Showing papers in "Thorax in 2019"

British Thoracic Society Guideline for bronchiectasis in adults

Abstract: ### How should the diagnosis of bronchiectasis be determined? #### Recommendations – Imaging #### Good practice points CT imaging protocol CT features of bronchiectasis General ### In whom should the diagnosis of bronchiectasis be suspected? #### Recommendations

Implementing lung cancer screening: baseline results from a community-based 'Lung Health Check' pilot in deprived areas of Manchester.

Abstract: We report baseline results of a community-based, targeted, low-dose CT (LDCT) lung cancer screening pilot in deprived areas of Manchester. Ever smokers, aged 55–74 years, were invited to ‘lung health checks’ (LHCs) next to local shopping centres, with immediate access to LDCT for those at high risk (6-year risk ≥1.51%, PLCOM2012 calculator). 75% of attendees (n=1893/2541) were ranked in the lowest deprivation quintile; 56% were high risk and of 1384 individuals screened, 3% (95% CI 2.3% to 4.1%) had lung cancer (80% early stage) of whom 65% had surgical resection. Taking lung cancer screening into communities, with an LHC approach, is effective and engages populations in deprived areas.

Therapeutic effects of human mesenchymal stem cell microvesicles in an ex vivo perfused human lung injured with severe E. coli pneumonia.

Abstract: Background We previously reported that microvesicles (MVs) released by human mesenchymal stem cells (MSC) were as effective as the cells themselves in both Escherichia coli lipopolysaccharide and live bacteria-induced acute lung injury (ALI) mice models. However, it remained unclear whether the biological effect of MSC MV can be applied to human ALI. Methods In the current study, we tested the therapeutic effects of MSC MVs in a well-established ex vivo perfused human model of bacterial pneumonia. Using human donor lungs not used for transplantation, we instilled E. coli bacteria intrabronchially and, 1 hour later, administered MSC MVs into the perfusate as therapy. Results After 6 hours, instillation of E. coli bacteria caused influx of inflammatory cells, which resulted in significant inflammation, lung protein permeability and pulmonary oedema formation. Administration of MSC MV significantly increased alveolar fluid clearance and reduced protein permeability and numerically lowered the bacterial load in the injured alveolus. The beneficial effect on bacterial killing was more pronounced with pretreatment of MSCs with a Toll-like receptor 3 agonist, polyinosinic:polycytidylic acid (Poly (I:C)), prior to the isolation of MVs. Isolated human alveolar macrophages had increased antimicrobial activity with MSC MV treatment in vitro as well. Although oxygenation and lung compliance levels were similar between injury and treatment groups, administration of MSC MVs numerically decreased median pulmonary artery pressure at 6 hours. Conclusions In summary, MSC MVs increased alveolar fluid clearance and reduced lung protein permeability, and pretreatment with Poly (I:C) enhanced the antimicrobial activity of MVs in an ex vivo perfused human lung with severe bacteria pneumonia.

Vitamin D to prevent exacerbations of COPD: systematic review and meta-analysis of individual participant data from randomised controlled trials

Abstract: Background Randomised controlled trials (RCTs) of vitamin D to prevent COPD exacerbations have yielded conflicting results. Individual participant data meta-analysis could identify factors that explain this variation. Methods PubMed, Embase, the Cochrane Central Register of Controlled Trials and Web of Science were searched from inception up to and including 5 October 2017 to identify RCTs of vitamin D supplementation in patients with COPD that reported incidence of acute exacerbations. Individual participant data meta-analysis was performed using fixed effects models adjusting for age, sex, Global Initiative for Chronic Obstructive Lung Disease spirometric grade and trial. Results Four eligible RCTs (total 560 participants) were identified; individual participant data were obtained for 469/472 (99.4%) participants in three RCTs. Supplementation did not influence overall rate of moderate/severe COPD exacerbations (adjusted incidence rate ratio (aIRR) 0.94, 95% CI 0.78 to 1.13). Prespecified subgroup analysis revealed that protective effects were seen in participants with baseline 25-hydroxyvitamin D levels Conclusions Vitamin D supplementation safely and substantially reduced the rate of moderate/severe COPD exacerbations in patients with baseline 25-hydroxyvitamin D levels Trial registration number CRD42014013953.

Effect of childhood pneumococcal conjugate vaccination on invasive disease in older adults of 10 European countries: implications for adult vaccination

Abstract: Background Pneumococcal conjugate vaccines (PCVs) have the potential to prevent pneumococcal disease through direct and indirect protection. This multicentre European study estimated the indirect effects of 5-year childhood PCV10 and/or PCV13 programmes on invasive pneumococcal disease (IPD) in older adults across 13 sites in 10 European countries, to support decision-making on pneumococcal vaccination policies. Methods For each site we calculated IPD incidence rate ratios (IRR) in people aged ≥65 years by serotype for each PCV10/13 year (2011–2015) compared with 2009 (pre-PCV10/13). We calculated pooled IRR and 95% CI using random-effects meta-analysis and PCV10/13 effect as (1 − IRR)*100. Results After five PCV10/13 years, the incidence of IPD caused by all types, PCV7 and additional PCV13 serotypes declined 9% (95% CI −4% to 19%), 77% (95% CI 67% to 84%) and 38% (95% CI 19% to 53%), respectively, while the incidence of non-PCV13 serotypes increased 63% (95% CI 39% to 91%). The incidence of serotypes included in PCV13 and not in PCV10 decreased 37% (95% CI 22% to 50%) in six PCV13 sites and increased by 50% (95% CI −8% to 146%) in the four sites using PCV10 (alone or with PCV13). In 2015, PCV13 serotypes represented 20–29% and 32–53% of IPD cases in PCV13 and PCV10 sites, respectively. Conclusion Overall IPD incidence in older adults decreased moderately after five childhood PCV10/13 years in 13 European sites. Large declines in PCV10/13 serotype IPD, due to the indirect effect of childhood vaccination, were countered by increases in non-PCV13 IPD, but these declines varied according to the childhood vaccine used. Decision-making on pneumococcal vaccination for older adults must consider the indirect effects of childhood PCV programmes. Sustained monitoring of IPD epidemiology is imperative.

Help, hinder, hide and harm: what can we learn from the interactions between Pseudomonas aeruginosa and Staphylococcus aureus during respiratory infections?

Abstract: Recent studies of human respiratory secretions using culture-independent techniques have found a surprisingly diverse array of microbes. Interactions among these community members can profoundly impact microbial survival, persistence and antibiotic susceptibility and, consequently, disease progression. Studies of polymicrobial interactions in the human microbiota have shown that the taxonomic and structural compositions, and resulting behaviours, of microbial communities differ substantially from those of the individual constituent species and in ways of clinical importance. These studies primarily involved oral and gastrointestinal microbiomes. While the field of polymicrobial respiratory disease is relatively young, early findings suggest that respiratory tract microbiota members also compete and cooperate in ways that may influence disease outcomes. Ongoing efforts therefore focus on how these findings can inform more ‘enlightened’, rational approaches to combat respiratory infections. Among the most common respiratory diseases involving polymicrobial infections are cystic fibrosis (CF), non-CF bronchiectasis, COPD and ventilator-associated pneumonia. While respiratory microbiota can be diverse, two of the most common and best-studied members are Staphylococcus aureus and Pseudomonas aeruginosa, which exhibit a range of competitive and cooperative interactions. Here, we review the state of research on pulmonary coinfection with these pathogens, including their prevalence, combined and independent associations with patient outcomes, and mechanisms of those interactions that could influence lung health. Because P. aeruginosa–S. aureus coinfection is common and well studied in CF, this disease serves as the paradigm for our discussions on these two organisms and inform our recommendations for future studies of polymicrobial interactions in pulmonary disease.

A potential role of microvesicle-containing miR-223/142 in lung inflammation.

Abstract: Background Uncontrolled lung inflammation is one of the prominent features in the pathogenesis of lung infection- associated acute lung injury (ALI). Microvesicles (MVs) are extracellular nanovesicles that are generated via direct membrane budding. Methods Bronchoalveolar lavage fluid (BALF) samples were collected from mice with or without intratracheal lipopolysaccharide (LPS) instillation. BALF MVs were characterised and MV-containing microRNA (miRNA) profiles were assessed and confirmed. Secretion and function of MV-containing miR-223/142 (MV-miR-223/142) were analysed in vivo. Results In BALF, MVs are mainly derived from macrophages in response to LPS. After intratracheal instillation (i.t.) of LPS or Klebsiella pneumoniae, MV-containing miR-223/142 are dramatically induced in both BALF and serum. Mechanistically, miRNA 3′ end uridylation mediates the packing of miR-223/142 into MVs. To investigate the functional role of MV-miR-223/142, we loaded miR-223/142 mimics into unstimulated MVs and delivered them into the murine lungs via i.t. The miR-223/142 mimics-enriched MVs selectively targeted lung macrophages and suppressed the inflammatory lung responses that were triggered by LPS or K. pneumoniae. Mechanistically, miR-223 and miR-142 synergistically suppress Nlrp3 inflammasome activation in macrophages via inhibition of Nlrp3 and Asc, respectively. Conclusions In the pathogenesis of lung macrophage-mediated inflammatory responses, MV-miR-223/142 secretion is robustly enhanced and detectable in BALF and serum. Furthermore, restoration of intracellular miR-223/142 via vesicle-mediated delivery suppresses macrophage activation and lung inflammation via inhibition of Nlrp3 inflammasome activation.

Holistic services for people with advanced disease and chronic breathlessness: a systematic review and meta-analysis

Abstract: Background Breathlessness is a common, distressing symptom in people with advanced disease and a marker of deterioration. Holistic services that draw on integrated palliative care have been developed for this group. This systematic review aimed to examine the outcomes, experiences and therapeutic components of these services. Methods Systematic review searching nine databases to June 2017 for experimental, qualitative and observational studies. Eligibility and quality were independently assessed by two authors. Data on service models, health and cost outcomes were synthesised, using meta-analyses as indicated. Data on recipient experiences were synthesised thematically and integrated at the level of interpretation and reporting. Results From 3239 records identified, 37 articles were included representing 18 different services. Most services enrolled people with thoracic cancer, involved palliative care staff and comprised 4–6 contacts over 4–6 weeks. Commonly used interventions included breathing techniques, psychological support and relaxation techniques. Meta-analyses demonstrated reductions in Numeric Rating Scale distress due to breathlessness (n=324; mean difference (MD) −2.30, 95% CI −4.43 to −0.16, p=0.03) and Hospital Anxiety and Depression Scale (HADS) depression scores (n=408, MD −1.67, 95% CI −2.52 to −0.81, p Conclusion Holistic services for chronic breathlessness can reduce distress in patients with advanced disease and may improve psychological outcomes of anxiety and depression. Therapeutic components of these services should be shared and integrated into clinical practice. Registration number CRD42017057508.

Biomarkers and clinical outcomes in COPD: a systematic review and meta-analysis.

Abstract: Background Conventional measures to evaluate COPD may fail to capture systemic problems, particularly musculoskeletal weakness and cardiovascular disease. Identifying these manifestations and assessing their association with clinical outcomes (ie, mortality, exacerbation and COPD hospital admission) is of increasing clinical importance. Objective To assess associations between 6 min walk distance (6MWD), heart rate, fibrinogen, C reactive protein (CRP), white cell count (WCC), interleukins 6 and 8 (IL-6 and IL-8), tumour necrosis factor-alpha, quadriceps maximum voluntary contraction, sniff nasal inspiratory pressure, short physical performance battery, pulse wave velocity, carotid intima-media thickness and augmentation index and clinical outcomes in patients with stable COPD. Methods We systematically searched electronic databases (August 2018) and identified 61 studies, which were synthesised, including meta-analyses to estimate pooled HRs, following Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results Shorter 6MWD and elevated heart rate, fibrinogen, CRP and WCC were associated with higher risk of mortality. Pooled HRs were 0.80 (95% CI 0.73 to 0.89) per 50 m longer 6MWD, 1.10 (95% CI 1.02 to 1.18) per 10 bpm higher heart rate, 3.13 (95% CI 2.14 to 4.57) per twofold increase in fibrinogen, 1.17 (95% CI 1.06 to 1.28) per twofold increase in CRP and 2.07 (95% CI 1.29 to 3.31) per twofold increase in WCC. Shorter 6MWD and elevated fibrinogen and CRP were associated with exacerbation, and shorter 6MWD, higher heart rate, CRP and IL-6 were associated with hospitalisation. Few studies examined associations with musculoskeletal measures. Conclusion Findings suggest 6MWD, heart rate, CRP, fibrinogen and WCC are associated with clinical outcomes in patients with stable COPD. Use of musculoskeletal measures to assess outcomes in patients with COPD requires further investigation. Trial registration number CRD42016052075.

Sputum exosomes: promising biomarkers for idiopathic pulmonary fibrosis.

Abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease of unknown aetiology which leads rapidly to death. As diagnosis of IPF is complex, we aimed to characterise microRNA (miRNA) content of exosomes from sputum of patients with IPF. Using miRNA quantitative PCR array, we found a substantial dysregulation of sputum exosomal miRNA levels between patients with IPF and healthy subjects and identified a unique signature of three miRNAs. Interestingly, we found a negative correlation between miR-142-3p and diffusing capacity of the lungs for carbon monoxide/alveolar volume. This is the first characterisation of miRNA content of sputum-derived exosomes in IPF that identified promising biomarkers for diagnosis and disease severity.

Second round results from the Manchester 'Lung Health Check' community-based targeted lung cancer screening pilot

Abstract: We report results from the second annual screening round (T1) of Manchester’s ‘Lung Health Check’ pilot of community-based lung cancer screening in deprived areas (undertaken June to August 2017). Screening adherence was 90% (n=1194/1323): 92% of CT scans were classified negative, 6% indeterminate and 2.5% positive; there were no interval cancers. Lung cancer incidence was 1.6% (n=19), 79% stage I, treatments included surgery (42%, n=9), stereotactic ablative radiotherapy (26%, n=5) and radical radiotherapy (5%, n=1). False-positive rate was 34.5% (n=10/29), representing 0.8% of T1 participants (n=10/1194). Targeted community-based lung cancer screening promotes high screening adherence and detects high rates of early stage lung cancer.

Respiratory syncytial virus (RSV): a scourge from infancy to old age.

Abstract: Respiratory syncytial virus (RSV) is the most common single cause of respiratory hospitalisation of infants and is the second largest cause of lower respiratory infection mortality worldwide. In adults, RSV is an under-recognised cause of deterioration in health, particularly in frail elderly persons. Infection rates typically rise in late autumn and early winter causing bronchiolitis in infants, common colds in adults and insidious respiratory illness in the elderly. Virus detection methods optimised for use in children have low detection rate in adults, highlighting the need for better diagnostic tests. There are many vaccines under development, mostly based on the surface glycoprotein F which exists in two conformations (prefusion and postfusion). Much of the neutralising antibody appears to be to the prefusion form. Vaccines being developed include live attenuated, subunit, particle based and live vectored agents. Different vaccine strategies may be appropriate for different target populations: at-risk infants, school-age children, adult caregivers and the elderly. Antiviral drugs are in clinical trial and may find a place in disease management. RSV disease is one of the major remaining common tractable challenges in infectious diseases and the era of vaccines and antivirals for RSV is on the near horizon.

Mechanical stress-induced mast cell degranulation activates TGF-β1 signalling pathway in pulmonary fibrosis

Abstract: Background The role of mast cells accumulating in idiopathic pulmonary fibrosis (IPF) lungs is unknown. Objectives We investigated the effect of fibrotic extracellular matrix (ECM) on mast cells in experimental and human pulmonary fibrosis. Results In IPF lungs, mast cell numbers were increased and correlated with disease severity (control vs 60% 90% vs 60% 90% vs FVC Conclusion This study suggests that mast cells may contribute to the progression of pulmonary fibrosis.

PGC1α repression in IPF fibroblasts drives a pathologic metabolic, secretory and fibrogenic state

Abstract: Idiopathic pulmonary fibrosis (IPF) is a fatal ageing-related disease linked to mitochondrial dysfunction. The present study aimed to determine whether peroxisome proliferator activated receptor gamma co-activator 1-alpha (PPARGC1A, encoding PGC1α), a master regulator of mitochondrial biogenesis, is diminished in IPF and controls pathologic fibroblast activation. Primary human IPF, control lung fibroblasts and fibroblasts sorted from bleomycin-injured mice were used to evaluate the expression and function of PGC1α. In vitro PGC1α manipulation was performed by small interfering RNA knockdown or overexpression. Fibroblast activation was assessed by quantitative PCR, Western blotting, matrix deposition, secreted cytokine array, immunofluorescence and traction force microscopy. Mitochondrial function was assessed by Seahorse analyzer and mitochondria mass and number by flow cytometry, mitochondrial DNA quantification and transmission electron microscopy (TEM). We found that PGC1α levels are stably repressed in IPF fibroblasts. After bleomycin injury in young mice, PGC1α expression drops transiently but then increases prior to fibrosis resolution. In contrast, PGC1α expression fails to recover in aged mice with persistent fibrosis. PGC1α knockdown alone in normal human lung fibroblasts reduces mitochondrial mass and function while enhancing contractile and matrix synthetic fibroblast activation, senescence-related gene expression and soluble profibrotic and prosenescence signalling. Re-expression of PGC1α in IPF fibroblasts ameliorates all of these pathological cellular functions. Pharmacological treatment of IPF fibroblasts with rosiglitazone, but not thyroid hormone, elevated PGC1α expression and attenuated fibroblast activation. The sustained repression of PGC1α and beneficial effects of its rescue in IPF fibroblasts identifies PGC1α as an important regulator of the fibroblast’s pathological state in IPF.

Nanotechnology based therapeutics for lung disease.

Abstract: Nanomedicine is a multidisciplinary research field with an integration of traditional sciences such as chemistry, physics, biology and materials science. The application of nanomedicine for lung diseases as a relatively new area of interdisciplinary science has grown rapidly over the last 10 years. Promising research outcomes suggest that nanomedicine will revolutionise the practice of medicine, through the development of new approaches in therapeutic agent delivery, vaccine development and nanotechnology-based medical detections. Nano-based approaches in the diagnosis and treatment of lung diseases will, in the not too distant future, change the way we practise medicine. This review will focus on the current trends and developments in the clinical translation of nanomedicine for lung diseases, such as in the areas of lung cancer, cystic fibrosis, asthma, bacterial infections and COPD.

Minimum important difference of the Epworth Sleepiness Scale in obstructive sleep apnoea: estimation from three randomised controlled trials

Abstract: Background The Epworth Sleepiness Scale (ESS) is a widely used tool for assessing sleepiness in patients with obstructive sleep apnoea (OSA). We aimed to estimate the minimal important difference (MID) in patients with OSA. Methods We used individual data from three randomised controlled trials (RCTs) in patients with OSA where the preintervention to postintervention change in ESS was used as a primary outcome. We used anchor-based linear regression and responder analysis approaches to estimate the MID. For anchors, we used the change in domains of the Functional Outcomes of Sleep Questionnaire and 36-Item Short Form Health Survey. We also used the distribution-based approaches Cohen’s effect size, SE of measurement and empirical rule effect size to support the anchor-based estimates. The final MID was determined by triangulating all estimates to a single MID. Findings A total of 639 patients with OSA were included in our analyses across the three RCTs with a median (IQR) baseline ESS score of 10 (6–13). The median (IQR) ESS change score overall was −2 (−5 to 1). The anchor-based estimates of the MID were between −1.74 and −4.21 points and estimates from the responder analysis were between −1 and −3 points. Distribution-based estimates were smaller, ranging from −1.46 to −2.36. Interpretation We propose an MID for the ESS of 2 points in patients with OSA with a disease severity from mild to severe. This estimate provides the means to plan trials and interpret the clinical relevance of changes in ESS. Trial registration number Provent, NCT01332175; autoCPAP trial, NCT00280800; MOSAIC,ISRCTN (3416388).

Urbanisation and asthma in low-income and middle-income countries: a systematic review of the urban-rural differences in asthma prevalence.

Abstract: Background Urbanisation has been associated with temporal and geographical differences in asthma prevalence in low-income and middle-income countries (LMICs). However, little is known of the mechanisms by which urbanisation and asthma are associated, perhaps explained by the methodological approaches used to assess the urbanisation-asthma relationship. Objective This review evaluated how epidemiological studies have assessed the relationship between asthma and urbanisation in LMICs, and explored urban/rural differences in asthma prevalence. Methods Asthma studies comparing urban/rural areas, comparing cities and examining intraurban variation were assessed for eligibility. Included publications were evaluated for methodological quality and pooled OR were calculated to indicate the risk of asthma in urban over rural areas. Results Seventy articles were included in our analysis. Sixty-three compared asthma prevalence between urban and rural areas, five compared asthma prevalence between cities and two examined intraurban variation in asthma prevalence. Urban residence was associated with a higher prevalence of asthma, regardless of asthma definition: current-wheeze OR:1.46 (95% CI:1.22 to 1.74), doctor diagnosis OR:1.89 (95% CI:1.47 to 2.41), wheeze-ever OR:1.44 (95% CI:1.15 to 1.81), self-reported asthma OR:1.77 (95% CI:1.33 to 2.35), asthma questionnaire OR:1.52 (95% CI:1.06 to 2.16) and exercise challenge OR:1.96 (95% CI:1.32 to 2.91). Conclusions Most evidence for the relationship between urbanisation and asthma in LMICs comes from studies comparing urban and rural areas. These studies tend to show a greater prevalence of asthma in urban compared to rural populations. However, these studies have been unable to identify which specific characteristics of the urbanisation process may be responsible. An approach to understand how different dimensions of urbanisation, using contextual household and individual indicators, is needed for a better understanding of how urbanisation affects asthma. PROSPERO registration number CRD42017064470.

Effects of mindfulness training programmes delivered by a self-directed mobile app and by telephone compared with an education programme for survivors of critical illness: a pilot randomised clinical trial

Abstract: Background Patients who are sick enough to be admitted to an intensive care unit (ICU) commonly experience symptoms of psychological distress after discharge, yet few effective therapies have been applied to meet their needs. Methods Pilot randomised clinical trial with 3-month follow-up conducted at two academic medical centres. Adult (≥18 years) ICU patients treated for cardiorespiratory failure were randomised after discharge home to 1 of 3 month-long interventions: a self-directed mobile app-based mindfulness programme; a therapist-led telephone-based mindfulness programme; or a web-based critical illness education programme. Results Among 80 patients allocated to mobile mindfulness (n=31), telephone mindfulness (n=31) or education (n=18), 66 (83%) completed the study. For the primary outcomes, target benchmarks were exceeded by observed rates for all participants for feasibility (consent 74%, randomisation 91%, retention 83%), acceptability (mean Client Satisfaction Questionnaire 27.6 (SD 3.8)) and usability (mean Systems Usability Score 89.1 (SD 11.5)). For secondary outcomes, mean values (and 95% CIs) reflected clinically significant group-based changes on the Patient Health Questionnaire depression scale (mobile (−4.8 (−6.6, −2.9)), telephone (−3.9 (−5.6, −2.2)), education (−3.0 (−5.3, 0.8)); the Generalized Anxiety Disorder scale (mobile −2.1 (−3.7, −0.5), telephone −1.6 (−3.0, −0.1), education −0.6 (−2.5, 1.3)); the Post-Traumatic Stress Scale (mobile −2.6 (−6.3, 1.2), telephone −2.2 (−5.6, 1.2), education −3.5 (−8.0, 1.0)); and the Patient Health Questionnaire physical symptom scale (mobile −5.3 (−7.0, −3.7), telephone −3.7 (−5.2, 2.2), education −4.8 (−6.8, 2.7)). Conclusions Among ICU patients, a mobile mindfulness app initiated after hospital discharge demonstrated evidence of feasibility, acceptability and usability and had a similar impact on psychological distress and physical symptoms as a therapist-led programme. A larger trial is warranted to formally test the efficacy of this approach. Trial registration number Results, NCT02701361.

Experimental and quantitative imaging techniques in interstitial lung disease.

Abstract: Interstitial lung diseases (ILDs) are a heterogeneous group of conditions, with a wide and complex variety of imaging features. Difficulty in monitoring, treating and exploring novel therapies for these conditions is in part due to the lack of robust, readily available biomarkers. Radiological studies are vital in the assessment and follow-up of ILD, but currently CT analysis in clinical practice is qualitative and therefore somewhat subjective. In this article, we report on the role of novel and quantitative imaging techniques across a range of imaging modalities in ILD and consider how they may be applied in the assessment and understanding of ILD. We critically appraised evidence found from searches of Ovid online, PubMed and the TRIP database for novel and quantitative imaging studies in ILD. Recent studies have explored the capability of texture-based lung parenchymal analysis in accurately quantifying several ILD features. Newer techniques are helping to overcome the challenges inherent to such approaches, in particular distinguishing peripheral reticulation of lung parenchyma from pleura and accurately identifying the complex density patterns that accompany honeycombing. Robust and validated texture-based analysis may remove the subjectivity that is inherent to qualitative reporting and allow greater objective measurements of change over time. In addition to lung parenchymal feature quantification, pulmonary vessel volume analysis on CT has demonstrated prognostic value in two retrospective analyses and may be a sign of vascular changes in ILD which, to date, have been difficult to quantify in the absence of overt pulmonary hypertension. Novel applications of existing imaging techniques, such as hyperpolarised gas MRI and positron emission tomography (PET), show promise in combining structural and functional information. Although structural imaging of lung tissue is inherently challenging in terms of conventional proton MRI techniques, inroads are being made with ultrashort echo time, and dynamic contrast-enhanced MRI may be used for lung perfusion assessment. In addition, inhaled hyperpolarised 129Xenon gas MRI may provide multifunctional imaging metrics, including assessment of ventilation, intra-acinar gas diffusion and alveolar-capillary diffusion. PET has demonstrated high standard uptake values (SUVs) of 18F-fluorodeoxyglucose in fibrosed lung tissue, challenging the assumption that these are 'burned out' and metabolically inactive regions. Regions that appear structurally normal also appear to have higher SUV, warranting further exploration with future longitudinal studies to assess if this precedes future regions of macroscopic structural change. Given the subtleties involved in diagnosing, assessing and predicting future deterioration in many forms of ILD, multimodal quantitative lung structure-function imaging may provide the means of identifying novel, sensitive and clinically applicable imaging markers of disease. Such imaging metrics may provide mechanistic and phenotypic information that can help direct appropriate personalised therapy, can be used to predict outcomes and could potentially be more sensitive and specific than global pulmonary function testing. Quantitative assessment may objectively assess subtle change in character or extent of disease that can assist in efficacy of antifibrotic therapy or detecting early changes of potentially pneumotoxic drugs involved in early intervention studies.

The contribution of viruses and bacteria to community-acquired pneumonia in vaccinated children: a case - control study

Abstract: Introduction Respiratory pathogens associated with childhood pneumonia are often detected in the upper respiratory tract of healthy children, making their contribution to pneumonia difficult to determine. We aimed to determine the contribution of common pathogens to pneumonia adjusting for rates of asymptomatic detection to inform future diagnosis, treatment and preventive strategies. Methods A case–control study was conducted among children Results From May 2015 to October 2017, 230 cases and 230 controls were enrolled. At least one respiratory virus was identified in 57% of cases and 29% of controls (aOR: 4.7; 95% CI: 2.8 to 7.8). At least one bacterial species was detected in 72% of cases and 80% of controls (aOR: 0.7; 95% CI: 0.4 to 1.2). Respiratory syncytial virus (RSV) detection was most strongly associated with pneumonia (aOR: 58.4; 95% CI: 15.6 to 217.5). Mycoplasma pneumoniae was the only bacteria associated with pneumonia (aOR: 14.5; 95% CI: 2.2 to 94.8). We estimated that RSV, human metapneumovirus (HMPV), influenza, adenovirus and Mycoplasma pneumoniae were responsible for 20.2% (95% CI: 14.6 to 25.5), 9.8% (5.6% to 13.7%), 6.2% (2.5% to 9.7%), 4% (1.1% to 7.1%) and 7.2% (3.5% to 10.8%) of hospitalisations for childhood pneumonia, respectively. Conclusions Respiratory viruses, particularly RSV and HMPV, are major contributors to pneumonia in Australian children.

Hyperpolarised xenon magnetic resonance spectroscopy for the longitudinal assessment of changes in gas diffusion in IPF

Abstract: Prognosticating idiopathic pulmonary fibrosis (IPF) is challenging, in part due to a lack of sensitive biomarkers. A recent article in Thorax described how hyperpolarised xenon magnetic resonance spectroscopy may quantify regional gas exchange in IPF lungs. In a population of patients with IPF, we find that the xenon signal from red blood cells diminishes relative to the tissue/plasma signal over a 12-month time period, even when the diffusion factor for carbon monoxide is static over the same time period. We conclude that hyperpolarised 129Xe MR spectroscopy may be sensitive to short-term changes in interstitial gas diffusion in IPF.

Randomised, double-blind, placebo-controlled pilot trial of omeprazole in idiopathic pulmonary fibrosis

Abstract: Background Cough is a common, disabling symptom of idiopathic pulmonary fibrosis (IPF), which may be exacerbated by acid reflux. Inhibiting gastric acid secretion could potentially reduce cough. This study aimed to determine the feasibility of a larger, multicentre trial of omeprazole for cough in IPF, to assess safety and to quantify cough. Methods Single-centre, double-blind, randomised, placebo-controlled pilot trial of the proton pump inhibitor (PPI) omeprazole (20 mg twice daily for 3 months) in patients with IPF. Primary objectives were to assess feasibility and acceptability of trial procedures. The primary clinical outcome was cough frequency. Results Forty-five participants were randomised (23 to omeprazole, 22 to placebo), with 40 (20 in each group) having cough monitoring before and after treatment. 280 patients were screened to yield these numbers, with barriers to discontinuing antacids the single biggest reason for non-recruitment. Recruitment averaged 1.5 participants per month. Geometric mean cough frequency at the end of treatment, adjusted for baseline, was 39.1% lower (95% CI 66.0% lower to 9.3% higher) in the omeprazole group compared with placebo. Omeprazole was well tolerated and adverse event profiles were similar in both groups, although there was a small excess of lower respiratory tract infection and a small fall in forced expiratory volume and forced vital capacity associated with omeprazole. Conclusions A large randomised controlled trial of PPIs for cough in IPF appears feasible and justified but should address barriers to randomisation and incorporate safety assessments in relation to respiratory infection and changes in lung function.

Cluster-randomised trial of a nurse-led advance care planning session in patients with COPD and their loved ones

Abstract: Rationale Advance care planning (ACP) is uncommon in patients with chronic obstructive pulmonary disease (COPD). Objectives To assess whether a nurse-led ACP-intervention can improve quality of patient-physician end-of-life care communication in patients with COPD. Furthermore, the influence of an ACP-intervention on symptoms of anxiety and depression in patients and loved ones was studied. Finally, quality of death and dying was assessed in patients who died during 2-year follow-up. Methods A multicentre cluster randomised-controlled trial in patients with advanced COPD was performed. The intervention group received an 1.5 hours structured nurse-led ACP-session. Outcomes were: quality of patient-physician end-of-life care communication, prevalence of ACP-discussions 6 months after baseline, symptoms of anxiety and depression in patients and loved ones and quality of death and dying. Results 165 patients were enrolled (89 intervention; 76 control). The improvement of quality of patient-physician end-of-life care communication was significantly higher in the intervention group compared with the control group (p 0.05). The quality of death and dying was comparable between both groups (p=0.17). Conclusion One nurse-led ACP-intervention session improves patient-physician end-of-life care communication without causing psychosocial distress in both patients and loved ones.

Feasibility of lung cancer prediction from low-dose CT scan and smoking factors using causal models

Abstract: Introduction Low-dose CT (LDCT) is currently used in lung cancer screening of high-risk populations for early lung cancer diagnosis. However, 96% of individuals with detected nodules are false positives. Methods In order to develop an efficient early lung cancer predictor from clinical, demographic and LDCT features, we studied a total of 218 subjects with lung cancer or benign nodules. Probabilistic graphical models (PGMs) were used to integrate demographics, clinical data and LDCT features from 92 subjects (training cohort) from the Pittsburgh Lung Screening Study cohort. Results Learnt PGMs identified three variables directly (causally) linked to malignant nodules and the largest benign nodule and used them to build the Lung Cancer Causal Model (LCCM), which was validated in a separate cohort of 126 subjects. Nodule and vessel numbers and years since the subject quit smoking were sufficient to discriminate malignant from benign nodules. Comparison with existing predictors in the training and validation cohorts showed that (1) incorporating LDCT scan features greatly enhances predictive accuracy; and (2) LCCM improves cancer detection over existing methods, including the Brock parsimonious model (p 0.001). Notably, the number of surrounding vessels, a feature not previously used in predictive models, significantly improves predictive efficiency. Based on the validation cohort results, LCCM is able to identify 30% of the benign nodules without risk of misclassifying cancer nodules. Discussion LCCM shows promise as a lung cancer predictor as it is significantly improved over existing models. Validated in a larger, prospective study, it may help reduce unnecessary follow-up visits and procedures.

Multidisciplinary home-based rehabilitation in inoperable lung cancer: a randomised controlled trial

Abstract: Background Lung cancer is associated with poor health-related quality of life (HRQoL) and high symptom burden. This trial aimed to assess the efficacy of home-based rehabilitation versus usual care in inoperable lung cancer. Methods A parallel-group, assessor-blinded, allocation-concealed, randomised controlled trial. Eligible participants were allocated (1:1) to usual care (UC) plus 8 weeks of aerobic and resistance exercise with behaviour change strategies and symptom support (intervention group (IG)) or UC alone. Assessments occurred at baseline, 9 weeks and 6 months. The primary outcome, change in between-group 6 min walk distance (6MWD), was analysed using intention-to-treat (ITT). Subsequent analyses involved modified ITT (mITT) and included participants with at least one follow-up outcome measure. Secondary outcomes included HRQoL and symptoms. Results Ninety-two participants were recruited. Characteristics of participants (UC=47, IG=45): mean (SD) age 64 (12) years; men 55%; disease stage n (%) III=35 (38) and IV=48 (52); radical treatment 46%. There were no significant between-group differences for the 6MWD (n=92) at 9 weeks (p=0.308) or 6 months (p=0.979). The mITT analyses of 6MWD between-group differences were again non-significant (mean difference (95% CI): 9 weeks: −25.4 m (−64.0 to 13.3), p=0.198 and 6 months: 41.3 m (−26.7 to 109.4), p=0.232). Significant 6-month differences, favouring the IG, were found for HRQoL (Functional Assessment of Cancer Therapy–Lung: 13.0 (3.9 to 22.1), p=0.005) and symptom severity (MD Anderson Symptom Inventory–Lung Cancer: −2.2 (−3.6 to –0.9), p=0.001). Conclusions Home-based rehabilitation did not improve functional exercise capacity but there were improvements in patient-reported exploratory secondary outcomes measures observed at 6 months. Trial registration Australian New Zealand Clinical Trials Registry (ACTRN12614001268639).

Gene correlation network analysis to identify regulatory factors in idiopathic pulmonary fibrosis.

Abstract: Background Idiopathic pulmonary fibrosis (IPF) is a severe lung disease characterised by extensive pathological changes. The objective for this study was to identify the gene network and regulators underlying disease pathology in IPF and its association with lung function. Methods Lung Tissue Research Consortium dataset with 262 IPF and control subjects (GSE47460) was randomly divided into two non-overlapping groups for cross-validated differential gene expression analysis. Consensus weighted gene coexpression network analysis identified overlapping coexpressed gene modules between both IPF groups. Modules were correlated with lung function (diffusion capacity, DL CO ; forced expiratory volume in 1 s, FEV 1 ; forced vital capacity, FVC) and enrichment analyses used to identify biological function and transcription factors. Module correlation with miRNA data (GSE72967) identified associated regulators. Clinical relevance in IPF was assessed in a peripheral blood gene expression dataset (GSE93606) to identify modules related to survival. Results Correlation network analysis identified 16 modules in IPF. Upregulated modules were associated with cilia, DNA replication and repair, contractile fibres, B-cell and unfolded protein response, and extracellular matrix. Downregulated modules were associated with blood vessels, T-cell and interferon responses, leucocyte activation and degranulation, surfactant metabolism, and cellular metabolic and catabolic processes. Lung function correlated with nine modules (eight with DL CO , five with FVC). Intermodular network of transcription factors and miRNA showed clustering of fibrosis, immune response and contractile modules. The cilia-associated module was able to predict survival (p=0.0097) in an independent peripheral blood IPF cohort. Conclusions We identified a correlation gene expression network with associated regulators in IPF that provides novel insight into the pathological process of this disease.

Risk factors for situs defects and congenital heart disease in primary ciliary dyskinesia.

Abstract: Primary ciliary dyskinesia (PCD) is associated with abnormal organ positioning (situs) and congenital heart disease (CHD). This study investigated genotype–phenotype associations in PCD to facilitate risk predictions for cardiac and laterality defects. This retrospective cohort study of 389 UK patients with PCD found 51% had abnormal situs and 25% had CHD and/or laterality defects other than situs inversus totalis. Patients with biallelic mutations in a subset of nine PCD genes had normal situs. Patients with consanguineous parents had higher odds of situs abnormalities than patients with non-consanguineous parents. Patients with abnormal situs had higher odds of CHD and/or laterality defects.

Evaluation of cardiovascular risk in a lung cancer screening cohort

Abstract: Introduction Lung cancer screening (LCS) by low-dose computed tomography (LDCT) offers an opportunity to impact both lung cancer and coronary heart disease mortality through detection of coronary artery calcification (CAC). Here, we explore the value of CAC and cardiovascular disease (CVD) risk assessment in LCS participants in the Lung Screen Uptake Trial (LSUT). Methods In this cross-sectional study, current and ex-smokers aged 60–75 were invited to a ‘lung health check’. Data collection included a CVD risk assessment enabling estimation of 10 year CVD risk using the QRISK2 score. Participants meeting the required lung cancer risk underwent an ungated, non-contrast LDCT. Descriptive data, bivariate associations and a multivariate analysis of predictors of statin use are presented. Results Of 1005 individuals enrolled, 680 were included in the final analysis. 421 (61.9%) had CAC present and in 49 (7.2%), this was heavy. 668 (98%) of participants had a QRISK2≥10% and QRISK2 was positively associated with increasing CAC grade (OR 4.29 (CI 0.93 to 19.88) for QRISK2=10%–20% and 12.29 (CI 2.68 to 56.1) for QRISK2≥20% respectively). Of those who qualified for statin primary prevention (QRISK2≥10%), 56.8% did not report a history of statin use. In the multivariate analysis statin use was associated with age, body mass index and history of hypertension and diabetes. Conclusions LCS offers an important opportunity for instituting CVD risk assessment in all LCS participants irrespective of the presence of LDCT-detected CAC. Further studies are needed to determine whether CAC could enhance uptake and adherence to primary preventative strategies.

MUC5B variant is associated with visually and quantitatively detected preclinical pulmonary fibrosis

Abstract: Background Relatives of patients with familial interstitial pneumonia (FIP) are at increased risk for pulmonary fibrosis. We assessed the prevalence and risk factors for preclinical pulmonary fibrosis (PrePF) in first-degree relatives of patients with FIP and determined the utility of deep learning in detecting PrePF on CT. Methods First-degree relatives of patients with FIP over 40 years of age who believed themselves to be unaffected by pulmonary fibrosis underwent CT scans of the chest. Images were visually reviewed, and a deep learning algorithm was used to quantify lung fibrosis. Genotyping for common idiopathic pulmonary fibrosis risk variants in MUC5B and TERT was performed. Findings In 494 relatives of patients with FIP from 263 families of patients with FIP, the prevalence of PrePF on visual CT evaluation was 15.6% (95% CI 12.6 to 19.0). Compared with visual CT evaluation, deep learning quantitative CT analysis had 84% sensitivity (95% CI 0.72 to 0.89) and 86% sensitivity (95% CI 0.83 to 0.89) for discriminating subjects with visual PrePF diagnosis. Subjects with PrePF were older (65.9, SD 10.1 years) than subjects without fibrosis (55.8 SD 8.7 years), more likely to be male (49% vs 37%), more likely to have smoked (44% vs 27%) and more likely to have the MUC5B promoter variant rs35705950 (minor allele frequency 0.29 vs 0.21). MUC5B variant carriers had higher quantitative CT fibrosis scores (mean difference of 0.36%), a difference that remains significant when controlling for age and sex. Interpretation PrePF is common in relatives of patients with FIP. Its prevalence increases with age and the presence of a common MUC5B promoter variant. Quantitative CT analysis can detect these imaging abnormalities.

Five-year mortality and morbidity impact of prolonged versus brief ICU stay: a propensity score matched cohort study

Abstract: Purpose Long-term outcomes of critical illness may be affected by duration of critical illness and intensive care. We aimed to investigate differences in mortality and morbidity after short ( Methods Former EPaNIC-trial patients were included in this preplanned prospective cohort, 5-year follow-up study. Mortality was assessed in all. For morbidity analyses, all long-stay and—for feasibility—a random sample (30%) of short-stay survivors were contacted. Primary outcomes were total and post-28-day 5-year mortality. Secondary outcomes comprised handgrip strength (HGF, %pred), 6-minute-walking distance (6MWD, %pred) and SF-36 Physical Function score (PF SF-36). One-to-one propensity-score matching of short-stay and long-stay patients was performed for nutritional strategy, demographics, comorbidities, illness severity and admission diagnosis. Multivariable regression analyses were performed to explore ICU factors possibly explaining any post-ICU observed outcome differences. Results After matching, total and post-28-day 5-year mortality were higher for long-stayers (48.2% (95%CI: 43.9% to 52.6%) and 40.8% (95%CI: 36.4% to 45.1%)) versus short-stayers (36.2% (95%CI: 32.4% to 40.0%) and 29.7% (95%CI: 26.0% to 33.5%), p Conclusion Longer duration of intensive care is associated with excess 5-year mortality and morbidity, partially explained by potentially modifiable ICU factors. Trail registration number NCT00512122.