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Background Patients with malignant pleural effusions (MPEs) experience breathlessness and poor survival. Breathlessness is associated with poor survival in other conditions. Research Question Is breathlessness, measured using a visual analog scale for dyspnea (VASD), associated with survival in patients with MPE? Study Design and Methods Individual patient data from five randomized controlled trials of 553 patients undergoing interventions for MPE were analyzed. VASD was recorded at baseline and daily after intervention. Patients were followed up until death or end of trial. Univariate and multivariable Cox regression were used to identify factors associated with survival. Results Baseline VASD was significantly associated with worse survival, with a hazard ratio of 1.10 (95% CI, 1.06-1.15) for a 10-mm increase in VASD. On multivariable regression, it remained a significant predictor of survival. Mean 7-day VASD and mean total VASD were also predictors of survival (mean 7-day VASD: hazard ratio [HR], 1.26 [95% CI, 1.19-1.34]; total VASD: HR, 1.25 [95% CI, 1.15-1.37]). Other predictors of survival were serum C-reactive protein level and tumor type. Previous treatment with chemotherapy, performance status, pleural fluid lactate dehydrogenase, serum albumin, hemoglobin, serum neutrophil:lymphocyte ratio, and size of effusion were associated with survival on univariate but not multivariable analysis. Interpretation Breathlessness, measured using VASD at baseline and postprocedure, is a predictor of survival in patients with MPE.

To determine the prevalence of pleural abnormalities and describe the computed tomography (CT) features observed in a well-characterised population of patients with pleural infection.A retrospective study of a subgroup of patients from the Second Multi-centre Intra-pleural Sepsis Trial (MIST 2) trial was carried out. Patients were diagnosed with pleural infection on robust clinical criteria. CT examinations were assessed by three observers independently for the presence of predefined features. Planned subgroup comparisons of patients with and without evidence of parenchymal infection were performed.Eighty-one patients were included. Parietal pleural thickening and enhancement were seen in 98.7% of patients. Visceral pleural changes were observed in most, including several previously undescribed features. Consolidation was observed in 61.7% of patients and there was a significant association of parenchymal consolidation with CT evidence of small airways infection (p0.001) and visceral pleural thickening and enhancement (p0.05). Features of parenchymal infection were absent in one third of patients.This study provides a comprehensive account of the parietal pleural, visceral pleural, and parenchymal changes of pleural infection on CT. Parenchymal infection is absent in a significant proportion of patients with pleural infection, suggesting that a pneumonic process may not be necessary for the development of pleural infection.

Richard M Bruce,1,2 Phi Anh Phan,2 Marzia Rigolli,3 Minh C Tran,2 Edmund Pacpaco,4 Najib M Rahman,4 Andrew D Farmery2 1Centre for Human and Applied Physiological Sciences, School of Basic and Medical Biosciences, King’s College London, London, UK; 2Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; 3University of Oxford Centre for Clinical Magnetic Resonance Research, University of Oxford, Oxford, UK; 4Oxford University Hospitals NHS Foundation Trust, Oxford Centre for Respiratory Medicine, Oxford, UKCorrespondence: Richard M BruceKing’s College London, Shepherd’s House, Guy’s Campus, London, SE1 1UL, UKTel +44 20 7848 6324Email Richard.bruce@kcl.ac.ukBackground: There is marked variability in the symptoms and outcomes of patients with chronic obstructive pulmonary disease (COPD) which are poorly predicted by spirometry/FEV1%pred. Furthermore, as spirometry requires the performance of potentially distressing respiratory manoeuvres which are to some extent user-effort dependent, there is need for non-invasive and simple-to-perform techniques to identify subtypes of COPD which are more closely related to clinically relevant outcomes.Materials and Methods: The inspired sinewave test (IST) sinusoidally modulates the inspired concentration of a tracer gas (N2O) over successive tidal breaths. A single-compartment tidal-ventilation lung model processes the amplitude/phase of the expired N2O sinewave and estimates cardiopulmonary variables including: effective lung volume and indices of ventilatory heterogeneity (VH; ELV180/FRCpleth and ELV180/ELVpred). 83 COPD patients and 53 healthy controls performed the IST test, standard pulmonary function tests (Spirometry, body plethysmography and the single breath test of carbon monoxide uptake), and symptom severity questionnaires (COPD assessment test, CAT; mMRC dyspnoea-scale, mMRC-DS; Cough+Mucus score; C+M score).Results: ELV180/FRCpleth and ELV180/ELVpred were significantly lower in patients with COPD vs healthy participants (0.34± 0.11 vs 0.68± 0.14 and 0.7± 0.27 vs 0.98± 0.15, respectively; P< 0.05). Multivariable regression analysis demonstrated that ELV180/FRCpleth was a stronger and independent predictor of CAT, mMRC-DS and C+M score vs FEV1%pred. ELV180/ELVpred was a stronger and independent and better predictor of C+M score vs FEV1%pred. Phenotyping patients, based upon ELV180/ELVpred and FRC%pred, uncovered significant symptomatic differences between groups.Conclusion: The IST indices of VH were superior and independent predictors of symptom severity vs FEV1%pred and has potential as a non-invasive and simple-to-perform method to stratify patients into subgroups related to clinically relevant features of COPD.Keywords: COPD, lung function test, nitrous oxide, medical device, ventilatory heterogeneity

Trypanosoma cruzi has three biochemically and morphologically distinct developmental stages that are programmed to rapidly respond to environmental changes the parasite faces during its life cycle. Unlike other eukaryotes, Trypanosomatid genomes contain protein coding genes that are transcribed into polycistronic pre-mRNAs and have their expression controlled by post-transcriptional mechanisms. Transcriptome analyses comparing three stages of the T. cruzi life cycle revealed changes in gene expression that reflect the parasite adaptation to distinct environments. Several genes encoding RNA binding proteins (RBPs), known to act as key post-transcriptional regulatory factors, were also differentially expressed. We characterized one T. cruzi RBP, named TcZH3H12, which contains a zinc finger domain and is up-regulated in epimastigotes compared to trypomastigotes and amastigotes. TcZC3H12 knockout (KO) epimastigotes showed decreased growth rates and increased capacity to differentiate into metacyclic trypomastigotes. Transcriptome analyses comparing wild type and TcZC3H12 KOs revealed a TcZC3H12-dependent expression of epimastigote-specific genes such as genes encoding amino acid transporters and proteins associated with differentiation (PADs). RNA immunoprecipitation assays showed that transcripts from the PAD family interact with TcZC3H12. Taken together, these findings suggest that TcZC3H12 positively regulates the expression of genes involved in epimastigote proliferation and also acts as a negative regulator of metacyclogenesis.

Background The management of recurrent pleural effusions remains a challenging issue for clinicians. Advances in management have led to increased use of indwelling tunneled pleural catheters (IPC) because of their effectiveness and ease of outpatient placement. However, with the increase in IPC placement there have also been increasing reports of complications, including infections. Currently there is minimal guidance in IPC-related management issues after placement. Research Question Our objective was to formulate clinical consensus statements related to perioperative and long-term IPC catheter management based on a modified Delphi process from experts in pleural disease management. Study Design and Methods Expert panel members used a modified Delphi process to reach consensus on common perioperative and long-term management options related to IPC use. Members were identified from multiple countries, specialties, and practice settings. A series of meetings and anonymous online surveys were completed. Responses were used to formulate consensus statements among panel experts, using a modified Delphi process. Consensus was defined a priori as greater than 80% agreement among panel constituents. Results A total of 25 physicians participated in this project. The following topics were addressed during the process: definition of an IPC infection, management of IPC-related infectious complications, interventions to prevent IPC infections, IPC-related obstruction/malfunction management, assessment of IPC removal, and instructions regarding IPC management by patients and caregivers. Strong consensus was obtained on 36 statements. No consensus was obtained on 29 statements. Interpretation The management of recurrent pleural disease with IPC remains complex and challenging. This statement offers statements for care in numerous areas related to IPC management based on expert consensus and identifies areas that lack consensus. Further studies related to long-term management of IPC are warranted.

Background: While the efficacy of Indwelling pleural catheters for palliation of malignant pleural effusions is supported by relatively robust evidence, there is less clarity surrounding the postinsertion management. Methods: The Trustworthy Consensus-Based Statement approach was utilized to develop unbiased, scientifically valid guidance for the management of patients with malignant effusions treated with indwelling pleural catheters. A comprehensive electronic database search of PubMed was performed based on a priori crafted PICO questions (Population/Intervention/Comparator/Outcomes paradigm). Manual searches of the literature were performed to identify additional relevant literature. Dual screenings at the title, abstract, and full-text levels were performed. Identified studies were then assessed for quality based on a combination of validated tools. Appropriateness for data pooling and formation of evidence-based recommendations was assessed using predetermined criteria. All panel members participated in development of the final recommendations utilizing the modified Delphi technique. Results: A total of 7 studies were identified for formal quality assessment, all of which were deemed to have a high risk of bias. There was insufficient evidence to allow for data pooling and formation of any evidence-based recommendations. Panel consensus resulted in 11 ungraded consensus-based recommendations. Conclusion: This manuscript was developed to provide clinicians with guidance on the management of patients with indwelling pleural catheters placed for palliation of malignant pleural effusions. Through a systematic and rigorous process, management suggestions were developed based on the best available evidence with augmentation by expert opinion when necessary. In addition, these guidelines highlight important gaps in knowledge which require further study.

A 45-year-old Caucasian woman was referred for investigation of recurrent chest infections. She had been treated over the previous 9 months for recurrent symptoms characterised by intermittent episodes of dyspnoea, cough productive of green sputum and pleuritic chest pain. Systemic enquiry was unremarkable; specifically, she had not experienced any weight loss or anorexia. On each episode, oxygen saturations were >94% and heart rate was

Sir William Osler’s great work and achievements are extensively documented. Less well known is his prolonged battle with postinfluenza pneumonia, lung abscess and pleural infection that eventually led to his demise. At the age of 70, he was a victim of the global Spanish influenza epidemic, and subsequently developed pneumonia. In the era before antibiotics, he received supportive care and opium for symptom control. The infection extended to the pleura and he required repeated thoracentesis which failed to halt his deterioration. He proceeded to open surgical drainage involving rib resection. Unfortunately, he died shortly after the operation from massive pleuropulmonary haemorrhage. In this article, we review the events leading up to Osler’s death and contrast his care 100 years ago with contemporary state-of-the-art management in pleural infection.

Objectives Recent observations indicate a potential survival benefit in patients with malignant pleural effusion (MPE) who achieve successful pleurodesis in comparison to patients who experience effusion recurrence post pleurodesis. This study aimed to explore this observation using two datasets of patients with MPE undergoing talc pleurodesis. Materials and Methods Dataset 1 comprised patients who underwent talc pleurodesis at Oxford Pleural Unit for MPE. Dataset 2 comprised patients enrolled in the TIME1 clinical trial. Pleurodesis success was defined as absence of need for further therapeutic procedures for MPE in the three months following pleurodesis. Data on various clinical, laboratory and radiological parameters were collected and survival was compared according to pleurodesis outcome (success vs. failure) after adjusting for the aforementioned parameters. Results Dataset 1 comprised 60 patients with mean age 74.1±10.3 years. The most common primary malignancies were mesothelioma, breast and lung cancer. 29 patients (48.3%) achieved pleurodesis. The adjusted odds ratio (aOR) for poor survival with pleurodesis failure was 2.85 (95% CI 1.08–7.50, =p 0.034). Dataset 2 comprised 259 patients from the TIME1 trial. The mean age was 70.8±10.3 and the most common primary malignancies were mesothelioma, lung and breast cancer. Pleurodesis was successful in 205 patients (79%). aOR for poor survival was 1.62 (95% CI 1.09–2.39, p = 0.015). Conclusion Achieving pleurodesis seems to impart a survival benefit in patients with MPE. Further studies are required to explore factors that may contribute to this phenomenon and to address the difference in survival between pleurodesis and indwelling pleural catheter interventions.

Advanced malignancy is a prevalent cause of exudative pleural effusion. The management of malignant pleural effusion (MPE) has been the subject of several recent randomized controlled trials and excellent reviews. Less attention has been focused on another controversial and challenging aspect of MPE: it's diagnosis. Prior to selecting the optimal management strategy, the presence of an MPE must first be correctly identified with an emphasis on minimizing invasiveness and discomfort in a patient afflicted with late-stage cancer. The aim of the present review is to summarize the current knowledge about MPE diagnostics and to propose an algorithm for the diagnosis of MPE in established or suspected malignancy.

Interpreting pleural fluid results correctly requires an awareness of the possible aetiologies of a pleural effusion and an understanding of the reliability of the outcome of each investigation. All results must be interpreted within each different clinical context and knowledge of the pitfalls for each test is necessary when the diagnosis is unclear. This review aims to discuss the common aetiologies of a pleural effusion and some of the pitfalls in interpretation that can occur when the diagnosis is unclear.

Background In patients with non-expandable lung, removal of pleural fluid can result in excessively negative pleural pressure, which is associated with chest discomfort, pneumothorax, and re-expansion pulmonary oedema. Pleural manometry is widely used to safeguard against pressure-related complications during thoracentesis despite little evidence to support the approach. We investigated whether monitoring of pleural pressure with manometry during thoracentesis could protect against complications compared with assessment of symptoms alone. Methods We did a prospective randomised single-blind trial involving patients with large pleural effusions at two academic medical centres in, Nashville, TN, and Baltimore, MD, USA. Eligible patients were adults with free-flowing effusions estimated to be at least 0·5 L who could remain seated throughout the procedure. Patients were randomly assigned 1:1 to receive thoracentesis guided by symptoms only (control) or by symptoms plus manometry at timepoints based on volume drained. The randomisation schedule was computer generated, used permuted blocks of four and six, and was stratified by participating institution. Patients, who were masked to study-group assignment, were asked to rate chest discomfort on 100 mm visual analogue scales before, during, and after drainage. In both groups drainage was discontinued before complete evacuation of pleural fluid if patients developed persistent chest discomfort, intractable cough, or other complications. In the manometry group, an additional criterion for stopping was if end-expiratory pleural pressure was lower than −20 cm H2O or declined by more than 10 cm H2O between two measurements to a value less than or equal to −10 cm H2O. The primary outcome was overall chest discomfort from before the start to after the procedure measured by patients 5 min after the end of drainage. Analysis was by modified intention to treat (ie, included all patients with any procedure or outcome data). This trial is registered with ClinicalTrials.gov, number NCT02677883. Findings Between March 4, 2016, and Sept 8, 2017, 191 patients were screened, of whom 128 were randomly assigned treatment and 124 were included in the final analysis (62 in each group). Four patients were excluded because of manometer malfunction (n=2), inability to access effusion due to pleural tumour burden (n=1), and inability to remain seated (n=1). Groups did not differ for the primary outcome (mean difference in chest discomfort score 2·4 mm, 95% CI −5·7 to 10·5, p=0·56). Six (10%) of 62 patients in the control group had asymptomatic pneumothorax ex vacuo compared with none in the manometry group (p=0·01). No serious complications occurred in either group. Interpretation Measurement of pleural pressure by manometry during large-volume thoracentesis does not alter procedure-related chest discomfort. Our findings do not support the routine use of this approach.

Cell wall glycopolymers on the surface of Gram-positive bacteria are fundamental to bacterial physiology and infection biology. These structures have also gained interest as vaccine antigens, in particular for the human pathogens Group AStreptococcus(GAS) andStreptococcus mutans. Streptococcal cell wall glycopolymers are considered to be functional homologues of wall teichoic acids but surprisingly lack the biologically-relevant and characteristic anionic charge. Here we identifygacH, a gene of unknown function in the GAS Group A Carbohydrate (GAC) biosynthetic cluster, in two independent transposon library screens for its ability to confer resistance to zinc and susceptibility to the bactericidal enzyme human group IIA secreted phospholipase A2. To understand the underlying mechanism of these phenotypes, we determined the structure of the extracellular domain of GacH and discover that it represents a new family of glycerol phosphate (GroP) transferases. Importantly, we demonstrate the presence of GroP in both the GAC and the homologous SerotypecCarbohydrate (SCC) fromS. mutans,which is conferred bygacHandsccHproducts, respectively. NMR analysis of GAC released from cell wall by non-destructive methods reveals that approximately 30% of the GAC GlcNAc side-chains are modified by GroP at the C6 hydroxyl group. This previously unrecognized structural modification impacts host-pathogen interaction and has implications for vaccine design.Graphical abstract

Background The outcome of indwelling pleural catheter (IPC) use in hepatic hydrothorax (HH) is unclear. This study aimed to review the safety and feasibility of the IPC in patients with refractory HH. Methods A retrospective multicenter study of patients with HH from January 2010 to December 2016 was performed. Inclusion criteria were refractory HH treated with an IPC and an underlying diagnosis of cirrhosis. Records were reviewed for patient demographics, operative reports, and laboratory values. The Kaplan-Meier method was used to estimate catheter time to removal. The Cox proportional hazard model was used to evaluate for independent predictors of pleurodesis and death. Results Seventy-nine patients were identified from eight institutions. Indication for IPC placement was palliation in 58 patients (73%) and bridge to transplant in 21 patients (27%). The median in situ dwell time of all catheters was 156 days (range, 16-1,978 days). Eight patients (10%) were found to have pleural space infection, five of whom also had catheter-site cellulitis. Two patients (2.5%) died secondary to catheter-related sepsis. Catheter removal secondary to spontaneous pleurodesis was achieved in 22 patients (28%). Median time from catheter insertion to pleurodesis was 55 days (range, 10-370 days). Older age was an independent predictor of mortality on multivariate analysis (hazard ratio, 1.05; P = .01). Conclusions We present, to our knowledge, the first multicenter study examining outcomes related to IPC use in HH. Ten percent infection risk and 2.5% mortality were identified. IPC placement may be a reasonable clinical option for patients with refractory HH, but it is associated with significant adverse events in this morbid population.

Thoracic oncology encompasses a broad spectrum of primary tumour entities originating from various pulmonary, tracheobronchial, pleural, mediastinal and chest wall tissues or distinct cell types within these compartments. Lung cancer represents by far the most frequent malignant tumour within the thoracic cavity, and is the most common type and largest killer among all cancers worldwide. Lung cancer leads mortality statistics in Europe, accounting for at least one fifth of all cancer-related deaths [1]. In addition, lung cancer causes a significant burden of symptoms in a population of patients with high comorbidity, providing significant challenges to national healthcare systems in the European Union, with the highest overall costs among all cancer types [2–4]. Contrary to the general stigma applied to lung cancer patients, where they are often assumed to suffer from a self-inflicted disease, it is now estimated that up to 10–20% of lung cancer patients are never-smokers [5, 6]. Even if numerically far lower, the remaining, The @EuroRespSoc launches a new thoracic oncology continuous professional development programme http://bit.ly/31ShuTp

Objectives: Patients with malignant pleural mesothelioma (MPM) or pleural metastases often present with malignant pleural effusion (MPE). This study aimed to analyse the effect of pleural fluid on cancer cells. Materials and Methods: Established patient-derived cancer cell cultures derived from MPE (MPM, breast carcinoma, lung adenocarcinoma) were seeded in 100% pleural fluid (exudate MPM MPE, transudate MPE, non-MPE transudate fluid) and proliferation was monitored. In addition, the establishment of new MPM cell cultures, derived from MPE specimens, was attempted by seeding the cells in 100% MPE fluid. Results: All established cancer cell cultures proliferated with similar growth rates in the different types of pleural fluid. Primary MPM cell culture success was similar with MPE fluid as with full culture medium. Conclusions: Pleural fluid alone is adequate for cancer cell proliferation in vitro, regardless of the source of pleural fluid. These results support the hypothesis that pleural fluid has important pro-growth biological properties, but the mechanisms for this effect are unclear and likely not malignant effusion specific., peer-reviewed

Background Current models of breathlessness often fail to explain disparities between patients' experiences of breathlessness and objective measures of lung function. While a mechanistic understanding of this discordance has thus far remained elusive, factors such as mood, attention and expectation have all been implicated as important modulators of breathlessness. Therefore, we have developed a model to better understand the relationships between these factors using unsupervised machine learning techniques. Subsequently we examined how expectation-related brain activity differed between these symptom-defined clusters of participants. Methods A cohort of 91 participants with mild-to-moderate chronic obstructive pulmonary disease (COPD) underwent functional brain imaging, self-report questionnaires and clinical measures of respiratory function. Unsupervised machine learning techniques of exploratory factor analysis and hierarchical cluster modelling were used to model brain–behaviour–breathlessness links. Results We successfully stratified participants across four key factors corresponding to mood, symptom burden and two capability measures. Two key groups resulted from this stratification, corresponding to high and low symptom burden. Compared with the high symptom burden group, the low symptom burden group demonstrated significantly greater brain activity within the anterior insula, a key region thought to be involved in monitoring internal bodily sensations (interoception). Conclusions This is the largest functional neuroimaging study of COPD to date, and is the first to provide a clear model linking brain, behaviour and breathlessness expectation. Furthermore, it was possible to stratify participants into groups, which then revealed differences in brain activity patterns. Together, these findings highlight the value of multimodal models of breathlessness in identifying behavioural phenotypes and for advancing understanding of differences in breathlessness burden., European Respiratory Journal, 58 (5), ISSN:0903-1936, ISSN:1399-3003

Malignant pleural effusion (MPE) is a common condition that presents with progressive breathlessness. Long term solutions are often required due to recurrence of effusion after simple drainage. Pleurodesis is one of the main options resorted to for long term control of MPE. There is data to suggest there may be a survival benefit for patients with MPE who achieve successful pleurodesis. A systematic review was carried out to explore this correlation and results suggest that there could be a survival difference according to pleurodesis outcome in patients with MPE. Fifteen studies (reported in 13 papers) were included; 13 (86.6%) of the studies showed survival difference in favour of pleurodesis success. The median [interquartile range] difference in survival between the two groups among the different studies was five [3.5–5.8] months. Most of the included studies suffered moderate to severe risk of bias and, thus, large prospective studies of patients undergoing pleurodesis are required to ascertain this effect.

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection carries a substantial risk of severe and prolonged illness; treatment options are currently limited. We assessed the efficacy and safety of inhaled nebulised interferon beta-1a (SNG001) for the treatment of patients admitted to hospital with COVID-19.MethodsWe did a randomised, double-blind, placebo-controlled, phase 2 pilot trial at nine UK sites. Adults aged 18 years or older and admitted to hospital with COVID-19 symptoms, with a positive RT-PCR or point-of-care test, or both, were randomly assigned (1:1) to receive SNG001 (6 MIU) or placebo by inhalation via a mouthpiece daily for 14 days. The primary outcome was the change in clinical condition on the WHO Ordinal Scale for Clinical Improvement (OSCI) during the dosing period in the intention-to-treat population (all randomised patients who received at least one dose of the study drug). The OSCI is a 9-point scale, where 0 corresponds to no infection and 8 corresponds to death. Multiple analyses were done to identify the most suitable statistical method for future clinical trials. Safety was assessed by monitoring adverse events for 28 days. This trial is registered with Clinicaltrialsregister.eu (2020-001023-14) and ClinicalTrials.gov (NCT04385095); the pilot trial of inpatients with COVID-19 is now completed.FindingsBetween March 30 and May 30, 2020, 101 patients were randomly assigned to SNG001 (n=50) or placebo (n=51). 48 received SNG001 and 50 received placebo and were included in the intention-to-treat population. 66 (67%) patients required oxygen supplementation at baseline: 29 in the placebo group and 37 in the SNG001 group. Patients receiving SNG001 had greater odds of improvement on the OSCI scale (odds ratio 2·32 [95% CI 1·07-5·04]; p=0·033) on day 15 or 16 and were more likely than those receiving placebo to recover to an OSCI score of 1 (no limitation of activities) during treatment (hazard ratio 2·19 [95% CI 1·03-4·69]; p=0·043). SNG001 was well tolerated. The most frequently reported treatment-emergent adverse event was headache (seven [15%] patients in the SNG001 group and five [10%] in the placebo group). There were three deaths in the placebo group and none in the SNG001 group.InterpretationPatients who received SNG001 had greater odds of improvement and recovered more rapidly from SARS-CoV-2 infection than patients who received placebo, providing a strong rationale for further trials.FundingSynairgen Research.

Background: Diagnostic yield (DY) and safety of computed tomography (CT)- and thoracic ultrasound (TUS)-guided biopsies in the diagnosis of pleural lesions have been investigated in a number of studies, but no synthesis of data from the literature has ever been performed. Objectives: We aimed to provide the first systematic review and meta-analysis on the DY and safety of CT- versus TUS-guided biopsy in the diagnosis of pleural lesions. Method: We searched MEDLINE and EMBASE for all studies reporting outcomes of interest published up to April 2018. Two authors reviewed all titles/abstracts and retrieved selected full text to identify studies according to predefined selection criteria. Summary estimates were derived using the random-effects model. Cumulative meta-analysis assessed the influence of increasing adoption of the procedures over time. Results: Thirty original studies were included in the present review; the number of studies on TUS-guided biopsy was almost three-fold higher than those on CT-guided biopsy. The pooled DYs of the 2 procedures were overall excellent and differed Conclusions: Data show that CT- and TUS-guided biopsies in the diagnosis of pleural lesions are both excellent procedures, without meaningful differences in DYs and safety. Considering that TUS is non-ionizing and easily performed at the bedside, it should be the preferred approach in presence of adequate skills.

Background The medium-term effects of Coronavirus disease (COVID-19) on organ health, exercise capacity, cognition, quality of life and mental health are poorly understood. Methods Fifty-eight COVID-19 patients post-hospital discharge and 30 age, sex, body mass index comorbidity-matched controls were enrolled for multiorgan (brain, lungs, heart, liver and kidneys) magnetic resonance imaging (MRI), spirometry, six-minute walk test, cardiopulmonary exercise test (CPET), quality of life, cognitive and mental health assessments. Findings At 2–3 months from disease-onset, 64% of patients experienced breathlessness and 55% reported fatigue. On MRI, abnormalities were seen in lungs (60%), heart (26%), liver (10%) and kidneys (29%). Patients exhibited changes in the thalamus, posterior thalamic radiations and sagittal stratum on brain MRI and demonstrated impaired cognitive performance, specifically in the executive and visuospatial domains. Exercise tolerance (maximal oxygen consumption and ventilatory efficiency on CPET) and six-minute walk distance were significantly reduced. The extent of extra-pulmonary MRI abnormalities and exercise intolerance correlated with serum markers of inflammation and acute illness severity. Patients had a higher burden of self-reported symptoms of depression and experienced significant impairment in all domains of quality of life compared to controls (p Interpretation A significant proportion of patients discharged from hospital reported symptoms of breathlessness, fatigue, depression and had limited exercise capacity. Persistent lung and extra-pulmonary organ MRI findings are common in patients and linked to inflammation and severity of acute illness. Funding NIHR Oxford and Oxford Health Biomedical Research Centres, British Heart Foundation Centre for Research Excellence, UKRI, Wellcome Trust, British Heart Foundation.

Group B Streptococcus (GBS) asymptomatically colonizes the female reproductive tract but is a common causative agent of meningitis. GBS meningitis is characterized by extensive infiltration of neutrophils carrying high concentrations of calprotectin, a metal chelator. To persist within inflammatory sites and cause invasive disease, GBS must circumvent host starvation attempts. Here, we identified global requirements for GBS survival during calprotectin challenge, including known and putative systems involved in metal ion transport. We characterized the role of zinc import in tolerating calprotectin stress in vitro and in a mouse model of infection. We observed that a global zinc uptake mutant was less virulent than the parental GBS strain and found calprotectin knockout mice to be equally susceptible to infection by wild-type (WT) and mutant strains. These findings suggest that calprotectin production at the site of infection results in a zinc-limited environment and reveals the importance of GBS metal homeostasis to invasive disease., Nutritional immunity is an elegant host mechanism used to starve invading pathogens of necessary nutrient metals. Calprotectin, a metal-binding protein, is produced abundantly by neutrophils and is found in high concentrations within inflammatory sites during infection. Group B Streptococcus (GBS) colonizes the gastrointestinal and female reproductive tracts and is commonly associated with severe invasive infections in newborns such as pneumonia, sepsis, and meningitis. Although GBS infections induce robust neutrophil recruitment and inflammation, the dynamics of GBS and calprotectin interactions remain unknown. Here, we demonstrate that disease and colonizing isolate strains exhibit susceptibility to metal starvation by calprotectin. We constructed a mariner transposon (Krmit) mutant library in GBS and identified 258 genes that contribute to surviving calprotectin stress. Nearly 20% of all underrepresented mutants following treatment with calprotectin are predicted metal transporters, including known zinc systems. As calprotectin binds zinc with picomolar affinity, we investigated the contribution of GBS zinc uptake to overcoming calprotectin-imposed starvation. Quantitative reverse transcriptase PCR (qRT-PCR) revealed a significant upregulation of genes encoding zinc-binding proteins, adcA, adcAII, and lmb, following calprotectin exposure, while growth in calprotectin revealed a significant defect for a global zinc acquisition mutant (ΔadcAΔadcAIIΔlmb) compared to growth of the GBS wild-type (WT) strain. Furthermore, mice challenged with the ΔadcAΔadcAIIΔlmb mutant exhibited decreased mortality and significantly reduced bacterial burden in the brain compared to mice infected with WT GBS; this difference was abrogated in calprotectin knockout mice. Collectively, these data suggest that GBS zinc transport machinery is important for combatting zinc chelation by calprotectin and establishing invasive disease.

Systemic inflammatory diseases are a heterogeneous family of autoimmune chronic inflammatory disorders that affect multiple systems within the human body. Connective tissue disease (CTD) is a large group within this family characterised by immune-mediated inflammation of the connective tissue. This group of disorders are often associated with pleural manifestations. CTD-induced pleuritis exhibits a wide variety of symptoms and signs including exudative pleural effusions and chest pain. Accurate estimation of prevalence for CTD-related pleuritis is challenging as small effusions are asymptomatic and remain undetected. Rheumatoid arthritis and systemic lupus erythematosus are frequent CTDs and present with pleural pathology in approximately 5–20% and 17–60% of cases, respectively. By contrast, pleural involvement in systemic sclerosis, eosinophilia–myalgia syndrome, mixed connective tissue disease, ankylosing spondylitis, polymyositis and dermatomyositis syndrome is rare. Clinical management depends on the severity of symptoms; however, most effusions resolve spontaneously. In this review we discuss the pathophysiological mechanisms and the clinical considerations of CTD-induced pleuritis., Chronic inflammatory diseases could cause pleural pathology. Clinical management depends on the severity of symptoms, but most effusions resolve spontaneously. https://bit.ly/333euHb

Background There are around 40,000 new cases of malignant pleural effusion in the UK each year. Insertion of talc slurry via a chest tube is the current standard treatment in the UK. However, some centres prefer local anaesthetic thoracoscopy and talc poudrage. There is no consensus as to which approach is most effective. Objective This trial tested the hypothesis that thoracoscopy and talc poudrage increases the proportion of patients with successful pleurodesis at 3 months post procedure, compared with chest drain insertion and talc slurry. Design This was a multicentre, open-label, randomised controlled trial with embedded economic evaluation. Follow-up took place at 1, 3 and 6 months. Setting This trial was set in 17 NHS hospitals in the UK. Participants A total of 330 adults with a confirmed diagnosis of malignant pleural effusion needing pleurodesis and fit to undergo thoracoscopy under local anaesthetic were included. Those adults needing a tissue diagnosis or with evidence of lung entrapment were excluded. Interventions Allocation took place following minimisation with a random component, performed by a web-based, centralised computer system. Participants in the control arm were treated with a bedside chest drain insertion and 4 g of talc slurry. In the intervention arm, participants underwent local anaesthetic thoracoscopy with 4 g of talc poudrage. Main outcome measures The primary outcome measure was pleurodesis failure at 90 days post randomisation. Secondary outcome measures included mortality and patient-reported symptoms. A cost–utility analysis was also performed. Results A total of 166 and 164 patients were allocated to poudrage and slurry, respectively. Participants were well matched at baseline. For the primary outcome, no significant difference in pleurodesis failure was observed between the treatment groups at 90 days, with rates of 36 out of 161 (22%) and 38 out of 159 (24%) noted in the poudrage and slurry groups, respectively (odds ratio 0.91, 95% confidence interval 0.54 to 1.55; p = 0.74). No differences (or trends towards difference) were noted in adverse events or any of the secondary outcomes at any time point, including pleurodesis failure at 180 days [poudrage 46/161 (29%), slurry 44/159 (28%), odds ratio 1.05, 95% confidence interval 0.63 to 1.73; p = 0.86], mean number of nights in hospital over 90 days [poudrage 12 nights (standard deviation 13 nights), slurry 11 nights (standard deviation 10 nights); p = 0.35] and all-cause mortality at 180 days [poudrage 66/166 (40%), slurry 68/164 (42%); p = 0.70]. At £20,000 per quality-adjusted life-year gained, poudrage would have a 0.36 probability of being cost-effective compared with slurry. Limitations Entry criteria specified that patients must be sufficiently fit to undergo thoracoscopy, which may make the results less applicable to those patients presenting with a greater degree of frailty. Furthermore, the trial was conducted on an open-label basis, which may have influenced the results of patient-reported measures. Conclusions The TAPPS (evaluating the efficacy of Thoracoscopy And talc Poudrage versus Pleurodesis using talc Slurry) trial has robustly demonstrated that there is no additional clinical effectiveness or cost-effectiveness benefit in performing talc poudrage at thoracoscopy over bedside chest drain and talc slurry for the management of malignant pleural effusion. Trial registration Current Controlled Trials ISRCTN47845793. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 26. See the NIHR Journals Library website for further project information.

Pleural diseases affect millions of people worldwide. Pleural infection, malignant pleural diseases and pneumothorax are common clinical challenges. A large number of recent clinical trials have provided an evidence-based platform to evaluate conventional and novel methods to drain pleural effusions/air which reduce morbidity and unnecessary interventions. These successes have generated significant enthusiasm and raised the profile of pleural medicine as a new subspecialty. The ultimate goal of pleural research is to prevent/stop development of pleural effusions/pneumothorax. Current research studies mainly focus on the technical aspects of pleural drainage. Significant knowledge gaps exist in many aspects such as understanding of the pathobiology of the underlying pleural diseases, pharmacokinetics of pleural drug delivery, etc. Answers to these important questions are needed to move the field forward. This article collates opinions of leading experts in the field in highlighting major knowledge gaps in common pleural diseases to provoke thinking beyond pleural drainage. Recognizing the key barriers will help prioritize future research in the quest to ultimately cure (rather than just drain) these pleural conditions.

Although our understanding of the pathogenesis of empyema has grown tremendously over the past few decades, questions still remain on how to optimally manage this condition. It has been almost a decade since the publication of the MIST2 trial, but there is still an extensive debate on the appropriate use of intrapleural fibrinolytic and deoxyribonuclease therapy in patients with empyema. Given the scarcity of overall guidance on this subject, we convened an international group of 22 experts from 20 institutions across five countries with experience and expertise in managing adult patients with empyema. We did a literature and internet search for reports addressing 11 clinically relevant questions pertaining to the use of intrapleural fibrinolytic and deoxyribonuclease therapy in adult patients with bacterial empyema. This Position Paper, consisting of seven graded and four ungraded recommendations, was formulated by a systematic and rigorous process involving the evaluation of published evidence, augmented with provider experience when necessary. Panel members participated in the development of the final recommendations using the modified Delphi technique. Our Position Paper aims to address the existing gap in knowledge and to provide consensus-based recommendations to offer guidance in clinical decision making when considering the use of intrapleural therapy in adult patients with bacterial empyema.

The SARS-CoV-2 can lead to severe illness with COVID-19. Outcomes of patients requiring mechanical ventilation are poor. Awake proning in COVID-19 improves oxygenation, but on data clinical outcomes is limited. This single-centre retrospective study aimed to assess whether successful awake proning of patients with COVID-19, requiring respiratory support (continuous positive airways pressure (CPAP) or high-flow nasal oxygen (HFNO)) on a respiratory high-dependency unit (HDU), is associated with improved outcomes. HDU care included awake proning by respiratory physiotherapists. Of 565 patients admitted with COVID-19, 71 (12.6%) were managed on the respiratory HDU, with 48 of these (67.6%) requiring respiratory support. Patients managed with CPAP alone 22/48 (45.8%) were significantly less likely to die than patients who required transfer onto HFNO 26/48 (54.2%): CPAP mortality 36.4%; HFNO mortality 69.2%, (p=0.023); however, multivariate analysis demonstrated that increasing age and the inability to awake prone were the only independent predictors of COVID-19 mortality. The mortality of patients with COVID-19 requiring respiratory support is considerable. Data from our cohort managed on HDU show that CPAP and awake proning are possible in a selected population of COVID-19, and may be useful. Further prospective studies are required.

Background Azithromycin is an orally active synthetic macrolide antibiotic with a wide range of anti-bacterial, anti-inflammatory and antiviral properties. It is a safe, inexpensive, generic licenced drug available worldwide and manufactured to scale and is a potential candidate therapy for pandemic coronavirus disease 2019 (COVID-19). Azithromycin was widely used to treat severe SARS-CoV and MERS-CoV, but to date, no randomised data are available in any coronavirus infections. Other ongoing trials are exploring short courses of azithromycin either in early disease, within the first 7 days of symptoms, when azithromycin’s antiviral properties may be important, or late in disease when anti-bacterial properties may reduce the risk of secondary bacterial infection. However, the molecule’s anti-inflammatory properties, including suppression of pulmonary macrophage-derived pro-inflammatory cytokines such as interleukins-1β, -6, -8, and -18 and cytokines G-CSF and GM-CSF may provide a distinct therapeutic benefit if given in as a prolonged course during the period of progression from moderate to severe disease. Methods ATOMIC2 is a phase II/III, multi-centre, prospective, open-label, two-arm randomised superiority clinical trial of azithromycin versus standard care for adults presenting to hospital with COVID-19 symptoms who are not admitted at initial presentation. We will enrol adults, ≥ 18 years of age assessed in acute hospitals in the UK with clinical diagnosis of COVID-19 infection where management on an ambulatory care pathway is deemed appropriate. Participants will be randomised in a 1:1 ratio to usual care or to azithromycin 500 mg orally daily for 14 days with telephone follow-up at days 14 and 28. The primary objective is to compare the proportion with either death or respiratory failure requiring invasive or non-invasive mechanical ventilation over 28 days from randomisation. Secondary objectives include mortality/respiratory failure in those with a PCR-confirmed diagnosis; all-cause mortality; progression to pneumonia; progression to severe pneumonia; peak severity of illness and mechanistic analysis of blood and nasal biomarkers. Discussion This trial will determine the clinical utility of azithromycin in patients with moderately severe, clinically diagnosed COVID-19 and could be rapidly applicable worldwide. Trial registration ClinicalTrials.gov NCT04381962. Registered on 11 May 2020. EudraCT identifier 2020-001740-26. Opened for accrual on 29 May 2020.

Objective: Malignant Pleural Mesothelioma (MPM) has a poor prognosis and high symptom burden. RESPECT-Meso was a multicenter randomized study examining the role of early specialist palliative care (SPC) on quality of life (QoL) with MPM. This is a post-hoc exploratory analysis of the symptom burden and unmet needs identified from RESPECT-Meso participants. Methods: Exploratory analysis from 174 participants using the General Health Status (GHS) measure (from the EORTC QLQ-C30 QoL questionnaire) and 87 participants using validated assessment questionnaires in those randomized to SPC. Eligibility for the study included confirmed MPM with diagnosis Results: Participants were predominantly male (79.9%), mean age 72.8 years, PS was 0 in 38%, 78% of MPM was epithelioid. At least 3 symptoms were reported in 69.8% of participants, including fatigue (81%), dyspnea (73.3%), pain (61.2%), weight loss (59.3%). Anxiety was reported by 54.7% of participants, 52.3% low mood and 48.8% anhedonia symptoms. After multivariable adjustment, only pain remained statistically significant with a hazard ratio (HR) 2.9 (95% CI 1.3-6.7; p = 0.01). For each 1 unit increase in GHS score, the HR for death was 0.987 (0.978-0.996; p = 0.006), indicating a worse reported QoL is related to shorter survival. Unmet needs were common: 25.9% wanted more information about their condition, 24.7% about their care and 21.2% about their treatment. 79.1% were concerned about the effect of their illness on family. Conclusion: There is a high symptom burden in mesothelioma despite good baseline performance status. A worse QoL is associated with a worse survival. Unmet needs are common, perhaps highlighting a need for improved communication and information sharing.

Background Solitary fibrous tumours of the pleura (SFTP), or pleural fibromas, are rare tumours that generally, but not universally, follow a benign course. Surgical resection is the standard treatment, but there are no evidence-based guidelines regarding the management of these tumours. Methods Five databases were searched from inception to April 1, 2019 for studies reporting on SFTP management. Results Twenty-seven studies met the inclusion criteria (1542 patients, all non-comparative case series); 98% of these patients underwent resection and all SFTP included were pathologically diagnosed. 394 out of 1299 cases (30.5%, 95% CI 27.8–32.8%) were malignant with recurrence rates of between 0% and 42.9%. A pleural effusion was always associated with a negative outcome, but no other features were consistently reported to have negative associations. Preoperative biopsies incorrectly reported malignant histology in two studies. Over 25% of cases of recurrence occurred when a complete (R0) resection had been achieved. The first recurrence occurred >5 years after the initial resection in at least 23% of cases. Conclusions There is strong evidence to support long-term surveillance after surgical resection of SFTP, even where a complete (R0) resection has been achieved; however, there is no clear evidence to inform clinicians regarding the selection of patients who should undergo resection. The rates of malignant SFTP and SFTP recurrence are higher than previously reported. Only those that were pathologically diagnosed or resected were included, which may bias the data towards more aggressive tumours. Data collection on radiologically diagnosed SFTP is required to draw conclusions regarding the timing and need for intervention., Long-term surveillance should be undertaken after a resection of solitary fibrous tumours of the pleura but further work is needed to determine which patients are likely to follow a malignant clinical course to decide timing and necessity of a resection https://bit.ly/2U10SaA

Pleural manometry enables the assessment of physiological abnormalities of lung mechanics associated with pleural effusion. Applying pleural manometry, we found small pleural pressure curve oscillations resembling the pulse tracing line. The aim of our study was to characterize the oscillations of pleural pressure curve (termed here as the pleural pressure pulse, PPP) and to establish their origin and potential significance. This was an observational cross-sectional study in adult patients with pleural effusion who underwent thoracentesis with pleural manometry. The pleural pressure curves recorded prior to and during fluid withdrawal were analyzed. The presence of PPP was assessed in relation to the withdrawn pleural fluid volume, lung expandability, vital and echocardiographic parameters, and pulmonary function testing. A dedicated device was developed to compare the PPP to the pulse rate. Fifty-four patients (32 women) median age 66.5 (IQR 58.5&ndash, 78.7) years were included. Well visible and poorly visible pressure waves were detected in 48% and 35% of the patients, respectively. The frequency of PPP was fully concordant with the pulse rate and the peaks of the oscillations reflected the period of heart diastole. PPP was more visible in patients with a slower respiratory rate (p = 0.008), a larger amount of pleural effusion, and was associated with a better heart systolic function assessed by echocardiography (p &lt, 0.05). This study describes a PPP, a new pleural phenomenon related to the cyclic changes in the heart chambers volume. Although the importance of PPP remains largely unknown, we hypothesize that it could be related to lung atelectasis or lower lung and visceral pleura compliance.

IntroductionThe rising incidence of pleural disease is seeing an international growth of pleural services, with physicians performing an ever-increasing volume of pleural interventions. These are frequently conducted at sites without immediate access to thoracic surgery or interventional radiology and serious complications such as pleural bleeding are likely to be under-reported.AimTo assess whether intercostal vessel screening can be performed by respiratory physicians at the time of pleural intervention, as an additional step that could potentially enhance safe practice.MethodsThis was a prospective, observational study of 596 ultrasound-guided pleural procedures conducted by respiratory physicians and trainees in a tertiary centre. Operators did not have additional formal radiology training. Intercostal vessel screening was performed using a low frequency probe and the colour Doppler feature.ResultsThe intercostal vessels were screened in 95% of procedures and the intercostal artery (ICA) was successfully identified in 53% of cases. Screening resulted in an overall site alteration rate of 16% in all procedures, which increased to 30% when the ICA was successfully identified. This resulted in procedure abandonment in 2% of cases due to absence of a suitable entry site. Intercostal vessel screening was shown to be of particular value in the context of image-guided pleural biopsy.ConclusionIntercostal vessel screening is a simple and potentially important additional step that can be performed by respiratory physicians at the time of pleural intervention without advanced ultrasound expertise. Whether the widespread use of this technique can improve safety requires further evaluation in a multi-centre setting with a robust prospective study.

To maintain homeostasis, macrophages must be capable of assuming either an inflammatory or an anti-inflammatory phenotype. To better understand the latter, we stimulated human macrophages in vitro with TLR ligands in the presence of high-density immune complexes (IC). This combination of stimuli resulted in a broad suppression of inflammatory mediators and an upregulation of molecules involved in tissue remodeling and angiogenesis. Transcriptomic analysis of TLR stimulation in the presence of IC predicted the downstream activation of AKT and the inhibition of GSK3. Consequently, we pretreated LPS-stimulated human macrophages with small molecule inhibitors of GSK3 to partially phenocopy the regulatory effects of stimulation in the presence of IC. The upregulation of DC-STAMP and matrix metalloproteases was observed on these cells and may represent potential biomarkers for this regulatory activation state. To demonstrate the presence of these anti-inflammatory, growth-promoting macrophages in a human infectious disease, biopsies from patients with leprosy (Hanseniasis) were analyzed. The lepromatous form of this disease is characterized by hypergammaglobulinemia and defective cell-mediated immunity. Lesions in lepromatous leprosy contained macrophages with a regulatory phenotype expressing higher levels of DC-STAMP and lower levels of IL-12, relative to macrophages in tuberculoid leprosy lesions. Therefore, we propose that increased signaling by FcγR cross-linking on TLR-stimulated macrophages can paradoxically promote the resolution of inflammation and initiate processes critical to tissue growth and repair. It can also contribute to infectious disease progression.

IntroductionCurrent guidelines recommend an initial pleural aspiration in the investigation and management of suspected malignant pleural effusions (MPEs) with the aim of establishing a diagnosis, identifying non-expansile lung (NEL) and, at times, providing a therapeutic procedure. A wealth of research has been published since the guidelines suggesting that results and outcomes from an aspiration may not always provide sufficient information to guide management. It is important to establish the validity of these findings in a ‘real world’ population.MethodsA retrospective analysis was conducted of all patients who underwent pleural fluid (PF) sampling, in a single centre, over 3 years to determine the utility of the initial aspiration.ResultsA diagnosis of MPE was confirmed in 230/998 (23%) cases, a further 95/998 (9.5%) were presumed to represent MPE. Transudative biochemistry was found in 3% of cases of confirmed MPE. Positive PF cytology was only sufficient to guide management in 45/140 (32%) cases. Evidence of pleural thickening on CT was associated with both negative cytology (χ2 1df=26.27, p2 1df=10.39, p=0.001). In NEL 44.4% of patients did not require further procedures after pleurodesis compared with 72.7% of those with expansile lung (χ2 1df=5.49, p=0.019). In patients who required a combined diagnostic and therapeutic aspiration 106/113 (93.8%) required further pleural procedures.ConclusionsAn initial pleural aspiration does not achieve either definitive diagnosis or therapy in the majority of patients. A new pathway prioritising symptom management while reducing procedures should be considered.

Thoracic ultrasound is increasingly considered to be an essential tool for the pulmonologist. It is used in diverse clinical scenarios, including as an adjunct to clinical decision making for diagnosis, a real-time guide to procedures and a predictor or measurement of treatment response. The aim of this European Respiratory Society task force was to produce a statement on thoracic ultrasound for pulmonologists using thoracic ultrasound within the field of respiratory medicine. The multidisciplinary panel performed a review of the literature, addressing major areas of thoracic ultrasound practice and application. The selected major areas include equipment and technique, assessment of the chest wall, parietal pleura, pleural effusion, pneumothorax, interstitial syndrome, lung consolidation, diaphragm assessment, intervention guidance, training and the patient perspective. Despite the growing evidence supporting the use of thoracic ultrasound, the published literature still contains a paucity of data in some important fields. Key research questions for each of the major areas were identified, which serve to facilitate future multicentre collaborations and research to further consolidate an evidence-based use of thoracic ultrasound, for the benefit of the many patients being exposed to clinicians using thoracic ultrasound.

Tuberculosis (TB) remains a long-standing life-threatening contagious disease and claimed approximately 1.5 million lives worldwide in 2018. Regional variations occur extensively with polarised incidence rates between low and high TB burden countries.1 TB is a social disease in partnership with poverty. TB burden fluctuates with the rises and falls of socioeconomic development despite the advancements in healthcare.2 Poverty-related components such as poor living conditions and malnutrition, which do not merely increase individual’s susceptibility to infection, but affect healthcare expenditure and loss of income associated with TB infection amplify the effect of poverty on TB treatment and prevention. Therefore, combating TB contributes to reducing impoverishment, meanwhile fighting impoverishment assists TB control efforts especially in restricted resource settings.3 A pragmatic …

The full British Thoracic Society (BTS) guideline for the use of long-term macrolides in adults with respiratory disease is published in Thorax. The following is a summary of the recommendations and good practice points. The sections referred to in the summary refer to the full guideline. The appendices are available in the full guideline and online appendices are available on the BTS website. This is the first BTS guideline to use the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach as part of the process of guideline development and the guideline was used to pilot the new methodology.

Chagas disease is caused by Trypanosoma cruzi, a protozoan parasite that has a heterogeneous population composed of a pool of strains with distinct characteristics, including variable levels of virulence. In previous work, transcriptome analyses of parasite genes after infection of human foreskin fibroblasts (HFF) with virulent (CL Brener) and non-virulent (CL-14) clones derived from the CL strain, revealed a reduced expression of genes encoding parasite surface proteins in CL-14 compared to CL Brener during the final steps of the intracellular differentiation from amastigotes to trypomastigotes. Here we analyzed changes in the expression of host genes during in vitro infection of HFF cells with the CL Brener and CL-14 strains by analyzing total RNA extracted from cells at 60 and 96 hours post-infection (hpi) with each strain, as well as from uninfected cells. Similar transcriptome profiles were observed at 60 hpi with both strains compared to uninfected samples. However, at 96 hpi, significant differences in the number and expression levels of several genes, particularly those involved with immune response and cytoskeleton organization, were observed. Further analyses confirmed the difference in the chemokine/cytokine signaling involved with the recruitment and activation of immune cells such as neutrophils upon T. cruzi infection. These findings suggest that infection with the virulent CL Brener strain induces a more robust inflammatory response when compared with the non-virulent CL-14 strain. Importantly, the RNA-Seq data also exposed an unexplored role of fibroblasts as sentinel cells that may act by recruiting neutrophils to the initial site of infection. This role for fibroblasts in the regulation of the inflammatory response during infection by T. cruzi was corroborated by measurements of levels of different chemokines/cytokines during in vitro infection and in plasma from Chagas disease patients as well as by neutrophil activation and migration assays., Author summary Trypanosoma cruzi is the causative agent of Chagas disease, a debilitating and often life-threatening illness that affects 6 to 7 million people mainly in Latin America. The parasite, transmitted to humans by an insect vector, needs to invade different cells from the infected person in order to multiply and spread the infection to various organs, including the heart and the gut. In this study, we investigated how the host cell responds to the infection by analyzing changes in the expression of human genes in fibroblasts infected with the CL Brener and CL-14 strains, which are strains that present highly distinct virulent phenotypes during infection in mice. We showed that human fibroblasts build a strong immune response upon infection by T. cruzi and that this response is different depending on the parasite strain: infection with the virulent CL Brener strain induces a more robust inflammatory response compared with the infection with the avirulent CL-14 strain. We also showed that, in response to the infection, fibroblasts produce molecules that can recruit and activate neutrophils, which are important immune cells that controls the infection.

Malignant pleural mesothelioma (MPM) is an aggressive cancer, associated with poor prognosis. We assessed the feasibility of patient-derived cell cultures to serve as an ex vivo model of MPM. Patient-derived MPM cell cultures (n=16) exhibited stemness features and reflected intratumour and interpatient heterogeneity. A subset of the cells were subjected to high-throughput drug screening and coculture assays with cancer-specific cytotoxic T cells and showed diverse responses. Some of the biphasic MPM cells were capable of processing and presenting the neoantigen SSX-2 endogenously. In conclusion, patient-derived MPM cell cultures are a promising and faithful ex vivo model of MPM.

Introduction There is ongoing research into the development of novel molecular markers that may complement fluid cytology malignant pleural effusion (MPE) diagnosis. In this exploratory pilot study, we hypothesized that there are distinct differences in the pleural fluid microbiome profile of malignant and non-malignant pleural diseases. Method From a prospectively enrolled pleural fluid biorepository, samples of MPE were included. Non-MPE effusion were included as comparators. 16S rRNA gene V4 region amplicon sequencing was performed. Exact Sequence Variants (ESVs) were used for diversity analyses. The Shannon and Richness indices of alpha diversity and UniFrac beta diversity measures were tested for significance using permutational multivariate analysis of variance. Analyses of Composition of Microbiome was used to identify differentially abundant bacterial ESVs between the groups controlled for multiple hypothesis testing. Results 38 patients with MPE and 9 with non-MPE were included. A subgroup of patients with metastatic adenocarcinoma histology were identified among MPE group (adenocarcinoma of lung origin (LA-MPE) = 11, breast origin (BA-MPE) = 11). MPE presented with significantly greater alpha diversity compared to non-MPE group. Within the MPE group, BA-MPE was more diverse compared to LA-MPE group. In multivariable analysis, ESVs belonging to family S24-7 and genera Allobaculum, Stenotrophomonas, and Epulopiscium were significantly enriched in the malignant group compared to the non-malignant group. Conclusion Our results are the first to demonstrate a microbiome signature according to MPE and non-MPE. The role of microbiome in pleural effusion pathogenesis needs further exploration.

A 64 year old male heating engineer was investigated for a persistent cough and found to have epithelioid mesothelioma with pleural effusion, lung nodules and increased thoracic lymph nodes. He declined standard of care treatment following his own research and he was enrolled in a named patient programme of IMM-101. He was advised to correct his low vitamin D3 level and to start using anti-inflammatories such as aspirin, bromelain and low dose Naltrexone. At review one year later a CT scan showed no change and he continued on the regimen. Four years after the diagnosis a CT scan showed that there was a modest but definite progression of the left malignant pleural thickening, and a new right-sided effusion, enlargement of several intrathoracic nodes which had been noted on the early scans. The chest wall lump eventually broke down and required local radiotherapy. He then developed abdominal pain and found to have peritoneal disease. Last year he obtained the cannabinoids CBD and THC which slowed down the disease and a CT scan after he had been on this for six months, showed that his disease was fairly stable with marginal progression. Keywords: Mesothelioma, Anti-inflammatory, Immunotherapy, IMM-101-015

Background Malignant pleural effusion (MPE) is common and imposes a significant burden on patients and health-care providers. Most patients require definitive treatment, usually drainage and chemical pleurodesis, to relieve symptoms and prevent fluid recurrence. Thoracic ultrasound (TUS) can identify the presence of pleural adhesions in other clinical scenarios, and could therefore have a role in predicting long-term pleurodesis success or failure in MPE. Methods Patients undergoing chest tube drainage and talc slurry pleurodesis for symptomatic MPE were recruited to a prospective observational cohort pilot study assessing whether TUS findings pre-talc and post-talc instillation predicted treatment outcome. Participants underwent TUS examination immediately before, and 24 h after talc slurry administration to derive pleural adherence scores for the affected hemithorax. The recorded TUS scans were additionally scored by two independent assessors blinded to the patient's clinical status. The primary outcome was pleurodesis success at 1-month and 3-month follow-up. Results Eighteen participants were recruited to the pilot study. Participants who suffered pleurodesis failure had a lower pleural adherence score at 24 h post-talc instillation than those who were successful (difference of 6.27; 95% CI, 3.94-8.59). TUS examination was acceptable to patients, while TUS scoring was highly consistent across all assessors (intraclass correlation coefficient, 0.762; 95% CI, 0.605-0.872). Conclusion A TUS-derived pleural adherence score may facilitate early prediction of long-term outcomes following chemical pleurodesis, with implications for personalized care and decision making in MPE. Further research is needed to evaluate this novel finding. Trial Registry ClinicalTrials.gov; No. NCT02625675; URL: www.clinicaltrials.gov.

Despite having been described over 3,000 years ago, pleural infection continues to be a challenging condition to treat. The last decade has seen a greater understanding of the pathogenesis and microbiology of pleural infection. There are now data to suggest that although the majority of cases are related to pneumonic consolidation, the varied microbiology and radiological findings suggest that primary pleural infection is a distinct entity requiring specific attention.

© 2018 Wolters Kluwer Health, Inc. Malignant pleural effusion is a common clinical problem with an increasing incidence that may be seen to complicate the management of almost all forms of cancer. It is associated with a very poor median survival leading to a palliative management approach. Several methods are available in the management of malignant pleural effusion including simple pleural aspiration, talc pleurodesis, or indwelling pleural catheters. Patient selection, however, remains difficult. The role for each management option, their indications, predictors of success, and factors influencing patient selection are all crucial considerations and are discussed here, as are the health economic impacts and future directions.

Background: Indwelling pleural catheters (IPC) offer an alternative to talc pleurodesis in recurrent effusion, especially in patients wishing to avoid hospitalization. Two randomized trials have demonstrated reduced time in hospital using IPCs versus talc pleurodesis in malignant pleural effusion (MPE). However, the impact of IPCs on hospital services and patients has not been well studied. Objectives: To analyze long-term outcomes of IPCs and understand the hospital burden in terms of requirement for hospital visits and contacts with healthcare, while the IPC was in situ. Methods: IPC insertions in a tertiary pleural center were analyzed retrospectively. Reviews of patients with IPCs in situ considered “additional” to routine clinical follow-up were defined pre-hoc. Results: A total of 202 cases were analyzed: 89.6% MPE group (n = 181) and 10.4% non-MPE group (n = 21). There were a median 3.0 (interquartile range [IQR] 3) and 2.0 (IQR 2) ipsilateral pleural procedures prior to each IPC insertion in non-MPE and MPE groups, respectively (p = 0.26), and a mean 1.3 (SD 1.7) planned IPC-related outpatient follow-up visits per patient. There were 2 (9.5%) and 14 (7.7%) IPC-related infections in non-MPE and MPE groups, respectively. Four (19.0%) and 44 (24.3%) patients required additional IPC-related reviews in non-MPE and MPE groups, respectively (p = 0.6), and these occurred within 250 days post IPC insertion. Conclusions: Although IPCs decrease initial length of hospital stay compared to talc pleurodesis via chest drain, IPCs are associated with significant hospital-visit burden, in addition to planned visits and regular home IPC drainages. IPC-using services need to be prepared for this additional work to run an IPC service effectively.

Focused thoracic ultrasound has become essential in the guidance and direction of pleural interventions to reduce unwanted complications and as a result now forms a crucial component of physician training. Current training standards along with assessment methods vary widely, and are often not robust enough to ensure adequate competence.This review assesses the current state of training and assessment of thoracic ultrasound competence in various settings, allowing comparison with alternative competency based programmes. Future directions for training and assessment of thoracic ultrasound competence are discussed.

Background Primary spontaneous pneumothorax occurs in otherwise healthy young patients. Optimal management is not defined and often results in prolonged hospitalisation. Data on efficacy of ambulatory options are poor. We aimed to describe the duration of hospitalisation and safety of ambulatory management compared with standard care. Methods In this open-label, randomised controlled trial, adults (aged 16–55 years) with symptomatic primary spontaneous pneumothorax were recruited from 24 UK hospitals during a period of 3 years. Patients were randomly assigned (1:1) to treatment with either an ambulatory device or standard guideline-based management (aspiration, standard chest tube insertion, or both). The primary outcome was total length of hospital stay including re-admission up to 30 days after randomisation. Patients with available data were included in the primary analysis and all assigned patients were included in the safety analysis. The trial was prospectively registered with the International Standard Randomised Clinical Trials Number, ISRCTN79151659. Findings Of 776 patients screened between July, 2015, and March, 2019, 236 (30%) were randomly assigned to ambulatory care (n=117) and standard care (n=119). At day 30, the median hospitalisation was significantly shorter in the 114 patients with available data who received ambulatory treatment (0 days [IQR 0–3]) than in the 113 with available data who received standard care (4 days [IQR 0–8]; p Interpretation Ambulatory management of primary spontaneous pneumothorax significantly reduced the duration of hospitalisation including re-admissions in the first 30 days, but at the expense of increased adverse events. This data suggests that primary spontaneous pneumothorax can be managed for outpatients, using ambulatory devices in those who require intervention. Funding UK National Institute for Health Research.

Background and Objective: Chemical pleurodesis is performed for patients with MPE with a published success rate of around 80%. It has been postulated that inflammation is key in achieving successful pleural symphysis, as evidenced by higher amounts of pain or detected inflammatory response. Patients with mesothelioma are postulated to have a lower rate of successful pleurodesis due to lack of normal pleural tissue enabling an inflammatory response. Methods: The TIME1 trial data set, in which pleurodesis success and pain were co‐primary outcome measures, was used to address a number of these assumptions. Pain score, systemic inflammatory parameters as a marker of pleural inflammation and cancer type were analysed in relation to pleurodesis success. Results: In total, 285 patients were included with an overall success rate of 81.4%. There was a significantly higher rise in CRP in the Pleurodesis Success group compared with the Pleurodesis Failure group (mean difference: 19.2, 95% CI of the difference: 6.2–32.0, P = 0.004) but no significant change in WCC. There was no significant difference in pain scores or analgesia requirements between the groups. Patients with mesothelioma had a lower rate of pleurodesis success than non‐mesothelioma patients (73.3% vs 84.9%, χ2 = 5.1, P = 0.023). Conclusion: Change in CRP during pleurodesis is associated with successful pleurodesis but higher levels of pain are not associated. Patients with mesothelioma appear less likely to undergo successful pleurodesis than patients with other malignancies, but there is still a significant rise in systemic inflammatory markers. The mechanisms of these findings are unclear but warrant further investigation.

Importance Malignant pleural effusion (MPE) is challenging to manage. Talc pleurodesis is a common and effective treatment. There are no reliable data, however, regarding the optimal method for talc delivery, leading to differences in practice and recommendations. Objective To test the hypothesis that administration of talc poudrage during thoracoscopy with local anesthesia is more effective than talc slurry delivered via chest tube in successfully inducing pleurodesis. Design, Setting, and Participants Open-label, randomized clinical trial conducted at 17 UK hospitals. A total of 330 participants were enrolled from August 2012 to April 2018 and followed up until October 2018. Patients were eligible if they were older than 18 years, had a confirmed diagnosis of MPE, and could undergo thoracoscopy with local anesthesia. Patients were excluded if they required a thoracoscopy for diagnostic purposes or had evidence of nonexpandable lung. Interventions Patients randomized to the talc poudrage group (n = 166) received 4 g of talc poudrage during thoracoscopy while under moderate sedation, while patients randomized to the control group (n = 164) underwent bedside chest tube insertion with local anesthesia followed by administration of 4 g of sterile talc slurry. Main Outcomes and Measures The primary outcome was pleurodesis failure up to 90 days after randomization. Secondary outcomes included pleurodesis failure at 30 and 180 days; time to pleurodesis failure; number of nights spent in the hospital over 90 days; patient-reported thoracic pain and dyspnea at 7, 30, 90, and 180 days; health-related quality of life at 30, 90, and 180 days; all-cause mortality; and percentage of opacification on chest radiograph at drain removal and at 30, 90, and 180 days. Results Among 330 patients who were randomized (mean age, 68 years; 181 [55%] women), 320 (97%) were included in the primary outcome analysis. At 90 days, the pleurodesis failure rate was 36 of 161 patients (22%) in the talc poudrage group and 38 of 159 (24%) in the talc slurry group (adjusted odds ratio, 0.91 [95% CI, 0.54-1.55]; P = .74; difference, –1.8% [95% CI, –10.7% to 7.2%]). No statistically significant differences were noted in any of the 24 prespecified secondary outcomes. Conclusions and Relevance Among patients with malignant pleural effusion, thoracoscopic talc poudrage, compared with talc slurry delivered via chest tube, resulted in no significant difference in the rate of pleurodesis failure at 90 days. However, the study may have been underpowered to detect small but potentially important differences. Trial Registration ISRCTN Identifier: ISRCTN47845793