated (M2) phenotype and the impaired TLR9-mediated signal transduction responses in CCR4-deficient cells were similar to the signaling responses observed in WT BMMΦ skewed to an alternatively activated phenotype. These results indicate that macrophages deficient in CCR4 impart a regulatory influence on TLR9-mediated innate immunity. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

DOI： 10.1002/eji.200838360

Scopus

Publisher：American Journal of Physiology - Lung Cellular and Molecular Physiology  

Although the endothelial expression of various adhesion molecules substantially differs between pulmonary microvessels, their importance for neutrophil and lymphocyte sequestration in ventilator-induced lung injury (VILI) has not been systematically analyzed. We investigated the kinetics of polymorphonuclear cells (PMN) and mononuclear cells (MN) in the acinar microcirculation of the isolated rat lung with VILI by real-time confocal laser fluorescence microscopy, with or without inhibition of ICAM-1, VCAM-1, or P-selectin by monoclonal antibodies (MAb). Adhesion molecules in each microvessel were estimated by intravital fluorescence microscopy or immunohistochemical staining. In high tidal volume-ventilated lungs, 1) ICAM-1, VCAM-1, and P-selectin were differently upregulated in venules, arterioles, and capillaries; 2) venular PMN rolling was improved by inhibition of ICAM-1, VCAM-1, or P-selectin, whereas arteriolar PMN rolling was improved by ICAM-1 or VCAM-1 inhibition; 3) capillary PMN entrapment was ameliorated only by anti-ICAM-1 MAb; and 4) MN rolling in venules and arterioles and MN entrapment in capillaries were improved by ICAM-1 and VCAM-1 inhibition. In conclusion, the contribution of endothelial adhesion molecules to abnormal leukocyte behavior in VILI-injured microcirculation is microvessel and leukocyte specific. ICAM-1- and VCAM-1-dependent, but P-selectin-independent, arteriolar PMN rolling, which is expected to reflect the initial stage of tissue injury, should be taken as a phenomenon unique to ventilator-associated lung injury. Copyright © 2006 the American Physiological Society.

DOI： 10.1152/ajplung.00365.2005

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Language：Japanese  

ヒト肺動脈血管内皮細胞(HPAEC)を用いてhypercapnic acidosisがNF-κB,ICAM-1ならびにIL-8発現に与える影響について検討した.その結果,hypercapnic acidosisがLPS刺激によるHPAECのNF-κB-DNA結合活性,ICAM-1およびIL-8の発現,LDHを指標とした内皮細胞傷害,好中球の接着を抑制することが明らかとなった

Language：Japanese  

Language：Japanese  

Language：English   Publisher：Journal of Immunology  

Although c-Jun NH2-terminal kinase (JNK) has been implicated in the pathogenesis of transplantation-induced ischemia/reperfusion (I/R) injury in various organs, its significance in lung transplantation has not been conclusively elucidated. We therefore attempted to measure the transitional changes in JNK and AP-1 activities in I/R-injured lungs. Subsequently, we assessed the effects of JNK inhibition by the three agents including SP600125 on the degree of lung injury assessed by means of various biological markers in bronchoalveolar lavage fluid and histological examination including detection of apoptosis. In addition, we evaluated the changes in p38, extracellular signal-regulated kinase, and NF-κB-DNA binding activity. I/R injury was established in the isolated rat lung preserved in modified Euro-Collins solution at 4°C for 4 h followed by reperfusion at 37°C for 3 h. We found that AP-1 was transiently activated during ischemia but showed sustained activation during reperfusion, leading to significant lung injury and apoptosis. The change in AP-1 was generally in parallel with that of JNK, which was activated in epithelial cells (bronchial and alveolar), alveolar macrophages, and smooth muscle cells (bronchial and vascular) on immunohistochemical examination. The change in NF-κB qualitatively differed from that of AP-1. Protein leakage, release of lactate dehydrogenase and TNF-α into bronchoalveolar lavage fluid, and lung injury were improved, and apoptosis was suppressed by JNK inhibition. In conclusion, JNK plays a pivotal role in mediating lung injury caused by I/R. Therefore, inhibition of JNK activity has potential as an effective therapeutic strategy for preventing I/R injury during lung transplantation.

DOI： 10.4049/jimmunol.172.4.2569

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PubMed

Language：Japanese   Publisher：メディカルビュー社  

Language：Japanese   Publisher：メディカルビュー社  

Language：Japanese   Publisher：メディカルビュー社  

Language：English   Publisher：American Journal of Respiratory Cell and Molecular Biology  

Although permissive hypercapnia improves the prognosis of patients with acute respiratory distress syndrome, it has not been conclusively determined whether hypercapnic acidosis (HA) is harmful or beneficial to sustained inflammation of the lung. The present study was designed to explore the molecular mechanism of HA in modifying lipopolysaccharide (LPS)-associated signals in pulmonary endothelial cells. LPS elicited degradation of inhibitory protein κB (IκB)-α, but not IκB-β, resulting in activation of nuclear factor (NF)-κB in human pulmonary artery endothelial cells. Exposure to HA significantly attenuated LPS-induced NF-κB activation through suppressing IκB-α degradation. Isocapnic acidosis and buffered hypercapnia showed qualitatively similar but quantitatively smaller effects. HA did not attenuate the LPS-enhanced activation of activator protein-1. Following the reduced NF-κB activation, HA suppressed the mRNA and protein levels of intercellular adhesion molecule-1 and interleukin-8, resulting in a decrease in both lactate dehydrogenase release into the medium and neutrophil adherence to LPS-activated human pulmonary artery endothelial cells. In contrast, HA did not inhibit LPS-enhanced neutrophil expression of integrin, Mac-1. Based on these findings, we concluded that hypercapnic acidosis would have anti-inflammatory effects essentially through a mechanism inhibiting NF-κB activation, leading to downregulation of intercellular adhesion molecule-1 and interleukin-8, which in turn inhibits neutrophil adherence to pulmonary endothelial cells.

DOI： 10.1165/rcmb.2002-0126OC

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PubMed

Language：Japanese  

CiNii Research

Language：Japanese  

PubMed

Publisher：Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society  

A 70-year-old man in whom nodular and reticular shadows had been noted on chest radiography since 1992 was admitted to our hospital with complaints of persistent cough and dyspnea on exertion in August, 2000. The definitive diagnosis of lung abnormalities was not confirmed by TBLB. He was re-admitted to our hospital to undergo a lung biopsy by video-assisted thoracoscopic surgery. Although desquamative interstitial pneumonia was diagnosed, respiratory failure developed rapidly after surgery. He responded well to high-dose steroid administration followed by maintenance therapy with a moderate dose of steroid, resulting in a considerable importance of the clinical condition associated with a significant decrease in the ground-glass opacities and infiltrative shadows. Although we could find no literature reporting acute exacerbation of DIP, our case demonstrates that DIP may also be acutely exacerbated when a severe insult is superimposed.

Scopus

Language：English   Publisher：European Respiratory Journal  

The aim of the present study was to compare microvessel responses to hypercapnic and isocapnic acidosis in hyperoxia-injured lungs and to assess the role of constitutive and inducible forms of nitric oxide synthase (NOS) and cyclo-oxygenase (COX). Real-time confocal luminescence microscopy was used to measure changes in the diameter of acinar arterioles, venules and capillaries in response to stimulation with hypercapnic and isocapnic acidosis in isolated rat lungs injured by 90% oxygen exposure for 48 h. Observations were made with and without inhibition of constitutive (endothelial constitutive NOS (ecNOS) and COX-1) and inducible isoforms (iNOS and COX-2) of NOS and COX. Upregulation of NOS was assessed by measuring enzyme levels in lung homogenates by Western blot analysis and enhancement of the COX-related pathway was judged from perfusate concentrations of 6-ketoprostaglandin F1α. ecNOS and COX-1, but not iNOS and COX-2, were upregulated in hyperoxia-injured lungs. The nitric oxide produced by ecNOS attenuated COX-1 activity in injured arterioles and venules, but carbon dioxide enhanced it, leading to paradoxical dilatation of these microvessels under hypercapnic conditions with ecNOS inhibition. Although a high hydrogen ion concentration was unnecessary for excitation of COX-1, venule constriction in response to H+ was enhanced by COX-1 inhibition. Constitutive, but not inducible, isoforms of cyclo-oxygenase and nitric oxide synthase play an important role in abnormal microvessel responses to carbon dioxide and hydrogen ions in hyperoxia-injured lungs.

DOI： 10.1183/09031936.02.00263502

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PubMed

Publisher：Journal of Applied Physiology  

The hydrogen ion is an important factor in the alteration of vascular tone in pulmonary circulation. Endothelial cells modulate vascular tone by producing vasoactive substances such as prostacyclin (PGI2) through a process depending on intracellular Ca2+ concentration ([Ca2+]i). We studied the influence of CO2-related pH changes on [Ca2+]i and PGI2 production in human pulmonary artery endothelial cells (HPAECs). Hypercapnic acidosis appreciably increased [Ca2+]i from 112 ± 24 to 157 ± 38 nmol/l. Intracellular acidification at a normal extracellular pH increased [Ca2+]i comparable to that observed during hypercapnic acidosis. The hypercapnia-induced increase in [Ca2+]i was unchanged by the removal of Ca2+ from the extracellular medium or by the depletion of thapsigargin-sensitive intracellular Ca2+ stores. Hypercapnic acidosis may thus release Ca2+ from pH-sensitive but thapsigargin-insensitive intracellular Ca2+ stores. Hypocapnic alkalosis caused a fivefold increase in [Ca2+]i compared with hypercapnic acidosis. Intracellular alkalinization at a normal extracellular pH did not affect [Ca2+]i. The hypocapnia-evoked increase in [Ca2+]i was decreased from 242 ± 56 to 50 ± 32 nmol/l by the removal of extracellular Ca2+. The main mechanism affecting the hypocapnia-dependent [Ca2+]i increase was thought to be the augmented influx of extracellular Ca2+ mediated by extracellular alkalosis. Hypercapnic acidosis caused little change in PGI2 production, but hypocapnic alkalosis increased it markedly. In conclusion, both hypercapnic acidosis and hypocapnic alkalosis increase [Ca2+]i in HPAECs, but the mechanisms and pathophysiological significance of these increases may differ qualitatively.

DOI： 10.1152/jappl.2001.90.6.2094

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Scopus

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publisher：(一社)日本結核・非結核性抗酸菌症学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本呼吸器学会  

Language：Japanese   Publisher：(一社)日本感染症学会  

Language：Japanese   Publisher：日本細菌学会