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BackgroundRisk stratification plays an essential role in the management of patients with pulmonary arterial hypertension (PAH). The current European guidelines propose a three-stratum model to categorise risk as low, intermediate or high, based on the expected 1-year mortality. However, with this model, most patients are categorised as intermediate risk. We investigated a modified approach based on four risk categories, with intermediate risk subdivided into intermediate-low and intermediate-high risk.MethodsWe analysed data from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), a European pulmonary hypertension registry, and calculated risk at diagnosis and first follow-up based on World Health Organization functional class, 6-min walk distance (6MWD) and serum levels of brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP), using refined cut-off values. Survival was assessed using Kaplan–Meier analyses, log-rank testing and Cox proportional hazards models.ResultsData from 1655 patients with PAH were analysed. Using the three-stratum model, most patients were classified as intermediate risk (76.0% at baseline and 63.9% at first follow-up). The refined four-stratum risk model yielded a more nuanced separation and predicted long-term survival, especially at follow-up assessment. Changes in risk from baseline to follow-up were observed in 31.1% of the patients with the three-stratum model and in 49.2% with the four-stratum model. These changes, including those between the intermediate-low and intermediate-high strata, were associated with changes in long-term mortality risk.ConclusionsModified risk stratification using a four-stratum model based on refined cut-off levels for functional class, 6MWD and BNP/NT-proBNP was more sensitive to prognostically relevant changes in risk than the original three-stratum model.

Background Anti-IL-5 antibodies represent an established therapy for severe eosinophilic asthma (SEA), but some patients show inadequate response. The objective of this study was to assess the effects of a switch to anti-IL-5Rα therapy in patients with inadequate response to anti-IL-5 therapy. Methods In this retrospective multi-centre, real-life study, we analysed all SEA patients switched from anti-IL-5 to anti-IL-5Rα therapy due to inadequate response or intolerability. Pulmonary function tests, blood gas analyses, asthma control tests (ACT) and oral corticosteroid (OCS) usage were analysed and compared at three timepoints: baseline (BL, before anti-IL-5 therapy), timepoint 1 (T1, under anti-IL-5 therapy) and timepoint 2 (T2, under anti-IL-5Rα therapy). Results Of 665 patients treated with anti-IL-5 antibodies, 70 were switched to anti-IL-5Rα and 60 were included in the analysis. Median treatment duration was 8 months [IQR 5; 15] for anti-IL-5 and 5 months [IQR 4; 6] for anti-IL-5Rα therapy. FEV1 was 61% of predicted at BL [IQR 41; 74], 61% [IQR 43; 79] at T1 and 68% [IQR 49; 87] at T2 (pT1-T2=0.011). ACT score was 10 [IQR 8; 13], 16 [IQR 10; 19] and 19 [IQR 14; 22], respectively (both p

Background: Recombinant human erythropoietin (rHuEPO), a hormone regulating the proliferation and differentiation of erythroid cells, is one of the prescription drugs used to treat cancer-associated anemia. However, administration of rHuEPO to cancer patients has been reported to be associated with decreased survival, and the mechanism by which it acts remains controversial. The present study aimed to investigate the expression of the EPO-receptor in lung cancer cell lines and whether rHuEPO treatment affected its growth and migration. Moreover, the angiogenic effects of rHuEPO were also explored in vivo. Methods: Expression of the EPO-receptor in lung cancer cell lines was measured by Western blotting and enzyme linked immunosorbent assays (ELISAs). Proliferation of the lung cancer cells was monitored in the presence of rHuEPO. Human umbilical vein endothelial cells (HUVECs) were used for tube formation assays in vitro, and transwell migration assays were performed to detect migration under rHuEPO treatment. Matrigel plug technology was employed to observe the angiogenic effects in both nude mice and Matrigel-containing lung cancer cell lines H838 or H1975. Microvessel density (MVD) was measured using CD31 Immunohistochemistry (IHC) staining. Results: EPO-receptor (EPO-R) was only detected in the cell lines H838 and H1339 by ELISA. However, the EPO-R protein was detected in all cell lines by Western blotting, which is in contradiction to the ELISA results. Proliferation and migration were not affected by rHuEPO treatment. However, rHuEPO promoted HUVEC tube formation in vitro and significantly induced the formation of new blood vessels in vivo. Furthermore, rHuEPO did not antagonize the inhibitory effects of Afatinib (epidermal growth factor receptor-tyrosine kinase inhibitor; EGFR-TKI) in simultaneous treatment with rHuEPO. In a 3D cell co-culture model, rHuEPO did not enhance the secretion of vascular endothelial growth factor (VEGF) in lung cancer cells or human lung fibroblast cell line MRC-5. Conclusions: We have shown that the role of EPO goes beyond erythropoiesis, also playing a strong role in angiogenesis by participating in new blood vessel formation in lung cancer models. Thus, rHuEPO may raise the risk of thrombosis and metastasis in vivo. Additionally, our results suggest that studies using commercially available EPO-R antibodies should be reexamined; some of these antibodies may not in fact recognize EPO-R.

BackgroundSince 2015, the European pulmonary hypertension guidelines recommend the use of combination therapy in most patients with pulmonary arterial hypertension (PAH). However, it is unclear to what extent this treatment strategy is adopted in clinical practice and if it is associated with improved long-term survival.MethodsWe analysed data from COMPERA, a large European pulmonary hypertension registry, to assess temporal trends in the use of combination therapy and survival of patients with newly diagnosed PAH between 2010 and 2019. For survival analyses, we looked at annualised data and at cumulated data comparing the periods 2010–2014 and 2015–2019.ResultsA total of 2531 patients were included. The use of early combination therapy (within 3 months after diagnosis) increased from 10.0% in patients diagnosed with PAH in 2010 to 25.0% in patients diagnosed with PAH in 2019. The proportion of patients receiving combination therapy 1 year after diagnosis increased from 27.7% to 46.3%. When comparing the 2010–2014 and 2015–2019 periods, 1-year survival estimates were similar (89.0% (95% CI 87.2–90.9%) and 90.8% (95% CI 89.3–92.4%), respectively), whereas there was a slight but nonsignificant improvement in 3-year survival estimates (67.8% (95% CI 65.0–70.8%) and 70.5% (95% CI 67.8–73.4%), respectively).ConclusionsThe use of combination therapy increased from 2010 to 2019, but most patients still received monotherapy. Survival rates at 1 year after diagnosis did not change over time. Future studies need to determine if the observed trend suggesting improved 3-year survival rates can be confirmed.

The COVID-19 pandemic has caused acute lung injury in millions of individuals worldwide. Some patients develop COVID-related acute respiratory distress syndrome (CARDS) and cannot be liberated from mechanical ventilation. Others may develop post-COVID fibrosis, resulting in substantial disability and need for long-term supplemental oxygen. In both of these situations, treatment teams often inquire about the possibility of lung transplantation. In fact, lung transplantation has been successfully employed for both CARDS and post-COVID fibrosis in a limited number of patients worldwide. Lung transplantation after COVID infection presents a number of unique challenges that transplant programs must consider. In those with severe CARDS, the inability to conduct proper psychosocial evaluation and pretransplantation education, marked deconditioning from critical illness, and infectious concerns regarding viral reactivation are major hurdles. In those with post-COVID fibrosis, our limited knowledge about the natural history of recovery after COVID-19 infection is problematic. Increased knowledge of the likelihood and degree of recovery after COVID-19 acute lung injury is essential for appropriate decision-making with regard to transplantation. Transplant physicians must weigh the risks and benefits of lung transplantation differently in a post-COVID fibrosis patient who is likely to remain stable or gradually improve in comparison with a patient with a known progressive fibrosing interstitial lung disease (fILD). Clearly lung transplantation can be a life-saving therapeutic option for some patients with severe lung injury from COVID-19 infection. In this review, we discuss how lung transplant providers from a number of experienced centers approach lung transplantation for CARDS or post-COVID fibrosis.

Since December 2020, the COVID-19 pandemic in Germany was influenced by two new major factors: detection of new virus Variants of Concern (VOC) and the start of the vaccination campaign...

Bronchiolitis obliterans; Clinical research; Lung transplantation Bronquiolitis obliterante; Investigación clínica; Trasplante de pulmón Bronquiolitis obliterant; Recerca clínica; Trasplantament de pulmó Long-term survival after lung transplantation is limited by chronic allograft dysfunction. The aim of this study was to investigate the effect of locally augmented immunosuppression with liposomal cyclosporine A for inhalation (L-CsA-i) for the prevention of bronchiolitis obliterans syndrome (BOS). In a randomized, double-blind, placebo-controlled, multi-center Phase 3 study, 180 LT recipients in BOS grade 0 were planned to receive L-CsA-i or placebo in addition to triple-drug immunosuppression. L-CsA-i was administered twice daily via an Investigational eFlow nebulizer to recipients of single (SLT) and bilateral lung transplants (BLT) within 6–32 weeks posttransplant, and continued for 2 years. The primary endpoint was BOS-free survival. 130 patients were enrolled before the study was prematurely terminated for business reasons. Despite a 2-year actuarial difference in BOS-free survival of 14.1% in favor of L-CsA-i in the overall study population, the primary endpoint was not met (p = .243). The pre-defined per protocol analysis of SLT recipients (n = 24) resulted in a treatment difference of 58.2% (p = .053). No difference was observed in the BLT (n = 48) subpopulation (p = .973). L-CsA-i inhalation was well tolerated. Although this study failed to meet its primary endpoint, the results warrant additional investigation of L-CsA-i in lung transplant recipients. The study was funded by PARI Pharma GmbH. Open access funding enabled and organized by ProjektDEAL.

The mechanisms tumor cells use to hijack the immune system are largely uncharted. Here we used bioluminescent nuclear factor (NF)-κB reporter mice and macrophages to discover that metastatic tumors trigger NF-κB activation in host macrophages, dependent on mutant KRAS signaling and delivered via secretory versican. Versican activates NF-κB in tumor-associated macrophages via inhibitor of NF-κB kinase (IKK) β, resulting in release of interleukin (IL)-1β into the tumor microenvironment. Versican silencing in cancer cells or conditional IKKβ deletion in macrophages prevents myeloid NF-κB activation and metastasis. Versican is overexpressed and/or mutated in human cancers and metastatic effusions with KRAS mutations, predicts poor survival, can aid in the development of diagnostic platforms for pleural metastasis, and is druggable via toll-like receptor (TLR) 1/2 inhibition. The data indicate a cardinal role for tumor-derived versican in establishing cross-talk with macrophage IKKβ during metastasis and may foster the development of new therapies and diagnostic tools.

While there is a good knowledge of the natural course of lung function in interstitial lung diseases (ILD) like idiopathic lung fibrosis (IPF), many ambiguities remain in patients with asbestosis. Therefore, we evaluated the change in lung function in asbestos exposed subjects with pleural plaques and asbestosis and analysed corresponding morphology of computer tomography of the thorax. Methods 93 asbestos exposed subjects with pleural plaques and asbestosis were analysed retrospectively at the Klinikum Bergmannsheil of the Ruhr-University of Bochum. Parameters of lung function were obtained at least twice and annual changes of FVC, TLC and DLCOsb were calculated. In addition, we assessed the predominant pattern in high-resolution computer tomography of the thorax (HRCT) and differentiated three phenotypes: p (pleural) –type, f (fibrosis) -type and m (mixed) –type. Results FU data are available in 56/93 (60.2%) patients. The annual deterioration (Mean ± SEM) of FVC is −31.46 ± 17.34 ml, of TLC -55.55 ± 25.67 ml, of DLCOsb −0.38 ± 0.07 mmol/min/kPa and of DLCOva −0.05 ± 0.01 mmol/min/kPa/L. A categorical change of FVC > −100 ml was found in 12/56 (21.4%) and 18/56 (32.1%) patients showed an annual loss of TLC > −100 ml. The greatest annual decline of FVC was observed in patients with the fibrotic phenotype on HRCT (−76.76 ± 66.43 ml) and the mixed phenotype (−81.52 ± 24.79 ml), while the pleural phenotype was less affected (−10.52 ± 25.07 ml). Conclusion More than 20% of our cohort have a progressive disease with an annual loss of FVC > −100 ml. Patients with the fibrotic-phenotype or mixed-phenotype on HRCT are particularly at risk.

Background In the SARS-CoV-2 pandemic, viral genomes are available at unprecedented speed, but spatio-temporal bias in genome sequence sampling precludes phylogeographical inference without additional contextual data. Aim We applied genomic epidemiology to trace SARS-CoV-2 spread on an international, national and local level, to illustrate how transmission chains can be resolved to the level of a single event and single person using integrated sequence data and spatio-temporal metadata. Methods We investigated 289 COVID-19 cases at a university hospital in Munich, Germany, between 29 February and 27 May 2020. Using the ARTIC protocol, we obtained near full-length viral genomes from 174 SARS-CoV-2-positive respiratory samples. Phylogenetic analyses using the Auspice software were employed in combination with anamnestic reporting of travel history, interpersonal interactions and perceived high-risk exposures among patients and healthcare workers to characterise cluster outbreaks and establish likely scenarios and timelines of transmission. Results We identified multiple independent introductions in the Munich Metropolitan Region during the first weeks of the first pandemic wave, mainly by travellers returning from popular skiing areas in the Alps. In these early weeks, the rate of presumable hospital-acquired infections among patients and in particular healthcare workers was high (9.6% and 54%, respectively) and we illustrated how transmission chains can be dissected at high resolution combining virus sequences and spatio-temporal networks of human interactions. Conclusions Early spread of SARS-CoV-2 in Europe was catalysed by superspreading events and regional hotspots during the winter holiday season. Genomic epidemiology can be employed to trace viral spread and inform effective containment strategies.

The term idiopathic pulmonary arterial hypertension (IPAH) is used to categorize patients with pre-capillary pulmonary hypertension of unknown origin. There is considerable variability in the clinical presentation of these patients. Using data from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension, we performed a cluster analysis of 841 patients with IPAH based on age, sex, diffusion capacity of the lung for carbon monoxide (DLCO

Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos-exposed individuals and rapidly leads to the development of pleural effusion and death. MPM harbours loss-of-function mutations in genes likeBAP1, NF2, CDKN2A, andTP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here we show that a significant proportion of human MPM harbour point mutations and copy number alterations in theKRASproto-oncogene. These mutations are likely pathogenic, since ectopic expression of mutantKRASG12Din the pleural mesothelium of conditional mice causes MPM. Murine MPM cell lines derived from these tumours carry the initiatingKRASG12Dlesions, secondaryBap1alterations, and human MPM-like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate thatKRASmutations likely play an important and underestimated role in MPM, which warrants further exploration.

Background: Riociguat in Patients with Symptomatic Pulmonary Hypertension associated with Idiopathic Interstitial Pneumonias (RISE-IIP), a randomized, controlled, phase 2b trial of riociguat for pulmonary hypertension associated with idiopathic interstitial pneumonia, was terminated early due to increased mortality in riociguat-treated patients. Baseline characteristics of enrolled patients demonstrated a low diffusing capacity of the lung for carbon monoxide (DLCO) with preserved lung volumes at baseline, suggesting the presence of combined pulmonary fibrosis and emphysema (CPFE) in some patients. This post hoc analysis of RISE-IIP was undertaken to explore lung morphology, assessed by high-resolution computed tomography, and associated clinical outcomes. Methods: Available baseline/pre-baseline high-resolution computed tomography scans were reviewed centrally by 2 radiologists. The extent of emphysema and fibrosis was retrospectively scored and combined to provide the total CPFE score. Results: Data were available for 65/147 patients (44%), including 15/27 fatal cases (56%). Of these, 41/65 patients (63%) had CPFE. Mortality was higher in patients with CPFE (12/41; 29%) than those without (3/24; 13%). Fourteen patients with CPFE had emphysema > fibrosis (4 died). No relationship was observed between CPFE score, survival status, and treatment assignment. A low DLCO, short 6-min walking distance, and high forced vital capacity:DLCO ratio at baseline also appeared to be risk factors for mortality. Conclusions: High parenchymal lung disease burden and the presence of more emphysema than fibrosis might have predisposed patients with pulmonary hypertension associated with idiopathic interstitial pneumonia to poor outcomes in RISE-IIP. Future studies of therapy for group 3 pulmonary hypertension should include centrally adjudicated imaging for morphologic phenotyping and disease burden evaluation during screening. © 2021 The Authors, Ikaria Sanofi Inova Health System Roche University of Texas Southwestern Medical Center Gilead Sciences AstraZeneca Boehringer Ingelheim, BI Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, SNF United Therapeutics Corporation Merck Sharp and Dohme, MSD Novartis Sunovion Actelion Pharmaceuticals Pfizer National Institutes of Health, NIH GlaxoSmithKline, GSK National Heart, Lung, and Blood Institute, NHLBI Lunge Zürich Bayer Merck Sharp and Dohme, MSD, The authors have reported to the Journal of Heart and Lung Transplantation the following: S. D. Nathan reports consultation fees and Inova Fairfax Hospital receiving research funding for work pertaining to the RISE-IIP study from Bayer AG. V. Cottin reports grants from Actelion, Boehringer Ingelheim, GSK, Pfizer, and Roche, and personal fees from Bayer AG, Biogen Idec, Boehringer Ingelheim, Gilead, GSK, Intermune, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Sanofi. J. Behr reports receiving personal fees from Actelion, Bayer AG, Biogen, BMS, Boehringer Ingelheim, Galapagos, and Roche for consulting and lectures. M. M. Hoeper reports consultancy fees from Actelion, Bayer AG, and Pfizer, and personal fees from Actelion, Bayer AG, Pfizer, and Merck Sharp & Dohme. F. J. Martinez reports grants from National Institutes of Health and National Heart, Lung and Blood Institute, and support from Academic CME, Amgen, Annenberg, AstraZeneca, ATS, Axon, Axon Communication, Biogen, Bioscale, Boehringer Ingelheim, California Society for Allergy and Immunology, Carden Jennings, Centocor, CME Incite, CSA Medical, Falco, Forest, Genentech, Genzyme, GSK, Gilead, Inova Health System, Haymarket Communications, Ikaria, Informa, Integritas, InThought, Ikaria/Bellerophon, Janssen, Johnson & Johnson, Kadmon, MedScape, Merck, Miller Medical, National Association for Continuing Education, Novartis, Nycomed/Takeda, Paradigm, Pearl, Peer Voice, Pfizer, Promedior, Roche, Spectrum Health System, St John's Hospital, St Mary's Hospital, Sunovion, Theravance, University of Texas Southwestern, Unity Biotechnology, UpToDate, Western Society of Allergy and Immunology, Vertex, and Veracyte. T. J. Corte reports grants and personal fees from Boehringer Ingelheim and Roche, grants from Bayer AG, Gilead, and Intermune, and personal fees from AstraZeneca. A. M. Keogh reports grants and personal fees from Bayer AG. H. Leuchte reports personal fees from Actelion, Bayer AG, GSK, Merck Sharp & Dohme, and Pfizer, and nonfinancial support from Bayer AG. N. Mogulkoc reports receiving personal fees from Boehringer Ingelheim, Roche, Actelion, Bayer AG, and Nobel for consulting and lectures. S. Ulrich reports personal fees from Actelion and Bayer AG, and grants from Swiss National Science Foundation, United Therapeutics, and Zurich Lung League. W. A. Wuyts reports grants from Boehringer Ingelheim, FWO Flanders, Roche, and National Institutes of Health. Z. Yao was an employee of Bayer AG during the conduct of the RISE-IIP study. J. Ley-Zaporozhan reports consultation fees from Bayer AG and Boehringer Ingelheim. U. G. Müller-Lisse reports no conflicts of interest. F-D. Scholle, G. Brüggenwerth, and S. Nikkho were employees of Bayer AG during the conduct of the RISE-IIP study. D. Busse was an employee of Chrestos Concept GmbH & Co. during the development of this manuscript. A. U. Wells reports personal fees from Bayer AG, Roche, and Boehringer Ingelheim., The RISE-IIP study was funded by Bayer AG, Berlin, Germany, and Merck Sharp & Dohme Corp. , a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. D.B. performed statistical analyses, funded by Bayer AG, Berlin, Germany.

The hemodynamic criteria for pulmonary hyperension (PH) has been recently changed according to the recommendation of the 6th world conference of PH 2018. The impact of the new haemodynamic criteria on PAH diagnosis in e.g. systemic sclerosis has been shown to be minimal (1). In the newly established Pulmonary Hypertension service at the Lung Center Munich-Gauting, 369 patients (118 female, mean age 69 (10) years) have undergone evaluation for suspected PH inculding right heart catheter. In 273 patients (77 female, mean age 70 (10) years) a manifest PH (mPAP >25 mmHg) was diagnosed. According to the new hemodynamic criteria (mPAP > 20 mmHg), the number of patients with manifest PH increased by 52 to 325 patients ( 19% increase), among them 231 patients with precapillary PH, 59 patients with postcapillary PH and 35 patients with combined pre-/postcapillary PH. In respect to the underlying diseases, the major increase was seen in PH due to left heart disease (Claas II PH, 32% increase) and PH in lung disease (class III PH, 19% increase) and in CTEPH (class IV, 13% increase), while PAH remained nearly stable. In our cohort, the new haemodynamic classification led to an increase of PH diagnosis of about 19%, mostly in PH due to left heart disease and PH due to lung disease. 1 Jaafar S, et al Eur Respir J. 2019;54(2):1900586.

Background Peripheral neuropathy is a common comorbidity in COPD. We aimed to investigate associations between alterations commonly found in COPD and peripheral neuropathy, with particular emphasize on the distinction between direct and indirect effects. Methods We used visit 4 data of the COPD cohort COSYCONET, which included indicators of polyneuropathy (repeated tuning fork and monofilament testing), excluding patients with diabetes a/o increased HbA1c. These indicators were analysed for the association with COPD characteristics, including lung function, blood gases, 6-min walk distance (6-MWD), timed-up-and-go-test (TUG), exacerbation risk according to GOLD, C-reactive protein (CRP), and ankle-brachial index (ABI). Based on the results of conventional regression analyses adjusted for age, BMI, packyears and gender, we utilized structural equation modelling (SEM) to quantify the network of direct and indirect relationships between parameters. Results 606 patients were eligible for analysis. The indices of polyneuropathy were highly correlated with each other and related to base excess (BE), ABI and TUG. ABI was linked to neuropathy and 6-MWD, exacerbations depended on FEV1, 6-MWD and CRP. The associations could be summarized into a SEM comprising polyneuropathy as a latent variable (PNP) with three measured indicator variables. Importantly, PNP was directly dependent on ABI and particularly on BE. When also including patients with diabetes and/or elevated values of HbA1c (n = 742) the SEM remained virtually the same. Conclusion We identified BE and ABI as major determinants of peripheral neuropathy in patients with COPD. All other associations, particularly those with lung function and physical capacity, were indirect. These findings underline the importance of alterations of the micromilieu in COPD, in particular the degree of metabolic compensation and vascular status.

Single cell genomics enables characterization of disease specific cell states, while improvements in mass spectrometry workflows bring the clinical use of body fluid proteomics within reach. The correspondence of cell state changes in diseased organs to peripheral protein signatures is currently unknown. Here, we leverage single cell RNA-seq and proteomic analysis of large pulmonary fibrosis patient cohorts to identify disease specific changes on the cellular level and their corresponding reflection in body fluid proteomes. We discovered and validated transcriptional changes in 45 cell types across three patient cohorts that translated into distinct changes in the bronchoalveolar lavage fluid and plasma proteome. These protein signatures correlated with diagnosis, lung function, smoking and injury status. Specifically, the altered expression of a novel marker of lung health, CRTAC1, in alveolar epithelium is robustly reflected in patient plasma. Our findings have direct implications for future non-invasive prediction and monitoring of pathological cell state changes in patient organs.Abstract Figure

The recommendation for pulmonary rehabilitation (PR) in idiopathic pulmonary fibrosis (IPF) is weak with low-quality evidence. Therefore, the aim of this study is to investigate short-term PR effects and their maintenance after a 3-month follow-up. Fifty-four IPF patients were randomized into a group receiving a 3-week comprehensive, inpatient PR (n = 34, FVC: 74 &plusmn, 19% pred.) or usual care (UC) (n = 17, FVC: 72 &plusmn, 20%pred.). Outcomes were measured at baseline (T1), after intervention (T2), and 3 months after T2 (T3). A 6-min walk distance (6MWD) was used as the primary outcome and chronic respiratory disease questionnaire (CRQ) scores as the secondary outcome. Change in 6MWD from T1 to T2 (&Delta, = 61 m, 95% CI (18.5&ndash, 102.4), p = 0.006) but not from T1 to T3 (∆ = 26 m, 95% CI (8.0&ndash, 61.5), p = 0.16) differed significantly between groups. Higher baseline FVC and higher anxiety symptoms were significant predictors of better short-term 6MWD improvements. For the change in CRQ total score, a significant between-group difference from T1 to T2 (∆ = 3.0 pts, 95% CI (0.7&ndash, 5.3), p = 0.01) and from T1 to T3 (∆ = 3.5 pts, 95% CI (1.5&ndash, 5.4), p = 0.001) was found in favour of the PR group. To conclude, in addition to the short-term benefits, inpatient PR is effective at inducing medium-term quality of life improvements in IPF. PR in the early stages of the disease seems to provoke the best benefits.

Background Pulmonary hypertension (PH) is commonly observed in patients with advanced idiopathic pulmonary fibrosis (IPF). Despite the availability of therapies for both IPF and PH, none are approved for PH treatment in the context of significant pulmonary disease. This study will investigate the use of sildenafil added to pirfenidone in patients with advanced IPF and risk of PH, who represent a group with a high unmet medical need. Methods This Phase IIb, randomised, double-blind, placebo-controlled trial is actively enrolling patients and will study the efficacy, safety and tolerability of sildenafil or placebo in patients with advanced IPF and intermediate or high probability of Group 3 PH who are receiving a stable dose of pirfenidone. Patients with advanced IPF (diffusing capacity for carbon monoxide ≤40% predicted) and risk of Group 3 PH (defined as mean pulmonary arterial pressure ≥20 mm Hg with pulmonary arterial wedge pressure ≤15 mm Hg on a previous right-heart catheterisation [RHC], or intermediate/high probability of Group 3 PH as defined by the 2015 European Society of Cardiology/European Respiratory Society guidelines) are eligible. In the absence of a previous RHC, patients with an echocardiogram showing a peak tricuspid valve regurgitation velocity ≥2.9 m/s can enrol if all other criteria are met. The primary efficacy endpoint is the proportion of patients with disease progression over a 52-week treatment period. Safety will be evaluated descriptively. Discussion Combination treatment with sildenafil and pirfenidone may warrant investigation of the treatment of patients with advanced IPF and pulmonary vascular involvement leading to PH.

Rationale: Current diagnosis of chronic hypersensitivity pneumonitis (cHP) involves considering a combination of clinical, radiological, and pathological information in multidisciplinary team discussions. However, this approach is highly variable with poor agreement between centers. Objectives: We aimed to identify diagnostic criteria for cHP that reach consensus among international experts. Methods: A three-round modified Delphi survey was conducted between April and August 2017. A total of 45 experts in interstitial lung disease from 14 countries participated in the online survey. Diagnostic items included in round 1 were generated using expert interviews and literature review. During rounds 1 and 2, experts rated the importance of each diagnostic item on a 5-point Likert scale. The a priori threshold of consensus was 75% or greater of experts rating a diagnostic item as very important or important. In the third round, experts graded the items that met consensus as important and provided their level of diagnostic confidence for a series of clinical scenarios. Measurements and Main Results: Consensus was achieved on 18 of the 40 diagnostic items. Among these, experts gave the highest level of importance to the identification of a causative antigen, time relation between exposure and disease, mosaic attenuation on chest imaging, and poorly formed nonnecrotizing granulomas on pathology. In clinical scenarios, the diagnostic confidence of experts in cHP was heightened by the presence of these diagnostic items. Conclusions: This consensus-based approach for the diagnosis of cHP represents a first step toward the development of international guidelines for the diagnosis of cHP.

Background The INBUILD trial investigated nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs). We investigated the decline in forced vital capacity (FVC) in subgroups based on the inclusion criteria for ILD progression. Methods Subjects had a fibrosing ILD other than idiopathic pulmonary fibrosis and met the following criteria for ILD progression within the 24 months before screening despite management deemed appropriate in clinical practice: Group A, relative decline in FVC ≥10% predicted; Group B, relative decline in FVC ≥5–0.05 for heterogeneity). Conclusions The inclusion criteria used in the INBUILD trial, based on FVC decline or worsening of symptoms and extent of fibrosis on HRCT, were effective at identifying patients with progressive fibrosing ILDs. Nintedanib reduced the rate of decline in FVC across the subgroups based on the inclusion criteria related to ILD progression., In the INBUILD trial in patients with fibrosing ILDs, the relative effect of nintedanib versus placebo on reducing the rate of FVC decline was consistent across subgroups based on the criteria regarding ILD progression that patients fulfilled on trial entry https://bit.ly/35jpOiE

Background: This study compared therapeutic azole plasma trough levels (APL) of the azole antimycotics itraconazole (ITR), voriconazole (VOR), and posaconazole (POS) in lung transplant recipients and analyzed the influencing factors. In addition, intrapatient variability for each azole was determined. Methods: From July 2012 to July 2015, 806 APL of ITR, VOR, posaconazole liquid (POS-Liq), and posaconazole tablets (POS-Tab) were measured in 173 patients of the Munich Lung Transplantation Program. Therapeutic APL were defined as follows: ITR, ≥700 ng/mL; VOR, 1000–5500 ng/mL; and POS, ≥700 ng/mL (prophylaxis) and ≥1000 ng/mL (therapy). Results: VOR and POS-Tab reached the highest number of therapeutic APL, whereas POS-Liq showed the lowest percentage (therapy: ITR 50%, VOR 70%, POS-Liq 38%, and POS-Tab 82%; prophylaxis: ITR 62%, VOR 85%, POS-Liq 49%, and POS-Tab 76%). Risk factors for subtherapeutic APL of all azoles were the azole dose (ITR, P < 0.001; VOR, P = 0.002; POS-Liq, P = 0.006) and age over 60 years (ITR, P = 0.003; VOR, P = 0.002; POS-Liq, P = 0.039; POS-Tab, P < 0.001). Cystic fibrosis was a significant risk factor for subtherapeutic APL for VOR and POS-Tab (VOR, P = 0.002; POS-Tab, P = 0.005). Double lung transplantation (LTx) was significantly associated with less therapeutic APL for VOR and POS-Liq (VOR, P = 0.030; POS-Liq, P < 0.001). Concomitant therapy with 80 mg pantoprazole led to significantly fewer therapeutic POS APL as compared to 40 mg (POS-Liq, P = 0.015; POS-Tab, P < 0.001). VOR displayed the greatest intrapatient variability (46%), whereas POS-Tab showed the lowest (32%). Conclusions: Our study showed that VOR and POS-Tab achieve the highest percentage of therapeutic APL in patients with LTx; POS-Tab showed the lowest intrapatient variability. APL are significantly influenced by azole dose, age, cystic fibrosis, type of LTx, and comedication with proton-pump inhibitors. Considering the high number of subtherapeutic APL, therapeutic drug monitoring should be integrated in the post-LTx management.

Air pollution is a major risk factor for various respiratory diseases, in particular for disease progression in COPD. Therefore, it is very important to understand pathophysiological mechanisms that determine specific interactions between air pollutants and the bronchial epithelium, thereby informing future diagnostic and treatment regimen. Primary human bronchial epithelial cells (pHBECS) from healthy/ diseased lung tissue were exposed on air-liquid interface (ALI) with relevant aerosolized nanoparticles (NPs; Carbon black nanoparticles /CNP, Zinc oxide /ZnO) and LPS, using the ALICE-CLOUD system. The functional cell viability, inflammatory and anti-oxidant response were analyzed by TEER, WST-1, LDH, qPCR and ELISA. For further validation, a novel ex-vivo airway model was established by culturing native bronchial mucosa on ALI and analyzed by 3D confocal immunofluorescence. ZnO NPs (31,8µg/cm2) induced epithelial barrier impairment after 4h (81%) and reduced viability (37% after 4h and 23% after 24h). Only ZnO NPs revealed an antioxidant response with 100-fold increased HMOX-RNA expression after 24h. qPCR analysis suggested increased TNF (3-fold) and IL8-RNA (2-fold) expression, 24h after ZnO (31,8µg/cm2) exposure. The ELISA analysis suggested an 1,5-fold increased IL8 concentration 4h after ZnO (9,3ng/ml) or LPS (10,8ng/ml) exposure. ZnO but not CNP cause epithelial barrier and cell viability impairment with the involvement of inflammatory and antioxidant pathways. The novel ex-vivo culture model based on bronchial tissue might be an important tool to validate the differentiation of the pHBECs and to better understand the inflammatory processes at the level of main bronchi.

Lung injury activates quiescent stem and progenitor cells to regenerate alveolar structures. The sequence and coordination of transcriptional programs during this process has largely remained elusive. Using single cell RNA-seq, we first generated a whole-organ bird’s-eye view on cellular dynamics and cell-cell communication networks during mouse lung regeneration from ∼30,000 cells at six timepoints. We discovered an injury-specific progenitor cell state characterized by Krt8 in flat epithelial cells covering alveolar surfaces. The number of these cells peaked during fibrogenesis in independent mouse models, as well as in human acute lung injury and fibrosis. Krt8+ progenitors featured a highly distinct connectome of receptor-ligand pairs with endothelial cells, fibroblasts, and macrophages. To ‘sky dive’ into epithelial differentiation dynamics, we sequenced >30,000 sorted epithelial cells at 18 timepoints and computationally derived cell state trajectories that were validated by lineage tracing genetic reporter mice. Airway stem cells within the club cell lineage and alveolar type-2 cells underwent transcriptional convergence onto the same Krt8+ progenitor cell state, which later resolved by terminal differentiation into alveolar type-1 cells. We derived distinct transcriptional regulators as key switch points in this process and show that induction of TNF-alpha/NFkappaB, p53, and hypoxia driven gene expression programs precede a Sox4, Ctnnb1, and Wwtr1 driven switch towards alveolar type-1 cell fate. We show that epithelial cell plasticity can induce non-gradual transdifferentiation, involving intermediate progenitor cell states that may persist and promote disease if checkpoint signals for terminal differentiation are perturbed.

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.

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