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Abstract Background and objective Pooled analyses of previous randomized controlled trials reported that antifibrotics improved survival in patients with idiopathic pulmonary fibrosis (IPF), but the results were only based on short-term outcome data from selected patients who met strict criteria. Observational studies/meta-analyses also suggested that antifibrotics improve survival, but these studies failed to control for immortal time bias that considerably exaggerates drug effects. Therefore, whether antifibrotics truly improve long-term survival in patients with IPF in the real world remains undetermined and requires external validity. Methods We used data from the Japanese National Claims Database to estimate the intention-to-treat effect of antifibrotics on mortality. To address immortal time bias, we employed models treating antifibrotic initiation as a time-dependent covariate and target trial emulation (TTE), both incorporating new-user designs for antifibrotics and treating lung transplantation as a competing event. Results Of 30,154 patients with IPF, 14,525 received antifibrotics. Multivariate Fine–Gray models with antifibrotic initiation as a time-dependent covariate revealed that compared with no treatment, nintedanib (adjusted hazard ratio [aHR], 0.85; 95% confidence interval [CI], 0.81–0.89) and pirfenidone (aHR, 0.89; 95% CI, 0.86–0.93) were associated with reduced mortality. The TTE model also replicated the associations of nintedanib (aHR, 0.69; 95% CI, 0.65–0.74) and pirfenidone (aHR, 0.81; 95% CI, 0.78–0.85) with reduced mortality. Subgroup analyses confirmed this association regardless of age, sex, and comorbidities, excluding certain subpopulations. Conclusions The results of this large-scale real-world analysis support the generalizability of the association between antifibrotics and improved survival in various IPF populations.

Abstract Background COVID-19 patients with preexisting interstitial lung disease (ILD) were reported to have a high mortality rate; however, this was based on data from the early stages of the pandemic. It is uncertain how their mortality rates have changed with the emergence of new variants of concern as well as the development of COVID-19 vaccines and treatments. It is also unclear whether having ILD still poses a risk factor for mortality. As COVID-19 continues to be a major concern, further research on COVID-19 patients with preexisting ILD is necessary. Methods We extracted data on COVID-19 patients between January 2020–August 2021 from a Japanese nationwide insurance claims database and divided them into those with and without preexisting ILD. We investigated all-cause mortality of COVID-19 patients with preexisting ILD in wild-type-, alpha-, and delta-predominant waves, to determine whether preexisting ILD was associated with increased mortality. Results Of the 937,758 adult COVID-19 patients, 7,333 (0.8%) had preexisting ILD. The proportion of all COVID-19 patients who had preexisting ILD in the wild-type-, alpha-, and delta-predominant waves was 1.2%, 0.8%, and 0.3%, respectively, and their 60-day mortality was 16.0%, 14.6%, and 7.5%, respectively. The 60-day mortality significantly decreased from the alpha-predominant to delta-predominant waves (difference − 7.1%, 95% confidence intervals (CI) − 9.3% to − 4.9%). In multivariable analysis, preexisting ILD was independently associated with increased mortality in all waves with the wild-type-predominant, odds ratio (OR) 2.10, 95% CI 1.91–2.30, the alpha-predominant wave, OR 2.14, 95% CI 1.84–2.50, and the delta-predominant wave, OR 2.10, 95%CI 1.66–2.66. Conclusions All-cause mortality rates for COVID-19 patients with preexisting ILD decreased from the wild-type- to the more recent delta-predominant waves. However, these patients were consistently at higher mortality risk than those without preexisting ILD. We emphasize that careful attention should be given to patients with preexisting ILD despite the change in the COVID-19 environment.

Abstract Background Drug-induced interstitial lung disease (DIILD) is a serious adverse event potentially induced by any antineoplastic agent. Whether cancer patients are predisposed to a higher risk of DIILD after receiving immune checkpoint inhibitors (ICIs) is unknown. Methods This study retrospectively assessed the cumulative incidence of DIILD in consecutive cancer patients who received post-ICI antineoplastic treatment within 6 months from the final dose of ICIs. There was also a separate control cohort of 55 ICI-naïve patients with non-small cell lung cancer (NSCLC) who received docetaxel. Results Of 552 patients who received ICIs, 186 met the inclusion criteria. The cohort predominantly comprised patients with cancer of the lung, kidney/urinary tract, or gastrointestinal tract. The cumulative incidence of DIILD in the entire cohort at 3 and 6 months was 4.9% (95% confidence interval [CI] 2.4%–8.7%) and 7.2% (95% CI 4.0%–11.5%), respectively. There were significant differences according to cancer type (Gray’s test, P = .04), with the highest cumulative incidence of DIILD in patients with lung cancer being 9.8% (95% CI 4.3%–18.0%) at 3 months and 14.2% (95% CI 7.3%–23.3%) at 6 months. DIILD was caused by docetaxel in six of these 11 lung cancer patients (54.5%). After matching, the cumulative incidence of docetaxel-induced ILD in patients with NSCLC in the post-ICI setting was higher than that in the ICI-naïve setting: 13.0% (95% CI 3.3%–29.7%) vs 4.3% (95% CI 0.3%–18.2%) at 3 months; and 21.7% (95% CI 7.9%–39.9%) vs 4.3% (95% CI 0.3%–18.2%) at 6 months. However, these were not significant differences (hazard ratio, 5.37; 95% CI 0.64–45.33; Fine–Gray P = .12). Conclusions Patients with lung cancer were at high risk of developing DIILD in subsequent regimens after ICI treatment. Whether NSCLC patients are predisposed to additional risk of docetaxel-induced ILD by prior ICIs warrants further study.

ABSTRACTThe coronavirus disease 2019 (COVID-19) pandemic has dramatically changed because of virus mutations, vaccine dissemination, treatment development and policies, among other factors. These factors have a dynamic and complex effect on the characteristics and outcomes of patients. Therefore, there is an urgent need to understand those changes and update the evidence. We used a large-scale real-world data set of 937,758 patients with COVID-19 from a nationwide claims database that included outpatients and inpatients in Japan to investigate the changes in their characteristics, outcomes and risk factors for severity/mortality from the early pandemic to the delta variant-predominant waves. The severity of COVID-19 was defined according to the modified World Health Organization clinical-progression ordinal scale. With changing waves, mean patient age decreased, and proportion of patients with comorbidities decreased. The incidences of “severe COVID-19 or death (i.e. ≥severe COVID-19)” and “death” markedly declined (5.0% and 2.9%, wild-type-predominant; 4.6% and 2.2%, alpha variant-predominant and 1.4% and 0.4%, delta variant-predominant waves, respectively). Across the wave shift, risk factors for ≥ severe COVID-19 and death, including older age, male, malignancy, congestive heart failure and chronic obstructive pulmonary disease, were largely consistent. The significance of some factors, such as liver disease, varied as per the wave. This study, one of the largest population-based studies on COVID-19, showed that patient characteristics and outcomes changed during the waves. Risk factors for severity/mortality were similar across all waves, but some factors were inconsistent. These data suggest that the clinical status of COVID-19 will change further with the coming epidemic wave.

Background There has been no prospective trial for treatment of immune-related pneumonitis (irP) occurred after immune checkpoint inhibitors (ICIs).Methods In this single-arm phase II study, patients with cancer with grade ≥2 irP received oral prednisolone (1 mg/kg/day), tapered over 6 weeks. The primary endpoint was a pneumonitis control rate at 6 weeks from the start of the study treatment, defined as complete disappearance or partial improvement of irP in high-resolution CT of the chest.Results Among 57 patients enrolled, 56 were included in the final analysis. The most frequent cause of irP was single ICI therapy (51.8%), followed by combination with chemotherapy plus ICI (39.3%). Thirty-five (62.5%) patients had grade 2 irP and 21 (37.5%) had grade ≥3. Fifty-one (91.1%) patients completed the study treatment while 5 discontinued the study treatment because of relapse of irP (n=1), death from cancer (n=1), occurrence of immune-related hepatitis (n=1), extension of the treatment duration more than 6 weeks (n=1), and attending physician’s decision (n=1). Six weeks after the start of the study treatment, 16 (28.5%) patients demonstrated complete recovery from irP, 35 (62.5%) had a partial improvement in irP, 1 (1.8%) had a relapse of irP, and 4 (7.1%) were not evaluable. The pneumonitis control rate at 6 weeks was 91.1% (95% CI, 80.7% to 96.1%). Twelve weeks after the start of the study treatment, 5 (8.9%), 27 (48.2%), and 15 (26.8%) patients demonstrated complete recovery, partial improvement, and relapse, respectively, and 9 (16.1%) were not evaluable. The pneumonitis control rate at 12 weeks was 57.1% (95% CI, 44.1% to 69.2%). During the observation period, 18 (32.1%) patients experienced a relapse of irP, and of those, 17 received re-treatment with corticosteroids. Grade ≥3 adverse events occurred in 10 (17.9%) patients, in which hyperglycemia was most frequent (n=6). There was no treatment-related death.Conclusions In this first prospective study for irP, prednisolone at 1 mg/kg/day, tapered over 6 weeks, demonstrated a promising clinical benefit and manageable toxicity, suggesting a potential treatment option for irP.Trial registration number jRCT: 1041190029.

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

Background Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is characterised by upper lobe-dominant fibrosis involving the pleura and subpleural lung parenchyma, with advanced cases often complicated by progressive weight loss. Therefore, we hypothesised that nutritional status is associated with mortality in IPPFE. Methods This retrospective study assesses nutritional status at the time of diagnosis and 1 year after diagnosis in 131 patients with IPPFE. Malnutrition-related risk was evaluated using the Geriatric Nutritional Risk Index (GNRI). Results Of the 131 patients, 96 (73.8%) were at malnutrition-related risk at the time of diagnosis according to the GNRI. Of these, 21 patients (16.0%) were classified as at major malnutrition-related risk (GNRI

Background: Chronic obstructive pulmonary disease (COPD) is a major cause of mortality and morbidity worldwide. Many patients with COPD experience exacerbations that require hospitalization, which is associated with an increased risk of in-hospital death and impaired ability to perform activities of daily living (ADL). Declining ability to perform ADL is a critical issue for these patients. Objectives: To identify predictors of poor clinical outcomes, including in-hospital death and low ability to perform ADL at discharge, in patients who are hospitalized with exacerbation of COPD. Design: This retrospective study involved a cohort of patients with exacerbation of COPD who were admitted to Iwata City Hospital in Japan between July 2015 and October 2019. Methods: We collected clinical data, measured the cross-sectional area of the erector spinae muscles (ESM CSA ) on computed tomography (CT) scans at admission, and investigated the associations of poor clinical outcomes (in-hospital death and severe dependence when performing ADL, defined as a Barthel Index (BI) of ⩽40 at discharge) with clinical parameters. Results: Overall, 207 patients were hospitalized for exacerbation of COPD during the study period. The incidence of poor clinical outcomes was 21.3%, and the in-hospital mortality rate was 6.3%. Multivariate logistic regression analyses showed that older age, long-term oxygen therapy, an elevated D-dimer concentration, and a reduced ESM CSA on chest CT at admission were significantly associated with poor clinical outcomes (in-hospital death and a BI of ⩽40). Conclusion: Hospitalization for exacerbation of COPD was associated with high rates of in-hospital mortality and a BI of ⩽40 at discharge, which may be predicted by assessment of ESM CSA .

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

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 naïve 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.

Abstract 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.

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 Detection of idiopathic interstitial pneumonias (IIPs) on chest X-ray is difficult for non-specialist physicians, especially in patients with mild IIPs. The current study aimed to evaluate the usefulness of a simple method for detecting IIPs by measuring vertical lung length (VLL) in chest X-rays to quantify decreased lung volume. A total of 280 consecutive patients with IIPs were randomly allocated to exploratory and validation cohorts, and 140 controls were selected for each cohort by propensity score-matching. Upper (uVLL; from apex to tracheal carina), lower (lVLL; from carina to costophrenic angle), and total VLL (tVLL; from apex to costophrenic angle), and the l/uVLL ratio were measured on chest X-rays. Patients in the exploratory cohort had significantly decreased uVLL, lVLL, tVLL, and l/uVLL ratio compared with controls (all p

Introduction: Although recent advances in chemotherapy for lung cancer are remarkable, most clinical trials have excluded patients with interstitial lung disease (ILD) due to the concern of developing acute exacerbation (AE) of ILD. Hence, accumulating original evidence of cancer treatment for this population is important. Methods: Between 2016 and 2020, a prospective observational study was conducted across 11 Japanese hospitals. Patients with chemotherapy- naïve , inoperable, advanced lung cancer with ILD were included. The primary outcome was the frequency of AE-ILD after registration; the secondary outcomes were the risk factor of AE-ILD and the efficacy of chemotherapy. Results: Among 124 patients enrolled, 109 patients who received chemotherapy were analyzed. The median age was 72 years, and the majority showed usual interstitial pneumonia (UIP)/probable UIP pattern upon chest computed tomography. The median percent-predicted forced vital capacity (%FVC) was 81% (interquartile range: 66–95%). After registration, 23 patients (21.1%; 95% confidence interval [CI]: 14.4–29.7%) developed AE-ILD. The logistic analysis revealed that lower %FVC slightly but significantly increased the risk of AE-ILD (odds ratio per 10% decrease: 1.27; 95% CI: > 1.00–1.62). Overall response rates/median overall survival times in non-small-cell lung cancer and small-cell lung cancer for the first-line chemotherapy were 41% (95% CI: 31–53)/8.9 months (95% CI: 7.6–11.8) and 91% (95% CI: 76–98)/12.2 months (95% CI: 9.2–14.5), respectively. Conclusion: AE-ILD during chemotherapy is a frequent complication among patients with lung cancer with ILD, particularly those with lower %FVC. Conversely, even in this population, passable treatment response can be expected.

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 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.

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.

Introduction: MET amplification is an important genetic alteration in NSCLC. Unlike in patients with EGFR and ALK alterations, the efficacy of immune checkpoint inhibitors in patients with MET-amplified NSCLC remains unknown. Methods: An exploratory analysis of a prospective, multi-institutional cohort comprising 200 patients with advanced or recurrent NSCLC treated with nivolumab monotherapy was performed, and MET amplification was defined as a MET-to-CEP7 ratio of greater than or equal to 2 using fluorescent in situ hybridization. High-level and low-level MET gains were also defined as MET signals ≥10/nuclei and 10> MET signals ≥5/nuclei, respectively. Overall response rates (ORRs) and survival outcomes were evaluated on the basis of the MET gene copy number status. Results: Among 175 patients eligible for analysis, MET amplification was detected in 13 tumors (7.4%). Four (2.3%) high-level and 14 (8.0%) low-level MET gains were also detected. There were no considerable differences in ORRs in accordance with the MET gene copy number status. Similarly, no significant differences in both progression-free survival (PFS) and overall survival (OS) were observed between patients with and without MET-amplified NSCLC (log-rank, p = 0.813 for PFS, and p = 0.855 for OS). Among 101 adenocarcinomas, ORRs in patients with high-level and low-level MET gains (50.0% for both, p = 0.049) were significantly higher than those without MET gains (17.6%), yet survival outcomes for both PFS and OS did not improve. Conclusions: MET amplification was not associated with greater benefit of nivolumab treatment in patients with NSCLC. Further studies are warranted to prioritize immune checkpoint inhibitors in the treatment regimen for patients with MET amplification.

Pulmonary fibrosis is a progressive and fatal disorder characterized by dysregulated repair after recurrent injury. Destruction of the lung architecture with excess extracellular matrix deposition induces respiratory failure with hypoxia and progressive dyspnea. The impact of hypoxia on pulmonary endothelial cells during pulmonary fibrogenesis is unclear. Using a magnetic-activated cell sorting system, pulmonary endothelial cells were isolated from a mouse model of pulmonary fibrosis induced by intratracheally administered bleomycin. When endothelial cells were exposed to hypoxic conditions, a hypoxia-inducible factor (HIF)-2α protein was detected in CD31- and α-smooth muscle actin (SMA)-positive cells. Levels of plasminogen activator inhibitor 1, von Willebrand factor, and matrix metalloproteinase 12 were increased in endothelial cells isolated from bleomycin-treated mice exposed to hypoxic conditions. When endothelial cells were cultured under hypoxic conditions, levels of fibrotic mediators, transforming growth factor-β and connective tissue growth factor, were elevated only in endothelial cells from bleomycin-treated and not from saline-treated lungs. The increased expression of α-SMA and mesenchymal markers and collagen production in bleomycin- or hypoxia-stimulated endothelial cells were further elevated in endothelial cells from bleomycin-treated mouse lungs cultured under hypoxic conditions. Exposure to hypoxia damaged endothelial cells and enhanced fibrogenesis-related damage in bleomycin-treated pulmonary endothelial cells.

Background: The clinical utility of prophylactic granulocyte-colony stimulating factor (G-CSF) in patients receiving platinum agents plus etoposide for neuroendocrine carcinoma (NEC) is unknown. Methods: Chemotherapy-naïve patients with NEC who received platinum agents plus etoposide were retrospectively evaluated. The occurrence of severe neutropenia and febrile neutropenia (FN) and efficacy of chemotherapy were compared between patients who did (G-CSF group) and did not receive prophylactic G-CSF (non-G-CSF group). Results: Among 58 patients, 51 (87.9%) and 7 (12.1%) had small-cell lung cancer and large-cell NEC, respectively, and 24 (41.4%) and 34 (58.6%) received cisplatin and carboplatin, respectively. The G-CSF and non-G-CSF groups included 32 and 26 patients, respectively. The non-G-CSF group displayed significantly higher rates of grade 3–4 neutropenia {88.5% [95% confidence interval (CI) = 69.8% – 97.6%] vs. 56.2% [95% CI = 37.7% – 73.6%], P = 0.009} and FN [50.9% (95% CI = 30% – 70%) vs. 18.8% (95% CI = 7.2% – 36.4%), P = 0.023] than the G-CSF group. In multivariate analysis, non-G-CSF was an independent risk factor for grade 3–4 neutropenia and FN. The rate of treatment delay was significantly higher in the non-G-CSF group (69.2% vs. 31.2%, P = 0.001). The relative dose intensity was significantly higher in the G-CSF group (86.7% vs. 74.1%, P

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease (ILD). Currently, two antifibrotic drugs are available for reducing forced vital capacity (FVC) decline in IPF. However, many pulmonologists wait before initiating treatment, especially when IPF patients have stable disease. This study aimed to investigate the impact on survival outcome of FVC decline and a slow rate of FVC decline prior to and following treatment with these two antifibrotic drugs. Methods: Out of the 235 IPF patients treated with antifibrotic therapy that were screened, 105 cases were eligible, who then underwent physiological evaluation at 6 months prior to and following antifibrotic therapy. Clinical characteristics and prognostic outcomes were compared among groups, and prognostic factors were evaluated using a Cox proportional hazards analysis. Results: In terms of %FVC decline prior to the therapy and a slow rate of FVC decline, there was no significant difference between stable and worsened groups and responder and non-responder groups, respectively. On the other hand, in terms of %FVC decline (decline >5%) following antifibrotic therapy, the stable/improved group had significantly better prognosis than the worsened group. Prognostic analysis revealed that a stable/improved status following antifibrotic therapy [HR: 0.35 (0.15–0.87)] was significantly associated with a better prognosis. Conclusions: Concerning the FVC decline prior to and following antifibrotic therapy and a slow rate of FVC decline, only the FVC decline following the therapy is associated with a greater survival outcome. An early treatment decision may thus be beneficial for IPF. The reviews of this paper are available via the supplemental material section.

Background: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is well known as a life-threatening condition during its clinical course. However, the clinical features and prognosis in AE of unclassifiable idiopathic interstitial pneumonia (AE-UCIIP) remain to be elucidated. The aim of this study was to clarify the clinical features and prognosis of AE-UCIIP compared with those of AE-IPF. Methods: In 187 patients with UCIIP or IPF, 64 patients with AE-UCIIP or AE-IPF, who were diagnosed and treated at our hospital, were retrospectively evaluated. Results: A total of 24 patients with AE-UCIIP were significantly older ( p = 0.011), included more women ( p

Background: High-flow nasal cannula (HFNC) oxygen therapy provides effective respiratory management in patients with hypoxemic respiratory failure. However, the efficacy and tolerability of HFNC for patients with acute exacerbation of interstitial lung disease (AE-ILD) have not been established. This study was performed to assess the efficacy and tolerability of HFNC for patients with AE-ILD and identify the early predictors of the outcome of HFNC treatment. Methods: We retrospectively reviewed the records of patients with AE-ILD who underwent HFNC. Overall survival, the success rate of HFNC treatment, adverse events, temporary interruption of treatment, discontinuation of treatment at the patient’s request, and predictors of the outcome of HFNC treatment were evaluated. Results: A total of 66 patients were analyzed. Of these, 26 patients (39.4%) showed improved oxygenation and were successfully withdrawn from HFNC. The 30-day survival rate was 48.5%. No discontinuations at the patient’s request were observed, and no serious adverse events occurred. The pulse oximetric saturation to fraction of inspired oxygen (SpO 2 /FIO 2 ) ratio 24 h after initiating HFNC showed high prediction accuracy (area under the receiver operating characteristic curve, 0.802) for successful HFNC treatment. In the multivariate logistic regression analysis, an SpO 2 /FIO 2 ratio of at least 170.9 at 24 h after initiation was significantly associated with successful HFNC treatment (odds ratio, 51.3; 95% confidence interval, 6.13–430; p

BACKGROUND:Spontaneous pneumothorax is a complication that occurs in patients with connective tissue disease-associated interstitial lung disease (CTD-ILD); however, few studies on the clinical implications of pneumothorax for patients with CTD-ILD have been performed. OBJECTIVES:This study aimed to investigate the incidence and prognostic significance of pneumothorax and the risk factors for its onset in patients with CTD-ILD. METHODS:This study included 140 consecutive patients with CTD-ILD. Clinical characteristics, laboratory findings, pulmonary function test results, and chest high-resolution computed tomography (HRCT) images were retrospectively evaluated. RESULTS:A total of 18 patients (12.9%) developed pneumothorax during their clinical course. The cumulative incidence of pneumothorax from the time of CTD-ILD diagnosis was 6.5%, 8.7%, and 11.3% at 1, 3, and 5 years, respectively. The 10-year survival rate was significantly lower in patients with pneumothorax (29.6%) than that in those without pneumothorax (81.3%). The development of pneumothorax was significantly associated with poor prognosis (HR 22.0; p < 0.010). Furthermore, a lower body mass index, greater extent of reticular abnormalities on HRCT, and administration of methylprednisolone pulse therapy were significantly associated with the development of pneumothorax. CONCLUSION:Pneumothorax is a serious complication in the clinical course of patients with CTD-ILD and the onset of pneumothorax predicts a poor outcome.

Abstract Tuberculosis (TB) remains a leading cause of fatal infectious disease. Accumulations of macrophages are found in infected sites; thus, we hypothesized that a marker of activated macrophages may be related to prognosis of pulmonary TB (PTB). This study investigated serum soluble macrophage mannose receptor, sCD206, in PTB and examined its clinical significance. First, the concentration of sCD206 was measured in the sera of 96 patients with PTB (Tenryu cohort), and in pleural effusions from 29 patients with TB pleurisy. These were verified in another independent cohort (Shizuoka cohort). We found increased concentrations of sCD206 in sera, but not in pleural effusions of PTB patients. Notably, PTB patients with poor prognosis showed significantly higher levels of serum sCD206. At a cut-off value of 1,600 ng/mL in the Tenryu cohort, sCD206 predicted prognosis of PTB with area under the curve 0.847, sensitivity 77.3%, and specificity 86.5%. These results were validated in the Shizuoka cohort. Pathological analyses showed concordance of enhanced CD206 expression in lung and pleural tissues with caseating granuloma in TB. Serum sCD206 increased in PTB and was associated with prognosis. sCD206 is a potential biomarker for PTB.

An 85-year-old man who did not have any hematological or respiratory disorders was transferred to our hospital because of progressive dyspnea. Computed tomography (CT) findings showed ground-glass opacities with a centrilobular distribution and centrilobular micronodules with a “tree-in-bud” pattern. A biopsy of the lungs showed lymphocytic infiltrations in the parenchyma and these were positive for B cell markers. A diagnosis of chronic lymphocytic leukemia (CLL) was made and direct pulmonary involvement of CLL was confirmed simultaneously. One month after initiation of chemotherapy, his symptoms improved and a chest CT scan showed marked resolution. Pulmonary infiltrates of CLL should be included in the differential diagnosis when these signs are encountered on CT. Keywords: Chronic lymphocytic leukemia, Pulmonary infiltrate, Centrilobular micronodule, “Tree-in-bud” pattern

Idiopathic pleuroparenchymal fibroelastosis (PPFE) is a distinctive interstitial pneumonia with upper lobe predominance that shows unique morphological features among idiopathic interstitial pneumonias (IIPs). Affected patients have a variety of clinical presentations with heterogeneous clinical courses. Cluster analysis is a valuable tool for identifying distinct clinical phenotypes under heterogeneous conditions. This study aimed to identify the phenotypes of patients with idiopathic PPFE. Using cluster analysis, novel PPFE phenotypes were identified among subjects from our multicenter cohort, and outcomes were stratified according to phenotypic clusters. Among the subjects with baseline data (N = 84), four clusters were identified. Cluster 1 included younger male subjects with coexisting non-UIP-like patterns. Cluster 2 included elderly female nonsmokers with low body mass index (BMI). Cluster 3 included elderly male smokers with a coexisting IP-like pattern. Cluster 4 included younger male smokers without lower lobe lesions. Patients in cluster 3 had significantly worse survival outcomes than those in clusters 1, 2, and 4 (p < 0.001, p = 0.0041, and p = 0.0155, respectively). Among idiopathic PPFE patients, cluster analysis using baseline characteristics identified four distinct clinical phenotypes that might predict survival outcomes.

Acute exogenous lipoid pneumonia is a rare disorder in adults. A treatment of choice for lipoid pneumonia has not been established, and systemic corticosteroid use remains controversial. We report the case of a 32-year-old man with schizophrenia who presented with kerosene-induced acute exogenous lipoid pneumonia that was treated with a systemic corticosteroid. In this case, supportive therapy did not improve the patient's condition, so systemic corticosteroid therapy was commenced four days after he ingested the kerosene. After corticosteroid commencement, the patient's symptoms and hypoxia improved within a few days. Although some radiological characteristics of this disorder have been reported previously, the process of radiological improvement of exogenous lipoid pneumonia is not well known. In this case, computed tomography findings changed dramatically after corticosteroid therapy was initiated. Extensive bilateral consolidations that were observed on admission improved. Although pneumatoceles developed two weeks after corticosteroid commencement, they were nearly gone after two months of the treatment. While corticosteroid therapy is not suitable for all cases, it should be considered for severe or refractory cases.

Background: When a rescuer walks alongside a stretcher and compresses the patient’s chest, the rescuer produces low-quality chest compressions. We hypothesized that a stretcher equipped with wing boards allows for better chest compressions than the conventional method. Methods: In this prospective, randomized, crossover study, we enrolled 45 medical workers and students. They performed hands-on chest compressions to a mannequin on a moving stretcher, while either walking (the walk method) or riding on wings attached to the stretcher (the wing method). The depths of the chest compressions were recorded. The participants’ vital signs were measured before and after the trials. Results: The average compression depth during the wing method (5.40 ± 0.50 cm) was greater than during the walk method (4.85 ± 0.80 cm; p < 0.01). The average compression rates during the two minutes were 215 ± 8 and 217 ± 5 compressions in the walk and wing methods, respectively (p = ns). Changes in blood pressure (14 ± 11 vs. 22 ± 14 mmHg), heart rate (32 ± 13 vs. 58 ± 20 bpm), and modified Borg scale (4 (interquartile range: 2–4) vs. 6 (5–7)) were significantly lower in the wing method cohort compared to the walking cohort (p < 0.01). The rescuer’s size and physique were positively correlated with the chest compression depth during the walk method; however, we found no significant correlation in the wing method. Conclusions: Chest compressions performed on the stretcher while moving using the wing method can produce high-quality chest compressions, especially for rescuers with a smaller size and physique.

Inhaled corticosteroids are widely used in the treatment of chronic obstructive pulmonary disease (COPD). However, their use has been questioned for appropriate dose and a possible increased risk of pneumonia. Here, we reviewed patients with COPD who had received fluticasone–salmeterol combination treatment using data from a linked electronic medical record database. A total of 180 patients received salmeterol with 250 µg fluticasone propionate twice daily and 78 received salmeterol and 100 µg fluticasone propionate twice daily. In both groups, there was no difference in the improved forced expiratory volume in 1 second and COPD assessment test score and the proportion of patients with exacerbations. Although the incidence of common toxicity was approximately equal, that of pneumonia was much higher in the 250 µg group (8.9% vs 1.3%, P =.01). The beneficial effects of inhaled corticosteroids might be obtained at lower doses.

OBJECTIVE:Although a possible association among myeloperoxidase-anti-neutrophil cytoplasmic antibody (MPO-ANCA), microscopic polyangiitis (MPA), and idiopathic pulmonary fibrosis (IPF) has been suggested, the clinical significance of MPO-ANCA in idiopathic interstitial pneumonias (IIPs), including IPF and non-IPF, remains unclear. We aimed to investigate the frequency of MPO-ANCA positivity, as well as MPA incidence and risk factors for development in patients initially diagnosed with IIP. METHODS:We retrospectively analysed 305 consecutive patients who were initially diagnosed as IIP and had MPO-ANCA results available. RESULTS:Of the 305 patients, 26 (8.5%) were MPO-ANCA-positive. Baseline characteristics were similar between the MPO-ANCA-positive and -negative patients. The cumulative 5-year MPA incidence was 24.3% in the MPO-ANCA-positive patients and 0% in the -negative patients (P < 0.0001). MPO-ANCA was positive in 15 of 133 (11.3%) patients initially diagnosed with IPF and in 11 of 172 (6.3%) patients initially diagnosed with non-IPF (P = 0.56), with cumulative 5-year MPA incidence of 6.2% and 1.0%, respectively (P = 0.10). Multivariate analysis revealed that UIP pattern on HRCT (HR = 3.20, P < 0.01) and no treatment for IIP (HR = 3.52, P < 0.01) were independently associated with MPA development in MPO-ANCA-positive patients. CONCLUSION:MPO-ANCA positivity was uncommon, but was associated with subsequent MPA development in patients initially diagnosed with IIP, including both IPF and non-IPF cases. The study suggested that attention should be paid to MPA development in MPO-ANCA-positive IIP patients with UIP pattern on HRCT and those without treatment for IIP.

A 72-year-old man who had suffered from rheumatoid arthritis (RA) and Sjögren's syndrome (Sjs) since he was 66 years of age had been treated with methotrexate (MTX) for six years. He presented with a cough, sputum and dyspnea on exertion, and computed tomography findings showed multiple ground-glass opacities in both of his lungs. A biopsy of the lungs revealed low-grade mucosa-associated lymphoid tissue (MALT) type B-cell non-Hodgkin's lymphoma. Spontaneous complete remission of the lymphoma was achieved six months after withdrawing immune suppression with MTX. To our knowledge, no previous cases of spontaneous regression of pulmonary MALT-type lymphoma with Sjs treated with MTX for RA have been reported. Patients on MTX who are being treated for RA should be carefully monitored, especially when they have been diagnosed with coexistent Sjs.

Background: Combination therapy with an inhaled corticosteroid (ICS) and a long-acting β2-agonist (LABA) in a single inhaler is the mainstay of asthma management and salmeterol/fluticasone combination (SFC) and fixed-dose formoterol/budesonide combination (FBC) are currently available in Japan; however, there is nothing to choose between the two. The purpose of this study was to clarify the effect of switching from SFC to FBC in patients with asthma not adequately controlled under the former treatment regimen. Methods: This was a prospective, multicenter, open-label, uncontrolled longitudinal study in 87 adult patients with an Asthma Control Questionnaire, 5-item version (ACQ5) score of greater than 0.75 under treatment with SFC 50/250 μg one inhalation twice daily (bid). SFC was switched to FBC 4.5/160 μg two inhalations bid. Study outcomes included ACQ5 score, peak expiratory flow (PEF), FEV1, and fractional exhaled nitric oxide (FeNO) at the end of treatment period. Results: Eighty-three patients completed the study. ACQ5 scores improved and exceeded the clinically meaningful difference after 12 weeks of treatment and well-controlled asthma (ACQ5 score ≤0.75) was attained in 37 (44.6%) patients. Minimum and maximum PEF and FEV1 values improved significantly, but not FeNO values, after switching from SFC to FBC. Conclusions: Switching ICS/LABA combination therapy is a useful option in the management of asthma that is not optimally controlled.

The article focuses on a case study of a 34-year-old woman with pulmonary sarcoidosis, presenting a distinctive "bull's-eye" pattern on high-resolution computed tomography (HRCT). Topics include the radiological features of the bull's-eye sign in sarcoidosis, the patient's clinical course, and the longitudinal changes observed in HRCT over multiple presentations and discontinuation of treatment.