It has already been 2 years since we took the privilege of leading the European Respiratory Journal and we want to wish all of our readers, authors, reviewers and editors a very happy and successful 2020. It has been another busy and successful year at the journal. The ERJ editors wish all readers, authors, reviewers and editors a happy and successful 2020, and are ready to continue their work into the new decade!

Management of progressive fibrotic interstitial lung diseases (ILDs) has long been limited to compensatory oxygen therapy and/or corticosteroids, but work in recent years has established the efficacy of new antifibrotic treatments in slowing the decline of patients with idiopathic pulmonary fibrosis [1]. However, many factors contribute to the tolerance and efficacy of new drugs in patients with ILDs. The fate of patients with pulmonary fibrosis is also influenced by their frailty. Hence the urgent need to evaluate these patients beyond pulmonary involvement, and to consider the decline in pulmonary function as a late warning of homeostasis erosion.

Examination of the transcriptomic activity of an organ at single cell resolution is one of the major breakthroughs in modern biology. Single cell RNA sequencing (scRNA-seq) is built on the paradigm-shifting work of Brady and Iscove [1], who described a method for generating microgrammes of cDNA from samples as small as a single cell almost 30 years ago. This discovery was followed closely by single cell transcriptomic analysis in neurons, accomplished by microinjecting primer, nucleotides and reverse transcriptase enzyme into dissociated cells [2]. Single cell sequencing has identified new mesenchymal lineage markers in early human development, allowing for the more precise identification and characterisation of mesenchymal subpopulations in lung development and disease

Marie Curie is a legendary figure: her research had huge impact on medicine, and she was the first woman to receive a Nobel Prize. In fact, she received two, one in Physics in 1903, and one in Chemistry in 1911, and so early in the history of Nobel Prizes (they were first awarded in 1901) a woman was a laureate. This was before women's suffrage in most parts of the world, and before any notion of gender equality, when few women had a chance to follow a career in science or medicine or get any education, and Marie Curie showed that it was possible. She was admired, respected and a role model for women in science. But still, more than 100 years later, few women have followed her footsteps: Between 1901 and 2018, there have been 902 Nobel laureates and of those, 52 were women [1]. Few women are still promoted to leadership positions and there seems to be an unconscious bias that must be changed

Background Accelerated biological and functional ageing is common in fibrotic interstitial lung disease (ILD); however, their impact on adverse health outcomes has not been evaluated in this population. Methods Patients were prospectively recruited from a specialised ILD clinic. Functional ageing was determined by frailty index and biological age by measurement of absolute telomere length (aTL) from patients' peripheral blood leukocytes. Adverse health outcomes included health-related quality of life (St George's Respiratory Questionnaire), number and length of respiratory and non-respiratory hospitalisations, medication tolerability and time to death or lung transplantation. Multivariable models were used to determine the risks and rates of adverse health outcomes associated with the frailty index and aTL. Results 540 patients with fibrotic ILD, including 100 with idiopathic pulmonary fibrosis (IPF), provided 749 frailty index assessments, with 189 patients providing blood samples. The frailty index was strongly associated with quality of life, rate of hospitalisation, time to hospital discharge and mortality, including adjustment for age, sex, disease severity and IPF diagnosis. Mortality prognostication was improved by the addition of the frailty index to commonly used clinical parameters and previously validated composite indices. Conversely, aTL was not associated with most adverse health outcomes. The effect of chronological age on outcomes was mediated primarily by the frailty index, and to a lesser extent by aTL. Conclusions Functional ageing is associated with adverse health outcomes in patients with fibrotic ILD, indicating the need for consideration of the individual functional age into clinical decision-making. Frailty independently predicts adverse health outcomes in patients with fibrotic ILD; with functional ageing as the main driver of most age-related adverse health outcomes there is a need to recognise, prevent and treat frailty in this population

Background Airway obstruction and wheezing in preschool children with recurrent viral infections are a major clinical problem, and are recognised as a risk factor for the development of chronic asthma. We aimed to analyse whether gene expression profiling provides evidence for pathways that delineate distinct groups of children with wheeze, and in combination with clinical information could contribute to diagnosis and prognosis of disease development. Methods We analysed leukocyte transcriptomes from preschool children (6 months–3 years) at acute wheeze (n=107), and at a revisit 2–3 months later, comparing them to age-matched healthy controls (n=66). RNA-sequencing applying GlobinLock was used. The cases were followed clinically until age 7 years. Differential expression tests, weighted correlation network analysis and logistic regression were applied and correlations to 76 clinical traits evaluated. Findings Significant enrichment of genes involved in the innate immune responses was observed in children with wheeze. We identified a unique acute wheeze-specific gene-module, which was associated with vitamin D levels (p<0.005) in infancy, and asthma medication and FEV1%/FVC (forced expiratory volume in 1 s/forced vital capacity) ratio several years later, at age 7 years (p<0.005). A model that predicts leukotriene receptor antagonist medication at 7 years of age with high accuracy was developed (area under the curve 0.815, 95% CI 0.668–0.962). Interpretation Gene expression profiles in blood from preschool wheezers predict asthma symptoms at school age, and therefore serve as biomarkers. The acute wheeze-specific gene module suggests that molecular phenotyping in combination with clinical information already at an early episode of wheeze may help to distinguish children who will outgrow their wheeze from those who will develop chronic asthma. Gene expression profiles at acute preschool wheeze correlate with vitamin D, and asthma medication and lung function several years later. These profiles provide candidate prognostic biomarkers and support the role of immune response in preschool wheeze.

Rationale The lung mesenchyme gives rise to multiple distinct lineages of cells in the mature respiratory system, including smooth muscle cells of the airway and vasculature. However, a thorough understanding of the specification and mesenchymal cell diversity in the human lung is lacking. Methods We completed single-cell RNA sequencing analysis of fetal human lung tissues. Canonical correlation analysis, clustering, cluster marker gene identification and t-distributed stochastic neighbour embedding representation was performed in Seurat. Cell populations were annotated using ToppFun. Immunohistochemistry and in situ hybridisation were used to validate spatiotemporal gene expression patterns for key marker genes. Results We identified molecularly distinct populations representing “committed” fetal human lung endothelial cells, pericytes and smooth muscle cells. Early endothelial lineages expressed “classic” endothelial cell markers (platelet endothelial cell adhesion molecule/CD31 and claudin 5), while pericytes expressed platelet-derived growth factor receptor-β, Thy-1 membrane glycoprotein and basement membrane molecules (collagen IV, laminin and proteoglycans). We observed a large population of “nonspecific” human lung mesenchymal progenitor cells characterised by expression of collagen I and multiple elastin fibre genes ( ELN , MFAP2 and FBN1 ). We closely characterised the diversity of mesenchymal lineages defined by α2-smooth muscle actin ( ACTA2 ) expression. Two cell populations, with the highest levels of ACTA2 transcriptional activity, expressed unique sets of markers associated with airway or vascular smooth muscle cells. Spatiotemporal analysis of these marker genes confirmed early and persistent spatial specification of airway ( HHIP , MYLK and IGF1 ) and vascular ( NTRK3 and MEF2C ) smooth muscle cells in the developing human lung. Conclusion Our data suggest that specification of distinct airway and vascular smooth muscle cell phenotypes is established early in development and can be identified using the markers we provide. Data presented here provide novel information on molecular markers for multiple cell types within the fetal human lung. In particular, we identify new, putative markers capable of spatially distinguishing airway and vascular smooth muscle cells.

RNA sequencing is a powerful tool for high-resolution transcriptomic analysis and can be leveraged to better understand the molecular underpinnings of diverse lung diseases

Biobanked, cryopreserved lung cells obtained from human lung tissue are viable and valuable resources for large-scale molecular phenotyping

The gender imbalance in medicine has been a topic of increasing interest and discussion. There are increasing proportions of graduating female medical students globally, with 41.1% of Australian doctors, 47% of UK doctors and 46% of medical residents in the USA being female [1, 2]. However, in positions of influence, the proportions change, such that in the USA only 21% of medical professors and 16% of medical deans are female [3]. Postulated reasons for this include implicit and unconscious gender bias and fewer promotion opportunities available to women. Analysis of the sex distribution of presenters in national and international conferences in 2017 demonstrates a significantly lower proportion of women in more prominent roles compared with men

The Fleischner Society white paper and the American Thoracic Society (ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society (JRS)/Latin American Thoracic Association (ALAT) guidelines recently redefined the computed tomography (CT) scanning patterns of usual interstitial pneumonia (UIP) [1, 2]. Both publications confirmed honeycombing as the cornerstone of UIP pattern diagnosis, and introduced peripheral traction bronchiolectasis (PTB) as a key feature of the new “probable UIP” category. Therefore, improving the distinction between these two features may be critical, especially when the clinical likelihood of idiopathic pulmonary fibrosis (IPF) is uncertain; a lung biopsy should be discussed for patients with PTB without honeycombing, but is not recommended for patients presenting with clear honeycombing and typical UIP pattern [2]. On chest CT, post-processing with minimal intensity projection does not improve inter-reader agreement for the identification of peripheral traction bronchiolectasis and honeycombing in patients with suspected idiopathic interstitial pneumonia.

Bronchiectasis is a chronic and often progressive disease, which frequently is associated with significant symptom burden, requiring intensive treatment. Regardless of the multiple potential underlying aetiologies, the vicious cycle of airway inflammation, structural airway damage, impaired mucus clearance and airway pathogen acquisition is the crucial pathogenic pathway for the progression of disease [1]. Patients with clinically significant bronchiectasis featuring an eosinophilic inflammatory endotype who were treated with add-on mepolizumab or benralizumab showed a significant improvement of FEV1, symptom burden and quality of life

We read with interest the report of the results of the COPE-III trial by Lenferink et al. [1]. This large randomised trial continues on from the authors’ earlier COPE-II study [1], with personalised exacerbation action plans based on associated comorbidities. The action plans were detailed, and designed to determine symptom changes and the signs of an ensuing exacerbation. The study was negative for its primary endpoint (COPD exacerbation days) and no improvement in quality of life was found using the self-management intervention. COPD exacerbation self-management does not reduce COPD exacerbation days or hospitalisation, rather to more oral corticosteroid use and is rarely effective as it is not targeted

We are grateful to the editors of the European Respiratory Journal for the opportunity to respond to the letter to the editor by S. Ramakrishnan and M. Bafadhel, whom we thank for their thoughtful remarks about our COPE-III self-management trial [1]. Whereas our study did not show a significant difference in the number of COPD exacerbation days per year, the results showed that exacerbation action plans for COPD patients with comorbidities, embedded in a patient-tailored self-management intervention, reduced the duration of COPD exacerbations and the risk of respiratory-related hospitalisation, without increasing all-cause mortality [1]. In our study, we did not phenotype COPD exacerbations by airway eosinophilic inflammation prior to randomisation. Tailoring self-treatment by adding exacerbation phenotyping could be explored. Evidence on phenotyping effects, an accurate tool to identify eosinophilic exacerbations, and a validated cut-off point are needed before eosinophils can be used in practice.

In 2009, Elizabeth Blackburn, Jack Szostak and Carol Greider were awarded the Nobel Prize in Physiology or Medicine for their pioneering work that led to the discovery of telomeres and the enzyme complex telomerase responsible for maintaining its structure [1]. Over the past four decades, the classic view of telomeres protecting the natural ends of linear chromosomes and telomerase as telomere-terminal transferase necessary for the replication of chromosome ends has significantly evolved. Many diverse fields have matured, including the discovery of key molecular components of telomerase, implications for limits to cellular replication, and identification and characterisation of human genetic disorders that result in premature telomere shortening [2]. The association of shorter leukocyte telomere length and reduced survival in critical illness may prove crucial in our quest to improve outcomes

The morbidity and mortality from non-tuberculous mycobacterial (NTM) disease is increasing [1]. Treatment of NTM usually requires multidrug regimens and is often associated with poor tolerability, significant side-effects and high failure rates. Not all patients with pulmonary NTM disease need treatment, and deciding who and when to treat can be challenging. The management of NTM is significantly hampered by the lack of reliable and responsive biomarkers to assess disease activity, progression and response to therapy, and at present, clinical decisions are made with a combination of symptom, radiology and microbiological assessments. There is a pressing need for new therapies and approaches for pulmonary NTM disease, and this will require robust clinical endpoints to evaluate them. There is a pressing need for patient related outcome measures for pulmonary NTM disease, to assist with both clinical management decisions and as an endpoint for clinical studies. This NTM Module should be considered an important step in this development.

There are limited data on combining delamanid and bedaquiline in drug-resistant tuberculosis (DR-TB) regimens. Prospective long-term outcome data, including in HIV-infected persons, are unavailable. We prospectively followed up 122 South African patients (52.5% HIV-infected) with DR-TB and poor prognostic features between 2014 and 2018. We examined outcomes and safety in those who received a bedaquiline-based regimen (n=82) compared to those who received a bedaquiline–delamanid combination regimen (n=40). There was no significant difference in 6-month culture conversion (92.5% versus 81.8%; p=0.26) and 18-month favourable outcome rate (63.4% versus 67.5%; p=0.66) in the bedaquiline versus the bedaquiline–delamanid combination group, despite the latter having more advanced drug resistance (3.7% versus 22.5% resistant to at least five drugs; p=0.001) and higher pre-treatment failure rates (12.2% versus 52.5% with pre-treatment multidrug-resistant TB therapy failure; p<0.001). Although the proportion of prolongation of the QT interval corrected using Fridericia's formula was higher in the combination group (>60 ms from baseline (p=0.001) or >450 ms during treatment (p=0.001)), there were no symptomatic cases or drug withdrawals in either group. Results were similar in HIV-infected patients. A bedaquiline–delamanid combination regimen showed comparable long-term safety compared to a bedaquiline-based regimen in patients with DR-TB, irrespective of HIV status. These data inform regimen selection in patients with DR-TB from TB-endemic settings. A bedaquiline–delamanid combination regimen in drug-resistant tuberculosis patients with poor prognostic factors showed comparable efficacy and safety to those in a bedaquiline-based regimen

Ontologically distinct populations of macrophages differentially contribute to organ fibrosis through unknown mechanisms. We applied lineage tracing, single-cell RNA sequencing and single-molecule fluorescence in situ hybridisation to a spatially restricted model of asbestos-induced pulmonary fibrosis. We demonstrate that tissue-resident alveolar macrophages, tissue-resident peribronchial and perivascular interstitial macrophages, and monocyte-derived alveolar macrophages are present in the fibrotic niche. Deletion of monocyte-derived alveolar macrophages but not tissue-resident alveolar macrophages ameliorated asbestos-induced lung fibrosis. Monocyte-derived alveolar macrophages were specifically localised to fibrotic regions in the proximity of fibroblasts where they expressed molecules known to drive fibroblast proliferation, including platelet-derived growth factor subunit A. Using single-cell RNA sequencing and spatial transcriptomics in both humans and mice, we identified macrophage colony-stimulating factor receptor (M-CSFR) signalling as one of the novel druggable targets controlling self-maintenance and persistence of these pathogenic monocyte-derived alveolar macrophages. Pharmacological blockade of M-CSFR signalling led to the disappearance of monocyte-derived alveolar macrophages and ameliorated fibrosis. Our findings suggest that inhibition of M-CSFR signalling during fibrosis disrupts an essential fibrotic niche that includes monocyte-derived alveolar macrophages and fibroblasts during asbestos-induced fibrosis. Monocyte-derived alveolar macrophages orchestrate the development of the fibrotic niche, causally related to fibrosis and maintained via M-CSF/M-CSFR signalling

Shorter peripheral blood leukocyte (PBL) telomere length (TL) has been associated with poor outcomes in various chronic lung diseases. Whether PBL-TL is associated with survival from critical illness was tested in this study. We analysed data from a prospective observational cohort study of 937 critically ill patients at Vanderbilt University Medical Center (VUMC). PBL-TL was measured using quantitative PCR of DNA isolated from PBLs. Findings were validated in an independent cohort of 394 critically ill patients with sepsis admitted to the University of California San Francisco (UCSF). In the VUMC cohort, shorter PBL-TL was associated with worse 90-day survival (adjusted hazard ratio (aHR) 1.3, 95% CI 1.1–1.6 per 1 kb TL decrease; p=0.004); in subgroup analyses, shorter PBL-TL was associated with worse 90-day survival for patients with sepsis (aHR 1.5, 95% CI 1.2–2.0 per 1 kb TL decrease; p=0.001), but not trauma. Although not associated with development of acute respiratory distress syndrome (ARDS), among ARDS subjects, shorter PBL-TL was associated with more severe ARDS (OR 1.7, 95% CI 1.2–2.5 per 1 kb TL decrease; p=0.006). The associations of PBL-TL with survival (adjusted HR 1.6, 95% CI 1.2–2.1 per 1 kb TL decrease; p=0.003) and risk for developing severe ARDS (OR 2.5, 95% CI 1.1–6.3 per 1 kb TL decrease; p=0.044) were validated in the UCSF cohort. Short PBL-TL is strongly associated with worse survival and more severe ARDS in critically ill patients, especially patients with sepsis. These findings suggest that telomere dysfunction may contribute to outcomes from critical illness. Shorter peripheral blood leukocyte telomere length is strongly associated with worse survival and more severe ARDS in critically ill patients with sepsis

Introduction Nontuberculous mycobacteria (NTM) cause chronic, debilitating pulmonary disease. Patient-reported outcomes provide measures of symptoms, functioning and treatment response. Here we describe the preliminary validation of the recently developed NTM Module. Methods The study population included Northwest NTM Biobank patients in whom Mycobacterium avium complex (MAC) was isolated and who had ever met the 2007 American Thoracic Society/Infectious Diseases Society of America pulmonary disease criteria. The NTM Module was administered at enrolment and 12 months; a subset also completed the Quality of Life Questionnaire–Bronchiectasis (QOL-B). The NTM Module generates four domain scores (0–100; higher scores indicate better functioning) reflecting NTM-specific symptoms (NTM Symptoms, Body Image, Digestive Symptoms and Eating Problems). We described patient characteristics and mean scores, and evaluated psychometric properties, including response to treatment at 12 months, for each domain. Results Overall, 203 patients with pulmonary MAC disease were included. Average enrolment scores ranged from 76 (NTM Symptoms) to 84 (Eating Problems). Ceiling effects were observed for Body Image (26% of participants) and Eating Problems (52%). Internal consistency (Cronbach's alpha) ranged from 0.67 (Digestive Symptoms) to 0.89 (Eating Problems). The intraclass correlation for test–retest reproducibility (n=27) ranged from 0.72 (Body Image) to 0.94 (Eating Problems). Patients starting treatment (n=35) had statistically significant increases in scores for NTM Symptoms (+5, p=0.04), Digestive Symptoms (+7, p=0.002), Body Image (+7, p=0.03) and QOL-B Respiratory Symptoms (n=25, +10, p=0.006). NTM Symptoms scores increased by 15 points (p=0.002) in the 16 patients with scores ≤80 at enrolment. Conclusion The NTM Module generally performs well as a valid patient-reported outcome for pulmonary MAC disease and was responsive to MAC treatment. The NTM Symptom Module is a valid patient-reported outcome tool that can facilitate patient-centred care and may be used as an outcome in clinical trials to support labelling claims for regulatory bodies.

Similar to patients with cystic fibrosis (CF) and non-CF bronchiectasis, patients with primary ciliary dyskinesia (PCD) are prone to recurrent or chronic lung infections with Pseudomonas aeruginosa . Chronic P. aeruginosa lung infection has a prevalence of up to 39% in patients with PCD [1] and is associated with structural damage, affecting lung function. Treatment of P. aeruginosa infection is challenging because P. aeruginosa adapts to the host environment through genotypic/phenotypic changes, promoting a reduced immune response [2]. For the first time it is shown that the same Pseudomonas aeruginosa clone exists in both the upper and lower airways in patients with PCD, providing a solid support of the unified airway theory where the sinuses are a possible bacterial reservoir

The manifesto proposed by Roche et al . [1] is a most important plan to revolutionise respiratory clinical research. It also prompts a key question about the balance between the effort spent on randomised clinical trials (RCTs) versus real-life research (RLR), particularly in an era where frequent monitoring of patients capturing their real life, using wearable devices, home diagnostics, smartphones, smart inhalers, collections of contextual information, cloud connectivity and the ability to analyse large complex datasets is becoming increasingly feasible [2]. Real-life clinical research may be more valuable to achieve the aspirations of personalised medicine than the traditional “regulatory style” randomised clinical trials

We thank I. Gonda for outlining the promises and challenges of real-life research (RLR), following the publication of the Respiratory Effectiveness Group manifesto in the European Respiratory Journal [1]. As outlined in this correspondence, the ultimate goal of RLR is to improve patients' outcomes through more precise decision-making in the current era of personalised medicine. To this aim, RLR provides evidence complementing randomised controlled trials (RCTs), especially exploring benefit–risk–cost ratios in both large and specific subpopulations, while minimising the Hawthorne effect. I. Gonda underlines a particularly important aspect of RLR, i.e. how it can be revolutionised by new technologies. This is especially promising in the respiratory field, where therapy administered with inhalation devices plays a major role, while many chronic conditions are under the influence of environmental conditions that can now be continuously recorded. Assessment of m-Health tools needs to include high-quality real-life research studies. Reciprocally, real-life research can benefit highly from opportunities offered by connected devices.

A stepwise approach to the pharmacological treatment of asthma is a key feature of current asthma guidelines [1–4]. Through algorithms, treatment intensity is “stepped up” to obtain asthma control and reduce the risk of exacerbations, and “stepped down” after a period of prolonged control and absence of exacerbations. Traditional algorithms advocated short-acting β2-agonist (SABA) reliever therapy for all levels of severity, initially as sole therapy at Step 1, together with maintenance “low dose” inhaled corticosteroids (ICS) at Step 2, with maintenance ICS/long-acting β2-agonist (LABA) at “low”, “moderate” or “high” doses at Steps 3 and 4, and finally with “add-on” therapies at Step 5. A practical “anti-inflammatory reliever therapy”-based algorithm based on the GINA 2019 update is presented, together with a prototype action plan to facilitate its implementation.

Background and aim Hypoglossal nerve stimulation (HNS) decreases obstructive sleep apnoea (OSA) severity via genioglossus muscle activation and decreased upper airway collapsibility. This study assessed the safety and effectiveness at 6 months post-implantation of a novel device delivering bilateral HNS via a small implanted electrode activated by a unit worn externally, to treat OSA: the Genio™ system. Methods This prospective, open-label, non-randomised, single-arm treatment study was conducted at eight centres in three countries (Australia, France and the UK). Primary outcomes were incidence of device-related serious adverse events and change in the apnoea–hypopnoea index (AHI). The secondary outcome was the change in the 4% oxygen desaturation index (ODI). Additional outcomes included measures of sleepiness, quality of life, snoring and device use. This trial was registered with ClinicalTrials.gov, number [NCT03048604][1]. Results 22 out of 27 implanted participants (63% male, aged 55.9±12.0 years, body mass index (BMI) 27.4±3.0 kg·m−2) completed the protocol. At 6 months BMI was unchanged (p=0.85); AHI decreased from 23.7±12.2 to 12.9±10.1 events·h−1, a mean change of 10.8 events·h−1 (p<0.001); and ODI decreased from 19.1±11.2 to 9.8±6.9 events·h−1, a mean change of 9.3 events·h−1 (p<0.001). Daytime sleepiness (Epworth Sleepiness Scale; p=0.01) and sleep-related quality of life (Functional Outcomes of Sleep Questionnaire-10; p=0.02) both improved significantly. The number of bed partners reporting loud, very intense snoring, or leaving the bedroom due to participant snoring decreased from 96% to 35%. 91% of participants reported device use >5 days per week, and 77% reported use for >5 h per night. No device-related serious adverse events occurred during the 6-month post-implantation period. Conclusions Bilateral HNS using the Genio™ system reduces OSA severity and improves quality of life without device-related complications. The results are comparable with previously published HNS systems despite minimal implanted components and a simple stimulation algorithm. A new method of hypoglossal nerve stimulation to treat sleep apnoea does so bilaterally via an implanted neurostimulator activated externally. Its simplicity and relative non-invasiveness have not compromised its effectiveness relative to older methods. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03048604&atom=%2Ferj%2F55%2F1%2F1901320.atom

Little is known about the characteristics and treatments of patients with severe asthma across Europe, but both are likely to vary. This is the first study in the European Respiratory Society Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) Clinical Research Collaboration and it is designed to explore these variations. Therefore, we aimed to compare characteristics of patients in European severe asthma registries and treatments before starting biologicals. This was a cross-sectional retrospective analysis of aggregated data from 11 national severe asthma registries that joined SHARP with established patient databases. Analysis of data from 3236 patients showed many differences in characteristics and lifestyle factors. Current smokers ranged from 0% (Poland and Sweden) to 9.5% (Belgium), mean body mass index ranged from 26.2 (Italy) to 30.6 kg·m−2 (the UK) and the largest difference in mean pre-bronchodilator forced expiratory volume in 1 s % predicted was 20.9% (the Netherlands versus Hungary). Before starting biologicals patients were treated differently between countries: mean inhaled corticosteroid dose ranged from 700 to 1335 µg·day−1 between those from Slovenia versus Poland when starting anti-interleukin (IL)-5 antibody and from 772 to 1344 µg·day−1 in those starting anti-IgE (Slovenia versus Spain). Maintenance oral corticosteroid use ranged from 21.0% (Belgium) to 63.0% (Sweden) and from 9.1% (Denmark) to 56.1% (the UK) in patients starting anti-IL-5 and anti-IgE, respectively. The severe asthmatic population in Europe is heterogeneous and differs in both clinical characteristics and treatment, often appearing not to comply with the current European Respiratory Society/American Thoracic Society guidelines definition of severe asthma. Treatment regimens before starting biologicals were different from inclusion criteria in clinical trials and varied between countries. The severe asthma population in Europe is heterogeneous and differs in clinical characteristics and treatment. Harmonisation across registries and guidelines is needed and requires collection of same data across cohorts to enable future research in SHARP.

Asthma is a common condition caused by immune and respiratory dysfunction, and it is often linked to allergy. A systems perspective may prove helpful in unravelling the complexity of asthma and allergy. Our aim is to give an overview of systems biology approaches used in allergy and asthma research. Specifically, we describe recent “omic”-level findings, and examine how these findings have been systematically integrated to generate further insight. Current research suggests that allergy is driven by genetic and epigenetic factors, in concert with environmental factors such as microbiome and diet, leading to early-life disturbance in immunological development and disruption of balance within key immuno-inflammatory pathways. Variation in inherited susceptibility and exposures causes heterogeneity in manifestations of asthma and other allergic diseases. Machine learning approaches are being used to explore this heterogeneity, and to probe the pathophysiological patterns or “endotypes” that correlate with subphenotypes of asthma and allergy. Mathematical models are being built based on genomic, transcriptomic and proteomic data to predict or discriminate disease phenotypes, and to describe the biomolecular networks behind asthma. The use of systems biology in allergy and asthma research is rapidly growing, and has so far yielded fruitful results. However, the scale and multidisciplinary nature of this research means that it is accompanied by new challenges. Ultimately, it is hoped that systems medicine, with its integration of omics data into clinical practice, can pave the way to more precise, personalised and effective management of asthma. With the recent influx of “big data” in asthma research, clinicians and scientists need to become familiar with analytical approaches that use systems-based methods to make sense of large datasets

Obstructive sleep apnoea (OSA) and non-alcoholic fatty liver disease (NAFLD) are two of many diseases associated with obesity. NAFLD is a common condition ranging in severity from liver steatosis to non-alcoholic steatohepatitis and liver fibrosis, the last step of NAFLD progression. Numerous studies have investigated whether the frequent co-occurrence of OSA and NAFLD simply reflects their link to obesity, or whether there is an independent pathophysiological interconnection between the two diseases (see [1] for comprehensive review). In animal models, intermittent hypoxia mimicking OSA has been shown to cause insulin resistance, dysfunction of key steps in hepatic lipid metabolism, liver steatosis and fibrosis [1]. In patients with OSA and metabolic comorbidities, liver steatosis measured by magnetic resonance imaging is associated with male sex and insulin resistance, but not with OSA severity and nocturnal hypoxia The METABOL Group: Département de Pneumologie, CHU, Angers, France: Nicole Meslier, Pascaline Priou; Service d'Hépato-gastroentérologie, CHU, Angers, France: Frédéric Oberti, Isabelle Fouchard-Hubert, Adrien Lannes, Sandra Girres; Département d'Endocrinologie, Diabétologie, Nutrition, CHU, Angers, France: Ingrid Allix; Département de Médecine du Sport et Explorations Fonctionnelles Vasculaires, CHU, Angers, France: Georges Leftheriotis; INSERM UMR 1063 “SOPAM”, Univeristé d'Angers, Angers, France: Carmen Martinez, Soazig Le Lay, Raffaella Soleti, Luisa Vergori; Département de la Recherche Clinique et Innovation, CHU, Angers, France: Jean-Marie Chrétien; Centre de Resource Biologique, CHU, Angers, France: Odile Blanchet, Belaid Sekour; Laboratoire HIFIH, EA3859, Université d'Angers, France: Gilles Hunault.

We read with interest the study by Wolters et al . [1], reporting the results of radiographic tuberculosis (TB) entry screening of asylum seekers in the Netherlands. We agree with the authors that we lack sufficient studies concerning latent TB infection (LTBI) screening among minor asylum seekers, and we present our study investigating LTBI prevalence and the coverage of follow-up in terms of clinical evaluation and treatment of LTBI among minor asylum seekers arriving in Denmark. Screening among minor asylum seekers in Denmark revealed a high LTBI prevalence with heterogeneity in terms of clinical evaluation and initiating preventive treatment, underlining the need for uniform management of LTBI screening and treatment

The fraction of exhaled nitric oxide ( F eNO) is generally lower in individuals with cystic fibrosis (CF), compared to healthy controls. Two recent studies reported that the cystic fibrosis transmembrane conductance regulator (CFTR) potentiator ivacaftor resulted in an increase in F eNO after 4 weeks’ therapy [1, 2], suggesting that changes in F eNO have the potential to serve as biomarker of restored CFTR function. Ivacaftor results in a sustained increase in F eNO in children and adults with CF. The increase in F eNO may be related to changes in airway NO metabolism by myeloperoxidase. Lumacaftor–ivacaftor therapy does not have an immediate effect on F eNO. We thank all patients and families who participated in this research study. Mass spectrometry analyses were performed at the Analytical Facility for Bioactive Molecules (AFBM) of the Centre for the Study of Complex Childhood Diseases (CSCCD) at the Hospital for Sick Children (Toronto, ON, Canada). The CSCCD was supported by the Canadian Foundation for Innovation (CFI).

Despite highly effective antibiotics and intensive care support, the mortality associated with pneumonia has not substantially decreased since the 1960s [1]. Hence, there remains a major requirement for improved treatment and preventative strategies, which will need new knowledge on the pathogenesis of pneumonia. Animal models have obvious high value when investigating the molecular mechanisms involved in pneumonia pathogenesis, but they are also directly relevant for clinically orientated research into new therapies and vaccines, complications of pneumonia, and identifying high risk groups. In this article we describe how research using animal models will be essential if we are to reduce the immense morbidity and mortality associated with pneumonia. Animal models can provide incredibly detailed data on pathogenesis and immunology of lung infections, and will be essential for the development of novel therapeutic/preventative strategies to reduce the morbidity and mortality caused by pneumonia

In their 1987 community-acquired pneumonia (CAP) guidelines, the British Thoracic Society recommended amoxicillin with or without erythromycin (or tetracycline) in all admitted patients, with the coverage for Legionella being mandatory in seriously ill patients [1]. They also recommended intravenous flucloxacillin when Staphylococcus aureus was suspected and gentamicin or ceftazidime if a Gram-negative agent was suspected. This guideline, now more than 30 years old, also emphasised the need to identify critically ill patients based on objective physiological criteria so they could receive intensive care support, recommended obtaining culture specimens when possible and stated that antibiotics should be started immediately upon diagnosis. All of these 1987 recommendations were based on clinical studies on the aetiology of pneumonia, analysis of the predictors of outcome from pneumonia from clinical studies and a series of observational studies comparing outcomes of different antibiotic regimens in the prior three decades. Animal models of pneumonia are severely flawed and need to change if they are going to help us with new therapies

In May 2019, the third European Respiratory Society research seminar of the Thoracic Oncology Assembly entitled “New biomarkers, molecules and therapeutic sequences for non-small cell lung carcinoma (NSCLC) in the era of precision medicine” was held in Paris, France. The previous two seminars of the Thoracic Oncology Assembly were on targeted therapy (2015) [1] and immune checkpoint inhibitors (ICI, 2017) [2]. During this seminar, breakout sessions on difficult situations were organised. One of the most original and useful was on the current challenges in brain metastases (BM) management, that we propose to share with European Respiratory Journal readers. Brain metastases remain a major problem in NSCLC. Major improvements in systemic therapies have been observed during the past decade but their impact on brain metastases control as well as their combination with radiation techniques needs further research.

Uncertainties still surround high dose inhaled corticosteroids (ICS) use in asthma. In hindsight, certain aspects of the ICS development story can help elucidate why. In 1973, Cameron et al. [1] signed a brilliant paper reporting the results of a double blind, randomised controlled trial demonstrating the oral corticosteroid (OCS)-sparing effect of ICS as the primary outcome. A few years later, the assessment of this benefit was mitigated when a complete weaning of OCS remained unachievable [2]. The benefit of ICS was therefore understood to be mostly based on an improved safety profile purportedly due to reduced systemic diffusion. Thus, the understanding of how ICS was of any benefit to asthma patients when compared to OCS was mostly based on a greater safety profile supposedly due to a reduced systemic diffusion. Similarly, topically administered corticosteroids were also developed in the same time period for diseases affecting the skin, the eyes, the nose or the joints. As for ICS, whether or not these formulations reduce corticosteroid-associated adverse events remains largely debated [3]. If high doses of ICS are equivalent to low dose OCS, they should be considered as such

COPD is a major burden globally. According to the Global Burden of Disease study, COPD caused 3.2 million deaths in 2015, accounting for 5% of all deaths worldwide, making it the third leading cause of death in the world [1]. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines spirometrically confirmed COPD based on a forced expiratory volume during the first second (FEV1) to a forced vital capacity (FVC) ratio smaller than 0.7 [2]. The severity of airflow obstruction is further defined through GOLD severity grades based on the ratio of FEV1 to its predicted value, with GOLD 1, 2, 3 and 4 defined around cut-off points of 80%, 50%, and 30% [2]. Preserved ratio impaired spirometry (PRISm) is a prevalent, neglected condition whose prognosis is close to that of COPD

These guidelines incorporate the recent advances in chronic cough pathophysiology, diagnosis and treatment. The concept of cough hypersensitivity has allowed an umbrella term that explains the exquisite sensitivity of patients to external stimuli such a cold air, perfumes, smoke and bleach. Thus, adults with chronic cough now have a firm physical explanation for their symptoms based on vagal afferent hypersensitivity. Different treatable traits exist with cough variant asthma (CVA)/eosinophilic bronchitis responding to anti-inflammatory treatment and non-acid reflux being treated with promotility agents rather the anti-acid drugs. An alternative antitussive strategy is to reduce hypersensitivity by neuromodulation. Low-dose morphine is highly effective in a subset of patients with cough resistant to other treatments. Gabapentin and pregabalin are also advocated, but in clinical experience they are limited by adverse events. Perhaps the most promising future developments in pharmacotherapy are drugs which tackle neuronal hypersensitivity by blocking excitability of afferent nerves by inhibiting targets such as the ATP receptor (P2X3). Finally, cough suppression therapy when performed by competent practitioners can be highly effective. Children are not small adults and a pursuit of an underlying cause for cough is advocated. Thus, in toddlers, inhalation of a foreign body is common. Persistent bacterial bronchitis is a common and previously unrecognised cause of wet cough in children. Antibiotics (drug, dose and duration need to be determined) can be curative. A paediatric-specific algorithm should be used. New ERS guideline on chronic cough details the paradigm shift in our understanding. In adults, cough hypersensitivity has become the overarching diagnosis, and in children, persistent bacterial bronchitis explains most wet cough, changing treatment advice.

This document provides recommendations for monitoring and treatment of children in whom bronchopulmonary dysplasia (BPD) has been established and who have been discharged from the hospital, or who were >36 weeks of postmenstrual age. The guideline was based on predefined Population, Intervention, Comparison and Outcomes (PICO) questions relevant for clinical care, a systematic review of the literature and assessment of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. After considering the balance of desirable (benefits) and undesirable (burden, adverse effects) consequences of the intervention, the certainty of the evidence, and values, the task force made conditional recommendations for monitoring and treatment of BPD based on very low to low quality of evidence. We suggest monitoring with lung imaging using ionising radiation in a subgroup only, for example severe BPD or recurrent hospitalisations, and monitoring with lung function in all children. We suggest to give individual advice to parents regarding daycare attendance. With regards to treatment, we suggest the use of bronchodilators in a subgroup only, for example asthma-like symptoms, or reversibility in lung function; no treatment with inhaled or systemic corticosteroids; natural weaning of diuretics by the relative decrease in dose with increasing weight gain if diuretics are started in the neonatal period; and treatment with supplemental oxygen with a saturation target range of 90–95%. A multidisciplinary approach for children with established severe BPD after the neonatal period into adulthood is preferable. These recommendations should be considered until new and urgently needed evidence becomes available. This guideline provides recommendations on monitoring and treatment of children with established bronchopulmonary dyplasia older than 36 weeks postmenstrual age or after discharge from the hospital, based on PICO questions relevant for clinical care

This document provides clinical recommendations for the management of severe asthma. Comprehensive evidence syntheses, including meta-analyses, were performed to summarise all available evidence relevant to the European Respiratory Society/American Thoracic Society Task Force's questions. The evidence was appraised using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and the results were summarised in evidence profiles. The evidence syntheses were discussed and recommendations formulated by a multidisciplinary Task Force of asthma experts, who made specific recommendations on six specific questions. After considering the balance of desirable and undesirable consequences, quality of evidence, feasibility, and acceptability of various interventions, the Task Force made the following recommendations: 1) suggest using anti-interleukin (IL)-5 and anti-IL-5 receptor α for severe uncontrolled adult eosinophilic asthma phenotypes; 2) suggest using a blood eosinophil cut-point ≥150 μL−1 to guide anti-IL-5 initiation in adult patients with severe asthma; 3) suggest considering specific eosinophil (≥260 μL−1) and exhaled nitric oxide fraction (≥19.5 ppb) cut-offs to identify adolescents or adults with the greatest likelihood of response to anti-IgE therapy; 4) suggest using inhaled tiotropium for adolescents and adults with severe uncontrolled asthma despite Global Initiative for Asthma (GINA) step 4–5 or National Asthma Education and Prevention Program (NAEPP) step 5 therapies; 5) suggest a trial of chronic macrolide therapy to reduce asthma exacerbations in persistently symptomatic or uncontrolled patients on GINA step 5 or NAEPP step 5 therapies, irrespective of asthma phenotype; and 6) suggest using anti-IL-4/13 for adult patients with severe eosinophilic asthma and for those with severe corticosteroid-dependent asthma regardless of blood eosinophil levels. These recommendations should be reconsidered as new evidence becomes available. The ERS/ATS Task Force makes recommendations on the use of novel therapies for severe asthma, specifically biologicals for type 2 high asthma, and antimuscarinic agents and macrolides, as well as on biomarkers for predicting treatment response

Background The proportion of the efficacy of high-dose inhaled corticosteroids (ICS) in oral corticosteroid-dependent asthma that is due to systemic effects is uncertain. This study aimed to estimate the ICS dose–response relationship for oral corticosteroid-sparing effects in oral corticosteroid-dependent asthma, and to determine the proportion of oral corticosteroid-sparing effects due to their systemic effects, based on the comparative dose–response relationship of ICS versus oral corticosteroids on adrenal suppression. Methods Systematic review and meta-analysis of randomised controlled trials reporting oral corticosteroid-sparing effects of high-dose ICS in oral corticosteroid-dependent asthma. In addition, reports of oral corticosteroid to ICS dose-equivalence in terms of adrenal suppression were retrieved. The primary outcome was the proportion of the oral corticosteroid-sparing effect of ICS that could be attributed to systemic absorption, per 1000 µg increase of ICS, expressed as a ratio. This ratio estimates the oral corticosteroid sparing effect of ICS due to systemic effects. Results 11 studies including 1283 participants reporting oral corticosteroid-sparing effects of ICS were identified. The prednisone dose decrease per 1000 µg increase in ICS varied from 2.1 mg to 4.9 mg, depending on the type of ICS. The ratio of the prednisone-sparing effect due to the systemic effects per 1000 µg of fluticasone propionate was 1.02 (95% CI 0.68–2.08) and for budesonide was 0.93 (95% CI 0.63–1.89). Conclusion In patients with oral corticosteroid-dependent asthma, the limited available evidence suggests that the majority of the oral corticosteroid-sparing effect of high-dose ICS is likely to be due to systemic effects. In oral corticosteroid-dependent asthma, the majority of the oral corticosteroid-sparing effects of high-dose inhaled corticosteroids (ICS) are due to their systemic effects. Clinicians should be aware of this bioequivalence when prescribing high-dose ICS.

Preserved ratio impaired spirometry (PRISm) is a heterogeneous condition but its course and disease progression remain to be elucidated. We aimed to examine its prevalence, trajectories and prognosis in the general population. In the Rotterdam Study (population-based prospective cohort) we examined prevalence, trajectories and prognosis of subjects with normal spirometry (controls; forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ≥0.7, FEV1 ≥80%), PRISm (FEV1/FVC ≥0.7, FEV1 <80%) and chronic obstructive pulmonary disease (COPD) (FEV1/FVC <0.7) at two study visits. Hazard ratios with 95% confidence intervals for mortality (until December 30, 2018) were adjusted for age, sex, body mass index, current smoking and pack-years. Of 5487 subjects (age 69.1±8.9 years; 7.1% PRISm), 1603 were re-examined after 4.5 years. Of the re-examined PRISm subjects, 15.7% transitioned to normal spirometry and 49.4% to COPD. Median lung function decline was highest in subjects with incident PRISm (FEV1 −92.8 mL·year−1, interquartile range (IQR) −131.9– −65.8 mL·year−1; FVC −93.3 mL·year−1, IQR −159.8– −49.1 mL·year−1), but similar in persistent PRISm (FEV1 −30.2 mL·year−1, IQR −67.9– −7.5 mL·year−1; FVC −20.1 mL·year−1, IQR −47.7–21.7 mL·year−1) and persistent controls (FEV1 −39.6 mL·year−1, IQR −64.3–−12.7 mL·year−1; FVC −20.0 mL·year−1, IQR −55.4–18.8 mL·year−1). Of 5459 subjects with informed consent for follow-up, 692 (12.7%) died during 9.3 years (maximum) follow-up: 10.3% of controls, 18.7% of PRISm subjects and 20.8% of COPD subjects. Relative to controls, subjects with PRISm and COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2–4 had increased all-cause mortality (PRISm: HR 1.6, 95% CI 1.2–2.0; COPD GOLD 2–4: HR 1.7, 95% CI 1.4–2.1) and cardiovascular mortality (PRISm: HR 2.8, 95% CI 1.5–5.1; COPD 2–4: HR 2.1, 95% CI 1.2–3.6). Mortality within <1 year was highest in PRISm, with patients often having cardiovascular comorbidities (heart failure or coronary heart disease; 70.0%). PRISm is associated with increased mortality and this population encompasses at least three distinct subsets: one that develops COPD during follow-up, a second with high cardiovascular burden and early mortality, and a third with persistent PRISm and normal age-related lung function decline. Preserved ratio impaired spirometry, previously called restrictive spirometry, is a condition associated with increased mortality that encompasses distinct clinical subsets

Limited data are available regarding the prognostic factors for patients with nontuberculous mycobacterial pulmonary disease (NTM-PD). We investigated the prognostic factors associated with long-term mortality in NTM-PD patients after adjusting for individual confounders, including aetiological organism and radiological form. A total of 1445 patients with treatment-naïve NTM-PD who were newly diagnosed between July 1997 and December 2013 were included. The aetiological organisms were as follows: Mycobacterium avium (n=655), M. intracellulare (n=487), M. abscessus (n=129) and M. massiliense (n=174). The factors associated with mortality in NTM-PD patients were analysed using a multivariable Cox model after adjusting for demographic, radiological and aetiological data. The overall 5-, 10- and 15-year cumulative mortality rates for the NTM-PD patients were 12.4%, 24.0% and 36.4%, respectively. On multivariable analysis, the following factors were significantly associated with mortality in NTM-PD patients: old age, male sex, low body mass index, chronic pulmonary aspergillosis, pulmonary or extrapulmonary malignancy, chronic heart or liver disease and erythrocyte sedimentation rate. The aetiological organism was also significantly associated with mortality: M. intracellulare had an adjusted hazard ratio (aHR) of 1.40, 95% CI 1.03–1.91; M. abscessus had an aHR of 2.19, 95% CI 1.36–3.51; and M. massiliense had an aHR of 0.99, 95% CI 0.61–1.64, compared to M. avium . Mortality was also significantly associated with the radiological form of NTM-PD for the cavitary nodular bronchiectatic form (aHR 1.70, 95% CI 1.12–2.59) and the fibrocavitary form (aHR 2.12, 95% CI 1.57–3.08), compared to the non-cavitary nodular bronchiectatic form. Long-term mortality in patients with NTM-PD was significantly associated with the aetiological NTM organism, cavitary disease and certain demographic characteristics. The long-term mortality of patients with nontuberculous mycobacterial pulmonary disease was significantly associated with the aetiological organism, cavitary disease and certain demographic characteristics

Despite the use of preferred controller therapies (including inhaled corticosteroids (ICS) with or without additional long-acting β2-agonists (LABAs)), a large proportion of patients with asthma have poor disease control, leaving them at risk of recurring symptoms and episodes of asthma exacerbations and worsening [1, 2]. Such problems can be triggered by many different environmental factors including pollutants, respiratory infections or allergens [3]. They may occur sporadically, but are often determined by the seasons, mirroring seasonal patterns of allergen exposure and prevalence of respiratory viral infection [3, 4]. In adults with symptomatic severe asthma despite inhaled corticosteroid/long-acting β2-agonist therapy, tiotropium add-on therapy reduces seasonal peaks of asthma worsening, providing a year-round benefit The authors take full responsibility for the scope, direction, content and editorial decisions relating to the manuscript, were involved at all stages of development and have approved the submitted manuscript. Medical writing assistance, in the form of the preparation and revision of the draft manuscript, was supported financially by Boehringer Ingelheim and provided by Rosie Robson of MediTech Media (Manchester, UK), under the authors’ conceptual direction and based on feedback from the authors.

The World Health Organization (WHO) and other international organisations, including the Food and Agriculture Organization of the United Nations, the World Organisation for Animal Health and the International Union Against Tuberculosis and Lung Disease recently called for formally assessing and (re)prioritising the burden of zoonotic tuberculosis (TB) in people, due to Mycobacterium bovis [1, 2]. Its global contribution to human TB, otherwise principally caused by Mycobacterium tuberculosis , might be underestimated [2]. Nationally representative prevalence data are virtually non-existent on continents with the highest presumed burdens, i.e. in Africa and Asia [3]. In response to recent international calls, this study reveals the nationally representative prevalence of zoonotic tuberculosis in people in a non-high income country, highlighting the need for appropriate diagnostics and treatment of these patients S. El Achkar was supported by a fellowship from Association AZM and Saadeh. The study also benefitted from support by a national TB programme in Lebanon, International Organization for Migration, TDR/World Health Organization Eastern Mediterranean Region, Hamidi Medical Center in Tripoli, Lebanon, Ecole Doctorale en Sciences et Technologie (Université Libanaise), Centre Hospitalier Universitaire de Lille. Sara Amrieh, Taha Abdou, Mariam Yehya, Imane Darwish, and Clara Khairallah (LMSE, Lebanon) are gratefully thanked for technical assistance.

In the presence of normal CXR and examination perhaps FEV1 is a better diagnostic marker of COPD in primary care

Chronic respiratory symptoms in individuals with normal spirometry should lead to clinical follow-up

The use of macrolides in combination with betalactams to improve outcomes in patients with community-acquired pneumonia (CAP) remains a topic of controversy, mainly because most of the evidence comes from observational studies rather than from randomised clinical trials (RCTs). Some recent studies have suggested that macrolides are effective in patients with Streptococcus pneumoniae infection plus a high systemic inflammatory response [1]. However, macrolides can be harmful [2] and there is a clear need to identify CAP phenotypes that would benefit from macrolides without suffering negative effects. We are unlikely to solve this question using conventional study designs; rather, we need to explore new technologies, among them the use of models obtained with machine learning methodology. The article by König and co-workers paves the way for the selection of a subset of patients with CAP in whom combination initial therapy including macrolides could improve outcomes using a new and interesting mathematical approach

There is a constant and consistent message in the medical and lay press that obesity is a modern epidemic affecting the developed world. It causes and exacerbates multiple diseases including cardio-metabolic, musculoskeletal, cancer and respiratory diseases [1]. There is no doubt that improving diet and lifestyle to eliminate obesity has positive health benefits [1]. Although this truism is well-known and accepted, the impact of obesity on the immunobiology of disease [1–4] is only beginning to be unravelled and this might reveal more subtle, albeit profound, effects of obesity on chronic inflammatory diseases. Adipose tissue is increased around the airway in asthma and is associated with BMI, airway inflammation and disease severity. Fat in the airway might contribute both positively and negatively to the immunobiology of asthma. This paper contains independent research funded by the National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Centre. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

Pulmonary hypertension (PH) is a diverse collection of vascular disorders that cause remodelling of small pulmonary arteries, resulting in increases in pulmonary vascular resistance and pulmonary arterial pressure. The World Health Organization classifies these disorders into five groups. Group III includes pulmonary hypertension associated with hypoxic lung disorders such as COPD. While not everyone with COPD develops pulmonary hypertension, those who do are more likely to experience acute exacerbations, hospitalisations, and poorer outcomes. Because alveolar hypoxia is a key element driving this response, investigators have studied how chronic hypoxia contributes to the development of PH. HIF1 and HIF2 can play complementary, opposing or unrelated roles in mediating the response to low oxygen levels in different cell types. This study shows HIF2 plays a dominant role in mediating the development of PH in response to environmental hypoxia.

Background As a vulnerable population, children and adolescents with tuberculosis (TB) are faced with many challenges, even those who live in low TB incidence countries. We aimed to evaluate factors associated with TB treatment outcomes allowing more focused interventions to support this population once diagnosed. Methods A retrospective cohort study using a nationwide surveillance database was performed in children and adolescents (aged 0–18 years) treated for TB in the Netherlands from 1993 to 2018. Logistic regression analyses were used to estimate adjusted odds ratios (aOR) for associated factors of mortality and loss to follow-up (LTFU). Results Among 3253 eligible patients with known outcomes, 94.4% (95.9% children and 92.8% adolescents) were cured or completed treatment, 0.7% died during treatment and 4.9% were LTFU. There were no reported treatment failures. Risk factors of death included children aged 2–4 years (aOR 10.42), central nervous system TB (aOR 5.14), miliary TB (aOR 10.25), HIV co-infection (aOR 8.60), re-treated TB cases (aOR 10.12) and drug-induced liver injury (aOR 6.50). Active case-finding was a protective factor of death (aOR 0.13). Risk factors of LTFU were adolescents aged 15–18 years (aOR 1.91), illegal immigrants (aOR 4.28), urban domicile (aOR 1.59), unknown history of TB contact (aOR 1.99), drug-resistant TB (aOR 2.31), single adverse drug reaction (aOR 2.12), multiple adverse drug reactions (aOR 7.84) and treatment interruption >14 days (aOR 6.93). Treatment in recent years (aOR 0.94) and supervision by public health nurses (aOR 0.14) were protective factors of LTFU. Conclusion Highly successful treatment outcomes were demonstrated in children and adolescents routinely treated for TB. Special attention should be given to specific risk groups to improve treatment outcomes. High success rates for TB treatment were achieved in children and adolescents in the Netherlands. To further optimise care in this population, several risk factors particularly associated with mortality and loss to follow-up have been identified.

Background The role of macrolide/β-lactam combination therapy in community-acquired pneumonia (CAP) of moderate severity is a matter of debate. Macrolides expand the coverage to atypical pathogens and attenuate pulmonary inflammation, but have been associated with cardiovascular toxicity and drug interactions. We developed a decision tree based on aetiological and clinical parameters, which are available ex ante to support a personalised decision for or against macrolides for the best clinical outcome of the individual patient. Methods We employed machine learning in a cross-validation scheme based on a well-balanced selection of 4898 patients after propensity score matching to data available on admission of 6440 hospitalised patients with moderate severity (non-intensive care unit patients) from the observational, prospective, multinational CAPNETZ study. We aimed to improve the primary outcome of 180-day survival. Results We found a simple decision tree of patient characteristics comprising chronic cardiovascular and chronic respiratory comorbidities as well as leukocyte counts in the respiratory secretion at enrolment. Specifically, we found that patients without cardiovascular or patients with respiratory comorbidities and high leukocyte counts in the respiratory secretion benefit from macrolide treatment. Patients identified to be treated in compliance with our treatment suggestion had a lower mortality of 27% (OR 1.83, 95% CI 1.48–2.27; p<0.001) compared to the observed standard of care. Conclusion Stratifying macrolide treatment in patients following a simple treatment rule may lead to considerably reduced mortality in CAP. A future randomised controlled trial confirming our result is necessary before implementing this rule into the clinical routine. A simple decision tree distinguishes patients who benefit from macrolides from those who are harmed. In our model, the rule can lower mortality by 30% in hospitalised CAP patients with moderate disease. However, prospective evaluation is required.

Background As an increasing number of patients exhibit concomitant cardiac and pulmonary disease, limitations of standard diagnostic criteria are more frequently encountered. Here, we apply noninvasive 129Xe magnetic resonance imaging (MRI) and spectroscopy to identify patterns of regional gas transfer impairment and haemodynamics that are uniquely associated with chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), left heart failure (LHF) and pulmonary arterial hypertension (PAH). Methods Healthy volunteers (n=23) and patients with COPD (n=8), IPF (n=12), LHF (n=6) and PAH (n=10) underwent 129Xe gas transfer imaging and dynamic spectroscopy. For each patient, three-dimensional maps were generated to depict ventilation, barrier uptake (129Xe dissolved in interstitial tissue) and red blood cell (RBC) transfer (129Xe dissolved in RBCs). Dynamic 129Xe spectroscopy was used to quantify cardiogenic oscillations in the RBC signal amplitude and frequency shift. Results Compared with healthy volunteers, all patient groups exhibited decreased ventilation and RBC transfer (both p≤0.01). Patients with COPD demonstrated more ventilation and barrier defects compared with all other groups (both p≤0.02). In contrast, IPF patients demonstrated elevated barrier uptake compared with all other groups (p≤0.007), and increased RBC amplitude and shift oscillations compared with healthy volunteers (p=0.007 and p≤0.01, respectively). Patients with COPD and PAH both exhibited decreased RBC amplitude oscillations (p=0.02 and p=0.005, respectively) compared with healthy volunteers. LHF was distinguishable from PAH by enhanced RBC amplitude oscillations (p=0.01). Conclusion COPD, IPF, LHF and PAH each exhibit unique 129Xe MRI and dynamic spectroscopy signatures. These metrics may help with diagnostic challenges in cardiopulmonary disease and increase understanding of regional lung function and haemodynamics at the alveolar–capillary level. Different heart and lung diseases exhibit unique 129Xe MRI and spectroscopy signatures. These may help differentiate cardiopulmonary disease and increase our understanding of regional lung function and haemodynamics at the alveolar–capillary level.

Epidemiological studies report that overweight or obese asthmatic subjects have more severe disease than those of a healthy weight. We postulated that accumulation of adipose tissue within the airway wall may occur in overweight patients and contribute to airway pathology. Our aim was to determine the relationship between adipose tissue within the airway wall and body mass index (BMI) in individuals with and without asthma. Transverse airway sections were sampled in a stratified manner from post mortem lungs of control subjects (n=15) and cases of nonfatal (n=21) and fatal (n=16) asthma. The relationship between airway adipose tissue, remodelling and inflammation was assessed. The areas of the airway wall and adipose tissue were estimated by point count and expressed as area per mm of basement membrane perimeter (Pbm). The number of eosinophils and neutrophils were expressed as area densities. BMI ranged from 15 to 45 kg·m−2 and was greater in nonfatal asthma cases (p<0.05). Adipose tissue was identified in the outer wall of large airways (Pbm >6 mm), but was rarely seen in small airways (Pbm <6 mm). Adipose tissue area correlated positively with eosinophils and neutrophils in fatal asthma (Pbm >12 mm, p<0.01), and with neutrophils in control subjects (Pbm >6 mm, p=0.04). These data show that adipose tissue is present within the airway wall and is related to BMI, wall thickness and the number of inflammatory cells. Therefore, the accumulation of airway adipose tissue in overweight individuals may contribute to airway pathophysiology. In individuals with elevated BMI, adipose tissue accumulates within the airway wall, correlates with greater wall thickness and airway inflammation and represents a new mechanism for airway pathophysiology in obese asthmatic patients

Most published studies addressing the role of hypoxia inducible factors (HIFs) in hypoxia-induced pulmonary hypertension development employ models that may not recapitulate the clinical setting, including the use of animals with pre-existing lung/vascular defects secondary to embryonic HIF ablation or activation. Furthermore, critical questions including how and when HIF signalling contributes to hypoxia-induced pulmonary hypertension remain unanswered. Normal adult rodents in which global HIF1 or HIF2 was inhibited by inducible gene deletion or pharmacological inhibition (antisense oligonucleotides (ASO) and small molecule inhibitors) were exposed to short-term (4 days) or chronic (4–5 weeks) hypoxia. Haemodynamic studies were performed, the animals euthanised, and lungs and hearts obtained for pathological and transcriptomic analysis. Cell-type-specific HIF signals for pulmonary hypertension initiation were determined in normal pulmonary vascular cells in vitro and in mice (using cell-type-specific HIF deletion). Global Hif1a deletion in mice did not prevent hypoxia-induced pulmonary hypertension at 5 weeks. Mice with global Hif2a deletion did not survive long-term hypoxia. Partial Hif2a deletion or Hif2 -ASO (but not Hif1 -ASO) reduced vessel muscularisation, increases in pulmonary arterial pressures and right ventricular hypertrophy in mice exposed to 4–5 weeks of hypoxia. A small molecule HIF2 inhibitor (PT2567) significantly attenuated early events (monocyte recruitment and vascular cell proliferation) in rats exposed to 4 days of hypoxia, as well as vessel muscularisation, tenascin C accumulation and pulmonary hypertension development in rats exposed to 5 weeks of hypoxia. In vitro , HIF2 induced a distinct set of genes in normal human pulmonary vascular endothelial cells, mediating inflammation and proliferation of endothelial cells and smooth muscle cells. Endothelial Hif2a knockout prevented hypoxia-induced pulmonary hypertension in mice. Inhibition of HIF2 (but not HIF1) can provide a therapeutic approach to prevent the development of hypoxia-induced pulmonary hypertension. Future studies are needed to investigate the role of HIFs in pulmonary hypertension progression and reversal. Activation of HIF2 by hypoxia initiates vascular cell proliferation and recruitment of inflammatory cells at early stages of PH development through HIF2-dependent transcription of genes involved in these pathways in pulmonary vascular cells

Patients with idiopathic pulmonary fibrosis (IPF) frequently have a substantial burden of comorbidities [1]. Antifibrotic therapy is recommended to slow the progression of IPF [2]. Patients receiving antifibrotic therapy frequently receive concomitant medications for the management of comorbidities [1, 3–9]. Previous post hoc analyses of antacids, statins, metformin, anticoagulants and angiotensin modulators in patients with IPF enrolled in phase III randomised controlled trials (RCTs) have generated hypotheses on the impact of these treatments on IPF outcomes [3–9]. The effects of multiple concomitant medications in patients with IPF have been largely unexplored. The objective of the present analyses was to explore the association between use of combinations of frequently prescribed concomitant medications and disease outcomes in patients with IPF. This post hoc exploratory analysis found no clear associations between frequently used concomitant medication combinations and disease progression in 1450 patients with IPF enrolled in phase III trials, but several combinations may require further study.

Muscle group III (Aδ fibres) and IV (C fibres) sensory afferents are involved in the cardiorespiratory adaptation to exercise [1, 2]. Their inhibition with intrathecal fentanyl in the dorsal horn of the spinal cord to block their cortical projections decreases high-intensity constant workload endurance performance in healthy athlete subjects because of a blunted cardiorespiratory response to exercise. In this condition with high metabolic demand, any decrease in ventilation or haemodynamics would compromise performance because of a nearly maximal solicitation without any possibility for a compensatory strategy. In contrast, Gagnon et al . [3] have published that the use of spinal anaesthesia with fentanyl with the goal of inhibiting muscle group III and IV fibres in chronic obstructive pulmonary disease (COPD) patients improved dyspnoea and endurance capacity. This improvement was due to the blunted ventilatory response to exercise which improved physiological dead space, ventilatory efficiency and in turn, dyspnoea. Moreover, at this relatively lower external workload compared with healthy subjects, cardiac output and peripheral oxygen extraction were not maximal and any mitigation in cardiac output (if any) would be overcome by an increase in peripheral muscle oxygen extraction [3]. High-frequency or low-frequency transcutaneous electrical nerve stimulation (TENS) provide a less invasive alternative which activates opioid receptors, especially those located in the dorsal horn of the spinal cord [1, 4, 5]. This approach deserves to be studied during exercise and over a course of pulmonary rehabilitation in these patients. We performed a randomised double-blind study ([clinicaltrials.gov][1] [NCT03312322][2]) to assess whether high-frequency or low-frequency lumbar TENS could improve endurance exercise capacity in patients with COPD. Secondary objectives were to assess the influence of lumbar TENS on perceived exertion, ventilatory pattern and muscle oxygenation. We hypothesised that endurance capacity would be improved with lumbar TENS due to a blunted response in exercise ventilation, which would contribute to improve ventilatory efficacy and reduce exercise dyspnoea. Conversely, we hypothesised that any mitigation in cardiac output (if any) would be compensated by an increase in peripheral muscular oxygen extraction. Lumbar transcutaneous electrical nerve stimulation aimed to block muscle group III–IV sensory afferents does not improve endurance exercise capacity in patients with COPD [1]: http://clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03312322&atom=%2Ferj%2F54%2F6%2F1900784.atom

Acute hypoxemic respiratory failure (AHRF) in immunocompromised patients is a challenging clinical problem associated with mortality rates of 40–60% in children and adults [1, 2]. Thus, we read with great interest the results of a pre-planned secondary analysis of a large multicentre observational cohort of 1611 immunocompromised adults with AHRF, as reported by Bauer et al. [3]. The authors described the diagnostic yield and outcomes of fibreoptic bronchoscopy (FOB) in this group of vulnerable patients with the a priori hypothesis that “bronchoscopy, with limited complications, would reduce the number of unidentified causes of respiratory failure and be associated with reduced hospital mortality.” After a rigorous analysis of a highly annotated dataset, the authors conclude that “bronchoscopy was associated with improved diagnosis and changes in management but also increased hospital mortality.” A discussion of the strengths and limitations of recent data associating bronchoscopy with mortality in immunocompromised adults with acute hypoxaemic respiratory failure

In their letter to the Editor, M.S. Zinter and G-S. Cheng raise concerns about the conclusion of our study that immunocompromised patients with acute hypoxaemic respiratory failure who undergo fibreoptic bronchoscopy have inferior survival relative to those who do not undergo fibreoptic bronchoscopy. They offer an alternative explanation to our findings by emphasising the role of the time-varying nature of the bronchoscopy as well as the time-varying nature of other covariates, including illness severity leading up to bronchoscopy, when performing the propensity score matching. The decision-making process regarding whether to perform bronchoscopy in acute respiratory failure in immunosuppressed patients is complex and does not depend solely on severity

As part of the December issue, the European Respiratory Journal presents the latest in its series of podcasts. Chief Editor Martin Kolb interviews Jørgen Vestbo (ERS Advocacy Council Chair) about the European Respiratory Society's position on tobacco harm reduction published in this issue.

Medical experts and federal health officials in USA have recently warned the public from using e-cigarettes, as the number of people with a severe lung illness rose to over 1600 cases, 34 of these fatal. An illustrative case is reported in the European Respiratory Journal [1]. Health officials state that “vaping is a probable potential cause” but no firm conclusions can yet be drawn. In this light it is interesting to discuss the concept of tobacco harm reduction. The European Respiratory Society (ERS) Advocacy Council's Tobacco Control Committee has recently launched an ERS position paper on this topic [2]. From this paper we would like to draw attention to some of the major issues of harm reduction. ERS supports the World Health Organization's Framework Convention on Tobacco Control, which also provides regulation to novel products, and cannot recommend tobacco harm reduction as a population-based strategy J. Vestbo is supported by the NIHR Manchester BRC.

In all societies, the disease burden and the healthcare costs for people with allergic and chronic respiratory diseases are increasing rapidly [1]. Most economies are struggling to deliver consistent high-quality healthcare. There is a need to support the transformation of the healthcare system for integrated care through leveraging developments in digital health [2]. The term “digital health” refers to advanced medical technologies, disruptive innovations and digital communication tools aiming to provide best healthcare practice [3]. ARIA has evolved, with strong political commitment, from the first multimorbidity guideline in respiratory diseases to an exemplar for the future digital transformation of health and care for the management of patients with long-term conditions