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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.

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 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.

A 69-year-old woman presented with appetite loss, fatigue, and a low-grade fever. She had been receiving certolizumab pegol for rheumatoid arthritis for six years. Computed tomography of the chest showed multiple micronodules in both lungs and bilateral hilar and mediastinal lymphadenopathy. An ophthalmic examination showed the findings of uveitis. Lymphocytosis with an increased CD4/CD8 ratio was seen in the bronchoalveolar lavage fluid. Video-assisted thoracoscopic biopsy specimens obtained from the right lung and a right hilar lymph node showed noncaseous epithelioid cell granulomas. Anti-tumor necrosis factor-α-induced sarcoidosis was diagnosed, and she was successfully treated with cessation of certolizumab pegol and systemic corticosteroid therapy.

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.

Background: Allergic bronchopulmonary aspergillosis (ABPA) develops in the presence of predisposing conditions such as asthma and cystic fibrosis. Even ABPA accompanied by asthma is often complicated by chronic Pseudomonas aeruginosa or nontuberculous mycobacterial infection of the lower respiratory tract, rendering treatment with corticosteroids difficult. There have been several reports on the effectiveness of omalizumab, an anti-IgE antibody, in patients with ABPA. We analyzed the effectiveness and adverse effects of omalizumab in ABPA patients with chronic respiratory infections. Methods: Using our nationwide survey database and published case reports, we identified patients with severe asthma and ABPA who fulfilled the International Society for Human and Animal Mycology criteria and who had been treated with omalizumab. Exacerbation rates, control of symptoms, doses of oral corticosteroids, and pulmonary function were evaluated. Results: Among 25 patients with ABPA treated with omalizumab (median age 62 years, range 33–83 years), 12 patients had a chronic bacterial infection of the lower airways attributable to P. aeruginosa (n = 6) or nontuberculous mycobacteria (n = 6) at the initiation of omaliz­umab. Treatment with omalizumab reduced the frequency of exacerbations and systemic corticosteroid doses and improved pulmonary function. There were no significant adverse events or worsening of infection during treatment with omalizumab, except for injection-site reactions. Conclusions: Treatment with omalizumab was effective and safe in patients with ABPA, regardless of comorbid chronic respiratory tract infections.

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.

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.

A 71-year-old woman with congenital rubella syndrome (CRS) presented with prolonged cough. No physical findings suggested the presence of any connective tissue diseases. Chest computed tomography showed ground-glass opacities and consolidations in the bilateral lower lobes. She had elevated serum Krebs von den Lungen-6, hypoxemia and positive serum anti-Jo-1 antibody. Bronchoalveolar lavage fluid revealed lymphocytosis with a decreased CD4/CD8 ratio. A transbronchial lung biopsy specimen revealed organizing pneumonia. Based on a diagnosis of interstitial pneumonia with autoimmune features (IPAF), systemic corticosteroids were administered, and a good outcome was obtained. A possible relationship between CRS and IPAF is herein discussed.

An 81-year-old woman with rheumatoid arthritis (RA) who had been treated with bucillamine presented with dyspnea. Computed tomography of the chest showed ground-glass opacities and consolidations in both lungs and honeycombing in both basal lung areas. An elevation of the serum Krebs von den Lungen-6 level and hypoxemia were seen. Lymphocytosis with a decreased CD4/CD8 ratio was seen in the bronchoalveolar lavage fluid. A transbronchial lung biopsy specimen showed organizing pneumonia. Based on a diagnosis of bucillamine-induced pneumonitis (BIP) with RA-associated pre-existing interstitial pneumonia, she was successfully treated with the cessation of bucillamine and systemic corticosteroid therapy. The risk factors and prognosis of BIP are discussed.

IMPORTANCE: Robust predictors for response to anti–programmed death 1 and its ligand (PD-1/PD-L1) immunotherapy in non–small cell lung cancer (NSCLC) are not fully characterized. OBJECTIVE: To evaluate whether PD-L1 (CD274) copy number gains (CNGs), comprising amplification and polysomy, in pretreatment specimens assessed by fluorescence in situ hybridization are associated with response to nivolumab monotherapy in NSCLC. DESIGN, SETTING, AND PARTICIPANTS: This multicenter cohort study enrolled 200 patients, of whom 194 had assessable tumors, with advanced or recurrent NSCLC who were treated with nivolumab after progression following prior treatment at 14 institutions in Japan between July 2016 and December 2018. Median (interquartile range) duration of follow-up was 12.6 (5.6-20.4) months. Data were analyzed from December 2019 to February 2020. EXPOSURES: Sequential nivolumab was given on day 1 of a 14-day cycle. Response was assessed every 4 cycles using Response Evaluation Criteria in Solid Tumors version 1.1. MAIN OUTCOMES AND MEASURES: Overall response rate (ORR) according to the PD-L1 copy number status. Additional end points were progression-free survival, overall survival, and PD-L1 tumor proportion score (TPS) assessed by immunohistochemistry based on PD-L1 copy number status. RESULTS: A total of 6 of the 200 patients were excluded because of poor-quality tumor specimens for the biomarker study, resulting in 194 assessable patients. Of these, 155 (79.9%) were men, with a median (range) age of 69 (43-83) years. PD-L1 CNGs were identified in 32 patients (16.5%), including 5 (2.6%) with amplification and 27 (13.9%) with polysomy. The ORR among patients with and without PD-L1 CNGs was 28.1% (95% CI, 13.7%-46.7%) and 17.9% (95% CI, 12.3%-24.7%), respectively. Although patients with PD-L1 polysomy did not demonstrate improved ORR (18.5% [95% CI, 6.3%-38.1%]) compared with those without PD-L1 CNGs, 4 of 5 patients (80.0% [95% CI, 28.4%-99.5%]) with PD-L1 amplification showed response, among whom median duration of response was not reached. Patients with PD-L1 amplification showed excellent survival outcomes for progression-free and overall survival. Overall, 3 PD-L1-amplified tumors (60.0%) showed PD-L1 TPS of at least 80%, but 2 (40.0%) had PD-L1 TPS of 15% or less. CONCLUSIONS AND RELEVANCE: In this study, tumor PD-L1 amplification but not polysomy was associated with response to nivolumab monotherapy among patients with NSCLC. External validation with a larger sample size is warranted.

Method: Asthma-associated extra-airway eosinophilic diseases such as eosinophilic pneumonia and eosinophilic otitis media usually require systemic corticosteroid therapy, and relapse is common after treatment has ceased. Aims and Objectives: To investigate the usefulness of benralizumab in the treatment of severe asthma associated with extra-airway eosinophilic diseases, we conducted a retrospective study. Methods: A review of medical records of severe asthma patients who had extra-airway eosinophilic diseases and received benralizumab treatment was performed. Results: Subjects included one male and seven females with mean age of 75.8 years-old. Eosinophilic sinusitis, eosinophilic pneumonia, eosinophilic otitis media, eosinophilic gastroenteritis, and allergic bronchopulmonary aspergillosis were seen in seven, six, three, one, one of eight patients, respectively. Six patients required chronic low-dose systemic corticosteroid therapy because of frequent relapse of extra-airway eosinophilic diseases and asthma exacerbation. Asthma control test score and peripheral eosinophilia improved significantly after the initiation of benralizumab treatment. Benralizumab treatment significantly reduced the frequency of asthma exacerbation and relapse of extra-bronchial eosinophilic diseases, and all six patients who had been taking chronic low-dose systemic corticosteroid treatment could withdraw from such treatment without exacerbation of asthma and relapse of extra-airway eosinophilic diseases. Conclusion: Benralizumab is useful in the treatment of severe asthma associated with extra-airway eosinophilic diseases.

Background: Idiopathic pleuroparenchymal fibroelastosis (PPFE) is a rare form of idiopathic interstitial pneumonia that is characterized by predominantly upper lobe pleural and subpleural lung parenchymal fibrosis. Pneumothorax is one of the major respiratory complications in PPFE patients; however, its clinical features are poorly understood. Objective: We aimed to investigate the complication of pneumothorax in patients with idiopathic PPFE. Methods: A retrospective multicenter study involving 89 patients who had been diagnosed with idiopathic PPFE was conducted. We investigated the cumulative incidence, clinical features, and risk factors of pneumothorax after the diagnosis of idiopathic PPFE. Results: Pneumothorax developed in 53 patients (59.6%) with 120 events during the observation period (41.8 ± 35.0 months). The cumulative incidence of pneumothorax was 24.8, 44.9, and 53.9% at 1, 2, and 3 years, respectively. Most events of pneumothorax were asymptomatic (n = 85; 70.8%) and small in size (n = 92; 76.7%); 30 patients (56.6%) had recurrent pneumothorax. Chest drainage was required in 23 pneumothorax events (19.2%), and a persistent air leak was observed in 13 (56.5%). Patients with pneumothorax were predominantly male and frequently had pathological diagnoses of PPFE and prior history of pneumothorax and corticosteroid use; they also had significantly poorer survival than those without pneumothorax (log-rank test; p = 0.001). Multivariate analysis revealed that a higher residual volume/total lung capacity ratio was significantly associated with the development of pneumothorax after the diagnosis. Conclusion: Pneumothorax is often asymptomatic and recurrent in patients with idiopathic PPFE, leading to poor outcomes in some cases.

A 63-year-old woman presented with a fever, eruption, and sterile pyuria. A cystoscopic examination revealed submucosal nodular lesions in the trigone of the bladder, and a biopsy specimen showed epithelioid cell granulomas in the lamina propria of the bladder. Mycobacterium avium grew in the urine culture. Other organ involvement, such as the lungs, spleen, bones, muscles, and pelvic lymph nodes, was observed on radiological examinations, and M. avium was isolated from some organ lesions. Interferon-γ-neutralizing autoantibodies were detected in the patient's serum. Therefore, the patient was diagnosed with disseminated M. avium infection, which was resolved with antimycobacterial treatment.

A 63-year-old man with occupational exposure to silica presented with cutaneous ulcer, pleuritic pain, and a fever. Laboratory data showed lymphopenia and positive serum antinuclear and anti-DNA antibodies. Computed tomography of the chest showed egg shell-like calcification of the hilar and mediastinal lymph nodes without pulmonary parenchymal involvement of silicosis. A surgical biopsy showed silicotic nodules with surrounding infiltration of lymphocytes and plasma cells in the parietal pleura. With a diagnosis of systemic lupus erythematosus (SLE), systemic corticosteroid therapy was given, which led to the resolution of symptoms and laboratory abnormalities. We discuss the relationship between silica exposure and the development of SLE.

Pleuroparenchymal fibroelastosis (PPFE) is a rare interstitial pneumonia with upper lobe predominance and fibroelastosis. Although definite diagnosis requires surgical lung biopsy (SLB), SLB is often difficult because of its complications such as refractory pneumothorax.To evaluate urinary desmosines (degradation product of mature elastin) as a novel biomarker in patients with PPFE.Biopsy-proven patients with PPFE (n = 14) were prospectively enrolled. Levels of urinary desmosines in patients with PPFE were measured with liquid chromatography-tandem mass spectrometry (LC-MS/MS) and compared with those in patients with idiopathic pulmonary fibrosis (IPF), patients with chronic obstructive pulmonary disease (COPD), and controls.Levels of urinary desmosines were significantly higher in patients with PPFE than those in patients with IPF (48.4 vs. 28.6 ng/mg creatinine, p = 0.034), patients with COPD (8.0 ng/mg creatinine, p 0.001), or controls (17.4 ng/mg creatinine, p 0.001). Desmosines discriminated between PPFE and IPF (area under the curve [AUC] = 0.708), and between PPFE and controls (AUC = 0.956). However, levels of desmosines were not correlated with physiological parameters in patients with PPFE.Urinary desmosines may be a useful diagnostic biomarker in patients with PPFE. Measurement of desmosines combined with specific clinical and radiological features of PPFE may lead to an accurate diagnosis without SLB in patients with PPFE.

A 78-year-old man presented with acute-onset fever and dyspnea. He had been taking Sho-seiryu-to for allergic rhinitis. A chest radiograph showed diffuse bilateral ground-glass opacities with subpleural sparing, crazy-paving pattern, and traction bronchiectasis. The patient's bronchoalveolar lavage fluid was bloody and transbronchial lung biopsy specimens showed alveolitis, organizing pneumonia, and type 2 alveolar epithelial cell proliferation. There were no clinical and laboratory findings suggestive of respiratory tract infection or connective tissue disease. Based on the clinical course and the exclusion of other etiologies, Sho-seiryu-to-induced pneumonitis with diffuse alveolar hemorrhage was considered. The patient's pneumonitis resolved after the discontinuation of the drug and the administration of systemic corticosteroid therapy.

An 85-year-old, never-smoking man presented with exertional dyspnea. He had been exposed to silica dust in the work place. Chest computed tomography revealed bronchial wall thickening without emphysema. A pulmonary function test showed airflow obstruction without impaired gas transfer. Airway hyperresponsiveness and reversibility were not evident. A transbronchial lung biopsy showed findings suggestive of mineral dust exposure, such as fibrosis and slight pigmentation of bronchioles. He was diagnosed with non-smoking chronic obstructive pulmonary disease (COPD) due to occupational exposure to silica dust. His symptoms were improved using an inhaled long-acting bronchodilator. The clinical characteristics of non-smoking COPD are discussed in this report.

Background: Idiopathic pleuroparenchymal fibroelastosis (PPFE) is a distinctive interstitial pneumonia with upper lobe predominance that shows unique morphological features, and a relatively poor prognosis. However, patinets have various clinical presentations with a heterogeneous clinical course. Cluster analysis modeling is a valuable tool in identifying distinct clinical phenotypes in heterogeneous conditions. Methods: Using cluster analysis, novel PPFE phenotypes were identified among subjects from multicenter cohort, and outcomes were stratified according to phenotypic clusters. Results: Among subjects with complete data for baseline variables (N = 84), four clusters were identified. Cluster 1 (younger male subjects with coexistent non-UIP pattern) had the highest baseline FVC and diffusion capacity of the lung for carbon monoxide (DLCO). Cluster 2 (elderly female subjects non-smokers with lowest BMI) had intermediate FVC and DLCO. Cluster 3 (elderly male smokers with coexistent UIP pattern) had the lowest baseline FVC. Cluster 4 (younger male smokers without lower lobe lesion) had relatively higher baseline FVC and DLCO. In survival outcome, patients in Cluster 3 had significantly poor prognosis than Cluster 1, 2, and 4 (p Conclusions: Among diverse progressive idiopathic PPFE patients, cluster analysis using baseline characteristics identified four distinct clinical phenotypes that might predict survival outcome.

Background Optimal maintenance therapy for lung squamous cell carcinoma (SCC) has not been established. The aim of this study was to evaluate the efficacy and safety of switch maintenance therapy with S-1, an oral fluoropyrimidine, after induction therapy with carboplatin and nanoparticle albumin-bound paclitaxel (nab-paclitaxel) in chemotherapy-naive patients with advanced SCC. Methods Chemotherapy-naive patients with advanced SCC received induction therapy with four cycles of carboplatin (at an area under the curve of 6, day 1 of a 28-day cycle) and nab-paclitaxel (100 mg/kg, days 1, 8, and 15). Patients who achieved disease control after induction therapy received maintenance therapy with S-1 (80 mg/m2, days 1–14 of a 21-day cycle) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) from the start of maintenance therapy. Results Seventy-two patients with SCC were enrolled to the study. After four cycles of induction therapy, 35 (48.6%) patients achieved disease control, and 31 (43.1%) of these patients received maintenance therapy. Median PFS from the start of maintenance therapy was 3.0 months (95% confidence interval: 2.1–3.8 months). The most common toxicities of grade 3 or higher during maintenance therapy were nausea (13.3%), neutropenia (10.0%), and diarrhea (6.7%). Conclusions Switch maintenance therapy with S-1 after induction therapy with carboplatin and nab-paclitaxel was associated with moderate efficacy and acceptable safety and may represent a feasible treatment option for patients with advanced SCC.

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 &lt, 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.

Background The stepping down of asthma treatment can be considered when asthma symptoms have been well controlled with inhaled corticosteroids (ICSs)/long-acting β2 adrenergic agonists (LABAs). However, few data are available comparing the efficacy between two step-down strategies, to reduce ICS/LABA dose or to withdraw LABA continuing ICS, in well-controlled asthmatics. Methods This was a prospective multicentre randomized, two-arm, controlled study. Ninety-one asthmatic patients controlled by budesonide/formoterol combination (BFC) 320/9 μg twice daily were assigned to 2 stepping-down treatments as follows: the BFC group; BUD/FM 160/4.5 μg twice daily, and the ICS group; ICS (budesonide 400 μg twice daily or equivalent dose of ICS) without LABA, and followed for 12 weeks. The primary outcome was the incidence of asthma exacerbations. Asthma control, pulmonary function tests, and fraction of exhaled nitric oxide (FeNO) were evaluated at the beginning and end of the period. Results The incidence of exacerbations was 16.3% in the BFC groups and 12.5% in the ICS group, which were not different between the groups (p = 0.766). No significant differences were found in QOL score and FeNO between 0 week and 12 week in the both group. FEV1 and FEV1 percentage of the predicted value were lower at week 12 than at week 0 in the ICS group, but not in the BFC group. Conclusions The two step-down strategies for 12 weeks have equal acceptability in well-controlled asthmatics treated with medium-dose of BFC, however, withdrawal of LABA may have potential risk to deteriorate FEV1. Clinical trial registration This study was registered to UMIN-CTR ( http://www.umin.ac.jp/ctr/ ), UMIN000010333.

Objectives Single agent maintenance therapy is widely accepted for advanced non-squamous non small cell lung cancer (NSCLC). However, there is no consensus on the initial and maintenance phase regimens, and the clinical benefit of adding bevacizumab to cytotoxic drugs in the maintenance phase remains unclear. Methods Chemotherapy-naive patients with non-squamous NSCLC were randomly assigned to maintenance therapy with pemetrexed and bevacizumab or pemetrexed alone, after achieving disease control after four cycles of induction therapy with carboplatin (area under the curve = 6), pemetrexed (500 mg/m2), and bevacizumab (15 mg/kg). The primary end-point was 1-year progression-free survival (PFS) rate. Results One hundred ten patients were enrolled in the study, with 55 patients assigned to the two groups. The mean 1-year PFS rate was 43.9% (95% confidence interval [CI]: 29.6–59.2%) in the combination maintenance group and 35.2% (95% CI: 22.1–51.0%) in the pemetrexed maintenance group, and the difference was not significant (p = 0.433). Median PFS measured from enrolment was 11.5 months (95% CI: 7.1–19.0) in the combination maintenance group and 7.3 months (95% CI: 5.7–14.1, hazard ratio: 0.73, 95% CI: 0.44–1.19, log-rank p = 0.198) in the pemetrexed maintenance group. Nasal haemorrhage, hypertension, and proteinuria were significantly more frequent in the combination maintenance group, but they were mild and tolerable. Conclusion Both maintenance therapy with pemetrexed alone and pemetrexed and bevacizumab in combination were feasible in patients with non-squamous NSCLC who have achieved disease control after induction therapy with carboplatin, pemetrexed, and bevacizumab. According to the selection design, differences in the superiority between these maintenance therapies were not demonstrated.

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.

Objective Interstitial lung disease (ILD) is a condition characterized by a higher mortality rate in primary Sjogren's syndrome (pSS). However, factors influencing the outcome of patients with pSS-associated ILD remain unclear. The aim of the present study was to evaluate predictive factors associated with a worse prognosis in pSS-ILD. Methods This retrospective study included 99 consecutive patients with pSS-ILD. Clinical characteristics, laboratory findings, and pulmonary function tests at the time of diagnosis were analyzed. Chest HRCT images were reviewed by two experienced chest radiologists. Prognostic factors were assessed by univariate and multivariate analyses, using Cox proportional hazards regression model. Results Median age was 68 years (73% women). In the total patient population, the 5- and 10-year survival rates were 89.8% and 79.0%, respectively. Univariate analysis revealed a significant association between prognosis and age, serum Krebs von den Lungen-6 (KL-6) levels, and %FVC. None of the chest HRCT findings were related to patient outcomes. Based on multivariate analyses adjusted by age and gender, lower levels of %FVC and higher levels of KL-6 were significantly associated with poor outcomes. Using optimal cutoff levels, according to receiver operating characteristic curve analyses, KL-6 > 800 U/mL were significantly associated with worse prognosis (HR: 2.91, 95% CI: 1.04–8.10). Patients with elevated serum KL-6 levels (>800 U/mL) showed a higher mortality rate than those without elevated serum KL-6 levels (p = 0.02). Conclusions Lower %FVC and higher serum KL-6 levels are predictive factors for poor outcome in patients with pSS-ILD.

Switch maintenance therapy, using alternative agents that were not administered during induction chemotherapy, is a treatment option for advanced non-squamous non-small cell lung cancer (NSCLC). Bevacizumab is known to increase the efficacy of other chemotherapeutic agents; however, switch maintenance therapy with docetaxel and bevacizumab has not been adequately studied. The goal of this study was to evaluate the efficacy and safety of switch maintenance therapy with docetaxel and bevacizumab following induction therapy with cisplatin, pemetrexed, and bevacizumab. Chemotherapy-naive non-squamous NSCLC patients received induction therapy of four cycles of cisplatin (75 mg/m2), pemetrexed (500 mg/m2), and bevacizumab (15 mg/kg). Patients who achieved disease control after induction therapy then received maintenance therapy with docetaxel (50 mg/m2) and bevacizumab (15 mg/kg) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival from enrollment. This study enrolled 49 NSCLC patients, among which 38 (77.6%) completed the four cycles of induction therapy and received maintenance therapy. The median progression-free survival from enrollment was 7.8 months (95% confidence interval: 4.7–11.0 months). The most common toxicities of grade 3 or higher were neutropenia (68.4%), leukopenia (50.0%), febrile neutropenia (31.8%), and hypertension. Switch maintenance therapy with docetaxel and bevacizumab following induction therapy with cisplatin, pemetrexed, and bevacizumab demonstrated modest efficacy and frequent hematologic toxicity in non-squamous NSCLC patients.

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.

Background Combination therapy with a long-acting antimuscarinic agent and a long-acting β 2 -agonist are recommended in chronic obstructive pulmonary disease (COPD) if control is not adequate with one long-acting bronchodilator alone. We evaluated the effects of indacaterol and tiotropium combination therapy, including the effects of adding indacaterol to tiotropium (indacaterol add-on group) and adding tiotropium to indacaterol (tiotropium add-on group). Methods We recruited 79 patients with COPD already treated with tiotropium or indacaterol. We undertook pulmonary function tests, the COPD assessment test (CAT), and the multi-frequency forced oscillation technique (to measure respiratory resistance and reactance) before and after 8 weeks of indacaterol and tiotropium combination therapy. Results The median age was 72.1 years and the mean forced expiratory volume in 1 s (FEV 1 ) as a proportion of predicted was 57.2 ± 18.3%. After 8 weeks of combination therapy, FEV 1 and %predicted FEV 1 had increased significantly. There was no change in CAT score. For respiratory impedance, combination therapy improved resistance at 5 Hz (R5) and resistance at 20 Hz (R20) in the whole-breath, inspiratory and expiratory phases, and resonant frequency (Fres) in the inspiratory phase. The indacaterol add-on group (43 patients) and tiotropium add-on group (36 patients) showed improvements in FEV 1 and %predicted FEV 1 over monotherapy, although the CAT score fell significantly in the indacaterol add-on group ( p = 0.005). Conclusions Indacaterol and tiotropium combination therapy improved airflow limitation and respiratory resistances. Adding indacaterol to tiotropium, or tiotropium to indacaterol, had similar effects on airflow limitation.

In patients with chronic eosinophilic pneumonia (CEP), dramatic improvements are seen in response to corticosteroid therapy; however, relapse is common after treatment has ceased. The optimal duration of corticosteroid therapy remains unclear.In a randomised, open-label, parallel group study, eligible patients with CEP received oral prednisolone for either 3 months (3-month group) or 6 months (6-month group), followed by 2 years observation. All patients were treated with an initial dose of prednisolone of 0.5 mg·kg−1·day−1, which was then tapered and discontinued at either 3 or 6 months. The primary end-point was relapse during the follow-up period.In the final analysis, there were 23 patients in the 3-month group and 21 patients in the 6-month group. All patients showed a good response to prednisolone treatment. There were 12 (52.1%) relapses in the 3-month group and 13 (61.9%) relapses in the 6-month group. No significant difference was found in the cumulative rate of relapse (p=0.56). All relapse cases showed improvement upon resumption of prednisolone treatment.No difference was observed in the rate of relapse between the 3- and 6-month prednisolone treatment groups for patients with CEP.

Background Although the accurate diagnosis of pleuroparenchymal fibroelastosis (PPFE) requires pathologic evaluation, this diagnosis is often suggested when the radiologic findings are consistent with typical PPFE and when pulmonary apical cap, which radiologically and pathologically mimics PPFE, can be excluded by confirming disease progression. The aim of this study was to evaluate the validity of the clinical diagnosis of idiopathic PPFE. Methods We recruited 44 patients with idiopathic PPFE according to our modified diagnostic criteria: 1) a radiologic PPFE pattern (i.e., bilateral subpleural dense consolidation with or without pleural thickening in the upper lobes and less marked or absent involvement of the lower lobes), 2) radiologic confirmation of disease progression, and 3) exclusion of other lung diseases with identifiable etiologies. The patients' baseline characteristics and clinical course were reviewed. Results The median age was 70 years, and 28 patients were males. The majority revealed emaciation, hypercapnia, and a high ratio of residual volume to total lung capacity. On chest computed tomography, 39 patients showed abnormal shadows in the lower lobes; more than half were classified as having usual interstitial pneumonia (UIP)/possible UIP pattern. Pneumothorax was the most frequent complication (33/44). The median overall survival time after diagnosis was 35.3 months. The presence of lower lobe UIP/possible UIP pattern did not show a significant prognostic impact. Conclusions Using our diagnostic criteria, we could recruit relatively many patients with similar characteristics to those of idiopathic PPFE patients in the literature. The possibility of clinical diagnosis of idiopathic PPFE should be further discussed.

Chronic eosinophilic pneumonia (CEP) is characterized by the accumulation of eosinophils in the lung with unknown etiology. Although systemic corticosteroid administration leads to dramatic improvement, nearly half the patients with CEP experience relapse and some develop persistent impairment of pulmonary function. However, predictive factors for this persistent impairment have not been determined.To investigate the occurrence of persistent impairment of pulmonary function in CEP and determine its predictive factors.This observational study consisted of 133 consecutive patients with CEP who were followed for longer than 1 year. Spirometry was performed at the time of diagnosis and at follow-up.During the observational period (6.1 ± 4.1 years), relapse occurred in 75 patients (56.4%). Remarkably, 42 patients (31.6%) had a persistent pulmonary function defect (27 obstructive, 10 restrictive, and 4 obstructive and restrictive cases) at the last evaluation. Logistic analyses showed that the relapse was associated with neither persistent obstructive nor restrictive defects. Persistent obstructive defect was significantly associated with the comorbidity of asthma and obstructive defect at the initial CEP diagnosis, whereas persistent restrictive defect was significantly related to reticulation at high-resolution computer tomography and restrictive defect at diagnosis.Persistent impairment of pulmonary function is common in CEP. Concurrent asthma and obstructive defects at diagnosis were predictors for persistent obstructive impairments, whereas reticulation at high-resolution computer tomography and restrictive defect at diagnosis predicted persistent restrictive impairment. Attention should be paid to these persistent impairments in the management of CEP.http://www.umin.ac.jp/ctr/index-j.htm Identifier: UMIN000019092 (principal investigator, Takafumi Suda, MD, PhD).