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Setting Macrolides are a key drug class used for the treatment of Mycobacterium abscessus complex disease. Objective To verify the relationship between phenotypic susceptibility and genotypic resistance to clarithromycin (CLM). Design Subspecies of M. abscessus complex from 145 consecutive patients were identified using hsp65 and rpoB gene sequencing, and tested for CLM susceptibility, classification into the erm(41) sequevars responsible for inducible resistance and the presence of rrl mutations associated with acquired resistance. Results The isolates comprised 74 M. abscessus subsp. abscessus, 69 M. abscessus subsp. massiliense and two M. abscessus subsp. bolletii. M. abscessus subsp. abscessus isolates comprised 15 sequevars, with the majority corresponding to sequevar 1 (n = 24), sequevar 6 (n = 13) and sequevar 2 (n = 8). Interestingly, seven M. abscessus subsp. abscessus isolates (9.5%) presented genetically functional, but not phenotypic, inducible resistance. Moreover, rrl was mutated in only 14.3% (1/7) of acquired resistance isolates. However, M. abscessus subsp. massiliense and M. abscessus subsp. bolletii isolates with acquired resistance at day 3 showed mutations at positions 2057-2059 (P Conclusions Our study indicates that genotypic inducible and acquired resistance in M. abscessus subsp. abscessus does not always coincide with phenotypic susceptibility. Rigorous phenotypic evaluation is thus important because of the considerable impact on patients.

BACKGROUND: The efficacy and safety of benralizumab, an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody, for the prevention of exacerbations in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) are not known.METHODS: In the GALATHEA and TERRANOVA trials, we enrolled patients with COPD (at a ratio of approximately 2:1 on the basis of eosinophil count [≥220 per cubic millimeter vs. RESULTS: In GALATHEA, the estimates of the annualized exacerbation rate were 1.19 per year (95% confidence interval [CI], 1.04 to 1.36) in the 30-mg benralizumab group, 1.03 per year (95% CI, 0.90 to 1.19) in the 100-mg benralizumab group, and 1.24 per year (95% CI, 1.08 to 1.42) in the placebo group; the rate ratio as compared with placebo was 0.96 for 30 mg of benralizumab (P = 0.65) and 0.83 for 100 mg of benralizumab (P = 0.05). In TERRANOVA, the estimates of the annualized exacerbation rate for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year (95% CI, 0.87 to 1.13), 1.21 per year (95% CI, 1.08 to 1.37), 1.09 per year (95% CI, 0.96 to 1.23), and 1.17 per year (95% CI, 1.04 to 1.32), respectively; the corresponding rate ratios were 0.85 (P = 0.06), 1.04 (P = 0.66), and 0.93 (P = 0.40). At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial. Types and frequencies of adverse events were similar with benralizumab and placebo.CONCLUSIONS: Add-on benralizumab was not associated with a lower annualized rate of COPD exacerbations than placebo among patients with moderate to very severe COPD, a history of frequent moderate or severe exacerbations, and blood eosinophil counts of 220 per cubic millimeter or greater (Funded by AstraZeneca [GALATHEA and TERRANOVA] and Kyowa Hakko Kirin [GALATHEA]; GALATHEA and TERRANOVA ClinicalTrials.gov numbers, NCT02138916 and NCT02155660.).

Purpose. Macrolide susceptibility differs between subspecies in the Mycobacterium abscessus complex, likely due to differences in erm(41) sequevars. Patients with M. abscessus complex infection generally show poor clinical outcomes in response to antibiotic treatment. Here, the association between genotype and treatment outcome was investigated. Methodology. We collected 69 isolates from 35 patients with non-cystic fibrosis bronchiectasis: 24 had M. abscessus complex lung disease and non-cystic fibrosis bronchiectasis, and 11 were colonized. Outcome analysis was performed in the 24 infected patients. Molecular analyses, including erm(41) and rrl sequencing, and variable-number tandem-repeat (VNTR) analysis of 69 isolates, from 24 infected and 11 colonized patients, were performed to elucidate the influence of genotype on antibiotic susceptibility. Results. Among the 24 patients, 18 (14 infected with M. abscessus subsp. abscessus and 4 with M. abscessus subsp. massiliense) showed unfavourable outcomes; six (three infected with M. abscessus subsp. abscessus and three with M. abscessus subsp. massiliense) exhibited favourable outcomes. Patients with unfavourable outcomes showed acquired clarithromycin resistance (33.3 vs 0 %), mixed sequevars (38.9 vs 16.7 %) and differing VNTR patterns between initial and serial isolates (33.3 vs 16.7 %). In contrast, in the 11 colonized patients, M. abscessus subsp. abscessus C28 (sequevar 02) and M. abscessus subsp. massiliense were the most prevalent subspecies. Conclusion. Patients infected with multiple sequevars and genotypes were more likely to exhibit treatment failure and/or recurrence. The precise identification of subspecies and analyses of mycobacterial characteristics may help to predict treatment outcomes in patients with M. abscessus complex lung disease.

Background: Among Mycobacterium abscessus complex infections, patients with M. abscessus subsp. abscessus (MAA) lung disease are difficult to treat and no standard therapy has been established. Few reports have investigated the drug susceptibility of these strains. We retrospectively investigated how in vitro drug susceptibility testing (DST) of MAA affects the induction of sputum conversion using pharmacotherapy. Methods: Patients with MAA lung disease diagnosed and treated between 2010 and 2014 at our hospital were enrolled and divided into Group A (sputum conversion without relapse within 1 year) and Group B (persistent positive cultured or negative conversion with relapse). MAA was identified in M. abscessus using sequence with genotyping, and DST of MAA was performed. Results: We assessed 23 patients (9 males and 14 females). There were 8 patients in Group A and 15 in Group B. Higher prevalence of susceptible isolates for clarithromycin (CAM) susceptibility on day 14 was noted in Group A than in Group B (P = 0.03) and no significant difference observed in the two groups for other drugs. Conclusions: In vitro DST of MAA, especially CAM susceptibility on day 14, affected the results of negative conversion. No other drugs were found to affect sputum culture negative conversion.

Background The efficacy of nintedanib in progressive fibrosing interstitial lung diseases (ILDs) was demonstrated in the randomised, double-blind, placebo-controlled INBUILD trial. This subgroup analysis evaluated the efficacy and safety of nintedanib in the Japanese population. Methods Patients with progressive fibrosing ILDs (evaluated by physicians within 24 months of screening) were randomised (1:1) to twice-daily 150-mg nintedanib or placebo; treatment continued until the last patient completed 52 weeks. The primary endpoint was the annual rate of decline in forced vital capacity (FVC) over 52 weeks. Time-to-first acute ILD exacerbation or death and time-to-death up until the last patient had completed the week 52 visit were evaluated. This subgroup analysis included 108 Japanese patients. Results The adjusted annual rates of FVC decline (mL/year) over 52 weeks for Japanese patients were −148.31 (nintedanib) and −240.36 (placebo), adjusted difference: 92.05 (95% CI: −10.69–194.80) and for non-Japanese patients were −67.41 (nintedanib) and −177.65 (placebo), adjusted difference: 110.24 (95% CI: 64.97–155.52). No heterogeneity in treatment effect between Japanese and non-Japanese subgroups was observed (treatment-by-subgroup interaction, p = 0.75). The risks of “acute exacerbation or death” (hazard ratio, 0.30 [95% CI: 0.10–0.91]) and mortality (hazard ratio, 0.54 [95% CI: 0.14–2.11]) in Japanese patients were numerically lower for nintedanib than placebo. There were no new or unexpected safety findings. Conclusions In Japanese patients, nintedanib slowed ILD progression, evidenced by a reduction in the annual rate of decline in FVC vs placebo. The efficacy and safety of nintedanib in Japanese patients were consistent with the overall INBUILD population. Clinicaltrials.gov NCT02999178 (21-Dec-2016).

Background and objective Lymphangioleiomyomatosis (LAM) is a diffuse cystic lung disease that occurs in women of childbearing age. LAM can be diagnosed on a clinical basis in patients with typical high-resolution computed tomography (HRCT) patterns and at least one other corroborating disease feature, such as chylothorax, angiomyolipoma, tuberous sclerosis complex or elevated serum vascular endothelial growth factor (VEGF)-D. However, patients who do not meet these criteria require tissue confirmation for a definitive diagnosis, and the utility of methods that are less invasive than surgical lung biopsy, such as transbronchial lung biopsy (TBLB), are not well studied. We retrospectively studied the efficacy and safety of TBLB for the diagnosis of LAM. Methods From January 1991 to August 2015, 131 consecutive LAM patients were prospectively registered in our study, and a TBLB was conducted for 24 patients. We retrospectively studied the yield and safety of TBLB in this cohort. Results All 24 patients were women; the median age was 42 years. HRCT showed multiple round thin-walled cysts diffusely scattered throughout the lungs. The median level of serum VEGF-D was 2109 pg/mL. Characteristic pathological findings for LAM were identified in 17 patients (70.8%) by two expert pathologists. The %predicted value for diffusing capacity of carbon monoxide was significantly lower in the 17 TBLB-positive LAM patients compared to the seven TBLB-negative LAM patients (P = 0.046). There were no serious adverse events such as pneumothorax or uncontrollable bleeding due to TBLB. Conclusion TBLB is a safe and effective method for the pathological diagnosis of LAM.

Background and objective In Japan, the classification of disease severity of idiopathic pulmonary fibrosis (IPF) (J-system) has been used in making decisions on medical care subsidies. The present J-system consists of arterial partial pressure of oxygen (PaO2) and exercise desaturation in stages of I–IV. It provides a good prognostic classification in stages III and IV, but not in stages I and II. Therefore, we propose a revised system to improve discriminative ability in stages I and II. Methods We compared the revised J-system with the present J-system using Cox proportional hazards model to predict mortality rate. We also evaluated the recently proposed GAP (Gender, Age and Physiology) system in comparison to both J-systems. Results Two-hundred and fifteen IPF patients were studied retrospectively. A univariate model showed that the present and revised J-systems and a modified GAP system were all significant prognostic factors. The C-statistic for discriminating prognosis was higher in the revised J-system than the modified GAP system and the present J-system (0.677, 0.652 and 0.659, respectively). The C-statistics of these models produced from the 10 000 bootstrap samples were similar to those of the original models, suggesting good internal validation (0.665 (95% CI: 0.621–0.705), 0.645 (0.600–0.686) and 0.659 (0.616–0.700), respectively). Multivariate analysis revealed that the revised J-system (P = 0.0038) and the modified GAP system (P = 0.0029) were independent prognostic factors. Conclusion The revised J-system can provide a better mortality prediction than the present one. Both the revised J-system and the modified GAP system are independent and valuable tools for prognostication and clinical management for IPF.

Dyspnea is highly prevalent in patients with idiopathic interstitial pneumonias (IIPs).The objective of this study is to examine the effectiveness and safety of continuous subcutaneous morphine for dyspnea in terminally ill IIP patients.We retrospectively reviewed cases of terminally ill IIP patients who received continuous subcutaneous morphine for dyspnea.We reviewed dyspnea severity measured using numerical rating scale (NRS) and respiratory rate (RR) before and two and four hours after morphine initiation. We conducted subgroup analyses of patients with and without noninvasive positive pressure ventilation (NPPV).Twenty-five patients were included in this study. Median morphine dose at morphine initiation and two and four hours after treatment was 0.25, 0.25, and 0.5 mg/hour, respectively. Dyspnea NRS decreased significantly four hours after (mean ± standard deviation: 5.32 ± 2.58, p = 0.04) but not two hours (5.52 ± 2.43, p = 0.11) after morphine initiation compared with baseline (7.08 ± 2.33). RR did not change significantly either two or four hours after treatment compared with baseline. The median survival after morphine initiation was 47 hours. Patients who were not using NPPV showed significantly improved dyspnea both two and four hours after treatment compared with baseline, although patients who used NPPV showed no significant improvement with morphine. RR did not significantly change in either subgroup.Morphine might improve dyspnea in terminally ill IIP patients without decrease in RR.

Background and objective Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) (AE-IPF) is a poor prognostic disorder. AE is also reported to occur in other idiopathic interstitial pneumonias (IIPs). There are limited data available regarding the effectiveness of treatment for AE-IIPs. The objective of this study was to clarify the prognostic impact of the initial dose of prednisolone (PSL) for treating AE-IIPs. Methods Eighty-five patients with AE-IIPs, diagnosed according to the criteria of the Japanese Respiratory Society, were enrolled in this study (IPF/non-IPF: 63/22 patients) from 2004 to 2013. We performed multivariate Cox proportional hazard regression analysis to identify poor prognostic factors. HRCT patterns at the onset of AE-IIPs were classified as diffuse or non-diffuse. We evaluated the prognostic significance of the initial dose of PSL by adjusting for other prognostic factors. Results Median survival time (MST) after AE-IIPs diagnosis was 49 days. MST of AE-IPF and AE-non-IPF was 39 and 49 days, respectively. A diffuse HRCT pattern, lower serum IgG and higher serum surfactant protein-D at AE diagnosis, long-term oxygen therapy (LTOT) before AE and positive pressure ventilation (PPV) use for AE were significant poor prognostic factors for all patients, as were LTOT before AE and lower serum IgG for no-PPV patients. High-dose PSL ≥ 0.6 mg/kg was a significant prognostic factor for no-PPV patients after adjusting for other prognostic factors. Conclusion We concluded that a dose of PSL ≥ 0.6 mg/kg after i.v. high-dose methylprednisolone therapy should be recommended for the treatment of AE-IIPs.

Pulmonary Langerhans cell histiocytosis (PLCH) is a rare smoking-related lung disease characterized by dendritic cell (DC) accumulation, bronchiolocentric nodule formation, and cystic lung remodeling. Approximately 50% of patients with PLCH harbor somatic BRAF-V600E mutations in cells of the myeloid/monocyte lineage. However, the rarity of the disease and lack of animal models have impeded the study of PLCH pathogenesis. Here, we establish a cigarette smoke-exposed (CS-exposed) BRAF-V600E-mutant mouse model that recapitulates many hallmark characteristics of PLCH. We show that CD11c-targeted expression of BRAF-V600E increases DC responsiveness to stimuli, including the chemokine CCL20, and that mutant cell accumulation in the lungs of CS-exposed mice is due to both increased cellular viability and enhanced recruitment. Moreover, we report that the chemokine CCL7 is secreted from DCs and human peripheral blood monocytes in a BRAF-V600E-dependent manner, suggesting a possible mechanism for recruitment of cells known to dominate PLCH lesions. Inflammatory lesions and airspace dilation in BRAF-V600E mice in response to CS are attenuated by transitioning animals to filtered air and treatment with a BRAF-V600E inhibitor, PLX4720. Collectively, this model provides mechanistic insights into the role of myelomonocytic cells and the BRAF-V600E mutation and CS exposure in PLCH pathogenesis and provides a platform to develop biomarkers and therapeutic targets.

To understand assumptions about and approaches to interstitial lung disease (ILD), including those of the progressive phenotype (progressive fibrosing ILD), this multinational survey assessed physicians’ attitudes toward, knowledge of, and management strategies for progressive fibrosing ILD. This internet-based survey of physicians was conducted between November 2018 and February 2019. Practical management strategies for progressive fibrosing ILD, and current approaches to the assessment and treatment of ILD, were compared between countries/regions (Japan vs. United States and European Union) and specialties (pulmonologists vs. rheumatologists). The survey was completed by 574 respondents. Compared with Western countries, the progressive fibrosing phenotype concept was not widely understood by Japanese respondents, with no notable differences in the understanding of this phenotype between pulmonologists and rheumatologists. Across all regions, pulmonary function tests, diffusing capacity of the lungs for carbon monoxide assessments, and pulse oximeter measurements were commonly performed at intervals of ≤6 months. In general, physicians in the United States and European Union preferred physiologic approaches for follow-up, while those in Japan preferred imaging and blood monitoring. Compared with rheumatologists, pulmonologists performed more frequent monitoring of autoimmune ILDs, and the differences between specialties were most pronounced in Japan. Regional differences in treatment approaches were observed, probably reflecting the local availability of agents and healthcare environments. Awareness and management of progressive fibrosing ILD varied between specialties and regions, highlighting an unmet need for standardized diagnosis, treatment guidelines, and specialist education in this area.

Contains fulltext : 220721.pdf (Publisher’s version ) (Closed access) With more than 900 000 confirmed cases worldwide and nearly 50 000 deaths during the first 3 months of 2020, the coronavirus disease 2019 (COVID-19) pandemic has emerged as an unprecedented health care crisis. The spread of COVID-19 has been heterogeneous, resulting in some regions having sporadic transmission and relatively few hospitalized patients with COVID-19 and others having community transmission that has led to overwhelming numbers of severe cases. For these regions, health care delivery has been disrupted and compromised by critical resource constraints in diagnostic testing, hospital beds, ventilators, and health care workers who have fallen ill to the virus exacerbated by shortages of personal protective equipment. Although mild cases mimic common upper respiratory viral infections, respiratory dysfunction becomes the principal source of morbidity and mortality as the disease advances. Thoracic imaging with chest radiography and CT are key tools for pulmonary disease diagnosis and management, but their role in the management of COVID-19 has not been considered within the multivariable context of the severity of respiratory disease, pretest probability, risk factors for disease progression, and critical resource constraints. To address this deficit, a multidisciplinary panel comprised principally of radiologists and pulmonologists from 10 countries with experience managing patients with COVID-19 across a spectrum of health care environments evaluated the utility of imaging within three scenarios representing varying risk factors, community conditions, and resource constraints. Fourteen key questions, corresponding to 11 decision points within the three scenarios and three additional clinical situations, were rated by the panel based on the anticipated value of the information that thoracic imaging would be expected to provide. The results were aggregated, resulting in five main and three additional recommendations intended to guide medical practitioners in the use of chest radiography and CT in the management of COVID-19.

Very recently, a modest but significant efficacy of granulocyte–macrophage colony-stimulating factor (GM-CSF) inhalation therapy for the treatment of mild to moderate autoimmune pulmonary alveolar proteinosis (aPAP) has been reported. As the ability to measure the level of GM-CSF autoantibody (GMAb) in the serum is required to decide the indication for this therapy, we developed a high-performance GMAb testing kit for clinical use. As the kit succeeded in reducing nonspecific IgG binding to the ELISA plate, the predictive performance shown in the training study to discriminate aPAP patients from healthy subjects was perfect, providing a cut-off value of 1.65 U·mL−1 in 78 patients with aPAP and 90 healthy subjects in an operator-blinded manner using logistic regression analysis. As in the validation study, serum samples from another 213 patients with aPAP were also blinded and evaluated in an operator-blinded manner against external 207 samples from patients with other types of PAP and patients exhibiting various ground-glass opacities on chest high-resolution computed tomography that require discrimination from PAP. The logistic regression analysis of these validation data sets revealed values of 97.6% and 100% for specificity and sensitivity, respectively. Thus, this new GMAb testing kit is reliable for the diagnosis of aPAP and differential diagnosis of other lung diseases., Using a newly developed ELISA kit, the cut-off value for serological diagnosis of autoimmune pulmonary alveolar proteinosis can be reset to 1.65 U/mL, which is externally validated against patients with conditions other than autoimmune PAP http://bit.ly/2LgFmKk

International audience; BACKGROUND: Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by progressive surfactant accumulation and hypoxemia. It is caused by disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, which pulmonary alveolar macrophages require to clear surfactant. Recently, inhaled GM-CSF was shown to improve the partial pressure of arterial oxygen in patients with aPAP. METHODS: In a double-blind, placebo-controlled, three-group trial, we randomly assigned patients with aPAP to receive the recombinant GM-CSF molgramostim (300 μg once daily by inhalation), either continuously or intermittently (every other week), or matching placebo. The 24-week intervention period was followed by an open-label treatment-extension period. The primary end point was the change from baseline in the alveolar-arterial difference in oxygen concentration (A-aDo2) at week 24. RESULTS: In total, 138 patients underwent randomization; 46 were assigned to receive continuous molgramostim, 45 to receive intermittent molgramostim, and 47 to receive placebo. Invalid A-aDo2 data for 4 patients (1 in each molgramostim group and 2 in the placebo group) who received nasal oxygen therapy during arterial blood gas measurement were replaced by means of imputation. For the primary end point - the change from baseline in the A-aDo2 at week 24 - improvement was greater among patients receiving continuous molgramostim than among those receiving placebo (-12.8 mm Hg vs. -6.6 mm Hg; estimated treatment difference, -6.2 mm Hg; P = 0.03 by comparison of least-squares means). Patients receiving continuous molgramostim also had greater improvement than those receiving placebo for secondary end points, including the change from baseline in the St. George's Respiratory Questionnaire total score at week 24 (-12.4 points vs. -5.1 points; estimated treatment difference, -7.4 points; P = 0.01 by comparison of least-squares means). For multiple end points, improvement was greater with continuous molgramostim than with intermittent molgramostim. The percentages of patients with adverse events and serious adverse events were similar in the three groups, except for the percentage of patients with chest pain, which was higher in the continuous-molgramostim group. CONCLUSIONS: In patients with aPAP, daily administration of inhaled molgramostim resulted in greater improvements in pulmonary gas transfer and functional health status than placebo, with similar rates of adverse events. (Funded by Savara Pharmaceuticals; IMPALA ClinicalTrials.gov number, NCT02702180.). Copyright © 2020 Massachusetts Medical Society.

Masakazu Ichinose,1 Yasushi Fukushima,2 Yoshikazu Inoue,3 Osamu Hataji,4 Gary T Ferguson,5 Klaus F Rabe,6 Nobuya Hayashi,7 Hiroshi Okada,7 Mami Takikawa,7 Eric Bourne,8 Shaila Ballal,9 Kiernan DeAngelis,10 Magnus Aurivillius,11 Paul Dorinsky,8 Colin Reisner9 1Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; 2Department of Internal Medicine, Fukuwa Clinic, Tokyo, Japan; 3Clinical Research Center, National Hospital Organization, Kinki-Chuo Chest Medical Center, Osaka, Japan; 4Respiratory Center, Matsusaka Municipal Hospital, Matsusaka, Japan; 5Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA; 6LungenClinic Grosshansdorf and Christian-Albrechts University Kiel, Airway Research Center North, Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 7AstraZeneca K.K., Osaka, Japan; 8AstraZeneca, Durham, NC, USA; 9AstraZeneca, Morristown, NJ, USA; 10Formerly of AstraZeneca, Durham, NC, USA; 11AstraZeneca, Gothenburg, SwedenCorrespondence: Masakazu IchinoseDepartment of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, JapanTel +81-22-717-8534Email ichinose@rm.med.tohoku.ac.jpBackground: KRONOS, a Phase III, multicenter, randomized, double-blind study (NCT02497001) conducted in Canada, China, Japan, and the USA, assessed the efficacy and safety of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI), a triple fixed-dose combination therapy, relative to dual therapies in patients with moderate-to-very severe COPD. Here we present findings from the Japanese subgroup of KRONOS.Methods: Patients received BGF MDI 320/18/9.6μg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6μg, budesonide/formoterol fumarate (BFF) MDI 320/9.6μg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12μg twice-daily for 24 weeks. The primary endpoint was the change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) over Weeks 12–24. Symptoms, quality of life, exacerbations, and safety were also assessed.Results: In total, 416 Japanese patients (21.9% of the global KRONOS population) were randomized and treated with BGF MDI (n=139), GFF MDI (n=138), BFF MDI (n=70), or BUD/FORM DPI (n=69). Nominally significant improvements in the change from baseline in morning pre-dose trough FEV1 over Weeks 12–24 were observed for BGF MDI vs GFF MDI (least squares mean [LSM] difference 37 mL, 95% confidence interval [CI] 3, 72; P=0.0337) and BFF MDI (67 mL; 95% CI 25, 109; P=0.0020). Treatment with BGF MDI led to a nominally significant reduction in the rate of moderate/severe exacerbations vs GFF MDI (rate ratio 0.40, 95% CI 0.19, 0.83; P=0.0142). Compared with dual therapies, numerical improvements were observed with BGF MDI for Transition Dyspnea Index focal score and the change from baseline in Evaluating Respiratory Symptoms in COPD total score (P≤0.3899). All treatments were generally well tolerated.Conclusion: BGF MDI nominally significantly improved lung function and numerically improved symptoms vs GFF MDI and BFF MDI. BGF MDI nominally significantly reduced exacerbations vs GFF MDI in Japanese patients with COPD. Efficacy and safety findings were generally comparable to those in the global KRONOS population.Keywords: co-suspension delivery technology, ICS/LAMA/LABA, inhaled corticosteroid, long-acting muscarinic antagonist, long-acting β2-agonist, Japan

Introduction: Nintedanib is an approved treatment for idiopathic pulmonary fibrosis (IPF). Pre-clinical data suggest that nintedanib inhibits processes fundamental to progression of lung fibrosis irrespective of the aetiology. Aim: The INBUILD trial was designed to investigate the efficacy and safety of nintedanib in patients with various non-IPF chronic fibrosing ILDs with progressive phenotype. Methods: Eligible patients had diffuse fibrosing lung disease of >10% extent on HRCT, FVC ≥45% predicted, DLco ≥30– Results: 663 patients were randomised and treated (Table). Mean (±SD) age was 65.8±9.8 years, FVC was 69.0±15.7% predicted, DLco was 47.6±32.2% predicted. Conclusions: The INBUILD trial will provide insights into the natural history and role of nintedanib in treating patients with various progressive fibrosing ILDs. Results will be presented at the congress.

EgeUn###, Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases (n = 3,624) and control subjects (n = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1) individual common variants via logistic regression and 2) groups of rare variants via sequence kernel association tests. Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele (P = 9.60 3 102295). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals. Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence. Copyright © 2019 by the American Thoracic Society, Háskóli Íslands, HI University of Chicago University of Ulsan, UOU Monash University, MU University of Nottingham University of Edinburgh University of Colorado Denver Universitat de Barcelona University of Pittsburgh, Pitt Harvard School of Dental Medicine Massachusetts General Hospital, MGH University of Pennsylvania, Penn University College Cork, UCC City, University of London, City University of California, San Francisco, UCSF School of Medicine, Vanderbilt University Ege Üniversitesi University of Virginia, UV Aarhus Universitetshospital Central Manchester University Hospitals NHS Foundation Trust Columbia University Novartis Sunovion COPD Foundation Pfizer National Heart, Lung, and Blood Institute, NHLBI: R01-HL097163, UH3-HL123442, P01-HL092870 U.S. Department of Defense, DOD: W81XWH-17-1-0597, U01 HL089897, U01 HL089856 AstraZeneca Siemens Foundation North Carolina GlaxoSmithKline Foundation, 1National Jewish Health, Denver, Colorado; 2School of Public Health; 3Department of Medicine, and 54Department of Immunology, University of Colorado Denver, Denver, Colorado; 4Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; 5Brigham and Women’s Hospital, Harvard School of Medicine, Boston, Massachusetts; 6Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma;7Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 8MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom; 9Respiratory Medicine Unit, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom; 10Biomedical Research Centre, University of Nottingham, Nottingham, United Kingdom; 11Royal Brompton Hospital and Imperial College, London, United Kingdom; 12Simmons Center for Interstitial Lung Disease, University of Pittsburgh, Pittsburgh, Pennsylvania; 13Department of Medicine, University of California, San Francisco, San Francisco, California; 14Gilead Sciences, Foster City, California; 15Department of Medicine, University of Chicago, Chicago, Illinois; 16Department of Medicine, University of Virginia, Charlottesville, Virginia; 17Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; 18National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan; 19National Hospital Organization Tokyo National Hospital, Tokyo, Japan; 20Helmholtz Zentrum München, Neuherberg, Germany; 21University Hospital Munich, Munich, Germany; 22Department of Pulmonology, Ege University Hospital, Bornova, Izmir, Turkey; 23Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia; 24Alfred Hospital and Monash University, Melbourne, Australia; 25Pulmonary Medicine, GB Morgagni Hospital, Forlì, Italy; 26Department of Diseases of the Thorax, Ospedale GB Morgagni, Forlì, Italy; 27Université Paris Diderot and Hôpital Bichat, Paris, France; 28Royal Papworth Hospital and Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; 29Respiratory Department, University Hospital of Bellvitge, University of Barcelona, Barcelona, Spain; 30National University Hospital of Iceland, University of Iceland, Reykjavik, Iceland; 31Department of Medicine, Columbia University Irving Medical Center, New York, New York; 32Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, Massachusetts; 33Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark; 34Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas,” México City, México; 35Universidad Nacional Autónoma de México, México City, México; 36Cork University Hospital and University College Cork, Cork, Ireland; 37St. Vincent’s University Hospital, Dublin, Ireland; 38School of Medicine, University College Dublin, Dublin, Ireland; 39Department of Respiratory Medicine, First Faculty of Medicine Charles University and Thomayer Hospital, Prague, Czech Republic; 40University of British Columbia, Vancouver, Canada; 41Tokyo Medical and Dental University, Tokyo, Japan; 42Institute for Respiratory Health and; 43Centre for Cell Therapy and Regenerative Medicine, School of Biomedical Sciences, The University of Western Australia, Perth, Australia; 44Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island; 45Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia; 46Department of Pulmonary Medicine, Gazi University School of Medicine, Ankara, Turkey; 47Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; 48Ruhrlandklinik, University Hospital, University of Duisburg-Essen, Essen, Germany; 49Department of Medicine, Tallaght University Hospital, Trinity College Dublin, Dublin, Ireland; 50CardioPulmonary Reserach Center, Alliance Pulmonary Group, Guaynabo, Puerto Rico; 51Department of Internal Medicine, University of Genoa, Genoa, Italy; 52Biomedical Genomics Center, University of Minnesota; Minneapolis, Minnesota; and 53Northwest Genomics Center, University of Washington, Seattle, Washington -- This research was supported by grants from the NHLBI (R01-HL097163, P01-HL092870, and UH3-HL123442) and the Department of Defense (W81XWH-17-1-0597). The COPDGene project was supported by Award Number U01 HL089897 and Award Number U01 HL089856 from the NHLBI. The COPDGene project was also supported by the COPD Foundation through contributions made to an industry advisory board comprised of AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion.

Rationale: The level of diagnostic likelihood at which physicians prescribe antifibrotic therapy without requesting surgical lung biopsy (SLB) in patients suspected of idiopathic pulmonary fibrosis (IPF) is unknown. Objectives: To determine how often physicians advocate SLB in patient subgroups defined by IPF likelihood and risk associated with SLB, and to identify the level of diagnostic likelihood at which physicians prescribe antifibrotic therapy with requesting SLB. Methods: An international cohort of respiratory physicians evaluated 60 cases of interstitial lung disease, giving: 1) differential diagnoses with diagnostic likelihood; 2) a decision on the need for SLB; and 3) initial management. Diagnoses were stratified according to diagnostic likelihood bands described by Ryerson and colleagues. Measurements and Main Results: A total of 404 physicians evaluated the 60 cases (24,240 physician-patient evaluations). IPF was part of the differential diagnosis in 9,958/24,240 (41.1%) of all physician-patient evaluations. SLB was requested in 8.1%, 29.6%, and 48.4% of definite, provisional high-confidence and provisional low-confidence diagnoses of IPF, respectively. In 63.0% of provisional high-confidence IPF diagnoses, antifibrotic therapy was prescribed without requesting SLB. No significant mortality difference was observed between cases given a definite diagnosis of IPF (90-100% diagnostic likelihood) and cases given a provisional high-confidence IPF diagnosis (hazard ratio, 0.97; P = 0.65; 95% confidence interval, 0.90-1.04). Conclusions: Most respiratory physicians prescribe antifibrotic therapy without requesting an SLB if a provisional high-confidence diagnosis or "working diagnosis" of IPF can be made (likelihood>70%). SLB is recommended in only a minority of patients with suspected, but not definite, IPF.

ObjectivesDyspnoea in patients with chronic obstructive pulmonary disease (COPD) is frequent and often persists despite conventional treatment. This study aimed to evaluate the efficacy and safety of oral morphine for dyspnoea in Japanese COPD patients.MethodsWe conducted a multi-institutional, prospective, before–after study of morphine in COPD patients with dyspnoea at rest in seven hospitals. Patients received 12 mg of oral morphine per day (or 8 mg per day if low body weight or renal impairment). Primary outcome was change in the numerical rating scale (NRS) of current dyspnoea in the evening from Day 0 to Day 2. Secondary outcomes included changes in dyspnoea intensity in the evening from Day 0 to Day 1, dyspnoea intensity between the morning from Day 0 to Day 1 and Day 2, vital signs, nausea, somnolence, anorexia and other adverse events (AEs).ResultsA total of 35 patients were enrolled in this study between October 2014 and January 2018. One patient did not receive study treatment. Data from 34 patients was analysed. The NRS of dyspnoea intensity in the evening significantly decreased from 3.9 on Day 0 (95% CI: 3.1 to 4.8) to 2.4 on Day 2 (95% CI: 1.7 to 3.1; p=0.0002). Secondary outcomes significantly improved in a similar manner. There were no apparent changes in the mean scores of the opioid-related AEs and vital signs. One patient experienced grade 3 lung infection not associated with morphine. Other AEs were mild.ConclusionOral morphine is effective in alleviating dyspnoea in Japanese COPD patients.Trial registrationUMIN000015288 (http://www.umin.ac.jp/ctr/index.htm).

Thoracic diseases in patients with systemic lupus erythematosus (SLE), especially interstitial pneumonia (SLE-IP), are rare and have been poorly studied. The aims of this multicentre study were to evaluate SLE-IP and elucidate its clinical characteristics and prognosis. Fifty-five patients with SLE-IP who had attended the respiratory departments of participating hospitals were retrospectively evaluated in this multicentre study. Clinical information, high-resolution computed tomography (HRCT), and surgical lung biopsy/autopsy specimens were analysed by respiratory physicians, pulmonary radiologists, and pulmonary pathologists. IP patterns on HRCT and lung specimens were classified based on the international classification statement/guideline for idiopathic interstitial pneumonias. The most frequent form of SLE-IP at diagnosis was chronic IP (63.6%), followed by subacute (20.0%), and acute IP (12.7%). Radiologically, the most common HRCT pattern was “Unclassifiable” (54%). Histologically, “Unclassifiable” was the most frequently found (41.7%) among 12 patients with histologically proven IP. Interestingly, accompanying airway diseases were present in nine of these patients (75%). In multivariate analysis, current smoking (hazard ratio [HR] 6.105, p = 0.027), thrombocytopenia (HR 7.676, p = 0.010), anti-double-strand DNA titre (HR 0.956, p = 0.027), and nonspecific interstitial pneumonia (NSIP) + organizing pneumonia (OP) pattern on HRCT (vs. NSIP, HR 0.089, p = 0.023) were significant prognostic factors. In conclusion, chronic IP was the most frequent form of IP in patients with SLE-IP, and “Unclassifiable” was the commonest pattern radiologically and histologically.

IntroductionStandard treatment for nodular/bronchiectatic Mycobacterium avium complex lung disease (NB MAC-LD), excluding severe-status cases, differs between Japan and other countries. Internationally, three-drug combination intermittent treatment (three times a week administration) with macrolide, ethambutol and rifampicin is recommended, but a daily treatment regimen is recommended in Japan. To date, no randomised controlled study directly comparing intermittent treatment with daily treatment has been performed. The purpose of this study is to investigate the usefulness of intermittent treatment.Methods and analysisA total of 140 patients diagnosed with NB MAC-LD in Japan will be randomly assigned, in a 1:1 ratio, to intermittent treatment group or daily treatment group, and three-drug combination therapy with clarithromycin, rifampicin and ethambutol will be continued for 1 year. The primary endpoint is the proportion of patients requiring modification of the initial treatment regimen. Secondary endpoints are adverse events, sputum culture conversion, time to sputum culture conversion, improvement of chest CT findings, change in health-related quality of life score and development of clarithromycin resistance.Ethics and disseminationThis trial was approved by the National Hospital Organisation Review Board for Clinical Trials (Headquarters). The results of this study will be reported at a society meeting or published in a peer-review journal.

Background and objective Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive fibrosing interstitial pneumonia. Nintedanib significantly reduced the annual rate of decline in forced vital capacity (FVC) compared with placebo in patients with IPF in two replicate trials (INPULSIS®). We examined the efficacy and safety of nintedanib in Japanese patients. Methods We conducted pre-specified subgroup analyses of the annual rate of decline in FVC, time to first acute exacerbation (AE), change from baseline in St George's Respiratory Questionnaire (SGRQ) total score and safety using pooled data from the INPULSIS® trials for Japanese patients. Results In the overall population, 76 of 638 and 50 of 423 patients in the nintedanib and placebo groups, respectively, were Japanese. Results in Japanese patients were consistent with those in the overall population. In Japanese patients, the adjusted annual rate of decline in FVC was −135.9 mL/year in the nintedanib group and −267.7 mL/year in the placebo group (difference (95% CI): 131.9 (50.7, 213.1) mL/year); the hazard ratio for the time to first AE was 0.25 (0.06, 1.02); and the adjusted mean change from baseline in SGRQ total score at week 52 was 5.81 in the nintedanib group and 9.68 in the placebo group (difference: −3.87 (−8.51, 0.76)). Diarrhoea and liver-related adverse events were the most common events in the nintedanib group, but were reversible following dose reduction, drug interruption or symptomatic therapy. Conclusion The present results indicate that the efficacy and safety of nintedanib in Japanese patients are comparable with those in the overall population.

Sirolimus has been shown in a randomized, controlled clinical trial to stabilize lung function in patients with lymphangioleiomyomatosis (LAM) treated for a 12-month time period; however the pretreatment decline in lung function after the drug was discontinued indicated that continued exposure is required to suppress disease progression.To elucidate the durability and tolerability of long-term sirolimus treatment in Asian patients with LAM.We conducted a single-arm, open-label, investigator-initiated safety and efficacy study of sirolimus in 63 women with LAM at 9 sites in Japan. Subjects received sirolimus for 2 years at doses adjusted to maintain a trough blood level of 5-15 ng/ml.Fifty-two subjects (82.5%) completed the trial with mean drug compliance of more than 80% overall during the study. The number of adverse events was greatest during the initial 6 months of therapy, but they continued to occur with declining frequency throughout the 2-year study period. Of the 1,549 adverse events, 27 were classified as serious, including reversible sirolimus pneumonitis in 3 patients. New hypercholesterolemia occurred in 30 patients (48%); microcytosis in 10 patients; loss of body weight in 33 patients; and increase in blood pressure that required treatment in 5 patients. FEVAlthough long-term sirolimus treatment of Asian patients with LAM was associated with a large number of adverse events, including three episodes of pneumonitis, most patients completed the 2-year course of medication with good drug compliance and stable quality of life and lung function.

The CT findings of pulmonary fibrosis in patients with pulmonary alveolar proteinosis (PAP) are not yet well defined. The objective of this study was to evaluate the CT findings of PAP with a focus on pulmonary fibrosis secondary to PAP.High-resolution CT (HRCT) scans of 44 patients with PAP were evaluated retrospectively with a focus on pulmonary fibrosis: 33 patients had autoimmune PAP, and 11 patients had secondary PAP. The intervals between the initial and last CT examinations ranged from 1 to 284 months (median, 60 months). The HRCT images were assessed by two chest radiologists independently; when the two radiologists disagreed, a final decision was made by consensus.A crazy-paving pattern was a more common HRCT finding in patients with autoimmune PAP than in those with secondary PAP. Traction bronchiectasis was found in four patients (9%) on the initial scans and in 10 patients (23%) on the last scans. There was no honeycombing on the initial scans. Honeycombing developed in two patients (5%): It was detected on 2-year follow-up in one patient and on 6-year follow-up in the other patient. Among the patients with autoimmune PAP, those with fibrosis detected on HRCT during follow-up had a worse prognosis than those without fibrosis detected on HRCT (p = 0.041).Fibrosis develops in approximately 20% of patients with PAP. The CT findings of parenchymal fibrosis suggest a poor outcome.

Background and objective Acute exacerbations (AEs) of idiopathic pulmonary fibrosis (IPF) and other idiopathic interstitial pneumonia (IIP) have a poor prognosis. This study aims to clarify the incidence and prognosis of AE in IPF and the other IIP. Methods A total of 229 patients were enrolled, of whom 92 had IPF and 137 had ‘IIP other than IPF’ based on the American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association (ATS/ERS/JRS/ALAT) 2011 IPF Guidelines. IIP other than IPF included 11 patients with a surgical lung biopsy (SLB) and the remainder without such a biopsy. IIP other than IPF was further classified into IIP with a ‘possible usual interstitial pneumonia (UIP)’ pattern on HRCT (n = 75) and IIP with ‘inconsistent with UIP’ pattern (n = 62) based on published guidelines. Predictors of AE and the prognosis after AE were examined in these groups. Results The 1-year incidence of AE in IPF, IIP with possible UIP HRCT patterns and IIP with inconsistent with UIP HRCT patterns was 16.5%, 8.9% and 4.0%, respectively. AE occurred significantly more frequently in IPF than in IIP with possible UIP and inconsistent with UIP HRCT patterns after adjustment for BMI, modified Medical Research Council score and %forced vital capacity. Prognosis of AE-IIP with possible UIP HRCT pattern was significantly worse than that of AE-IPF. Conclusion Although AE occurred significantly less frequently in IIP with possible UIP and inconsistent with UIP HRCT patterns than in IPF, the prognosis of AE-IIP with possible UIP HRCT patterns might be worse than that of AE-IPF.

Background and objective In the two-replicate randomized Phase III INPULSIS® trials in patients with idiopathic pulmonary fibrosis (IPF), nintedanib 150 mg bd significantly reduced the annual rate of decline in forced vital capacity (FVC) compared with placebo. The key secondary endpoints were time to first investigator-reported acute exacerbation and change from baseline in St George's Respiratory Questionnaire total score, both over 52 weeks. Here, we assessed the effect of nintedanib in Asian patients. Methods Pre-specified subgroup analyses of the effect of nintedanib on the primary and key secondary endpoints in Asian versus White patients were undertaken based on pooled data from the two INPULSIS® trials. Safety data were analyzed descriptively. Results Of the treated patients, 322 were Asian (nintedanib n = 194; placebo n = 128) and 608 were White (nintedanib n = 360; placebo n = 248). In Asian patients, the nintedanib versus placebo difference in the adjusted annual rate of decline in FVC was 94.1 mL/year (95% CI: 33.7, 154.6). The treatment effect of nintedanib on the annual rate of decline in FVC in Asian and White patients was similar (treatment-by-subgroup interaction P = 0.72) and consistent with the overall population. No significant treatment-by-subgroup interaction was observed for the key secondary endpoints between Asian and White patients. In Asian patients, the most common adverse event in the nintedanib group was diarrhoea (56.2% of patients vs 15.6% for placebo). Conclusion In pre-specified subgroup analyses of Asian versus White patients with IPF in the INPULSIS® trials, race did not influence the effect of nintedanib on disease progression.

Background In lymphangioleiomyomatosis (LAM), predicting lung disease progression is essential for treatment planning. However, no previous Japanese studies have attempted to predict the reductions in pulmonary function that occur in LAM patients. Methods The data for 89 LAM patients who had undergone ≥3 spirometry tests and whose data had been registered in the Japanese National Research Project on Intractable Diseases database between October 2009 and March 2014 were analyzed after excluding patients who had undergone (1) a lung transplant; (2) mTOR inhibitor treatment; or (3) thoracic drainage, pleurodesis, surgery, or thoracic duct ligation during the study period. The rates of change (slope) in pulmonary parameters were calculated, and their associations with clinical background factors were investigated. Results Among the whole study population, the median (quartiles) slope of forced expiratory volume in one second (FEV 1 ) was −46.7 (−95.2; −15.0)mL per year. Episodes of conservatively treated pneumothorax during the study period were found to be associated with rapid reductions in FEV 1 (% predicted). Pregnancy during the study period was associated with a reduction in FEV 1 (% predicted). When the patients were divided into those who exhibited initial FEV 1 (% predicted) values of >70% (Group A) and ≤70% (Group B), Group B displayed significantly faster reductions in FEV 1 (% predicted) than Group A. Conclusions LAM patients whose initial FEV 1 (% predicted) values are ≤70% subsequently exhibit rapid reductions in their FEV 1 values, and hence, require treatment. However, the FEV 1 reduction rate varies markedly among individuals and should be monitored in all cases.

Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6–7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR] = 5.2; P = 2.4 × 10−12). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR = 4.8; P = 4.8 × 10−12), followed by an additional independent risk allele at HLA-DPβ1 amino acid position 8 (OR = 0.28; P = 3.4 × 10−7). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (β = 0.32; P = 0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production., Autoimmune pulmonary alveolar proteinosis (aPAP) is a complex lung disease caused by abnormal surfactant homeostasis. Here, the authors carry out a genome-wide association study of aPAP in a Japanese cohort, finding variants in the MHC and suggesting predisposition to abnormal antibody production.

IntroductionNintedanib slows disease progression in patients with idiopathic pulmonary fibrosis (IPF) by reducing the rate of decline in forced vital capacity, with an adverse event profile that is manageable for most patients. We used data from six clinical trials to characterise the safety and tolerability profile of nintedanib and to investigate its effects on survival.MethodsData from patients treated with ≥1 dose of nintedanib 150 mg two times per day or placebo in the 52-week TOMORROW trial and/or its open-label extension; the two 52-week INPULSIS trials and/or their open-label extension, INPULSIS-ON; and a Phase IIIb trial with a placebo-controlled period of ≥6 months followed by open-label nintedanib were pooled. All adverse events, irrespective of causality, were included in descriptive analyses. Parametric survival distributions were fit to pooled Kaplan-Meier survival data from the trials and extrapolated to estimate long-term survival.ResultsThere were 1126 patients in the pooled nintedanib group and 565 patients in the pooled placebo group. The mean duration of nintedanib treatment was 28 months. No new safety signals were observed. Incidence rates of bleeding, liver enzyme elevations and cardiovascular events were consistent with those observed in the INPULSIS trials. Diarrhoea was reported at a lower event rate in the pooled nintedanib group than in nintedanib-treated patients in the INPULSIS trials (76.5 vs 112.6 events per 100 patient exposure-years) and infrequently led to permanent treatment discontinuation (3.6 events per 100 patient exposure-years). Based on the Weibull distribution, mean (95% CI) survival was estimated as 11.6 (9.6, 14.1) years in nintedanib-treated patients and 3.7 (2.5, 5.4) years in placebo-treated patients.ConclusionsBased on pooled data from six clinical trials, the adverse event profile of nintedanib was manageable for most patients. Exploratory analyses based on extrapolation of survival data suggest that nintedanib extends life expectancy in patients with IPF.

Dramatic progress in targeted therapy and immunotherapy has been changing clinical practices in lung cancer. With the accumulation of clinical practice, it has become clear that pre-existing interstitial pneumonia (IP) could be a risk factor for drug-induced lung injury, which has enhanced awareness regarding the difficulty in treating lung cancer with comorbid IP. Unfortunately, there is only low-grade evidence in the field of lung cancer with comorbid IP, because almost all clinical trials exclude such patients. There have been very few specialized clinical trials for patients with lung cancer and underlying IPs thus far. Therefore, it is necessary to treat such cases empirically or to give up on the treatment itself. Considering these circumstances, establishing how to treat lung cancer with comorbid IP is an urgent issue. This paper is a summary of the official statement reported by the Diffuse Lung Disease/Thoracic Oncology Assembly and the Japanese Respiratory Society (JRS) in 2017, which attempts to approach lung cancer with comorbid IP systematically.

A 34-year-old woman experiencing shortness of breath was referred to our hospital. The patient was diagnosed with sporadic lymphangioleiomyomatosis based on the observation of bilateral diffuse multiple thin-walled cysts on computed tomography of the chest, chylous effusion, elevated serum vascular endothelial growth factor-D levels and transbronchial biopsy findings. This patient was a hepatitis B virus (HBV) carrier. Treatment with 1 mg daily of sirolimus was started after HBV DNA was brought below the cut-off level using entecavir. Sirolimus was effective, as the chylous effusion resolved completely and the dyspnea improved. The sirolimus dosage was increased to 2 mg daily without causing HBV reactivation.

Background Lymphangioleiomyomatosis (LAM) and connective tissue diseases (CTDs) occur more frequently among women than men. We investigated the frequency of comorbid CTD and positive serum autoantibody findings in patients with LAM. Methods A total of 152 patients with LAM were prospectively and consecutively registered in the National Hospital Organization Kinki-Chuo Chest Medical Centre cohort. The clinical data were retrospectively analysed, and patients were categorised into the following three groups: a CTD group, a non-CTD-autoantibody-positive group, and a non-CTD-autoantibody-negative group. Results All patients were women. We identified five patients with comorbid CTDs (3.3%): Sjögren’s syndrome (SjS) (n = 3), systemic lupus erythematosus (n = 1), and rheumatoid arthritis (n = 1). One patient with SjS was also diagnosed with antiphospholipid antibody syndrome. The positive rate for anti nuclear antibody was 31.5% and 6.9% at dilution of 1:40 or higher, and those of 1:160 or higher, respectively. It tended to be lower in patients with LAM than in healthy women. The positive rate for anti-SS-A and anti-SS-B antibody was 7.9% and 1.8%, respectively. No significant differences in age, type of LAM, smoking status, serum vascular endothelial growth factor D level, respiratory function, treatment, or prognosis were observed among the three groups. Conclusions Comorbid CTDs, especially SjS, in LAM patients should be considered.