CD14-positive extracellular vesicles in bronchoalveolar lavage fluid as a new biomarker of acute respiratory distress syndrome.

Recent studies have indicated that extracellular vesicles (EVs) may play a role in the pathogenesis of acute respiratory distress syndrome (ARDS). EVs have been identified as potential biomarkers of disease severity and prognosis in other pulmonary diseases. We sought to characterize the EV phenotype within bronchoalveolar lavage (BAL) fluid of patients with ARDS, and to determine whether BAL EV could be used as a potential biomarker in ARDS. BAL was collected from patients with sepsis with and without ARDS, and from esophagectomy patients postoperatively (of whom a subset later developed ARDS during hospital admission). BAL EVs were characterized with regard to size, number, and cell of origin. Patients with sepsis-related ARDS had significantly higher numbers of CD14+/CD81+ monocyte-derived BAL EV than patients with sepsis without ARDS (P = 0.015). However, the converse was observed in esophagectomy patients who later developed ARDS (P = 0.003). Esophagectomy patients who developed ARDS also had elevated CD31+/CD63+ and CD31+/CD81+ endothelial-derived BAL EV (P ≤ 0.02) compared with esophagectomy patients who did not develop ARDS. Further studies are required to determine whether CD31+ BAL EV may be a predictive biomarker for ARDS in esophagectomy patients. CD14+/CD81+ BAL EV numbers were significantly higher in those patients with sepsis-related ARDS who died during the 30 days following intensive care unit admission (P = 0.027). Thus, CD14+/CD81+ BAL EVs are a potential biomarker for disease severity and mortality in sepsis-related ARDS. These findings provide the impetus to further elucidate the contribution of these EVs to ARDS pathogenesis.

Cigarette smoke exposure and alveolar macrophages: mechanisms for lung disease.

Cigarette smoking is the leading cause of preventable death worldwide. It causes chronic lung disease and predisposes individuals to acute lung injury and pulmonary infection. Alveolar macrophages are sentinel cells strategically positioned in the interface between the airway lumen and the alveolar spaces. These are the most abundant immune cells and are the first line of defence against inhaled particulates and pathogens. Recently, there has been a better understanding about the ontogeny, phenotype and function of alveolar macrophages and their role, not only in phagocytosis, but also in initiating and resolving immune response. Many of the functions of the alveolar macrophage have been shown to be dysregulated following exposure to cigarette smoke. While the mechanisms for these changes remain poorly understood, they are important in the understanding of cigarette smoking-induced lung disease. We review the mechanisms by which smoking influences alveolar macrophage: (1) recruitment, (2) phenotype, (3) immune function (bacterial killing, phagocytosis, proteinase/anti-proteinase release and reactive oxygen species production) and (4) homeostasis (surfactant/lipid processing, iron homeostasis and efferocytosis). Further understanding of the mechanisms of cigarette smoking on alveolar macrophages and other lung monocyte/macrophage populations may allow novel ways of restoring cellular function in those patients who have stopped smoking in order to reduce the risk of subsequent infection or further lung injury.

Multiple simultaneous embolic cerebral infarctions 11 months after COVID-19.

BACKGROUND: The coronavirus disease (COVID-19) pandemic has led to an unprecedented worldwide burden of disease. However, little is known of the longer-term implications and consequences of COVID-19. One of these may be a COVID-19 associated coagulopathy that can present as a venous thromboembolism (VTE) and further, as multiple paradoxical cerebral emboli. CASE PRESENTATION: A 51 year old man presented to the emergency department with multiple simultaneous embolic cerebral infarctions 11 months after mild COVID-19. In the subacute phase of the COVID-19 illness the patient developed increasing shortness of breath and was found to have an elevated D-dimer and multiple bilateral segmental pulmonary emboli. He was subsequently treated with 3 months of anticoagulation for a provoked VTE. The patient then presented 11 months after the initial COVID-19 diagnosis with multiple simultaneous cerebral infarctions where no traditional underlying stroke etiology was determined. A patent foramen ovale (PFO) and an elevated D-dimer were found suggesting a paradoxical thromboembolic event due to an underlying coagulopathy. CONCLUSIONS: This case report highlights the one of the potentially more serious complications of long-term COVID-19 where VTE due to a persistent coagulopathy is seen almost a year after the initial illness. Due to the highly prevalent nature of PFO in the general population, VTE due to COVID-19 associated coagulopathy could lead to ischemic stroke. This case report highlights the possibility for an underlying COVID-19 associated coagulopathy which may persist for many months and beyond the initial illness.

Simvastatin Improves Neutrophil Function and Clinical Outcomes in Pneumonia. A Pilot Randomized Controlled Clinical Trial.

Rationale: Population studies suggest improved sepsis outcomes with statins, but the results of randomized controlled trials in patients with sepsis and organ dysfunction in critical care settings have broadly been negative. In vitro data suggest that statins modulate age-related neutrophil functions, improving neutrophil responses to infection, but only in older patients and at high doses.Objectives: To determine if high-dose simvastatin improves neutrophil functions and is safe and tolerated in hospitalized older adults with community-acquired pneumonia with sepsis (CAP + S) not admitted to critical care.Methods: We conducted a randomized, double-blind, placebo-controlled pilot study of simvastatin 80 mg or placebo for 7 days for patients with CAP + S aged 55 years or older admitted to a secondary care hospital. The Day 4 primary endpoint was change in neutrophil extracellular trap formation (NETosis). Day 4 secondary endpoints included neutrophil chemotaxis, safety and tolerability, Sequential Organ Failure Assessment score, mortality, readmission, and markers of tissue degradation/inflammation.Measurements and Main Results: Four days of simvastatin adjuvant therapy in patients with CAP + S was associated with improvements in systemic neutrophil function (NETosis and chemotaxis), a reduction in systemic neutrophil elastase burden, and improved Sequential Organ Failure Assessment scores compared with placebo. A post hoc analysis demonstrated that simvastatin therapy was associated with improved hospitalization-free survival compared with placebo. Simvastatin was well tolerated in this elderly and multimorbid patient group with common coprescription of macrolide antibiotics.Conclusions: This pilot study supports high-dose simvastatin as an adjuvant therapy for CAP + S in an older and milder disease cohort than assessed previously. A definitive multicenter study is now warranted in this population to assess the likelihood of benefit and harm.Clinical trial registered with EudraCT (2012-00343-29).

Pro-inflammatory effects of e-cigarette vapour condensate on human alveolar macrophages.

OBJECTIVE: Vaping may increase the cytotoxic effects of e-cigarette liquid (ECL). We compared the effect of unvaped ECL to e-cigarette vapour condensate (ECVC) on alveolar macrophage (AM) function. METHODS: AMs were treated with ECVC and nicotine-free ECVC (nfECVC). AM viability, apoptosis, necrosis, cytokine, chemokine and protease release, reactive oxygen species (ROS) release and bacterial phagocytosis were assessed. RESULTS: Macrophage culture with ECL or ECVC resulted in a dose-dependent reduction in cell viability. ECVC was cytotoxic at lower concentrations than ECL and resulted in increased apoptosis and necrosis. nfECVC resulted in less cytotoxicity and apoptosis. Exposure of AMs to a sub-lethal 0.5% ECVC/nfECVC increased ROS production approximately 50-fold and significantly inhibited phagocytosis. Pan and class one isoform phosphoinositide 3 kinase inhibitors partially inhibited the effects of ECVC/nfECVC on macrophage viability and apoptosis. Secretion of interleukin 6, tumour necrosis factor α, CXCL-8, monocyte chemoattractant protein 1 and matrix metalloproteinase 9 was significantly increased following ECVC challenge. Treatment with the anti-oxidant N-acetyl-cysteine (NAC) ameliorated the cytotoxic effects of ECVC/nfECVC to levels not significantly different from baseline and restored phagocytic function. CONCLUSIONS: ECVC is significantly more toxic to AMs than non-vaped ECL. Excessive production of ROS, inflammatory cytokines and chemokines induced by e-cigarette vapour may induce an inflammatory state in AMs within the lung that is partly dependent on nicotine. Inhibition of phagocytosis also suggests users may suffer from impaired bacterial clearance. While further research is needed to fully understand the effects of e-cigarette exposure in humans in vivo, we caution against the widely held opinion that e-cigarettes are safe.

Long-term impact of developing a postoperative pulmonary complication after lung surgery.

INTRODUCTION: Postoperative pulmonary complications (PPC) such as atelectasis and pneumonia are common following lung resection. PPCs have a significant clinical impact on postoperative morbidity and mortality. We studied the long-term effects of PPCs and sought to identify independent risk factors. METHODS: A prospective observational study involved all patients following lung resection in a regional thoracic centre over 4 years. PPCs were assessed daily in hospital using the Melbourne group scale based on chest X-ray, white cell count, fever, purulent sputum, microbiology, oxygen saturations, physician diagnosis and intensive therapy unit (ITU)/high-dependency unit readmission. Follow-up included hospital length of stay (LOS), 30-day readmissions, and mortality. RESULTS: 86 of 670 patients (13%) who had undergone a lung resection developed a PPC. Those patients had a significantly longer hospital LOS in days (13, 95% CI 10.5-14.9 vs 6.3, 95% CI 5.9 to 6.7; p<0.001) and higher rates of ITU admissions (28% vs 1.9%; p<0.001) and 30-day hospital readmissions (20.7% vs 11.9%; p<0.05). Significant independent risk factors for development of PPCs were COPD and smoking (p<0.05), not age. Excluding early postoperative deaths, developing a PPC resulted in a significantly reduced overall survival in months (40, 95% CI 34 to 44 vs 46, 95% CI 44 to 47; p=0.006). Those who developed a PPC had a higher rate of non-cancer-related deaths (11% vs 5%; p=0.020). PPC is a significant independent risk factor for late deaths in non-small cell lung cancer patients (HR 2.0, 95% CI 1.9 to 3.2; p=0.006). CONCLUSIONS: Developing a PPC after thoracic surgery is common and is associated with a poorer long-term outcome.

The increasing need for biomarkers in intensive care unit-acquired weakness--are microRNAs the solution?

There is an increasing focus on intensive care unit-acquired weakness, its underlying mechanisms and therapeutic options. In this article we offer a commentary on the paper by Bloch and colleagues entitled 'MiR-181a: a potential biomarker of acute muscle wasting following cardiac surgery'. There is a need for biomarkers for intensive care unit-acquired weakness, not only in clinical practice but also in order to streamline future therapeutic trials. MicroRNAs are attractive biomarkers, and may have an important role in this disease. We highlight the significance of the authors' finding of miR-181a, a novel plasma biomarker for the development of acute muscle wasting in post-operative cardiac surgery patients and discuss future research that is needed in this field following on from the study findings.

Feasibility study of a randomised controlled trial of preoperative and postoperative nutritional supplementation in major lung surgery.

OBJECTIVES: Malnutrition and weight loss are important risk factors for complications after lung surgery. However, it is uncertain whether modifying or optimising perioperative nutritional state with oral supplements results in a reduction in malnutrition, complications or quality of life. DESIGN: A randomised, open label, controlled feasibility study was conducted to assess the feasibility of carrying out a large multicentre randomised trial of nutritional intervention. The intervention involved preoperative carbohydrate-loading drinks (4×200 mL evening before surgery and 2×200 mL the morning of surgery) and early postoperative nutritional protein supplement drinks two times per day for 14 days compared with the control group receiving an equivalent volume of water. SETTING: Single adult thoracic centre in the UK. PARTICIPANTS: All adult patients admitted for major lung surgery. Patients were included if were able to take nutritional drinks prior to surgery and give written informed consent. Patients were excluded if they were likely unable to complete the study questionnaires, they had a body mass index <18.5 kg/m2, were receiving parenteral nutrition or known pregnancy. RESULTS: All patients presenting for major lung surgery were screened over a 6-month period, with 163 patients screened, 99 excluded and 64 (41%) patients randomised. Feasibility criteria were met and the study completed recruitment 5 months ahead of target. The two groups were well balanced and tools used to measure outcomes were robust. Compliance with nutritional drinks was 97% preoperatively and 89% postoperatively; 89% of the questionnaires at 3 months were returned fully completed. The qualitative interviews demonstrated that the trial and the intervention were acceptable to patients. Patients felt the questionnaires captured their experience of recovery from surgery well. CONCLUSION: A large multicentre randomised controlled trial of nutritional intervention in major lung surgery is feasible and required to test clinical efficacy in improving outcomes after surgery. TRIAL REGISTRATION NUMBER: ISRCTN16535341.

Vitamin D status: a U-shaped relationship for SARS-CoV-2 seropositivity in UK healthcare workers.

BACKGROUND: There is increasing evidence that vitamin D (VD) deficiency may increase individuals' risk of COVID-19 infection and susceptibility. We aimed to determine the relationship between VD deficiency and sufficiency and COVID-19 seropositivity within healthcare workers. METHODS: The study included an observational cohort of healthcare workers who isolated due to COVID-19 symptoms from 12 May to 22 May 2020, from the University Hospitals Birmingham National Health Service Foundation Trust. Data collected included SARS-CoV-2 seroconversion status, serum 25(OH)D3 levels, age, body mass index (BMI), sex, ethnicity, job role and comorbidities. Participants were grouped into four VD categories: (1) Severe VD deficiency (VD<30 nmol/L); (2) VD deficiency (30 nmol/L ≤VD<50 nmol/L); (3) VD insufficiency (50 nmol/L ≤VD<75 nmol/L); (4) VD sufficiency (VD≥75 nmol/L). RESULTS: When VD levels were compared against COVID-19 seropositivity rate, a U-shaped curve was identified. This trend repeated when participants were split into subgroups of age, sex, ethnicity, BMI and comorbidity status. Significant difference was identified in the COVID-19 seropositivity rate between VD groups in the total population and between groups of men and women; black, Asian and minority ethnic (BAME) group; BMI<30 (kg/m2); 0 and +1 comorbidities; the majority of which were differences when the severely VD deficient category were compared with the other groups. A larger proportion of those within the BAME group (vs white ethnicity) were severely VD deficient (p<0.00001). A larger proportion of the 0 comorbidity subgroup were VD deficient in comparison to the 1+ comorbidity subgroup (p=0.046). CONCLUSIONS: Our study has shown a U-shaped relationship for COVID-19 seropositivity in UK healthcare workers. Further investigation is required to determine whether high VD levels can have a detrimental effect on susceptibility to COVID-19 infection. Future randomised clinical trials of VD supplementation could potentially identify 'optimal' VD levels, allowing for targeted therapeutic treatment for those at risk.

Dysregulated Neutrophil Phenotype and Function in Hospitalised Non-ICU COVID-19 Pneumonia.

Rationale: Infection with the SARS-CoV2 virus is associated with elevated neutrophil counts. Evidence of neutrophil dysfunction in COVID-19 is based on transcriptomics or single functional assays. Cell functions are interwoven pathways, and understanding the effect across the spectrum of neutrophil function may identify therapeutic targets. Objectives: Examine neutrophil phenotype and function in 41 hospitalised, non-ICU COVID-19 patients versus 23 age-matched controls (AMC) and 26 community acquired pneumonia patients (CAP). Methods: Isolated neutrophils underwent ex vivo analyses for migration, bacterial phagocytosis, ROS generation, NETosis and receptor expression. Circulating DNAse 1 activity, levels of cfDNA, MPO, VEGF, IL-6 and sTNFRI were measured and correlated to clinical outcome. Serial sampling on day three to five post hospitalization were also measured. The effect of ex vivo PI3K inhibition was measured in a further cohort of 18 COVID-19 patients. Results: Compared to AMC and CAP, COVID-19 neutrophils demonstrated elevated transmigration (p = 0.0397) and NETosis (p = 0.0332), and impaired phagocytosis (p = 0.0036) associated with impaired ROS generation (p < 0.0001). The percentage of CD54+ neutrophils (p < 0.001) was significantly increased, while surface expression of CD11b (p = 0.0014) and PD-L1 (p = 0.006) were significantly decreased in COVID-19. COVID-19 and CAP patients showed increased systemic markers of NETosis including increased cfDNA (p = 0.0396) and impaired DNAse activity (p < 0.0001). The ex vivo inhibition of PI3K γ and δ reduced NET release by COVID-19 neutrophils (p = 0.0129). Conclusions: COVID-19 is associated with neutrophil dysfunction across all main effector functions, with altered phenotype, elevated migration and NETosis, and impaired antimicrobial responses. These changes highlight that targeting neutrophil function may help modulate COVID-19 severity.

Utility of severity assessment tools in COVID-19 pneumonia: a multicentre observational study.

BACKGROUND: Severity scores in pneumonia and sepsis are being applied to SARS-CoV-2 infection. We aimed to assess whether these severity scores are accurate predictors of early adverse outcomes in COVID-19. METHODS: We conducted a multicentre observational study of hospitalised SARS-CoV-2 infection. We assessed risk scores (CURB65, qSOFA, Lac-CURB65, MuLBSTA and NEWS2) in relation to admission to intensive care or death within 7 days of admission, defined as early severe adverse events (ESAE). The 4C Mortality Score was also assessed in a sub-cohort of patients. FINDINGS: In 2,387 participants, the overall mortality was 18%. In all scores examined, increasing score was associated with increased risk of ESAE. Area under the curve (AUC) to predict ESAE for CURB65, qSOFA, Lac-CURB65, MuLBSTA and NEWS2 were 0.61, 0.62, 0.59, 0.59 and 0.68, respectively. AUC to predict ESAE was 0.60 with ISARIC 4C Mortality Score. CONCLUSION: None of the scores examined accurately predicted ESAE in SARS-CoV-2 infection. Non-validated scores should not be used to inform clinical decision making in COVID-19.

Assessment of Alveolar Macrophage Dysfunction Using an in vitro Model of Acute Respiratory Distress Syndrome.

Background: Impaired alveolar macrophage (AM) efferocytosis may contribute to acute respiratory distress syndrome (ARDS) pathogenesis; however, studies are limited by the difficulty in obtaining primary AMs from patients with ARDS. Our objective was to determine whether an in vitro model of ARDS can recapitulate the same AM functional defect observed in vivo and be used to further investigate pathophysiological mechanisms. Methods: AMs were isolated from the lung tissue of patients undergoing lobectomy and then treated with pooled bronchoalveolar lavage (BAL) fluid previously collected from patients with ARDS. AM phenotype and effector functions (efferocytosis and phagocytosis) were assessed by flow cytometry. Rac1 gene expression was assessed using quantitative real-time PCR. Results: ARDS BAL treatment of AMs decreased efferocytosis (p = 0.0006) and Rac1 gene expression (p = 0.016); however, bacterial phagocytosis was preserved. Expression of AM efferocytosis receptors MerTK (p = 0.015) and CD206 (p = 0.006) increased, whereas expression of the antiefferocytosis receptor SIRPα decreased following ARDS BAL treatment (p = 0.036). Rho-associated kinase (ROCK) inhibition partially restored AM efferocytosis in an in vitro model of ARDS (p = 0.009). Conclusions: Treatment of lung resection tissue AMs with ARDS BAL fluid induces impairment in efferocytosis similar to that observed in patients with ARDS. However, AM phagocytosis is preserved following ARDS BAL treatment. This specific impairment in AM efferocytosis can be partially restored by inhibition of ROCK. This in vitro model of ARDS is a useful tool to investigate the mechanisms by which the inflammatory alveolar microenvironment of ARDS induces AM dysfunction.

COVID-19 admission risk tools should include multiethnic age structures, multimorbidity and deprivation metrics for air pollution, household overcrowding, housing quality and adult skills.

BACKGROUND: Ethnic minorities account for 34% of critically ill patients with COVID-19 despite constituting 14% of the UK population. Internationally, researchers have called for studies to understand deterioration risk factors to inform clinical risk tool development. METHODS: Multicentre cohort study of hospitalised patients with COVID-19 (n=3671) exploring determinants of health, including Index of Multiple Deprivation (IMD) subdomains, as risk factors for presentation, deterioration and mortality by ethnicity. Receiver operator characteristics were plotted for CURB65 and ISARIC4C by ethnicity and area under the curve (AUC) calculated. RESULTS: Ethnic minorities were hospitalised with higher Charlson Comorbidity Scores than age, sex and deprivation matched controls and from the most deprived quintile of at least one IMD subdomain: indoor living environment (LE), outdoor LE, adult skills, wider barriers to housing and services. Admission from the most deprived quintile of these deprivation forms was associated with multilobar pneumonia on presentation and ICU admission. AUC did not exceed 0.7 for CURB65 or ISARIC4C among any ethnicity except ISARIC4C among Indian patients (0.83, 95% CI 0.73 to 0.93). Ethnic minorities presenting with pneumonia and low CURB65 (0-1) had higher mortality than White patients (22.6% vs 9.4%; p<0.001); Africans were at highest risk (38.5%; p=0.006), followed by Caribbean (26.7%; p=0.008), Indian (23.1%; p=0.007) and Pakistani (21.2%; p=0.004). CONCLUSIONS: Ethnic minorities exhibit higher multimorbidity despite younger age structures and disproportionate exposure to unscored risk factors including obesity and deprivation. Household overcrowding, air pollution, housing quality and adult skills deprivation are associated with multilobar pneumonia on presentation and ICU admission which are mortality risk factors. Risk tools need to reflect risks predominantly affecting ethnic minorities.

Ex vivo modelling of PD-1/PD-L1 immune checkpoint blockade under acute, chronic, and exhaustion-like conditions of T-cell stimulation.

Blockade of PD-1/PD-L1 interactions is proving an exciting, durable therapeutic modality in a range of cancers whereby T cells are released from checkpoint inhibition to revive their inherent anti-tumour activity. Here we have studied various ways to model ex vivo T cell function in order to compare the impact of the clinically utilised anti-PD-1 antibody, pembrolizumab (Keytruda) on the activation of human T cells: focussing on the release of pro-inflammatory IFNγ and anti-inflammatory IL-10 to assess functionality. Firstly, we investigated the actions of pembrolizumab in an acute model of T-cell activation with either immature or mature allogeneic dendritic cells (DCs); pembrolizumab enhanced IFNγ and IL-10 release from purified CD4+ T-cells in the majority of donors with a bias towards pro-inflammatory cytokine release. Next, we modelled the impact of pembrolizumab in settings of more chronic T-cell activation. In a 7-day antigen-specific response to EBV peptides, the presence of pembrolizumab resulted in a relatively modest increase in both IFNγ and IL-10 release. Where pembrolizumab was assessed against long-term stimulated CD4+ cells that had up-regulated the exhaustion markers TIM-3 and PD-1, there was a highly effective enhancement of the otherwise exhausted response to allogeneic DCs with respect to IFNγ production. By contrast, the restoration of IL-10 production was considerably more limited. Finally, to assess a direct clinical relevance we investigated the consequence of PD-1/PD-L1 blockade in the disease setting of dissociated cells from lung and colon carcinomas responding to allogeneic DCs: here, pembrolizumab once more enhanced IFNγ production from the majority of tumour preparations whereas, again, the increase in IL-10 release was modest at best. In conclusion, we have shown that the contribution of PD-1-revealed by using a canonical blocking antibody to interrupt its interaction with PD-L1-to the production of an exemplar pro- and anti-inflammatory cytokine, respectively, depends in magnitude and ratio on the particular stimulation setting and activation status of the target T cell. We have identified a number of in vitro assays with response profiles that mimic features of dissociated cell populations from primary tumours thereby indicating these represent disease-relevant functional assays for the screening of immune checkpoint inhibitors in current and future development. Such in vitro assays may also support patient stratification of those likely to respond to immuno-oncology therapies in the wider population.

Protocol for a feasibility study of smoking cessation in the surgical pathway before major lung surgery: Project MURRAY.

INTRODUCTION: Smoking prior to major thoracic surgery is the biggest risk factor for development of postoperative pulmonary complications, with one in five patients continuing to smoke before surgery. Current guidance is that all patients should stop smoking before elective surgery yet very few are offered specialist smoking cessation support. Patients would prefer support within the thoracic surgical pathway. No study has addressed the effectiveness of such an intervention in this setting on cessation. The overall aim is to determine in patients who undergo major elective thoracic surgery whether an intervention integrated (INT) into the surgical pathway improves smoking cessation rates compared with usual care (UC) of standard community/hospital based NHS smoking support. This pilot study will evaluate feasibility of a substantive trial. METHODS AND ANALYSIS: Project MURRAY is a trial comparing the effectiveness of INT and UC on smoking cessation. INT is pharmacotherapy and a hybrid of behavioural support delivered by the trained healthcare practitioners (HCPs) in the thoracic surgical pathway and a complimentary web-based application. This pilot study will evaluate the feasibility of a substantive trial and study processes in five adult thoracic centres including the University Hospitals Birmingham NHS Foundation Trust. The primary objective is to establish the proportion of those eligible who agree to participate. Secondary objectives include evaluation of study processes. Analyses of feasibility and patient-reported outcomes will take the form of simple descriptive statistics and where appropriate, point estimates of effects sizes and associated 95% CIs. ETHICS AND DISSEMINATION: The study has obtained ethical approval from NHS Research Ethics Committee (REC number 19/WM/0097). Dissemination plan includes informing patients and HCPs; engaging multidisciplinary professionals to support a proposal of a definitive trial and submission for a full application dependent on the success of the study. TRIAL REGISTRATION NUMBER: NCT04190966.

Dysregulated alveolar function and complications in smokers following oesophagectomy.

Acute respiratory distress syndrome (ARDS) has a significant impact on post-operative morbidity and mortality following oesophagectomy. Smoking is a risk factor for the development of ARDS, although the mechanism is unclear. We examined the effect of smoking on alveolar and systemic inflammation, in addition to alveolar-capillary permeability, leading to ARDS in patients undergoing oesophagectomy. We compared clinical, biomarker and PiCCO system data between current smokers (n=14) and ex-smokers (n=36) enrolled into a translational substudy of the BALTI-P (Beta Agonist Lung Injury Trial Prevention) trial. Current smokers compared with ex-smokers had significantly higher numbers of circulating neutrophils, elevated bronchoalveolar lavage (BAL) interleukin (IL)-1 receptor antagonist (IL-1ra), soluble tumour necrosis factor receptor-1 and pre-operative plasma soluble intercellular adhesion molecule-1, and lower BAL vascular endothelial growth factor and post-operative plasma IL-17 (p<0.05). On post-operative day 1, current smokers had higher extravascular lung water index (9.80 versus 7.90; p=0.026) and pulmonary vascular permeability index (2.09 versus 1.70; p=0.013). Current smokers were more likely to develop ARDS (57% versus 25%; p=0.031) and had a significantly reduced post-operative median survival (421 versus 771 days; p=0.023). Smoking prior to oesophagectomy is associated with dysregulated inflammation, with higher concentrations of inflammatory mediators and lower concentrations of protective mediators. This translates into a higher post-operative inflammatory alveolar oedema, greater risk of ARDS and poorer long-term survival.

Risk factors and short-term outcomes of postoperative pulmonary complications after VATS lobectomy.

BACKGROUND: Postoperative pulmonary complications (PPCs) are associated with poor outcomes following thoracotomy and lung resection. Video-assisted thoracoscopic surgery (VATS) for lobectomy is now frequently utilised as an alternative to thoracotomy, however patients remain at risk for development of PPC. There is little known of the short-term outcome associated with PPC following VATS lobectomy and if there are any potential risk factors that could be modified to prevent PPC development; our study aimed to investigate this. METHODS: A prospective observational study of consecutive patients undergoing VATS lobectomy for lung cancer over a 4-year period in a regional centre was performed (2012-2016). Exclusion criteria included re-do VATS or surgery for pulmonary infection. All patients received physiotherapy as necessary from postoperative day 1 (POD1) and PPC was determined using the Melbourne Group Scale. Outcomes included hospital LOS, intensive therapy unit (ITU) admission and hospital mortality. RESULTS: Of the 285 patients included in the study, 137 were male (48.1%), the median (IQR) age was 69 (13) years and the mean (±SD) FEV1% predicted was 87% (±19). Patients that developed a PPC (n = 21; 7.4%) had a significantly longer hospital LOS (4 vs. 3 days), higher frequency of ITU admission (23.8% vs. 0.5%) and higher hospital mortality (14.3% vs. 0%) (p < 0.001). PPC patients also required more physiotherapy contacts/time, emergency call-outs and specific pulmonary therapy (p < 0.05). Current smoking and COPD diagnosis were significantly associated with development of PPC on univariate analysis (p < 0.05), however only current smoking was a significant independent risk factor on multivariate analysis (p = 0.015). CONCLUSIONS: Patients undergoing VATS lobectomy remain at risk of developing a PPC, which is associated with an increase in physiotherapy requirements and a worse short-term morbidity and mortality. Current smoking is the only independent risk factor for PPC after VATS lobectomy, thus vigorous addressing of preoperative smoking cessation is urgently needed.