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Abstract Background Interstitial pneumonia with autoimmune features (IPAF), which does not meet any of the criteria for connective tissue diseases (CTD), has been attracting an attention in patients with idiopathic interstitial pneumonia (IIP). However, the biomarkers that reflect the clinical course of these patients have not been fully elucidated. Objective To identify useful serum biomarkers reflecting CTD-related features and favorable prognoses in patients with IIP. Methods This was a post hoc analysis of a prospective and multicenter cohort study between 2015 and 2020. Newly diagnosed patients with IIP were consecutively enrolled, and 74 autoimmune features and autoantibodies were comprehensively checked during IIP diagnosis. Serum levels of CXCL10, CXCL1, CCL2, BAFF, angiopoietin-2, and leptin were evaluated at the time of IIP diagnosis. Results Two hundred twenty-two patients (159 men and 63 women) with IIP were enrolled. The median observation duration was 36 months. The median age was 71 years old, and median %forced vital capacity (FVC) was 84.1% at the time of IIP diagnosis. The proportion of patients who met the classification criteria for IPAF was 11.7%. In patients with high serum CXCL10, changes in both %FVC and %diffusion lung capacity for carbon monoxide at one year were significantly higher than those in patients with low CXCL10 (p = 0.014 and p = 0.009, respectively), whereas these changes were not significant for other chemokines and cytokines. High CXCL10 levels were associated with acute/subacute onset (p

Abstract Background Acute exacerbation (AE) of systemic autoimmune disease-related interstitial lung diseases (SAID-ILD) is less common than AE of idiopathic pulmonary fibrosis (IPF) and the details of AE-SAID-ILD have not been elucidated, but the prognosis is similarly devastating. This study was undertaken to determine the incidences of AE-ILD in each SAID and to elucidate the proportion of progressive fibrosing (PF)-ILD in AE-SAID-ILD. Methods We retrospectively analysed data for patients with SAID-ILD who were diagnosed and observed at our hospital between 1999 and 2020. Results Two hundred and thirty-two patients with SAID-ILD were enrolled, with a mean observation period of 100.2 months. AE-SAID-ILD was found in 25 patients (10.78%), mainly in patients with RA (17 patients, 68%) and elderly male patients with a smoking history. The overall incidence of AE-SAID-ILD was 1.29%/person-year, and the incidence for each SAID was as follows: RA 2.193, microscopic polyarteritis (MPA) 3.203, systemic sclerosis (SSc) 2.277, primary Sjögren syndrome 0.426, and polymyositis/dermatomyositis 0.222. The incidence of AE of RA/MPA/SSc-ILD was significantly higher than that of other AE-SAID-ILD (p

Abstract 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

Abstract 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.

Abstract Background Mucociliary 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. Methods Wild-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. Results Intranasal 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. Conclusions LAMAs 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.

Abstract 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.

Abstract 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.

Abstract 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

Abstract 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

Abstract 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.

Abstract Background Currently, there are two antifibrotics used to treat idiopathic pulmonary fibrosis (IPF): pirfenidone and nintedanib. Antifibrotics slow disease progression by reducing the annual decline of forced vital capacity (FVC), which possibly improves outcomes in IPF patients. During treatment, patients occasionally switch antifibrotic treatments. However, prognostic implication of changing antifibrotics has not yet been evaluated. Methods This multi-center retrospective cohort study examined 262 consecutive IPF patients who received antifibrotic therapy. Antifibrotic agents were switched in 37 patients (14.1%). The prognoses were compared between the patient cohort that switched antifibrotics (Switch-IPF) and those without (Non-Switch-IPF) using propensity-score matched analyses. Results The median period between the initiation of antifibrotic therapy and the drug switch was 25.8 (12.7–35.3) months. The most common reasons for the switch were disease progression (n = 17) followed by gastrointestinal disorders (n = 12). Of the 37 patients that switched antifibrotics, only eight patients disrupted switched antifibrotics by their adverse reactions. The overall prognosis of the Switch-IPF cohort was significantly better than the Non-Switch-IPF cohort (median periods: 67.2 vs. 27.1 months, p

Abstract Background Idiopathic non-specific interstitial pneumonia (iNSIP), idiopathic pleuroparenchymal fibroelastosis (iPPFE), and unclassifiable idiopathic interstitial pneumonia (IIP) are IIPs with chronic fibrotic phenotypes, and unlike idiopathic pulmonary fibrosis, they have often been treated with anti-inflammatory drugs, including corticosteroids and immunosuppressants. However, the impact of bronchoalveolar lavage (BAL) lymphocytosis on the effects of anti-inflammatory therapy has never been evaluated. This study aimed to elucidate whether BAL lymphocytosis can be used to predict the efficacy of anti-inflammatory drugs for iNSIP, iPPFE, and unclassifiable IIP. Methods Japanese patients diagnosed with iNSIP, iPPFE, and unclassifiable IIP by multidisciplinary discussion were identified using the nationwide registry. Eligible patients were stratified into four groups with and without BAL lymphocytosis and anti-inflammatory therapy to compare overall survival (OS) and changes in lung function. BAL lymphocytosis was defined as a lymphocyte differential count > 15%, and the cut-off was corroborated by survival classification and regression tree analysis. Results Overall, 186 patients (37 iNSIP, 16 iPPFE, and 133 unclassifiable IIP) were analyzed. Limited to patients treated with anti-inflammatory drugs (n = 123), patients with BAL lymphocytosis had a better prognosis [hazard ratio (HR), 0.26; 95% confidence interval (CI), 0.11–0.63; P = 0.003], higher slope of forced vital capacity (FVC) % predicted for 2 years, and longer OS (log-rank test, P = 0.012) than those without BAL lymphocytosis. On multivariate analysis, BAL lymphocytosis (HR 0.31; 95% CI 0.13–0.75; P = 0.009) was a prognostic factor for OS, along with age and FVC % predicted. Conversely, for patients managed without anti-inflammatory therapy (n = 63), the presence or absence of BAL lymphocytosis had no prognostic value. Conclusions BAL lymphocytosis is associated with good outcomes in patients treated with anti-inflammatory drugs, but has no prognostic value when anti-inflammatory drugs are not used. BAL lymphocytosis may provide a predictive biomarker for identifying patients with iNSIP, iPPFE and unclassifiable IIP who are likely to benefit from anti-inflammatory drugs.

Abstract Background The precise classification of idiopathic interstitial pneumonia (IIP) is essential for selecting treatment as well as estimating clinical outcomes; however, this is sometimes difficult in clinical practice. Therefore, cluster analysis was used to identify the clinical phenotypes of IIPs, and its usefulness for predicting clinical outcomes was evaluated. Methods Cluster analysis was performed using clinical features including patients’ demographics; histories; pulmonary function test data; and laboratory, physical and radiological findings. Results In 337 patients with IIPs, four clusters were identified: Cluster I, in which > 80% of the patients had autoimmune features; Cluster II, which had the lowest rate of smoking, the lowest percent predicted forced vital capacity (%FVC) and the lowest body mass index (BMI); Cluster III, which had the highest rate of smoking, the highest rate of dust exposure, the second lowest %FVC and normal BMI; and Cluster IV, which exhibited maintenance of %FVC and normal BMI. Cluster IV had significantly longer overall survival than Clusters II and III. Clusters I and III had significantly longer overall survival than Cluster II. Clusters II and III had a significantly higher cumulative incidence of acute exacerbation than Cluster IV. Conclusion Cluster analysis using clinical features identified four clinical phenotypes of IIPs, which may be useful for predicting the risk of acute exacerbation and overall survival.

Abstract Background Viral 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. Methods Tracheal 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. Results Short-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. Conclusions IAV 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.

Abstract 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.

Abstract Background Pulmonary fibrosis is a progressive and lethal disease characterized by damage to the lung parenchyma with excess extracellular matrix deposition. The involvement of endothelial cells in fibrosis development is unclear. Methods We isolated pulmonary endothelial cells, using a magnetic-activated cell sorting system, from mice with pulmonary fibrosis induced by intratracheal bleomycin. We characterized endothelial cells isolated at various times in the course of pulmonary fibrosis development. Results Inflammatory cell infiltration was observed at 7 days after bleomycin administration, and fibrotic changes with increased collagen content were observed on day 21. Endothelial cells were isolated at these two timepoints. Levels of von Willebrand factor, plasminogen activator inhibitor-1 and matrix metalloproteinase-12 were elevated in lung endothelial cells isolated from bleomycin-treated mice at days 7 and 21. This indicated that intratracheal bleomycin administration induced endothelium injury. Expression of fibrogenic mediators, transforming growth factor (TGF)-β, connective tissue growth factor and platelet-derived growth factor-C was elevated in the cells from bleomycin-treated, compared with untreated, lungs. When endothelial cells were treated with TGF-β, α-smooth muscle actin (SMA) expression and collagen production were increased only in those cells from bleomycin-treated mouse lungs. Thapsigargin-induced prostaglandin I2 and nitric oxide production, decreased in endothelial cells from bleomycin-treated mouse lungs, compared with controls, was further suppressed by TGF-β. Conclusion Bleomycin administration induced functional changes in lung endothelial cells, indicating potential involvement of endothelium in pulmonary fibrogenesis.