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Asthma is a chronic airway inflammatory disease characterized by airway hyperreactivity (AHR) and eosinophilic airway inflammation. Dendritic cells (DCs) are essential for the development of asthma via presenting allergens, causing Th2 skewing and eosinophil inflammation. Recent studies have revealed that CD109, a glycosylphosphatidylinositol-anchored glycoprotein, is involved in the pathogenesis of inflammatory diseases such as rheumatoid arthritis and psoriasis. However, no study has addressed the role of CD109 in asthma. This study sought to address the role of CD109 on DCs in the development of AHR and allergic inflammation. CD109 deficient mice (CD109-/- mice) were sensitized with house dust mite (HDM) or ovalbumin and compared to wild-type (WT) mice for induction of AHR and allergic inflammation. CD109-deficient mice had reduced AHR and eosinophilic inflammation together with lower Th2 cytokine expression compared to WT mice. Interestingly, CD109 expression was induced in lung conventional DC2s (cDC2s), but not lung cDC1s, upon allergic challenge. Lung cDC2s from CD109-/- mice had a poor ability to induce cytokine production in ex vivo DC-T cell cocultures with high expression of RUNX3, resulting in suppression of Th2 differentiation. Adoptive transfer of bone-marrow-derived CD109-/- DCs loaded with HDM failed to develop AHR and eosinophilic inflammation. Finally, administration of monoclonal anti-CD109 antibody reduced airway eosinophils and significantly decreased AHR. Our results suggest the involvement of CD109 in asthma pathogenesis. CD109 is a novel therapeutic target for asthma.

The occurrence of immune-related adverse events (irAEs) after immune checkpoint inhibitors (ICIs) is unpredictable. Profiles of peripheral blood mononuclear cells (PBMCs) represent the host immune system and have the potential to predict irAEs. We analyzed PBMC subsets using multicolor flow cytometry before and at weeks 2 and 8 after the start of ICIs in patients with non-small cell lung cancer. Sixteen eligible patients were evaluated. The irAEs occurred in 6 patients (37.5%): diarrhea in 2, diarrhea and a rash in 1, pituitary dysfunction in 1, cholangitis in 1, and pneumonitis in 1. Patients experiencing irAEs had higher levels of CD86(+)plasmacytoid dendritic cells (pDCs) at the baseline and weeks 2 and 8 after the ICIs than those not experiencing irAEs (p = 0.005, 0.038, and 0.050, respectively). In patients experiencing irAEs, the levels of CD86(+)pDCs significantly decreased at weeks 2 and 8 compared to the baseline (p = 0 .034 and 0.025, respectively) but did not change in those not experiencing irAEs. The levels of other PBMC subsets were not significantly associated with irAEs. Higher levels of natural killer (NK) cells were significantly associated with an overall objective response (p = 0.024). In conclusion, higher levels of CD86(+)pDCs at the baseline and a reduction in those levels 2 and 8 weeks after ICIs were associated with the occurrence of irAEs. Higher levels of NK cells were associated with an objective response to ICIs. Evaluation of PBMCs may help to predict the efficacy and safety of ICIs.

A 67-year-old man was admitted to our hospital with cough and fatigue. He had had long-term exposure to silica due to cement processing. Chest computed tomography showed bilateral centrilobular nodules, and hilar and mediastinal lymphadenopathy with calcification, suggesting chronic silicosis. Within a few months, these nodules enlarged, and bilateral patchy consolidations appeared. A lung biopsy revealed sarcoid-like granulomas with birefringent particles under polarized light without malignancy or infection. He was diagnosed with silicosis-associated sarcoid-like granulomatous lung disease, rather than sarcoidosis, according to the clinicopathological findings. His pulmonary manifestations improved after the discontinuation of silica exposure and combination therapy of corticosteroid and azathioprine.

Background Combination therapy with dexamethasone, remdesivir, and baricitinib has become a promising treatment for moderate or severe COVID-19; however, we have observed transient leukocytopenia in COVID-19 patients who received combination therapy. Methods Twelve consecutive COVID-19 patients treated with combination therapy were included in this retrospective analysis. Blood cell counts collected at the following three time points were analyzed: before the start of therapy (period 1), within 24 h of starting therapy (period 2), and within 48 h of period 2 (period 3). Results The leukocyte count significantly decreased in period 2 compared to period 1 and then significantly increased in period 3 without withdrawal of baricitinib. The neutrophil count transiently decreased in period 2 and recovered in period 3. Conclusions Clinicians should be aware of transient leukocytopenia in patients with COVID-19 during the early phase of combination therapy.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is associated with a poor prognosis with variable clinical course. Early identification of patients at high risk for disease progression and death would lead to early therapeutic intervention and thereby improvement of outcomes. Cold-inducible RNA-binding protein (CIRBP) is produced in response to cellular stresses, which is implicated in multiple biological processes, including cell survival and proliferation.RESEARCH QUESTION: Is CIRBP a useful biomarker for predicting the outcomes of patients with IPF?STUDY DESIGN AND METHODS: This study included 95 and 93 patients with IPF from two independent hospitals (derivation and validation cohorts, respectively). The association s of serum CIRBP level upon IPF diagnosis with disease progression within 1 year after diagnosis (i.e. ≥10% relative decline in percent predicted forced vital capacity or death) and all-cause mortality were retrospectively analysed. Discrimination performances for predicting these outcomes were evaluated using the c-index. RESULTS: Serum and lung tissue CIRBP levels were higher in patients with IPF than in control subjects. In the derivation cohort, the CIRBP high sub-group had significantly higher 1-year disease progression rates and lower cumulative survival rates than the CIRBP low sub-group, and the results were replicated in the validation cohort. In multivariate analyses, high serum CIRBP level was independently associated with higher 1-year disease progression and all-cause mortality rates in both cohorts. Combining the Gender-Age-Physiology and serum CIRBP models improved the c-indices for predicting 1-year disease progression and all-cause mortality compared with that of each model alone. The c-indices of serum CIRBP were particularly high in patients with Gender-Age-Physiology stage I.INTERPRETATION: This study successfully validated that serum CIRBP level was an independent predictor of 1-year disease progression and all-cause mortality in IPF. CIRBP is a promising biomarker that can help identify high-risk patients with IPF, especially in the early stage.

Background The nutritional status can potentially affect the efficacy of cancer therapy. The Geriatric Nutritional Risk Index (GNRI), a simple index for evaluating nutritional status calculated from body weight and serum albumin levels, has been reported to be associated with the prognosis of various diseases. However, the relationships between GNRI and the efficacy of platinum-based chemotherapy in patients with non-small-cell lung cancer (NSCLC) are unknown. Methods The pretreatment levels of GNRI were retrospectively evaluated in 148 chemo-naïve patients with advanced NSCLC who received first-line platinum-based chemotherapy and scored as low or high. Results Patients with a high GNRI had a significantly higher overall response rate (ORR; 44.5% [95% confidence interval {CI} = 35.6%–53.9%] vs. 15.8% [95% CI = 7.4%–30.4%, p = 0.002), longer median progression-free survival (PFS; 6.3 months [95% CI = 5.6–7.2 months] vs. 3.8 months [95% CI = 2.5–4.7 months], p p p Conclusions GNRI was predictive of prolonged survival in patients with NSCLC who received first-line platinum-based chemotherapy and second-line non-platinum chemotherapy. Assessment of the nutritional status may be useful for predicting the efficacy of chemotherapy.

Background: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a devastating and life-threatening condition during its clinical course. Biomarkers for precisely anticipating the prognosis of AE-IPF remain to be fully established. The objective of this study was to clarify whether S100A8 and S100A9, which are calcium-binding proteins mainly produced by activated neutrophils, are significant prognostic biomarkers in AE-IPF.Methods: Thirty-seven patients with AE-IPF who were diagnosed and treated at our hospital were retrospectively evaluated. The serum levels of S100A8 and S100A9 were measured using enzyme-linked immunosorbent assay, and the relationships between these levels and clinical parameters or prognosis were evaluated.Results: The serum levels of S100A8 (median 386.5ng/mL) and S100A9 (median 60.2ng/mL) in patients with AE-IPF were significantly higher than those in age-matched healthy controls and in patients at IPF diagnosis (p

The prognosis of patients with connective tissue disease (CTD) has improved significantly in recent years, but interstitial lung disease (ILD) associated with connective tissue disease (CTD-ILD) remains a refractory condition, which is a leading cause of mortality. Because it is an important prognostic factor, many observational and interventional studies have been conducted to date. However, CTD is a heterogeneous group of conditions, which makes the clinical course, treatment responses, and prognosis of CTD-ILD extremely diverse. To summarize the current understanding and unsolved questions, the Japanese Respiratory Society and the Japan College of Rheumatology collaborated to publish the world's first guide focusing on CTD-ILD, based on the evidence and expert consensus of pulmonologists and rheumatologists, along with radiologists, pathologists, and dermatologists. The task force members proposed a total of 27 items, including 7 for general topics, 9 for disease-specific topics, 3 for complications, 4 for pharmacologic treatments, and 4 for non-pharmacologic therapies, with teams of 2-4 authors and reviewers for each item to prepare a consensus statement based on a systematic literature review. Subsequently, public opinions were collected from members of both societies, and a critical review was conducted by external reviewers. Finally, the task force finalized the guide upon discussion and consensus generation. This guide is expected to contribute to the standardization of CTD-ILD medical care and is also useful as a tool for promoting future research by clarifying unresolved issues.

Background: The immune-related adverse events (irAEs) is unpredictable. Peripheral blood mononuclear cell (PBMC) profiles have potential for predicting irAEs. Methods: PBMCs were measured using multicolor flow cytometry before and at weeks 2 and 8 after the immune checkpoint inhibitors (ICIs) in lung cancere patients. Results: Sixteen patients were eligible for the analysis. The irAEs occurred in 6 (37.5%) patients. Patients with irAEs demonstrated higher levels of CD86+plasmacytoid dendritic cells (pDCs) at baseline and weeks 2 and 8 after the ICIs than patients without irAEs (p = 0.005, 0.038, and 0.050, respectively). Higher levels of natural killer (NK) cells were significantly associated with overall objective response (p = 0.024). Conclusions: Higher levels of CD86+pDCs at baseline and the reduction at 2 and 8 weeks after the ICIs were associated with the occurrence of irAEs. Higher levels of NK cells were associated with therapeutic efficacy. Measurements of PBMCs may be useful for predicting the efficacy and safety of ICIs.

Background: The occurrence of immune-related adverse events (irAEs) after immune checkpoint inhibitors (ICIs) is unpredictable. Peripheral blood mononuclear cell (PBMC) profiles, representing host immune status, have potential for predicting irAEs. Methods: PBMC subsets were measured using multicolor flow cytometry before and at weeks 2 and 8 after the initiation of ICIs in patients with non-small cell lung cancer. Results: Sixteen evaluable patients were eligible for the analysis. The following irAEs occurred in 6 (37.5%) patients: diarrhea (n = 2), diarrhea and rash (n = 1), pneumonitis (n = 1), pituitary dysfunction (n = 1), and cholangitis (n = 1). Patients with irAEs demonstrated higher levels of CD86+plasmacytoid dendritic cells (pDCs) at baseline and weeks 2 and 8 after the ICIs than patients without irAEs (p = 0.005, 0.038, and 0.050, respectively). In patients with irAEs, the levels of CD86+pDCs decreased at weeks 2 and 8 compared with baseline (p =0 .034 and 0.025, respectively) but did not change in patients without irAEs. Other PBMC subsets had no significant associations with irAEs. Higher levels of natural killer (NK) cells were significantly associated with overall objective response (p = 0.024). Conclusions: Higher levels of CD86+pDCs at baseline and the reduction at 2 and 8 weeks after the ICIs were associated with the occurrence of irAEs. Higher levels of NK cells were associated with therapeutic efficacy. Measurements of PBMCs may be useful for predicting the efficacy and safety of ICIs.

The nutritional status has the potential to affect cancer immunity. We evaluated the relationship between the nutritional status and the efficacy of nivolumab in patients with non-small cell lung cancer (NSCLC). This study was a post hoc analysis of a prospective, multicenter cohort study conducted at 14 institutions in Japan between July 2016 and December 2018. The Geriatric Nutritional Risk Index (GNRI), calculated from body weight and serum albumin, was evaluated in 158 patients with NSCLC who received nivolumab. GNRI was graded as low, moderate, and high. Low GNRI was associated with significantly shorter progression-free survival [median, 1.9 mo; 95% confidence interval (CI)=0.6-3.3 mo] than moderate (median, 4.0 mo; 95% CI=2.3-5.8 mo; P=0.017) and high GNRI (median, 3.0 mo; 95% CI=1.9-7.2 mo; P=0.014). Low GNRI was also linked to significantly shorter overall survival (OS) (median, 7.8 mo; 95% CI=2.6-12.0 mo) than moderate (median, 13.0 mo; 95% CI=9.6-15.2 mo; P=0.006) and high GNRI (median, 20.6 mo; 95% CI=15.6 mo-not reached; P

BackgroundSome patients with idiopathic interstitial pneumonia (IIP) show autoimmune features. Interstitial pneumonia with autoimmune features (IPAF) was recently proposed as a research concept in these patients. However, retrospective studies reported conflicting results of its prognosis. Therefore, this study was conducted to prospectively evaluate the clinical significance of autoimmune features in patients with IIP.MethodsThis nationwide multicentre study prospectively enrolled consecutive patients with IIP. At the diagnosis, we systematically evaluated 63 features suggestive of connective tissue diseases using a checklist including symptoms/signs and autoantibodies, which contained most items of the IPAF criteria and followed up with the patients. Clinical phenotypes were included in a cluster analysis.ResultsIn 376 patients with IIP enrolled, 70 patients (18.6%) met the IPAF criteria. The proportion of patients with IPAF was significantly lower in idiopathic pulmonary fibrosis (IPF) than in non-IPF (6.0% vs 24.3%, respectively). During a median observation period of 35 months, patients with IPAF more frequently developed systemic autoimmune diseases and had less frequent acute exacerbation of IIPs than patients with non-IPAF. IPAF diagnosis was significantly associated with better survival and was an independent positive prognostic factor in total and patients with non-IPF. Cluster analysis by similarity of clinical phenotypes identified a cluster in which there was a higher number of women, and patients had more autoimmune features and a better prognosis than other clusters.InterpretationThese observations suggest that some patients with IIP show autoimmune features with distinct characteristics and favourable prognosis. However, we were not able to determine the appropriate therapies for these patients.

Genotyping epidermal growth factor receptor (EGFR) is an essential process to indicate lung adenocarcinoma patients for the most appropriate treatment. Liquid biopsy using circulating tumor DNA (ctDNA) potentially complements the use of tumor tissue biopsy for identifying genotype-specific mutations in cancer cells. We assessed the performance of a high-fidelity sequencing method that uses molecular barcodes called the nonoverlapping integrated read sequencing system (NOIR-SS) for detecting EGFR L858R-mutated alleles in 33 advanced or recurrent patients with L858R mutation-positive lung adenocarcinoma revealed by matched tissue biopsy. We compared NOIR-SS with site-specific droplet digital PCR (ddPCR), which was taken as the reference, in terms of sensitivity and ability to quantify L858R variant allele fractions (VAFs). NOIR-SS and ddPCR had sensitivities of 87.9% (29/33) and 78.8% (26/33) for detecting L858R alleles, respectively. The VAFs measured by each assay were strongly correlated. Notably, one specimen was positive with a VAF of 30.12% for NOIR-SS but marginally positive with that of 0.05% for ddPCR because of a previously poorly recognized mechanism: two-base substitution-induced L858R (c.2573_2574delinsGA). These results indicate that NOIR-SS is a useful method for detecting ctDNA, potentially overcoming a limitation of ddPCR which highly depends on the binding ability of primers to specific targeting sequences.

Several biomarkers for detecting pulmonary hypertension (PH) have been reported. However, these biomarkers are deemed insufficient to detect PH in its early stages. We evaluated the utility of serum angiopoietin (ANGP), a glycoprotein related to angiogenesis, as a diagnostic and prognostic biomarker of PH. Patients with PH who underwent right-heart catheterization, were retrospectively studied. Serum concentrations of ANGP-1 and ANGP-2 were measured using an enzyme-linked immunosorbent assay in patients with PH (n = 32), those with idiopathic pulmonary fibrosis (IPF) without PH (as a disease control, n = 75), and age-matched healthy controls (HC, n = 60). Nineteen patients (59.4%) with PH had World Health Organization group 3 PH. Serum ANGP-2 concentration, but not ANGP-1, in patients with PH was significantly higher compared with that in HC (p = 0.025) and in patients with IPF without PH (p = 0.008). Serum ANGP-2 concentration in patients with PH positively and significantly correlated with N-terminal pro-B-type natriuretic peptide (r = 0.769, p

Background Follicular helper T (Tfh) cells represent a unique subset of helper CD4+ T cells in lymphoid follicles. Recently, Tfh cells were shown to play an important role in asthma through B cell differentiation. Conventional lung DCs are classified into two major subsets: conventional type 1 (cDC1) and type 2 (cDC2). Although the two subsets are different in driving particular T cell responses, the subset that induces Tfh cells in the asthmatic lung primarily has yet to be fully elucidated. Methods We evaluated Tfh cells, defined by the expression of CD4 and CXCR5, in HDM-challenged mice. Next, we characterized cDC1 and cDC2 purified from antigen-primed lung and examined their Tfh cell-inducing capacity. Additionally, the ability of lung DC-induced Tfh cells to cause germinal center B (GCB) cells to produce antigen-specific IgE was assessed. Results In HDM-challenged mice, Bcl-6-expressing Tfh cells were significantly increased in the mediastinal lymph nodes. Lung cDC2, but not lung cDC1, increased after HDM priming, and cDC2 secreted larger amounts of IL-6 with higher ICOS-L expression than cDC1. In the co-cultures with OVA-specific naive CD4+ T cells, cDC2 from OVA-primed lung induced Bcl-6-expressing Tfh cells more efficiently, together with larger amounts of IL-6 and IL-21, than cDC1. Blockage of IL-6 or ICOS-L significantly reduced Tfh cell induction. Finally, cDC2-induced Tfh cells enabled GCB cells to produce OVA-specific IgE. Conclusions In asthmatic lung, cDC2 is the primary DC subset responsible for Tfh cell differentiation and plays an important role in humoral immunity in asthma by inducing Tfh cells.

Background Lipids have immunomodulatory functions and the potential to affect cancer immunity. Methods The associations of pretreatment serum cholesterol and long-chain fatty acids with the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated in 148 patients with non-small cell lung cancer who received nivolumab. Results When each lipid was separately evaluated, increased low-density lipoprotein (LDL)-cholesterol (P P = 0.014), total cholesterol (P = 0.007), lauric acid (P = 0.015), myristic acid (P = 0.022), myristoleic acid (P = 0.035), stearic acid (P = 0.028), linoleic acid (P = 0.005), arachidic acid (P = 0.027), eicosadienoic acid (P = 0.017), dihomo-γ-linolenic acid (P = 0.036), and behenic acid levels (P = 0.032) were associated with longer PFS independent of programmed death ligand 1 (PD-L1) expression. Meanwhile, increased LDL-cholesterol (P P = 0.009), total cholesterol (P = 0.036), linoleic acid (P = 0.014), and lignoceric acid levels (P = 0.028) were associated with longer OS independent of PD-L1 expression. When multiple lipids were evaluated simultaneously, LDL-cholesterol (P = 0.003), HDL-cholesterol (P = 0.036), and lauric acid (P = 0.036) were independently predictive of PFS, and LDL-cholesterol (P = 0.008) and HDL-cholesterol (P = 0.031) were predictive of OS. ORR was not associated with any serum lipid. Conclusions Based on the association of prolonged survival in patients with increased serum cholesterol and long-chain fatty acid levels, serum lipid levels may be useful for predicting the efficacy of immune checkpoint inhibitor therapy.

BACKGROUND: Presence of interstitial lung disease (ILD) is believed to be associated with mortality in microscopic polyangiitis (MPA); however, evidence on MPA-ILD remains lacking. Acute exacerbation (AE) refers to rapidly progressive, fatal respiratory deterioration that may develop in patients with various ILDs. No study has investigated the clinical significance of AE in MPA-ILD.QUESTION: We aimed to determine the clinical picture and prognostic factors, the incidence of AE and its risk factors in patients with MPA-ILD.STUDY DESIGN AND METHODS: Eighty-four consecutive patients with MPA-ILD and 95 patients with MPA-non-ILD were analyzed. We also compared 80 patients with MPA-ILD and 80 patients with idiopathic interstitial pneumonia without myeloperoxidase-anti-neutrophil cytoplasmic antibody-positivity (ILD-alone), who were matched for age, sex, and chest high-resolution computed tomography pattern.RESULTS: The MPA-ILD group had a higher frequency of men and smokers and was associated with higher mortality than the MPA-non-ILD group. The matched MPA-ILD group had a higher mortality rate than the matched ILD-alone group. There was no significant difference in AE incidence between the matched MPA-ILD and ILD-alone groups (1-year AE cumulative incidence rate: 7.5% and 5.2%, respectively, P=0.75). In the MPA-ILD group, a lower percent-predicted forced vital capacity (%FVC) was independently associated with a higher mortality rate (hazard ratio [HR]: 0.96 per 1% increase, P

One of the human natural defense systems protects against nontuberculous mycobacterial (NTM) infection by IFN-γ producing T lymphocyte cells. Most disseminated NTM infections usually occur in severe immune-compromised patients, such as HIV infection or after organ transplant patients. However, there have been several reports of non-compromised patients with disseminated NTM infection, including antibiotic resistance cases and the presence of a neutralizing antibody against IFN-γ. We elucidated the anti-IFN-γ neutralizing antibody in a 65 year-old Japanese man whose legs were paralyzed because of multiple abscesses in vertebral bodies. Although his vertebral bodies were released due to an operation and antibiotics were administered, this treatment efficacy was poor. Patient's plasma demanded not only IFN-γ expression in peripheral blood mononuclear cells (PBMC) obtained from healthy controls, but also recombinant human IFN-γ expression. Furthermore, IFN-γ receptor expression was increased, compared to the healthy control. Finally, anti-IFN-γ antibody was detected in his plasma. These results suggested that anti-IFN-γ antibody induced an incurable NTM infection. IFN-γ was subcutaneously administrated with antibiotics, and then the abscesses diminished and his general condition was successfully improved. This therapy might be useful against severe NTM infections.

Numerous studies investigated patients with IPF; however, only a few examined patients with idiopathic interstitial pneumonias (IIPs).The Japanese Idiopathic Interstitial Pneumonias (JIPS) Registry, which was initiated in December 2016, is a multicenter prospective observational study of patients newly diagnosed with IIPs from 86 facilities treating ILDs. The plan is to enroll more than 600 new patients during the 2-year enrolment period and to follow their progress for 3 years after the last case enrolment. If additional consent is obtained, the study will continue for another 2 years. Research questions mainly focus on identifying the frequency by IIP classification, patient background, and diagnostic methods during enrolment, survival, acute exacerbation rate, changes in high-resolution CT imaging, forced vital capacity, and interstitial pneumonia markers over time. Other research questions, including those regarding disease behavior in patients with progressive fibrosing-ILD and new biomarkers associated with genetic predispositions, will be investigated.The JIPS Registry will provide a comprehensive description of the disease progression, prognosis, treatment status, new biomarkers, and validity of guidelines and central multidisciplinary decisions for IPF and similar diseases that can be differentiated from IPF among IIPs.Ethical approval was obtained from the institutional review board of Kanagawa Cardiovascular and Respiratory Center (KCRC-16-0005), and that of Jichi Medical University approved the biobank part (I18-005). Results will be published in peer-reviewed journals and will be presented at national and international conferences.ClinTrials.gov Registry (NCT03041623, first posted on February 3, 2017).

BackgroundDiffuse pulmonary ossification is a specific lung condition that is accompanied by underlying diseases. However, idiopathic dendriform pulmonary ossification (IDPO) is extremely rare, and the clinical features remain unclear. In this study, we aimed to report the clinical characteristics of IDPO.MethodsWe conducted a nationwide survey of patients with IDPO from 2017 to 2019 in Japan and evaluated the clinical, radiological, and histopathological findings of patients diagnosed with IDPO.ResultsTwenty-two cases of IDPO were identified. Most subjects (82%) were male, aged 22–56 years (mean (SD), 37.9 (9.1)) at diagnosis. Nearly 80% of the subjects were asymptomatic, and the condition was discovered during a medical check-up. However, 36% of the subjects showed a decline in forced vital capacity (%FVC) predicted )) at diagnosis. Nearly 80% of the subjects were asymptomatic, and the condition was discovered during a medical check-up. However, 36% of the subjects showed a decline in forced vital capacity (%FVC) predicted ConclusionsIDPO develops at a young age with gradually progressive phenotype. Further research and long-term (>20 years) follow-up are required to clarify the pathogenesis and clinical findings in IDPO.

Bronchoalveolar lavage (BAL) plays a role in the diagnosis of diffuse parenchymal lung diseases (DPLD); however, poor BAL fluid (BALF) recovery results in low diagnostic reliability. BAL is relatively safe, but its indications should be carefully considered in patients with risks. Therefore, estimating the likelihood of recovery failure is helpful in clinical practice. This study aimed to clarify predictors of BALF recovery failure and to develop its simple-to-use prediction models. We detected the predictors applying a logistic regression model on clinical, physiological, and radiological data from 401 patients with DPLD (derivation cohort). The discrimination performance of the prediction models using these factors was evaluated by the c-index. In the derivation cohort, being a man, the forced expiratory volume in one second/forced vital capacity, and a BAL target site other than right middle lobe or left lingula were independent predictors. The c-indices of models 1 and 2 that we developed were 0.707 and 0.689, respectively. In a separate cohort of 234 patients (validation cohort), the c-indices of the models were 0.689 and 0.670, respectively. In conclusion, we developed and successfully validated simple-to-use prediction models useful for pulmonologists considering BAL indications or target sites, based on independent predictors for BALF recovery failure.

Background and objective The efficacy of combination therapy with corticosteroids and CNI, TAC and CsA, for PM/DM-ILD has been described retrospectively. However, it remains unknown which CNI treatment regimens, TAC or CsA regimens, are more effective as initial treatments for patients with PM/DM-ILD. Methods We conducted a prospective multicentre, open-label, randomized, 52-week phase 2 trial. Patients with PM/DM-ILD were randomly allocated to receive PSL plus TAC (TAC group) or PSL plus CsA (CsA group). The primary endpoint was PFS rate in the intention-to-treat population at 52 weeks. The secondary endpoints were OS rate at 52 weeks, changes in pulmonary function tests from baseline to 52 weeks and AE. Results Fifty-eight patients were randomly assigned to the TAC group (n = 30) and the CsA group (n = 28). The PFS rates at 52 weeks were 87% in the TAC group and 71% in the CsA group (P = 0.16). The OS rates at 52 weeks were 97% in the TAC group and 93% in the CsA group (P = 0.50). The %FVC at 52 weeks in the per-protocol populations significantly increased in both groups. None of the patients discontinued the treatment due to AE. Conclusion PSL plus TAC treatment may achieve a better short-term PFS rate compared with PSL plus CsA treatment. Further studies must be conducted to evaluate the long-term efficacy and safety of such treatment.

Context Although idiopathic pulmonary fibrosis (IPF) has worse outcomes compared with most malignancies, patients with IPF receive poor access to optimal palliative care. Objectives This study aimed to characterize the practice of pulmonologists regarding palliative care and end-of-life communication for patients with IPF and identify perceived difficulties and barriers thereto. Methods Self-administered questionnaires were sent by mail to representative pulmonologists from Shizuoka prefecture, Japan. Physician-reported practice, difficulties, timing of end-of-life communication, and barriers related to palliative care were investigated. Results Among the 135 participants, 130 (96%) completed the questionnaire. Most of the participants reported that patients with IPF complained of dyspnea and cough. However, less morphine was prescribed for IPF than for lung cancer. The participants experienced greater difficulty in providing palliative care for IPF than for lung cancer. Moreover, actual end-of-life discussions in patients with IPF were conducted later than the physician-perceived ideal timing. Among the barriers identified, few established treatment and difficulty in predicting prognosis (odds ratio [OR] 2.0; P = 0.04), discrepancies in understanding and care goals among patients, family, and medical staff (OR 2.2; P = 0.03), and inadequate communication about goal of care (OR 2.3; P = 0.003) were significantly associated with the physician-perceived difficulties in providing palliative care for patients with IPF. Conclusion Pulmonologists experienced greater difficulty in providing palliative care to patients with IPF than to those with lung cancer. Clinical studies on the optimal palliative care for patients with IPF are urgently required.

BackgroundViral respiratory tract infections, such as influenza A virus (IAV), are common and life-threatening illnesses worldwide. The mechanisms by which viruses are removed from the respiratory tract are indispensable for airway host defense. Mucociliary clearance is an airway defense mechanism that removes pathogens from the respiratory tract. The coordination and modulation of the ciliary beating of airway epithelial cells play key roles in maintaining effective mucociliary clearance. However, the impact of respiratory virus infection on ciliary activity and mucociliary clearance remains unclear.MethodsTracheal samples were taken from wild-type (WT) and Toll-like receptor 3 (TLR3)-knockout (KO) mice. Transient organ culture of murine trachea was performed in the presence or absence of IAV, polyI:C, a synthetic TLR3 ligand, and/or reagents. Subsequently, cilia-driven flow and ciliary motility were analyzed. To evaluate cilia-driven flow, red fluorescent beads were loaded into culture media and movements of the beads onto the tracheal surface were observed using a fluorescence microscope. To evaluate ciliary motility, cilia tips were labeled with Indian ink diluted with culture medium. The motility of ink-labeled cilia tips was recorded by high-speed cameras.ResultsShort-term IAV infection significantly increased cilia-driven flow and ciliary beat frequency (CBF) compared with the control level in WT culture. Whereas IAV infection did not elicit any increases of cilia-driven flow and CBF in TLR3-KO culture, indicating that TLR3 was essential to elicit an increase of cilia-driven flow and CBF in response to IAV infection. TLR3 activation by polyI:C readily induced adenosine triphosphate (ATP) release from the trachea and increases of cilia-driven flow and CBF in WT culture, but not in TLR3-KO culture. Moreover, blockade of purinergic P2 receptors (P2Rs) signaling using P2R antagonist, suramin, suppressed polyI:C-mediated increases of cilia-driven flow and CBF, indicating that TLR3-mediated ciliary activation depended on released extracellular ATP and the autocrine ATP-P2R loop.ConclusionsIAV infection readily increases ciliary activity and cilia-driven flow via TLR3 activation in the airway epithelium, thereby hastening mucociliary clearance and “sweeping” viruses from the airway as an initial host defense response. Mechanically, extracellular ATP release in response to TLR3 activation promotes ciliary activity through autocrine ATP-P2R loop.

Purpose: The efficacy and safety of combination therapy with erlotinib and bevacizumab in elderly patients with non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) gene mutations are unknown.Methods: Elderly patients aged ≥75 years old with advanced or recurrent NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) received erlotinib (150 mg, daily) and bevacizumab (15 mg/kg on day 1 of a 21-day cycle) until disease progression or the occurrence of unacceptable toxicities. The primary endpoint was progression-free survival from enrollment.Results: Twenty-five patients were enrolled in this study, and the median age was 80 years. Fifteen (60.0%) and 10 patients (40.0%) had exon 21 L858R mutations and exon 19 deletions, respectively. The median progression-free survival from enrollment was 12.6 months [95% confidence interval (CI): 8.0–33.7 months]. The objective response rate was 88.0% [95% CI: 74.0%–99.0%], and the disease control rate was 100% [95 % CI: 88.7%–100%]. Grade 3 or higher adverse events occurred in 12 patients (48.0%), and rash and nausea were the most common. Grade 3 or higher bevacizumab-related toxicities occurred in 4 (16.0%) patients, including proteinuria (n=2), gastrointestinal perforation (n=1) and pneumothorax (n=1). A dose reduction of erlotinib and cessation of bevacizumab was required in 16 (64.0%) and 18 patients (72.0%), respectively.Conclusion: Erlotinib and bevacizumab combination therapy showed a minimal survival benefit with frequent dose reductions and/or treatment discontinuations in elderly patients with EGFR-positive NSCLC.

Immune checkpoint inhibitors have provided a breakthrough in cancer therapy. Pneumonitis related to immune checkpoint inhibitors is a serious immune-related adverse event that can be fatal. However, the response to corticosteroids and clinical course of pneumonitis remain poorly understood. We retrospectively reviewed the records of patients who received monotherapy with anti-programmed death 1 (PD-1) antibody, nivolumab, or pembrolizumab, and examined cases with anti-PD-1 antibody-related pneumonitis. The incidence, response to treatment, and recurrence of pneumonitis were investigated. Of 592 patients who received nivolumab or pembrolizumab, 79 developed anti-PD-1 antibody-related pneumonitis. The incidence of all-grade and grade 3–5 pneumonitis was 13.3% and 5.1%, respectively. Despite corticosteroid therapy, 16.5% of pneumonitis cases did not improve, which occurred significantly more frequently in patients with poor performance status, low serum albumin level, and pleural effusion. Among patients with improved pneumonitis, 12.3% experienced recurrence of pneumonitis without re-administration of anti-PD-1 antibody. Anti-PD-1 antibody was re-administered in 16 patients after initial clinical improvement, and five (31.2%) patients experienced a second recurrence of pneumonitis. The incidence of pneumonitis was not rare in real-world settings. Even after improvement of pneumonitis, pneumonitis flare can occur with and without PD-1 antibody re-administration.

This retrospective, multicentre study investigated the prevalence of radiological PPFE in patients with MAC lung disease and its association with clinical features and outcomes. Radiological PPFE was diagnosed on the basis of HRCT findings. Prognostic factors were identified using Cox proportional hazards and Fine-Gray models.Of 850 consecutive patients with definite MAC lung disease, 101 (11.9%) exhibited radiological PPFE. Patients with radiological PPFE had unique characteristics, such as lower body mass index, lower survival rate (5-year cumulative survival rate, 63.1% vs 91.7%; p0.001) and a higher incidence of respiratory-related death (5-year cumulative incidence, 31.1% vs 3.6%; p0.001), than those without radiological PPFE. In the multivariable analysis, the presence of radiological PPFE was independently associated with all-cause mortality (adjusted HR, 4.78; 95% CI, 2.87 to 7.95; p0.001) and respiratory-related death (adjusted HR, 3.88; 95% CI, 2.14 to 7.01; p0.001).This large-scale study demonstrated that in patients with MAC lung disease, radiological PPFE was common, a phenotype associated with unique clinical features and poor prognosis, particularly respiratory-related death. The specific management of this subgroup should be established.

Background Fatty acids have diverse immunomodulatory functions and the potential to be associated with inflammatory responses in sarcoidosis. Methods The serum levels of multiple long-chain fatty acids (LCFAs) were compared between 63 patients with sarcoidosis and 38 healthy controls. The associations of LCFAs with clinical outcomes of sarcoidosis were also evaluated. Results The patients with sarcoidosis had significantly lower levels of n-3 poly-unsaturated fatty acids (PUFAs) (p p

Background Fatty acids have diverse immunomodulatory functions and the potential to be associated with inflammatory responses in sarcoidosis. Methods The serum levels of multiple long-chain fatty acids (LCFAs) were compared between 63 patients with sarcoidosis and 38 healthy controls. The associations of LCFAs with clinical outcomes of sarcoidosis were also evaluated. Results The patients with sarcoidosis had significantly lower levels of n-3 poly-unsaturated fatty acids (PUFAs) (p p Conclusions Assessment of LCFA profiles may be useful for the diagnosis of sarcoidosis and evaluation of the disease activity.

Obesity is a common comorbidity in patients with asthma, and obese asthma patients present the most refractory phenotype among patients with severe asthma. Similar to the observations in non-obese asthma patients, clinical studies have revealed heterogeneity in obese asthma patients, including the occurrences of T helper (Th)2-high and Th2-low phenotypes. However, the mechanisms underlying obesity-related asthma are not completely understood. Though macroautophagy/autophagy is involved in asthma and obesity, its role in obesity-associated asthma is unknown. We hypothesized that autophagy is involved in the pathogenesis of obese asthma. For our investigations, we used high-fat diet-induced Atg5 (autophagy related 5)-deficient mice and epithelial cell-specific atg5−/− (Scgb1a1/CCSP-atg5−/−) obesity-induced mice. House dust mite (HDM)-sensitized atg5−/− obese mice exhibited marked eosinophilic inflammation and airway hyper-reactivity (AHR), compared to wild-type (WT) obese mice. Analyses of atg5−/− obese mice showed increased levels of Th2 cells but not ILC2s together with elevated expression of Th2 cytokines in the lung. In response to the HDM challenge, activated epithelial autophagy was observed in lean but not obese WT mice. Epithelium-specific deletion of Atg5 induced eosinophilic inflammation in Scgb1a1/CCSP-atg5−/− obese mice, and genetic analyses of epithelial cells from HDM-immunized atg5−/− obesity-induced mice showed an elevated expression of thymic stromal lymphopoietin (TSLP) and IL33. Notably, HDM-sensitized atg5−/− mice developed TSLP- and IL33-dependent eosinophilic inflammation and AHR. Our results suggest that autophagy contributes to the exacerbation of eosinophilic inflammation in obese asthma. Modulations of autophagy may be a therapeutic target in obesity-associated asthma. Abbreviations: AHR: airway hyper-reactivity; BAL: bronchoalveolar lavage; Cdyn: dynamic compliance; BM: bone marrow; HDM: house dust mite; HFD: high-fat diet; ILC2s: type 2 innate lymphocyte cells; ROS: reactive oxygen species; RL: lung resistance; TSLP: thymic stromal lymphopoietin; TCC: total cell count; WT: wild type.

Background The assessment of lung physiology via pulmonary function tests (PFTs) is essential for patients with idiopathic pulmonary fibrosis (IPF). However, PFTs require active participation, which can be challenging for patients with severe respiratory failure, such as during moments of acute exacerbation (AE) of IPF. Recent advances have enabled the re-construction of 3-dimensional computed-tomography (3D-CT) images. This study established a standardisation method and quantitative analysis of lung volume (LV) based on anthropometry using 3D-CT images. Methods This is a retrospective multi-center cohort study. The standardised 3D-CT LV in patients with IPF at diagnosis (n = 140) and during AE (cohort1; n = 61 and cohort2; n = 50) and those of controls (n = 53) were assessed. Results The standardised 3D-CT LVs at IPF diagnosis were less than those of control patients, especially in the lower lung lobes. The standardised 3D-CT LVs were correlated with forced vital capacity (FVC) and validated using the modified Gender-Age-Physiology (GAP) index. The standardised 3D-CT LVs at IPF diagnosis were independently associated with prognosis. During AE, PFTs were difficult to perform, 3D-CT analyses revealed reduced lung capacity in both the upper and lower lobes compared to those obtained at diagnosis. Lower standardised 3D-CT LVs during AE were independently associated with worse outcomes in the two independent cohorts. In particular, volume loss in the upper lobe at AE had prognostic values. Conclusions A novel image quantification method for assessing pulmonary physiology using standardised 3D-CT-derived LVs was developed. This method successfully predicts mortality in patients with IPF and AE of IPF, and may be a useful alternative when PFTs cannot be performed.

Background Patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD), like those with idiopathic pulmonary fibrosis (IPF), might develop an unexpected acute exacerbation (AE)—a rapidly progressing and deadly respiratory decline. Although AE incidence and risk factors in RA-ILD patients are known, their post-AE clinical course remains unknown owing to the rarity of AE-RA-ILD. This multicentre retrospective study evaluated post-AE mortality and prognostic variables in AE-RA-ILD patients and created a mortality prediction model for AE-RA-ILD. Methods This research comprised 58 patients with AE-RA-ILD and 96 with AE-IPF (a control disease). Multivariate Cox regression analysis was performed to identify prognostic variables. A prediction model was created with recursive partitioning (decision tree). Results The post-AE 90-day mortality rate in the overall AE-RA-ILD group was 48.3%; percent predicted forced vital capacity within 12 months before AE onset (baseline %FVC) and PaO2/FiO2 ratio at AE onset (P/F at AE) were independent predictors of mortality. Post-AE 90-day mortality rates were 40.6% and 43.8%, respectively, in AE-RA-ILD and AE-IPF patients propensity score-matched for age, sex, baseline %FVC and P/F at AE (P = 1.0000). In AE-RA-ILD patients, C-indices of baseline %FVC and P/F at AE to predict post-AE 90-day mortality were 0.604 and 0.623, respectively. A decision tree model based on these prognostic factors classified AE-RA-ILD patients into mild, moderate and severe groups (post-AE 90-day mortality rates: 20.8%, 64.0% and 88.9%, respectively; P = 0.0002); the C-index improved to 0.775. Conclusions Post-AE mortality was high in AE-RA-ILD patients similar to AE-IPF patients. The discovered prognostic factors and our mortality prediction model may aid in the management of AE-RA-ILD patients.

BackgroundMycobacterium aviumcomplex (MAC) causes chronic respiratory infectious diseases with diverse clinical features and prognoses. Pleuroparenchymal fibroelastosis (PPFE) is a rare disease characterised by pleural fibrosis with subjacent intra-alveolar fibrosis and alveolar septal elastosis, with unique chest high-resolution CT (HRCT) features (radiological PPFE). An association between recurrent respiratory infections and PPFE formation has been hypothesised; however, the clinical significance of PPFE in MAC lung disease remains unclear.MethodsThis retrospective, multicentre study investigated the prevalence of radiological PPFE in patients with MAC lung disease and its association with clinical features and outcomes. Radiological PPFE was diagnosed on the basis of HRCT findings. Prognostic factors were identified using Cox proportional hazards and Fine-Gray models.ResultsOf 850 consecutive patients with definite MAC lung disease, 101 (11.9%) exhibited radiological PPFE. Patients with radiological PPFE had unique characteristics, such as lower body mass index, lower survival rate (5-year cumulative survival rate, 63.1% vs 91.7%; pInterpretationThis large-scale study demonstrated that in patients with MAC lung disease, radiological PPFE was common, a phenotype associated with unique clinical features and poor prognosis, particularly respiratory-related death. The specific management of this subgroup should be established.

Background Clinical efficacy of immune checkpoint inhibitors (ICIs) for non-small cell lung cancer (NSCLC) with uncommon histology (uNSCLC) is unknown. Methods Patients with NSCLC treated with ICI monotherapy between January 2014 and December 2018 in 10 Japanese hospitals were retrospectively evaluated. The patients were divided into: (1) NSCLC with common histology (cNSCLC), defined as adenocarcinoma and squamous cell carcinoma; and (2) uNSCLC, defined as incompatibility with morphological and immunohistochemical criteria for adenocarcinoma or squamous cell carcinoma. Propensity score matching was performed to balance the two groups. Results Among a total of 175 patients included, 44 with uNSCLC (10 pleomorphic carcinomas, 9 large cell neuroendocrine carcinomas, 2 large cell carcinomas, and 23 not otherwise specified) and 44 with matched cNSCLC (32 adenocarcinomas and 12 squamous cell carcinomas) were selected for analyses. Median progression-free survival (PFS) (4.4 months, 95% confidence interval [CI] 1.8–7.7 months) and overall survival (OS) (11.4 months, 95% CI 7.4–27.4 months) in the uNSCLC patients were not significantly different from those in matched cNSCLC patients (5.4 months, 95% CI 3.1–7.6 months, p = 0.761; and 14.1 months, 95% CI 10.6–29.6 months, p = 0.381). In multivariate analysis, Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0–1 and programmed death ligand-1 (PD-L1) expression were predictive for PFS and OS in uNSCLC. Conclusions ICIs had similar clinical efficacy for treatment of uNSCLC and cNSCLC. Good ECOG-PS and PD-L1 expression were predictive for efficacy of ICIs in uNSCLC.

Patients with idiopathic pulmonary fibrosis (IPF) are at a high risk of lung cancer (LC). Antifibrotic therapy slows disease progression and possibly prolongs survival. However, whether antifibrotic therapy affects LC development in patients with IPF remains unknown. This multicentre retrospective study evaluated 345 patients with IPF. The incidence and prevalence of LC were significantly lower in patients with IPF receiving antifibrotic therapy than those not receiving. Subsequently, LC-related mortality was significantly lower in patients with IPF receiving antifibrotic therapy. These results suggest that antifibrotic therapy was possibly associated with a reduced risk of LC development in patients with IPF, which may be partly associated with its survival benefit.

Background Pleuroparenchymal fibroelastosis (PPFE) is characterised by predominant upper lobe pleural and subpleural lung parenchymal fibrosis. Radiological PPFE-like lesion has been associated with various types of interstitial lung diseases. However, the prevalence and clinical significance of radiological PPFE-like lesion in patients with idiopathic interstitial pneumonias (IIPs) are not fully understood. We aimed to determine the prevalence and clinical impact on survival of radiological PPFE-like lesion in patients with IIPs. Methods A post-hoc analysis was conducted using data from the Japanese nationwide cloud-based database of patients with IIPs. All the patients in the database were diagnosed as having IIPs by multidisciplinary discussion. Patients diagnosed with idiopathic PPFE were excluded. Clinical data and chest computed tomography (CT) image of 419 patients with IIPs were analysed. The presence of radiological PPFE-like lesion was independently evaluated by two chest radiologists blind to the clinical data. Results Of the 419 patients with IIPs, radiological PPFE-like lesions were detected in 101 (24.1%) patients, mainly in idiopathic pulmonary fibrosis (IPF) and unclassifiable IIPs, but less in idiopathic nonspecific interstitial pneumonia. Prognostic analyses revealed that radiological PPFE-like lesion was significantly associated with poor outcome in patients with IIPs, which was independent of age, IPF diagnosis and %FVC. In survival analyses, the patients with radiological PPFE-like lesions had poor survival compared with those without (log-rank, p Conclusion Radiological PPFE-like lesion is a condition that could exist in IIPs, mainly in IPF and unclassifiable IIPs. Importantly, the radiological PPFE-like lesion is a non-invasive marker to predict poor outcome in patients with IIPs, which should be carefully considered in clinical practice.

Background Respiratory modalities applied at the end of life may affect the burden of distressing symptoms and quality of dying and death (QODD) among patients with end-stage interstitial lung disease (ILD); however, there have been few studies into respiratory modalities applied to these patients near death. We hypothesized that high-flow nasal cannula (HFNC) might contribute to improved QODD and symptom relief in patients with end-stage ILD. Objectives This multicenter study examined the proportion of end-of-life respiratory modalities in a hospital setting and explored its impact on QODD and symptom relief among patients dying with ILD. Methods Consecutive patients with ILD who died in four participating hospitals in Japan from 2015 to 2019 were identified and divided into four groups according to end-of-life respiratory modality: conventional oxygen therapy (COT), HFNC, non-invasive ventilation (NIV), and invasive mechanical ventilation (IMV). In addition, a mail survey was performed to quantify the QODD and symptom relief at their end of life from a bereaved family’s perspective. QODD and symptom relief were quantified using the Good Death Inventory (GDI) for patients with a completed bereavement survey. The impact of end-of-life respiratory modalities on QODD and symptom relief was measured by multivariable linear regression using COT as a reference. Results Among 177 patients analyzed for end-of-life respiratory modalities, 80 had a completed bereavement survey. The most common end-of-life respiratory modality was HFNC (n = 76, 42.9%), followed by COT (n = 62, 35.0%), NIV (n = 27, 15.3%), and IMV (n = 12, 6.8%). Regarding the place of death, 98.7% of patients treated with HFNC died outside the intensive care unit. Multivariable regression analyses revealed patients treated with HFNC had a higher GDI score for QODD [partial regression coefficient (B) = 0.46, 95% CI 0.07–0.86] and domain score related to symptom relief (B = 1.37, 95% CI 0.54–2.20) than those treated with COT. Conclusion HFNC was commonly used in patients with end-stage ILD who died in the hospital and was associated with higher bereaved family ratings of QODD and symptom relief. HFNC might contribute to improved QODD and symptom relief in these patients who die in a hospital setting.

Antifibrotic therapy (AFT) slows disease progression in patients with idiopathic pulmonary fibrosis (IPF). The Gender-Age-Physiology (GAP) index, was developed based on data at IPF diagnosis before the introduction of AFT and has not been evaluated in the AFT context. Further, recent advances have revealed the importance of body-composition factors in prognosis of IPF treated with AFT. This multi-centre, retrospective study aimed to evaluate the GAP index and body mass index (BMI) at the time of AFT initiation for predicting prognosis in patients with IPF. This study included two patient cohorts of IPF receiving AFT, Hamamatsu cohort (n = 110) and Seirei cohort (n = 119). The distribution of GAP stages I, II, and III was 38.2%, 43.6%, and 18.2%, respectively, in Hamamatsu cohort; in Seirei cohort, it was 41.2%, 50.4%, and 8.4%, respectively. In both cohorts, the GAP index distinctly classified prognosis into three groups (log-rank test). Interestingly, a lower BMI showed prognostic value independent of the GAP index in multivariate analyses. Subsequently, combining the GAP index with BMI at AFT initiation successfully divided the patients with IPF into four distinct prognoses. Assessment of the GAP index and BMI measurement at AFT initiation are important for predicting prognosis in patients with IPF.

BackgroundMucociliary clearance (MCC) is an essential defense mechanism in airway epithelia for removing pathogens from the respiratory tract. Impaired ciliary functions and MCC have been demonstrated in asthma and chronic obstructive pulmonary disease (COPD). Long-acting muscarinic antagonists (LAMAs) are a major class of inhaled bronchodilators, which are used for treating asthma and COPD; however, the effects of LAMAs on ciliary function remain unclear. This study aimed to identify the effects of LAMAs on airway ciliary functions.MethodsWild-type BALB/c mice were treated with daily intranasal administrations of glycopyrronium for 7 days, and tracheal samples were collected. Cilia-driven flow and ciliary activity, including ciliary beat frequency (CBF), ciliary beating amplitude, effective stroke velocity, recovery stroke velocity and the ratio of effective stroke velocity to recovery stroke velocity, were analyzed by imaging techniques. Using in vitro murine models, tracheal tissues were transiently cultured in media with/without LAMAs, glycopyrronium or tiotropium, for 60 min. Cilia-driven flow and ciliary activity were then analyzed. Well-differentiated normal human bronchial epithelial (NHBE) cells were treated with glycopyrronium, tiotropium, or vehicle for 60 min, and CBF was evaluated. Several mechanistic analyses were performed.ResultsIntranasal glycopyrronium administration for 7 days significantly increased cilia-driven flow and ciliary activity in murine airway epithelium. In the murine tracheal organ culture models, treatment with glycopyrronium or tiotropium for 60 min significantly increased cilia-driven flow and ciliary activity in airway epithelium. Further, we confirmed that 60-min treatment with glycopyrronium or tiotropium directly increased CBF in well-differentiated NHBE cells. In the mechanistic analyses, neither treatment with glycopyrronium nor tiotropium affected intracellular calcium ion concentrations in well-differentiated NHBE cells. Glycopyrronium did not increase protein kinase A activity in well-differentiated NHBE cells. Moreover, glycopyrronium had no effect on extracellular adenosine triphosphate concentration.ConclusionsLAMAs exert a direct effect on airway epithelium to enhance ciliary function, which may improve impaired MCC in asthma and COPD. Further investigations are warranted to elucidate the underlying mechanisms of the effects of LAMAs on the promotion of airway ciliary function.

Background Lung fibrosis is a serious life-threatening condition whose manifestation varies according to the localization and characteristics of fibroblasts, which are considered heterogeneous. Therefore, to better understand the pathology and improve diagnosis and treatment of this disease, it is necessary to elucidate the nature of this heterogeneity and identify markers for the accurate classification of human lung fibroblast subtypes. Methods We characterized distinct mouse lung fibroblast subpopulations isolated by fluorescence-activated cell sorting (FACS) and performed microarray analysis to identify molecular markers that could be useful for human lung fibroblast classification. Based on the expression of these markers, we evaluated the fibroblast-like cell subtype localization in normal human lung samples and lung samples from patients with idiopathic pulmonary fibrosis (IPF). Results Mouse lung fibroblasts were classified into Sca-1high fibroblasts and Sca-1low fibroblasts by in vitro biological analyses. Through microarray analysis, we demonstrated CD248 and integrin alpha-8 (ITGA8) as cell surface markers for Sca-1high fibroblasts and Sca-1low fibroblasts, respectively. In mouse lungs, Sca-1high fibroblasts and Sca-1low fibroblasts were localized in the collagen fiber-rich connective tissue and elastic fiber-rich connective tissue, respectively. In normal human lungs and IPF lungs, two corresponding major fibroblast-like cell subtypes were identified: CD248highITGA8low fibroblast-like cells and CD248lowITGA8high fibroblast-like cells, localized in the collagen fiber-rich connective tissue and in the elastic fiber-rich connective tissue, respectively. Conclusion CD248highITGA8low fibroblast-like cells and CD248lowITGA8high fibroblast-like cells were localized in an almost exclusive manner in human lung specimens. This human lung fibroblast classification using two cell surface markers may be helpful for further detailed investigations of the functions of lung fibroblast subtypes, which can provide new insights into lung development and the pathological processes underlying fibrotic lung diseases.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with a poor prognosis. There are no established serum biomarkers for predicting the outcomes of IPF. S100 calcium-binding protein A4 (S100A4) is considered as a marker of fibroblasts; however, its clinical application remains to be investigated. We evaluated the clinical relevance of S100A4 in IPF patients.Serum S100A4 levels in 95 consecutive IPF patients and 50 healthy controls (HC) were measured using enzyme-linked immunosorbent assay. S100A4 expression in lung tissues was determined using immunohistochemistry/immunofluorescence and its association with disease progression (defined as deterioration in lung function or death) and mortality was assessed using Kaplan-Meier method and Cox hazards analysis.Serum S100A4 levels were undetectable in all HC but were detectable in 26 (27.3%) of the 95 IPF patients (P 0.01). Immunostaining of lung tissues from IPF patients showed aggregation of numerous S100A4-expressing cells around the fibroblastic foci and mature fibrotic regions. IPF patients with higher serum S100A4 levels had a significantly worse prognosis than those with low serum levels (2-year cumulative survival rate: 41.7% vs 77.0%, respectively, P 0.01). On multivariate analyses, baseline serum S100A4 levels (per 10 ng/mL increase) were independently associated with higher disease progression rate (odds ratio: 1.06, P = 0.01) and higher mortality (hazard ratio: 1.18, P = 0.03).S100A4 is a promising serum biomarker that may help predict disease progression/mortality. Our findings may help establish treatment strategies for IPF.

Background: The prevalence of pulmonary infections caused by nontuberculous mycobacteria (NTM) is increasing worldwide. Furthermore, the treatment of infections caused by the Mycobacterium avium-intracellulare complex (MAC) remains challenging. The cytochrome P450 (CYP) enzyme inducer, rifampicin, and the CYP inhibitor, clarithromycin, have clinical activity against MAC and key drugs in the treatment of MAC infection. The interaction of rifampicin and clarithromycin may influence the therapeutic process. Methods: Thirty-one Japanese chemo-naive patients with pulmonary MAC infection were included in the study. Before and after 7-day administration of rifampicin and clarithromycin, the pharmacokinetics of midazolam, a CYP3A-specific probe, were analyzed. The concentrations of midazolam were determined by liquid chromatography-tandem mass spectrometry. None of the patients were receiving any other medications that might affect CYP3A activity. Results: Of the patients, 24 (77.4%) were infected with Mycobacterium avium ( M. avium ) and 7 (22.6%) were infected with Mycobacterium intracellulare ( M. intracellulare ). The concentrations of midazolam were significantly reduced with administration of rifampicin and clarithromycin [the median (range) was 1.75 (0.70–8.22) to 1.04 (0.30–2.63) ng/mL, P Conclusions: Coadministration of rifampicin and clarithromycin may increase CYP3A enzymatic activity.

Background Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor, has been shown to improve survival in non-small cell lung cancer (NSCLC). The possible involvement of PD-1 axis in the pathogenesis of inflammatory lung disease, such as chronic obstructive pulmonary disease (COPD) has also been reported. However, effects of PD-1 blockade on the respiratory system remain unknown. Objectives This prospective study aimed to investigate whether inhibition of the PD-1 axis altered lung inflammation and pulmonary function in NSCLC patients with and without COPD. Method This was a prospective multi-center study. Measurements of fractioned exhaled nitric oxide (FeNO) and pulmonary function were performed before and after 4 cycles of nivolumab therapy. Results A total of 137 patients with NSCLC were initially enrolled, and subsequently 95 patients (41 COPD and 54 non-COPD) receiving 4 cycles of nivolumab administration were included. After anti-PD-1 therapy, FeNO levels were significantly elevated together with increase in peripheral eosinophils. Interestingly, significant FeNO elevation was only found in COPD patients without increased peripheral eosinophils, but this was not the case in non-COPD patients. Additionally, COPD patients exhibited significant increases in FVC and FEV1 but no changes in dyspnea scales, and acute exacerbation did not occur during the therapy. Conclusion Our observations suggest that anti-PD-1 therapy changed FeNO levels and pulmonary function in NSCLC patients. This therapy does not worsen COPD in terms of symptoms, pulmonary function, or acute exacerbation.

Weight loss progresses with the progression of idiopathic pulmonary fibrosis (IPF), and acute exacerbation of IPF (AE-IPF) frequently occurs in its advanced stage. Adiponectin and leptin are adipokines produced from adipose tissue, and are related to thinness and obesity, respectively. Additionally, these adipokines are implicated in the regulation of inflammation and fibrosis centering on peroxisome proliferator-activated receptor γ (PPARγ). However, the relationship between adiponectin/leptin and AE-IPF remains poorly known. We conducted this study to evaluate levels of serum adiponectin/leptin, and to elucidate the clinical importance of adiponectin and leptin in patients with AE-IPF. Thirty-two patients (39 episodes) who were diagnosed with AE-IPF at our hospital from 1997 to 2016 were retrospectively studied. Serum adiponectin and leptin concentrations were measured with enzyme-linked immunosorbent assay. Patients with AE-IPF showed higher levels of serum adiponectin and leptin than those at initial diagnosis of IPF (p = 0.007 and p = 0.027, respectively). Serum adiponectin/leptin (A/L) ratio was negatively correlated with body mass index at AE-IPF (r = −0.456, p = 0.003) and PaO2 before AE-IPF (r = −0.498, p = 0.034), and positively correlated with C-reactive protein at AE-IPF (r = 0.316, p = 0.049). Patients with higher A/L ratios had worse survival than those with lower A/L ratios (log-rank, p = 0.026). Further, in multivariate analysis, serum A/L ratio was a significant prognostic factor in patients with AE-IPF (HR 2.60, p = 0.042). In conclusion, the higher adiponectin/leptin ratio may be associated with a poor prognosis in patients with AE-IPF.

A 69-year-old man developed bilateral polyarthritis, edematous extremities, and skin desquamation on the fingers and ears. He did not meet the criteria for any connective tissue disease, including rheumatoid arthritis. An examination revealed advanced lung cancer. His systemic manifestations were attributed to paraneoplastic Bazex syndrome and remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome. Treatment with pembrolizumab (an anti-programmed death-1 antibody) for lung cancer relieved his symptoms and shrank the lung tumor. Bazex and RS3PE syndromes are rare paraneoplastic diseases. We herein report this unique case of synchronous development of these two paraneoplastic syndromes in the presence of advanced lung cancer.

A 71-year-old woman with abnormal pulmonary shadows and multiple enlarged thoracic lymph nodes was diagnosed with stage IIB lung adenocarcinoma, pulmonary sarcoidosis, and sarcoidosis-associated lymphadenopathy after biopsies from multiple organ sites. She also had rapidly progressive renal dysfunction, microhematuria, and high myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) concentrations. A renal biopsy revealed granulomatous tubulointerstitial nephritis and necrotizing glomerulonephritis with crescent formation. She was diagnosed with nephritis caused by both sarcoidosis and ANCA-associated vasculitis. Oral prednisolone was administered to treat her nephritis, resulting in improvement in both her renal dysfunction and her sarcoidosis-associated lymphadenopathy.

Purpose The diagnosis and severity of chronic obstructive pulmonary disease (COPD) are defined by airflow limitation using spirometry. However, COPD has diverse clinical features, and several phenotypes based on non-spirometric data have been investigated. To identify novel phenotypes of COPD using radiologic data obtained by three-dimensional computed tomography (3D-CT). Patients and methods The inner luminal area and wall thickness of third- to sixth-generation bronchi and the percentage of the low-attenuation area (less than -950 HU) of the lungs were measured using 3D-CT in patients with COPD. Using the radiologic data, hierarchical clustering was performed. Respiratory reactance and resistance were measured to evaluate functional differences among the clusters. Results Four clusters were identified among 167 patients with COPD: Cluster I, mild emphysema with severe airway changes, severe airflow limitation, and high exacerbation risk; Cluster II, mild emphysema with moderate airway changes, mild airflow limitation, and mild dyspnea; Cluster III, severe emphysema with moderate airway changes, severe airflow limitation, and increased dyspnea; and Cluster IV, moderate emphysema with mild airway changes, mild airflow limitation, low exacerbation risk, and mild dyspnea. Cluster I had the highest respiratory resistance among the four clusters. Clusters I and III had higher respiratory reactance than Clusters II and IV. Conclusions The 3D-CT-based radiologic phenotypes were associated with the clinical features of COPD. Measurement of respiratory resistance and reactance may help to identify phenotypic differences.