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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., 「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.

Tetsuo Tani,1– 3 Ichiro Nakachi,1,4 Shinnosuke Ikemura,1 Shigenari Nukaga,1,5 Keiko Ohgino,1,6 Aoi Kuroda,1,7 Hideki Terai,1,8 Keita Masuzawa,1,8 Taro Shinozaki,1 Kota Ishioka,1,9 Yohei Funatsu,1,2 Hidefumi Koh,1,2 Koichi Fukunaga,1 Kenzo Soejima1,10 On behalf of the Keio Lung Oncology Group (KLOG)1Department of Medicine, Keio University School of Medicine, Tokyo, Japan; 2Department of Internal Medicine, Tachikawa Hospital, Tokyo, Japan; 3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; 4Department of Internal Medicine, Saiseikai Utsunomiya Hospital, Utsunomiya, Tochigi, Japan; 5Department of Respiratory Medicine, National Hospital Organization Tokyo Medical Center, Tokyo, Japan; 6Department of Pulmonary Medicine, Kawasaki Municipal Hospital, Kawasaki, Kanagawa, Japan; 7Department of Respiratory Medicine, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan; 8Department of Pulmonary Medicine, Kitasato University Kitasato Institute Hospital, Tokyo, Japan; 9Department of Medicine, Tokyo Saiseikai Central Hospital, Tokyo, Japan; 10Clinical and Translational Research Center, Keio University Hospital, Tokyo, JapanCorrespondence: Ichiro NakachiDepartment of Internal Medicine, Saiseikai Utsunomiya Hospital, 911-1 Takebayashimachi, Utsunomiya, Tochigi, 321-0974, JapanTel +81- 28-626-5500Fax +81- 28-626-5594Email nichiro4747@gmail.comBackground: Metastatic peritoneal carcinomatosis (MPC) is not common in patients with non-small cell lung cancer (NSCLC), and the clinical characteristics and treatment outcomes are still unclear.Patients and Methods: We recruited 46 NSCLC patients with MPC at Keio University and affiliated hospitals (Keio Lung Oncology Group) between January 2011 and December 2017, then retrospectively investigated their clinical characteristics and the impact of treatment interventions on their survival.Results: The profile of histological subtype was predominantly adenocarcinoma and 15 patients harbored driver oncogenes. Univariate and multivariate analysis demonstrated that performance status and the presence of a driver oncogene were significantly associated with the prolonged overall survival (OS). Regarding treatment, the median OS in the treatment group (9.3 months) was significantly longer than in the best supportive care group (1.3 months) (P < 0.0001).Conclusion: The prognosis of MPC in NSCLC patients who receive only the best supportive care is poor, but therapeutic intervention may improve prognosis.Keywords: metastatic peritoneal carcinomatosis, NSCLC, EGFR, malignant ascites, peritoneal nodule, intraperitoneal dissemination

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., LZTFL1, FOXP4, ABO, and IFNAR2), but also found a variant on 5p35 (rs60200309-A at DOCK2) that was significantly associated with severe COVID-19 in younger (-8 (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.

Background Prognostic understanding in advanced cancer patients and their caregivers may have an impact on the delivery of effective care. The aims of this study were to explore prognostic understanding at diagnosis in both patients with advanced lung cancer and their caregivers and to investigate correlates of their understanding. Subjects, Materials, and Methods A total of 193 patients with newly diagnosed advanced lung cancer and their 167 caregivers were enrolled at 16 hospitals in Japan. We assessed their perceptions of prognosis and goals of therapy and examined their associations with their sociodemographic characteristics, clinical status, quality of life, mood symptoms, and the status of disclosure of information by their treating physicians. Results One fifth of patients and caregivers (21.7% and 17.6%, respectively) mistakenly believed that the patients’ cancer was “completely curable.” Substantial proportions of them (16.9% and 10.3%, respectively) mistakenly believed that the primary goal of therapy was to remove all the cancer. Levels of anxiety and depression in both patients and caregivers were significantly higher among those who had accurate understanding of prognosis. In multivariate analyses, inaccurate perceptions of prognosis in patients were associated with sex, better emotional well-being, and lower lung cancer-specific symptom burden. Caregivers’ inaccurate perceptions of patients’ prognoses were associated with better performance status and better emotional well-being of patients. Conclusion Substantial proportions of advanced lung cancer patients and their caregivers misunderstood their prognosis. Interventions to improve their accurate prognostic understanding should be developed with careful attention paid to its associated factors. Implications for Practice This study demonstrated that substantial proportions of patients with newly diagnosed advanced lung cancer and their caregivers had misunderstandings about their prognosis. Accurate perceptions of prognosis, which are indispensable in the delivery of effective care, were associated with elevated levels of anxiety and depression in both patients and caregivers, warranting psychosocial care and support for them immediately after diagnosis. Inaccurate perceptions of prognosis in patients were associated with better emotional well-being and lower lung cancer-specific symptom burden. Illness understanding in caregivers was associated with patients’ physical and mental status. Those findings provide insight into how they obtain accurate illness understanding.

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.

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.

IntroductionThe 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 analysisIn 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 disseminationThis 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.

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.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.The mean maximum concentration (CThe 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.

Intimal sarcoma is a rare disease with a poor prognosis. We herein report the case of a 71-year-old man with intimal sarcoma of the pulmonary artery treated with pazopanib. The tumor showed regression after 1 month of treatment. Hand-foot syndrome led to cessation of pazopanib, which triggered a disease flare. Pazopanib should be considered in patients with intimal sarcoma of the pulmonary artery that is unresectable or recurrent after surgery or cytotoxic chemotherapy. We must be careful about drug cessation, as it can lead to a disease flare.

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 Conclusions Although the prognostic impact was limited, ESMCSA was significantly associated with HRQL and prognostic physiological parameters, such as BMI and pulmonary function.

BackgroundThere 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.MethodsWe 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.ResultsMean 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 (%FEV1), nodular lung lesions, and bronchiectasis worsened significantly in the observation group during follow-up. In the treatment group, BMI, and %FEV1 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.ConclusionsMild 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.

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.

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.

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.

Introduction: While multidrug regimen including inhaled amikacin (AMK) instead of intravenous administration has been recently used for the treatment of refractory non-tuberculous mycobacterial lung diseases (NTM-LD), available evidence is limited. Aims and objectives: We investigated the efficacy, safety and feasibility of inhaled AMK therapy administered to patients with refractory NTM-LD. Methods: The study population consisted of the 27 patients with NTM lung diseases due to Mycobacterium avium complex (MAC: N=24) and M. abscessus (Mab: N=3) who received the combination chemotherapy with inhalation of injectable AMK at Keio University Hospital (Tokyo, Japan) from January 2014 through May 2016. The efficacy, safety, and feasibility of the treatment were retrospectively evaluated. The Research Ethics Committee of Keio University Hospital reviewed and approved this study, and patient informed consent was obtained. Results: Twenty-three out of 27 cases (85.2%), comprising 21/24 MAC cases (87.5%) and 2/3 Mab cases (66.7%) were administered inhaled AMK for >3 months. Ten out of 23 cases (43.5%), comprising eight MAC cases (38.1%) and all two Mab cases (100%) showed sputum conversion defined as two consecutive culture negativity, with symptomatic improvement including cough and sputum. In addition, the serum AMK levels just before the second inhalation were Conclusions: Taken together inhaled AMK therapy is a safe and feasible therapy for refractory NTM-LD.

Background and objective Osteoporosis is an important systemic comorbidity of chronic obstructive pulmonary disease (COPD). However, neither its mechanisms nor its risk factors have been fully elucidated. With regard to genetic factors, low-density lipoprotein receptor-related protein 5 (LRP5) A1330V is known to be associated with osteoporosis in the general population, but the influence of this polymorphism in COPD is unknown. The aim of this study was to investigate the potential risk factors of COPD-related bone loss and fracture. Methods Keio University and affiliated hospitals have enrolled an observational cohort to investigate the management of COPD comorbidities. To assess risk factors for osteopenia and osteoporosis, bone mineral density (BMD) of the hip and lumbar spine, presence of vertebral fracture, quantitative data on emphysema and airway wall on computed tomography, as well as LRP5 genotype were analysed in patients with or at risk for COPD (n = 270). Results The percentage of subjects with osteoporosis (T-score ≤ −2.5), osteopenia (T-score between −1 and −2.5) and a normal BMD (T-score ≥ −1) was 15.2%, 35.9% and 48.9%, respectively. T-score was significantly decreased in subjects with LRP5 TT genotype (n = 15) compared with that in those with CC/CT genotype (n = 255) (−1.83 vs. −0.98, P = 0.0167). On multivariate logistic regression analysis, female gender (odds ratio (OR) 10.4; P

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.

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.

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 CRTH2−/− 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.

Osteoporosis is an important systemic comorbidity of chronic obstructive pulmonary disease (COPD). However, neither its mechanisms nor its risk factors have been fully elucidated. With regard to genetic factors, low-density lipoprotein receptor-related protein 5 (LRP5) A1330V is known to be associated with osteoporosis in the general population, but the influence of this polymorphism in COPD is unknown. The aim of this study was to investigate the potential risk factors of COPD-related bone loss and fracture.Keio University and affiliated hospitals have enrolled an observational cohort to investigate the management of COPD comorbidities. To assess risk factors for osteopenia and osteoporosis, bone mineral density (BMD) of the hip and lumbar spine, presence of vertebral fracture, quantitative data on emphysema and airway wall on computed tomography, as well as LRP5 genotype were analysed in patients with or at risk for COPD (n = 270).The percentage of subjects with osteoporosis (T-score ≤ -2.5), osteopenia (T-score between -1 and -2.5) and a normal BMD (T-score ≥ -1) was 15.2%, 35.9% and 48.9%, respectively. T-score was significantly decreased in subjects with LRP5 TT genotype (n = 15) compared with that in those with CC/CT genotype (n = 255) (-1.83 vs. -0.98, P = 0.0167). On multivariate logistic regression analysis, female gender (odds ratio (OR) 10.4; P0.0001), severe emphysema (OR 2.3; P = 0.013) and LRP5 TT genotype (OR 3.7; P = 0.031) independently increased the risk of osteopenia/osteoporosis.This study confirmed the complex pathophysiology of COPD-related osteoporosis, including the influence of gender, clinical phenotype and genetic factors.

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)αand 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 E2(PGE2) secreted by the MSCs. PGE2enhanced extracellular signal-related kinase (ERK) signaling and suppressed nuclear factor-κB (NF-κB) signaling. Enhanced ERK signaling contributed to enhanced IL-10 production, and suppression of NF-κB 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.

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.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.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 (DL(CO))/alveolar volume (V(A)) 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 DL(CO)/V(A), and positively correlated with composite physiological index (CPI) and the extent of areas of low attenuation on CT.Increased CXC chemokine levels in the airspaces may be associated with emphysematous lung changes in patients with pulmonary fibrosis.

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-alpha, MCP-1, HMGB1, IL-8, IL-6, IL-10, and IFN-gamma 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 beta-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.

Percutaneous cryotherapy (PCT) under computed tomographic guidance is minimally invasive, with satisfactory local control of primary lung cancer and pulmonary metastatic lesions. We report a case of acute respiratory distress syndrome (ARDS) in a patient who underwent PCT for lung metastasis of recurrent esophageal cancer. The patient responded to pulse steroid therapy and recovered from severe respiratory failure. Excessive inflammatory response to necrotic debris might contribute to the development of ARDS. To the best of our knowledge, this is the first report describing the details of ARDS following PCT.

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. 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. The SF-36 scores for the 235 patients (median age, 69 years; 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. 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. Clinical trial registered with UMIN ( UMIN000007964 ).