Search

Severe coronavirus disease 2019 (COVID-19) manifests as a life-threatening microvascular syndrome. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the Spike (S) protein to engage with its receptors and infect host cells. To date, it is still not known whether heart vascular pericytes (PCs) are infected by SARS-CoV-2, and if the S protein alone provokes PC dysfunction. Here, we aimed to investigate the effects of the S protein on primary human cardiac PC signalling and function. Results show, for the first time, that cardiac PCs are not permissive to SARS-CoV-2 infection in vitro, whilst a recombinant S protein alone elicits functional alterations in PCs. This was documented as: (1) increased migration, (2) reduced ability to support endothelial cell (EC) network formation on Matrigel, (3) secretion of pro-inflammatory molecules typically involved in the cytokine storm, and (4) production of pro-apoptotic factors responsible for EC death. Next, adopting a blocking strategy against the S protein receptors angiotensin-converting enzyme 2 (ACE2) and CD147, we discovered that the S protein stimulates the phosphorylation/activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) through the CD147 receptor, but not ACE2, in PCs. The neutralisation of CD147, either using a blocking antibody or mRNA silencing, reduced ERK1/2 activation and rescued PC function in the presence of the S protein. In conclusion, our findings suggest that circulating S protein prompts vascular PC dysfunction, potentially contributing to establishing microvascular injury in organs distant from the site of infection. This mechanism may have clinical and therapeutic implications.Clinical perspectiveSevere COVID-19 manifests as a microvascular syndrome, but whether SARS-CoV-2 infects and damages heart vascular pericytes (PCs) remains unknown.We provide evidence that cardiac PCs are not infected by SARS-CoV-2. Importantly, we show that the recombinant S protein alone elicits cellular signalling through the CD147 receptor in cardiac PCs, thereby inducing cell dysfunction and microvascular disruption in vitro.This study suggests that soluble S protein can potentially propagate damage to organs distant from sites of infection, promoting microvascular injury. Blocking the CD147 receptor in patients may help protect the vasculature not only from infection, but also from the collateral damage caused by the S protein.

The SARS‐CoV‐2 virus causes COVID‐19, an infection capable of causing severe disease and death but which can also be asymptomatic or oligosymptomatic. We investigated whether ABO blood group or secretor status was associated with COVID‐19 severity. We investigated secretor status because expression of ABO glycans on secreted proteins and non‐erythroid cells are controlled by a fucosyltransferase (FUT2), and inactivating FUT2 mutations result in a non‐secretor phenotype which protects against some viral infections. Data combined from healthcare records and our own laboratory tests (n = 275) of hospitalized SARS‐CoV‐2 polymerase chain reaction positive patients confirmed higher than expected numbers of blood group A individuals compared to O (RR = 1.24, CI 95% [1.05, 1.47], p = 0.0111). There was also a significant association between group A and COVID‐19‐related cardiovascular complications (RR = 2.56, CI 95% [1.43, 4.55], p = 0.0011) which is independent of gender. Molecular analysis revealed that group A non‐secretors are significantly less likely to be hospitalized than secretors. Testing of convalescent plasma donors, among whom the majority displayed COVID‐19 symptoms and only a small minority required hospitalization, group A non‐secretors were slightly over‐represented. Our findings showed that group A non‐secretors are not resistant to infection by SARS‐CoV‐2, but are more likely to experience a less severe form of associated disease.

Background Pleural infection is a complex condition with a considerable healthcare burden. The average hospital stay for pleural infection is 14 days. Current standard of care defaults to chest tube insertion and intravenous antibiotics. There have been no randomised trials on the use of therapeutic thoracentesis (TT) for pleural fluid drainage in pleural infection. Aims and objectives To assess the feasibility of a full-scale trial of chest tube vs TT for pleural infection in a single UK centre. The primary outcome was defined as the acceptability of randomisation to patients. Methods Adult patients admitted with a pleural effusion felt to be related to infection and meeting criteria for drainage (based on international guidelines) were eligible for randomisation. Participants were randomised (1:1) to chest tube insertion or TT with daily review assessing need for further drainages or other therapies. Neither participant nor clinician were blinded to treatment allocation. Patients were followed up at 90 days post-randomisation. Results From September 2019 to June 2021, 51 patients were diagnosed with pleural infection (complex parapneumonic effusion/empyema). Eleven patients met the inclusion criteria for trial and 10 patients were randomised (91%). The COVID-19 pandemic had a substantial impact on recruitment. Data completeness was high in both groups with no protocol deviations. Patients randomised to TT had a significantly shorter overall mean hospital stay (5.4 days, SD 5.1) compared to the chest tube control group (13 days, SD 6.0), p = 0.04. Total number of pleural procedures required per patient were similar, 1.2 in chest tube group and 1.4 in TT group. No patient required a surgical referral. Adverse events were similar between the groups with no readmissions related to pleural infection. Conclusions The ACTion trial met its pre-specified feasibility criteria for patient acceptability but other issues around feasibility of a full-scale trial remain. From the results available the hypothesis that TT can reduce length of stay in pleural infection should be explored further. Trial registration: ISRCTN: 84674413.

Pulmonary function tests are fundamental to the diagnosis and monitoring of respiratory diseases. There is uncertainty around whether potentially infectious aerosols are produced during testing and there are limited data on mitigation strategies to reduce risk to staff. Healthy volunteers and patients with lung disease underwent standardised spirometry, peak flow and FENO assessments. Aerosol number concentration was sampled using an aerodynamic particle sizer and an optical particle sizer. Measured aerosol concentrations were compared with breathing, speaking and voluntary coughing. Mitigation strategies included a standard viral filter and a full-face mask normally used for exercise testing (to mitigate induced coughing). 147 measures were collected from 33 healthy volunteers and 10 patients with lung disease. The aerosol number concentration was highest in coughs (1.45–1.61 particles/cm3), followed by unfiltered peak flow (0.37–0.76 particles/cm3). Addition of a viral filter to peak flow reduced aerosol emission by a factor of 10 without affecting the results. On average, coughs produced 22 times more aerosols than standard spirometry (with filter) in patients and 56 times more aerosols in healthy volunteers. FENO measurement produced negligible aerosols. Cardiopulmonary exercise test (CPET) masks reduced aerosol emission when breathing, speaking and coughing significantly. Lung function testing produces less aerosols than voluntary coughing. CPET masks may be used to reduce aerosol emission from induced coughing. Standard viral filters are sufficiently effective to allow guidelines to remove lung function testing from the list of aerosol-generating procedures.

RationaleStreptococcus pneumoniaeepidemiology is changing in response to vaccination and some data suggest empyema incidence is increasing. However, differences exist between UK and USA studies. We describe trends in the clinical phenotype of adult pneumococcal pleural infection, including simple parapneumonic effusions (SPE) in the pneumococcal conjugate vaccination (PCV) era.ObjectivesTo determine whether there were differences in pneumococcal disease presentation and severity associated with pleural infection.MethodsA retrospective cohort study, all adults ≥16 years admitted to three large UK hospitals, 2006-2018 with pneumococcal disease. 2477 invasive pneumococcal cases were identified: 459 SPE and 100 pleural infection cases. Medical records were reviewed for each clinical episode. Serotype data were obtained from the UK Health Security Agency national reference laboratory.ResultsIncidence increased over time, including non-PCV-serotype disease. PCV7-serotype disease declined following paediatric PCV7 introduction, but the effect of PCV13 was less apparent as disease caused by the additional six serotypes plateaued with serotypes 1 and 3 causing such parapneumonic effusions from 2011 onwards.Patients with pleural infection had a median survival 468 days (95% CI 340-590), versus 286 days (95% CI 274-335) in those with SPE. Pleural infection associated with frank pus had lower 90-day mortality than pleural infection without pus (0% versus 29%,PP=0.049).ConclusionsPneumococcal infection continues to cause severe disease despite the introduction of PCVs. The predominance of serotype 1 and 3 in this adult UK cohort is in keeping with previous studies in paediatric and non-UK studies. Rising non-PCV serotype disease and limited impact of PCV13 on cases caused by serotypes 1 and 3 offset the reductions in adult pneumococcal parapneumonic effusion disease burden observed following introduction of the childhood PCV7 programme.KEY MESSAGESWhat is already known on this topicThe epidemiology of pneumococcal infection is changing in both adults and children following pneumococcal conjugate vaccine (PCV) introduction, as a result of direct and indirect vaccine effects. Other studies have reported that serotypes 1 and 3 disproportionately cause pneumococcal pleural disease; however, the clinical phenotype of parapneumonic effusions associated with pneumococcal infection in adults following PCV introduction is not well described.What this study addsIn this study which presents the largest cohort of patients with a single-organism pleural infection, we demonstrate an increasing incidence of parapneumonic effusions related toStreptococcus pneumoniaein adults, attributable to serotype 1 and 3 disease, despite the introduction of PCV13 in the UK childhood vaccination programme. Interestingly, our data suggest that pneumococcal pleural infection is associated with improved survival up to one-year compared to patients with pneumococcal simple parapneumonic effusions.How this study might affect research, practice or policyCareful assessment of the need for specialist respiratory and thoracic surgical intervention in the context of increasing incidence of adult parapneumonic effusions related toStreptococcus pneumoniaewill be required, in addition to ongoing monitoring of the effect on serotype distribution and clinical phenotype of current and future vaccines against pneumococcus.

[No abstract]

IntroductionDexamethasone has been shown to reduce mortality for patients hospitalised with acute COVID-19 pneumonia. However, a significant proportion of patients suffer persistent symptoms following COVID-19 and little is known about the longer-term impact of this intervention on symptom burden.MethodsPatients initially hospitalised with COVID-19 were prospectively recruited to an observational study (April-August 2020) with follow-up at 8 months (Dec 2020-April 2021) post-admission. A review of ongoing symptoms using a standardised systems-based proforma was performed alongside health-related quality of life assessment. In the UK, patients with COVID-19 (requiring oxygen) only received dexamethasone following the pre-print of the RECOVERY trial (June 2020), or as part of randomisation to that trial, allowing for a comparison between patients treated and not treated with dexamethasone.ResultsBetween April to August 2020, 198 patients were recruited to this observational study. 87 required oxygen and were followed up at 8-months, so were eligible for this analysis. Of these 39 received an inpatient course of dexamethasone (cases) and 48 did not (controls). The groups were well matched at baseline in terms of age, comorbidity and frailty score. Over two-thirds of patients reported at least 1 ongoing symptom at 8-month follow-up. Patients in the dexamethasone group reported fewer symptoms (n=73, 1.9 per patient) than the non-dexamethasone group (n=152, 3.2 per patient) (p = 0.01).ConclusionsIn conclusion, in this case-control observational study, patients who received oral dexamethasone for hospitalised COVID-19 were less likely to experience persistent symptoms at 8-month follow-up. These are reassuring results for physicians administering dexamethasone to this patient group.

Background The impact of COVID-19 on physical and mental health and employment after hospitalisation with acute disease is not well understood. The aim of this study was to determine the effects of COVID-19-related hospitalisation on health and employment, to identify factors associated with recovery, and to describe recovery phenotypes. Methods The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a multicentre, long-term follow-up study of adults (aged ≥18 years) discharged from hospital in the UK with a clinical diagnosis of COVID-19, involving an assessment between 2 and 7 months after discharge, including detailed recording of symptoms, and physiological and biochemical testing. Multivariable logistic regression was done for the primary outcome of patient-perceived recovery, with age, sex, ethnicity, body-mass index, comorbidities, and severity of acute illness as covariates. A post-hoc cluster analysis of outcomes for breathlessness, fatigue, mental health, cognitive impairment, and physical performance was done using the clustering large applications k-medoids approach. The study is registered on the ISRCTN Registry (ISRCTN10980107). Findings We report findings for 1077 patients discharged from hospital between March 5 and Nov 30, 2020, who underwent assessment at a median of 5·9 months (IQR 4·9–6·5) after discharge. Participants had a mean age of 58 years (SD 13); 384 (36%) were female, 710 (69%) were of white ethnicity, 288 (27%) had received mechanical ventilation, and 540 (50%) had at least two comorbidities. At follow-up, only 239 (29%) of 830 participants felt fully recovered, 158 (20%) of 806 had a new disability (assessed by the Washington Group Short Set on Functioning), and 124 (19%) of 641 experienced a health-related change in occupation. Factors associated with not recovering were female sex, middle age (40–59 years), two or more comorbidities, and more severe acute illness. The magnitude of the persistent health burden was substantial but only weakly associated with the severity of acute illness. Four clusters were identified with different severities of mental and physical health impairment (n=767): very severe (131 patients, 17%), severe (159, 21%), moderate along with cognitive impairment (127, 17%), and mild (350, 46%). Of the outcomes used in the cluster analysis, all were closely related except for cognitive impairment. Three (3%) of 113 patients in the very severe cluster, nine (7%) of 129 in the severe cluster, 36 (36%) of 99 in the moderate cluster, and 114 (43%) of 267 in the mild cluster reported feeling fully recovered. Persistently elevated serum C-reactive protein was positively associated with cluster severity. Interpretation We identified factors related to not recovering after hospital admission with COVID-19 at 6 months after discharge (eg, female sex, middle age, two or more comorbidities, and more acute severe illness), and four different recovery phenotypes. The severity of physical and mental health impairments were closely related, whereas cognitive health impairments were independent. In clinical care, a proactive approach is needed across the acute severity spectrum, with interdisciplinary working, wide access to COVID-19 holistic clinical services, and the potential to stratify care. Funding UK Research and Innovation and National Institute for Health Research.

Objectives SARS-CoV-2 antibody assays are needed for serological surveys and as a complement to molecular tests to confirm COVID-19. However, the kinetics of the humoral response against SARS-CoV-2 remains poorly described and relies on the performance of the different serological tests. Methods In this study, we evaluated the performance of six CE-marked point-of-care tests (POC) and three ELISA assays for the diagnosis of COVID-19 by exploring seroconversions in hospitalized patients who tested positive for SARS-CoV-2 RNA. Results Both the ELISA and POC tests were able to detect SARS-CoV-2 antibodies in at least half of the samples collected seven days or more after the onset of symptoms. After 15 days, the rate of detection rose to over 80% but without reaching 100%, irrespective of the test used. More than 90% of the samples collected after 15 days tested positive using the iSIA and Accu-Tell® POC tests and the ID.Vet IgG ELISA assay. Seroconversion was observed 5 to 12 days after the onset of symptoms. Three assays suffer from a specificity below 90% (EUROIMMUN IgG and IgA, UNscience, Zhuhai Livzon). Conclusions The second week of COVID-19 seems to be the best period for assessing the sensitivity of commercial serological assays. To achieve an early diagnosis of COVID-19 based on antibody detection, a dual challenge must be met: the immunodiagnostic window period must be shortened and an optimal specificity must be conserved.

Background As promising novel treatments develop for malignant pleural mesothelioma (MPM), early prognostication has become increasingly important. Circulating and local inflammatory cells are known to play a significant role in other tumour types. We assessed the proportion of lymphocyte populations within blood, pleural fluid and tumour stroma to prognosticate patients with MPM at diagnosis. Methods Consecutive patients diagnosed with biopsy-proven MPM were prospectively recruited to an observational cohort study and followed up for a minimum of 7.5 years. Blood and pleural fluid results at presentation were extracted from the medical records. Biopsy specimens were independently reviewed by 2 pathologists who scored the degree of lymphocytic and neutrophilic infiltration. Results Baseline results were available for 184 patients. The predominant pleural fluid cell type was calculable for 84 patients and 118 patients had biopsy specimens available for review. A low blood neutrophil/lymphocyte ratio (NLR p p p Conclusions Lymphocyte predominance within tumour stroma, pleural fluid or blood infers a better prognosis in patients with MPM.

BACKGROUND: Randomized trials are generally performed from a frequentist perspective, which can conflate absence of evidence with evidence of absence. The RECOVERY trial evaluated convalescent plasma for patients hospitalized with coronavirus disease 2019 (COVID-19) and concluded that there was no evidence of an effect. Re-analysis from a Bayesian perspective is warranted. METHODS: Outcome data were extracted from the RECOVERY trial by serostatus and time of presentation. A Bayesian re-analysis with a wide variety of priors (vague, optimistic, sceptical, and pessimistic) was performed, calculating the posterior probability for: any benefit, an absolute risk difference of 0.5% (small benefit, number needed to treat 200), and an absolute risk difference of one percentage point (modest benefit, number needed to treat 100). RESULTS: Across all patients, when analysed with a vague prior, the likelihood of any benefit or a modest benefit with convalescent plasma was estimated to be 64% and 18%, respectively. The estimated chance of any benefit was 95% if presenting within 7 days of symptoms, or 17% if presenting after this. In patients without a detectable antibody response at presentation, the chance of any benefit was 85%. However, it was only 20% in patients with a detectable antibody response at presentation. CONCLUSIONS: Bayesian re-analysis suggests that convalescent plasma reduces mortality by at least one percentage point among the 39% of patients who present within 7 days of symptoms, and that there is a 67% chance of the same mortality reduction in the 38% who are seronegative at the time of presentation. This is in contrast to the results in people who already have antibodies when they present. This biologically plausible finding bears witness to the advantage of Bayesian analyses over misuse of hypothesis tests to inform decisions.

IntroductionCOVID-19 has an unpredictable clinical course, so prognostic biomarkers would be invaluable when triaging patients on admission to hospital. Many biomarkers have been suggested using large observational datasets but sample timing is crucial to ensure prognostic relevance. The DISCOVER study prospectively recruited patients with COVID-19 admitted to a UK hospital and analysed a panel of putative prognostic biomarkers on the admission blood sample to identify markers of poor outcome.MethodsConsecutive patients admitted to hospital with proven or clinicoradiological suspected COVID-19 were consented. Admission bloods were extracted from the clinical laboratory. A panel of biomarkers (interleukin-6 (IL-6), soluble urokinase plasminogen activator receptor (suPAR), Krebs von den Lungen 6, troponin, ferritin, lactate dehydrogenase, B-type natriuretic peptide, procalcitonin) were performed in addition to routinely performed markers (C reactive protein (CRP), neutrophils, lymphocytes, neutrophil:lymphocyte ratio). Age, National Early Warning Score (NEWS2), CURB-65 and radiographic severity score on initial chest radiograph were included as comparators. All biomarkers were tested in logistic regression against a composite outcome of non-invasive ventilation, intensive care admission or death, with area under the curve (AUC) (figures calculated).Results187 patients had 28-day outcomes at the time of analysis. CRP (AUC: 0.69, 95% CI: 0.59 to 0.78), lymphocyte count (AUC: 0.62, 95% CI: 0.53 to 0.72) and other routine markers did not predict the primary outcome. IL-6 (AUC: 0.77, 0.65 to 0.88) and suPAR (AUC: 0.81, 0.72 to 0.88) showed some promise, but simple clinical features alone such as NEWS2 score (AUC: 0.70, 0.60 to 0.79) or age (AUC: 0.70, 0.62 to 0.77) performed nearly as well.DiscussionAdmission blood biomarkers have only moderate predictive value for predicting COVID-19 outcomes, while simple clinical features such as age and NEWS2 score outperform many biomarkers. IL-6 and suPAR had the best performance, and further studies should focus on the additive value of these biomarkers to routine care.

Preservatives play an essentially role in ensuring that cosmetic formulations remain safe for use via control of microbial contamination. Commonly used preservatives include organic acids, alcohols and phenols and these play an essential role in controlling the growth of bacteria, fungi and moulds in substrates that can potentially act as a rich food source for microbial contaminants. Whilst the activity of these compounds is clear, both in vitro and in formulation, little information exists on the potential impact that common preservative systems, in full formulation, have on the skin’s resident microbiome. Dysbiosis of the skin’s microbiome has been associated with a number of cosmetic conditions but there currently are no in vivo studies investigating the potential for preservative ingredients, when included in personal care formulations under normal use conditions, to impact the cutaneous microbiome. Here we present an analysis of four in vivo studies that examine the impact of different preservation systems in full formulation, in different products formats, with varying durations of application. This work demonstrates that despite the antimicrobial efficacy of the preservatives in vitro, the skin microbiome is not impacted by preservative containing products in vivo.

There is widespread interest in the capacity for SARS-CoV-2 evolution in the face of selective pressures from host immunity, either naturally acquired post-exposure or from vaccine acquired immunity. Allied to this is the potential for long perm persistent infections within immune compromised individuals to allow a broader range of viral evolution in the face of sub-optimal immune driven selective pressure. Here we report on an immunocompromised individual who is hypogammaglobulinaemic and was persistently infected with SARS-CoV-2 for over 290 days, the longest persistent infection recorded in the literature to date. During this time, nine samples of viral nucleic acid were obtained and analysed by next-generation sequencing. Initially only a single mutation (L179I) was detected in the spike protein relative to the prototypic SARS-CoV-2 Wuhan-Hu-1 isolate, with no further changes identified at day 58. However, by day 155 the spike protein had acquired a further four amino acid changes, namely S255F, S477N, H655Y and D1620A and a two amino acid deletion (ΔH69/ΔV70). Infectious virus was cultured from a nasopharyngeal sample taken on day 155 and next-generation sequencing confirmed that the mutations in the virus mirrored those identified by sequencing of the corresponding swab sample. The isolated virus was susceptible to remdesivirin vitro, however a 17-day course of remdesivir started on day 213 had no effect on the viral RT-PCR cycle threshold (Ct) value. On day 265 the patient was treated with the combination of casirivimab and imdevimab. The patient experienced progressive resolution of all symptoms over the next 8 weeks and by day 311 the virus was no longer detectable by RT-PCR. The ΔH69/ΔV70 deletion in the N-terminus of the spike protein which arose in our patient is also present in the B.1.1.7 variant of concern and has been associated with viral escape mutagenesis after treatment of another immunocompromised patient with convalescent plasma. Our data confirms the significance of this deletion in immunocompromised patients but illustrates it can arise independently of passive antibody transfer, suggesting the deletion may be an enabling mutation that compensates for distant changes in the spike protein that arise under selective pressure.

The nosocomial spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has focused attention on the risk of aerosol generating procedures (AGPs) in healthcare [1]. SARS-CoV-2 has been isolated from pleural fluid, which has the potential to infect staff or patients if viraemic fluid is aerosolised during procedures [2, 3]. However, evidence for aerosol generation from pleural procedures is very limited. Current guidelines for appropriate use of personal protective equipment (PPE) while performing pleural procedures are based on expert opinion and application of the precautionary principle [4]. We set out to quantify if pleural procedures generated appreciable aerosol (aerosolised liquid particles that have the potential to carry virus) compared to aerosol sampled during normal respiratory activities of breathing and coughing., Percutaneous pleural procedures should not be considered aerosol generating. This study should inform future iterations of guidelines on the appropriate use of PPE when performing these procedures. https://bit.ly/3xFF71d

IntroductionRandomised trials are generally performed from a frequentist perspective reporting point estimates and 95% confidence intervals. This approach can confuse “evidence of no effect” with “no evidence of an effect” and does not allow for contextual knowledge. The RECOVERY trial evaluated convalescent plasma for patients hospitalised with COVID-19, the interaction test for the primary outcome was not statistically significant, and the trial concluded no evidence of an effect. From the clinical immunology perspective, there is strong justification to expect differential responses to convalescent plasma in patients who already have their own antibodies to SARS-CoV2 (seropositive) versus those who do not (seronegative).MethodsOutcome data was extracted from the RECOVERY trial both overall and for seronegative participants. A Bayesian re-analysis with a wide variety of priors (vague, optimistic, skeptical and pessimistic) was performed calculating the posterior probability for both any benefit or a modest benefit (number needed to treat of 100).ResultsAcross all patients, when analysed with a vague prior the likelihood of any benefit or a modest benefit was estimated to be 64% and 18% respectively. In contrast, in the seronegative subgroup, the likelihood of any benefit or a modest benefit was estimated to be 90% and 74%. Results were broadly consistent across all prior distributions.ConclusionPerforming clinical trials during a pandemic is challenging, and RECOVERY has provided high quality evidence for numerous therapies. However, the use of frequentist hypothesis testing in this trial has led to the trialists and governing bodies to conclude a strong evidence of no effect. Based on this trial, and other prior knowledge there remains a strong probability that convalescent plasma provides at least a modest benefit in seronegative patients.

Background Continuous positive airways pressure (CPAP) and high-flow nasal oxygen (HFNO) are considered ‘aerosol-generating procedures’ in the treatment of COVID-19. Objective To measure air and surface environmental contamination with SARS-CoV-2 virus when CPAP and HFNO are used, compared with supplemental oxygen, to investigate the potential risks of viral transmission to healthcare workers and patients. Methods 30 hospitalised patients with COVID-19 requiring supplemental oxygen, with a fraction of inspired oxygen ≥0.4 to maintain oxygen saturation ≥94%, were prospectively enrolled into an observational environmental sampling study. Participants received either supplemental oxygen, CPAP or HFNO (n=10 in each group). A nasopharyngeal swab, three air and three surface samples were collected from each participant and the clinical environment. Real-time quantitative polymerase chain reaction analyses were performed for viral and human RNA, and positive/suspected-positive samples were cultured for the presence of biologically viable virus. Results Overall 21/30 (70%) participants tested positive for SARS-CoV-2 RNA in the nasopharynx. In contrast, only 4/90 (4%) and 6/90 (7%) of all air and surface samples tested positive (positive for E and ORF1a) for viral RNA respectively, although there were an additional 10 suspected-positive samples in both air and surfaces samples (positive for E or ORF1a). CPAP/HFNO use or coughing was not associated with significantly more environmental contamination than supplemental oxygen use. Only one nasopharyngeal sample was culture positive. Conclusions The use of CPAP and HFNO to treat moderate/severe COVID-19 did not appear to be associated with substantially higher levels of air or surface viral contamination in the immediate care environment, compared with the use of supplemental oxygen.

IntroductionAlthough the efficacy of SARS-CoV-2 vaccination to prevent symptomatic COVID-19 is well established, there are no published studies on the impact on symptoms in patients with Long Covid. Anecdotal reports have suggested both a potential benefit and worsening of symptoms post vaccination with the uncertainty leading to some vaccine hesitancy amongst affected individuals.MethodsPatients initially hospitalised with COVID-19 were prospectively recruited to an observational study with clinical follow-up at 3 months (June-July 2020) and 8 months (Dec 2020-Jan 2021) post-admission. Participants who received the Pfizer-BioNTech (BNT162b2) or Oxford-AstraZeneca (ChAdOx1 nCoV-19) vaccine between January to February 2021 were identified and matched 2:1 (in terms of 8-month symptoms) with participants from the same cohort who were unvaccinated. All were re-assessed at 1 month post vaccination (or matched timepoint for unvaccinated cohort). Validated quality of life (SF-36), mental wellbeing (WEMWBS) and ongoing symptoms were assessed at all timepoints. Formal statistical analysis compared the effect of vaccination on recent quality of life using baseline symptoms, age, and gender in linear regression.ResultsForty-four vaccinated participants were assessed at a median of 32 days (IQR 20-41) post vaccination with 22 matched unvaccinated participants. Most were highly symptomatic of Long Covid at 8 months (82% in both groups had at least 1 persistent symptom), with fatigue (61%), breathlessness (50%) and insomnia (38%) predominating. There was no significant worsening in quality-of-life or mental wellbeing metrics pre versus post vaccination. Nearly two-thirds (n=27) reported transient (When compared to matched unvaccinated participants from the same cohort, those who had receive a vaccine had a small overall improvement in Long Covid symptoms, with a decrease in worsening symptoms (5.6% vaccinated vs 14.2% unvaccinated) and increase in symptom resolution (23.2% vaccinated vs 15.4% unvaccinated) (p=0.035). No difference in response was identified between Pfizer-BioNTech or Oxford-AstraZeneca vaccines.ConclusionsReceipt of vaccination with either an mRNA or adenoviral vector vaccine was not associated with a worsening of Long Covid symptoms, quality of life, or mental wellbeing. Individuals with prolonged COVID-19 symptoms should receive vaccinations as suggested by national guidance.

IntroductionLung function tests are fundamental diagnostic and monitoring tools for patients with respiratory symptoms. There is significant uncertainty around whether potentially infectious aerosol is produced during different lung function testing modalities; and limited data on possible mitigation strategies to reduce risk to staff and limit fallow time.MethodsHealthy volunteers were recruited in an ultraclean, laminar flow theatre and had standardised spirometry as per ERS/ATS guidance, as well as peak flow measurement and FENO assessment of airway inflammation. Aerosol emission was sampled minimum once each second using both an Aerodynamic Particle Sizer (APS) and Optical Particle Sizer (OPS), and compared to breathing, speaking and coughing. Mitigation strategies such as a peak flow viral filter and a CPET facemask (to mitigate induced coughing) were tested.Results33 healthy volunteers were recruited. Aerosol emission was highest in cough (1.61 particles/cm3/sample), followed by unfiltered peak flow (0.76 particles/cm3/sample). Filtered spirometry produced lower peak aerosol emission (0.11 particles/ cm3/sample) than that of a voluntary cough, and addition of a viral filter to the mouthpiece reduced peak flow aerosol emission to similar levels. The filter made little difference to recorded FEV peak flow values. Peak aerosol FENO measurement produced negligible aerosol. Reusable CPET masks with filter reduced aerosol emission when breathing, speaking, and coughing significantly.ConclusionsCompared to voluntary coughing, all lung function testing produced fewer aerosol particles. Filtered spirometry produces lower peak aerosol emission than peak voluntary coughing, and should not be deemed an aerosol generating procedure. The use of viral filters reduces aerosol emission in peak flow by > 10 times, and has little impact on recorded peak flow values. CPET masks are a useful option to reduce aerosol emission from induced coughing while performing spirometry.

ObjectiveRefractory symptomatic transudative pleural effusions are an indication for pleural drainage. There has been supportive observational evidence for the use of indwelling pleural catheters (IPCs) for transudative effusions, but no randomised trials. We aimed to investigate the effect of IPCs on breathlessness in patients with transudative pleural effusions when compared with standard care.MethodsA multicentre randomised controlled trial, in which patients with transudative pleural effusions were randomly assigned to either an IPC (intervention) or therapeutic thoracentesis (TT; standard care). The primary outcome was mean daily breathlessness score over 12 weeks from randomisation.Results220 patients were screened from April 2015 to August 2019 across 13 centres, with 33 randomised to intervention (IPC) and 35 to standard care (TT). Underlying aetiology was heart failure in 46 patients, liver failure in 16 and renal failure in six. In primary outcome analysis, the mean±sd breathlessness score over the 12-week study period was 39.7±29.4 mm in the IPC group and 45.0±26.1 mm in the TT group (p=0.67). Secondary outcomes analysis demonstrated that mean±sd drainage was 17 412±17 936 mL and 2901±2416 mL in the IPC and TT groups, respectively. A greater proportion of patients had at least one adverse event in the IPC group (p=0.04).ConclusionWe found no significant difference in breathlessness over 12 weeks between IPCs or TT. TT is associated with fewer complications and IPCs reduced the number of invasive pleural procedures required. Patient preference and circumstances should be considered in selecting the intervention in this cohort.

BackgroundRisk of aerosolisation of SARS-CoV-2 directly informs organisation of acute healthcare and PPE guidance. Continuous positive airways pressure (CPAP) and high-flow nasal oxygen (HFNO) are widely used modes of oxygen delivery and respiratory support for patients with severe COVID-19, with both considered as high risk aerosol generating procedures. However, there are limited high quality experimental data characterising aerosolisation during oxygen delivery and respiratory support.MethodsHealthy volunteers were recruited to breathe, speak, and cough in ultra-clean, laminar flow theatres followed by using oxygen and respiratory support systems. Aerosol emission was measured using two discrete methodologies, simultaneously. Hospitalised patients with COVID-19 were also recruited and had aerosol emissions measured during breathing, speaking, and coughing.FindingsIn healthy volunteers (n = 25 subjects; 531 measures), CPAP (with exhalation port filter) produced less aerosols than breathing, speaking and coughing (even with large >50L/m facemask leaks). HFNO did emit aerosols, but the majority of these particles were generated from the HFNO machine, not the patient. HFNO-generated particles were small (InterpretationIn healthy volunteers, CPAP is associated with less aerosol emission than breathing, speaking or coughing. Aerosol emission from the respiratory tract does not appear to be increased by HFNO. Although direct comparisons are complex, cough appears to generate significant aerosols in a size range compatible with airborne transmission of SARS-CoV-2. As a consequence, the risk of SARS-CoV-2 aerosolisation is likely to be high in all areas where patients with Covid-19 are coughing. Guidance on personal protective equipment policy should reflect these updated risks.FundingNIHR-UKRI Rapid COVID call (COV003), Wellcome Trust GW4-CAT Doctoral Training Scheme (FH), MRC CARP Fellowship(JD, MR/T005114/1). Natural Environment Research Council grant (BB, NE/P018459/1)Research in contextEvidence before this studyPubMed was searched from inception until 10/1/21 using the terms ‘aerosol’, and variations of ‘non-invasive positive pressure ventilation’ and ‘high-flow nasal oxygen therapy’. Studies were included if they measured aerosol generated from volunteers or patients receiving non-invasive positive pressure ventilation (NIV) or high flow nasal oxygen therapy (HFNO), or provided experimental evidence on a simulated human setting. One study was identified (Gaeckle et al, 2020) which measured aerosol emission with one methodology (APS) but was limited by high background concentration of aerosol and a low number of participants (n = 10).Added value of this studyThis study used multiple methodologies to measure aerosol emission from the respiratory tract before and during CPAP and high-flow nasal oxygen, in an ultra-clean, laminar flow theatre with near-zero background aerosol and recruited patients with COVID-19 to ensure similar aerosol distributions. We conclude that there is negligible aerosol generation with CPAP, that aerosol emission from HFNO is from the machine and not the patient, coughing emits aerosols consistent with airborne transmission of SARS CoV2 and that healthy volunteers are a reasonable proxy for COVID-19 patients.Implications of all the available evidenceCPAP and HFNO should not be considered high risk aerosol generating procedures, based on our study and that of Gaeckle et al. Recorded aerosol emission from HFNO stems from the machine. Cough remains a significant aerosol risk. PPE guidance should be updated to ensure medical staff are protected with appropriate PPE in situations when patients with suspected or proven COVID-19 are likely to cough.

Background Solitary fibrous tumours of the pleura (SFTP) are rare and account for around 5% of pleural based tumours with rates of malignancy of around 30%. Published data primarily includes histologically proven SFTP, but there is little evidence regarding the outcomes of radiologically diagnosed SFTP. Methods A service evaluation of radiologically diagnosed SFTP was completed in 12 UK centres, searching the local radiology database reports for the terms ‘Pleural fibroma’ OR ‘fibrous tumour of the pleura’ OR ‘SFTP’ between 01/01/2005 and 31/12/2015. Scans were determined to demonstrate a ‘typical’ SFTP, ‘unlikely’ SFTP or SFTP that was ‘within the differential diagnosis’. Data were collected to establish subsequent diagnoses and what follow up was undertaken. Results A total of 246 cases were included, table 1 exhibits the outcomes in each radiological group. Of patients with typical appearances for SFTP, 20/44 were histologically confirmed to represent a fibroma, 19/44 underwent radiological follow up only and 4/44 were confirmed not to represent SFTP. Of the patients who underwent radiological follow-up; there were 9 deaths, none of which were known to be related to SFTP, the median longest diameter was 30 mm (IQR 25–40) and the median follow-up time was 62 months (IQR 17–106). Of the 61 cases histologically confirmed SFTP, 17/61 were malignant, 37/61 benign and 7/61 unknown. A total of 26 patients died, 5 secondary to SFTP, 12 unrelated to SFTP and 9 of unknown cause. Conclusion A large proportion of patients with radiologically typical SFTP features do not undergo biopsy or resection and did not have SFTP related adverse outcomes in this small series. Further analysis is needed to determine whether any radiological features can predict clinical outcomes.

The SARS-CoV-2 virus causes COVID-19, an infection capable of causing severe disease and death but which may also be asymptomatic or oligosymptomatic in many individuals. While several risk factors, including age, have been described, the mechanisms of this variation are poorly understood. Several studies have described associations between blood group and COVID-19 severity, while others do not. Expression of ABO glycans on secreted proteins and non-erythroid cells is controlled by a fucosyltransferase (FUT2). Inactivating mutations result in a non-secretor phenotype which is known to protect against some viral infections. We investigated whether ABO or secretor status was associated with COVID-19 severity. Data combined from healthcare records and laboratory tests (n=275) of SARS-CoV-2 PCR positive patients hospitalised with COVID-19, confirmed higher than expected numbers of blood group A individuals compared to O (RR=1.24, CI 95% [1.05,1.47], P=0.0111). There was also a significant association between group A and COVID-19-related cardiovascular complications (RR=2.56, CI 95% [1.43,4.55], P=0.0011) which is independent of gender. Molecular analysis of phenotype revealed that group A patients who are non-secretors are significantly less likely to be hospitalised than secretors. In a larger cohort of 1000 convalescent plasma donors, among whom the majority displayed COVID-19 symptoms and only a small minority required hospitalisation, group A non-secretors were slightly over-represented. Our findings indicate that group A non-secretors are not resistant to infection by SARS-CoV-2, but they are likely to experience a less severe form of its associated disease.Key PointsBlood group type A is associated with an increased risk of cardiovascular complications in COVID-19 patients.FUT2 “non-secretor” status reduces the risk of severe COVID-19 outcomes in patients with blood group A.

Pleural empyema represents a significant healthcare burden due to extended hospital admissions and potential requirement for surgical intervention. This study aimed to assess changes in incidence and management of pleural empyema in England over the past 10 years and the potential impact of influenza on rates. Hospital Episode Statistics data were used to identify patients admitted to English hospitals with pleural empyema between 2008 and 2018. Linear regression was used to analyse the relationship between empyema rates and influenza incidence recorded by Public Health England. The relationship between influenza and empyema was further explored using serological data from a prospective cohort study of patients presenting with pleural empyema. Between April 2008 and March 2018 there were 55 530 patients admitted with pleural empyema. There was male predominance (67% versus 33%), which increased with age. Cases have increased significantly from 4447 in 2008 to 7268 in 2017. Peaks of incidence correlated moderately with rates of laboratory-confirmed influenza in children and young adults (r=0.30). For nine of the 10 years studied, the highest annual point incidence of influenza coincided with the highest admission rate for empyema (with a 2-week lag). In a cohort study of patients presenting to a single UK hospital with pleural empyema/infection, 24% (17 out of 72) had serological evidence of recent influenza infection, compared to 7% in seasonally matched controls with simple parapneumonic or cardiogenic effusions (p, Rates of pleural empyema are increasing in English hospitals without any improvement in patient outcomes. This study also found that male predominance of empyema increased with age, and rates increased in winter and during peaks of influenza. https://bit.ly/3oiJ870

BackgroundCOVID-19 causes a wide spectrum of disease. The incidence and severity of sequelae after the acute infection is uncertain. Data measuring the longer-term impact of COVID-19 on symptoms, radiology and pulmonary function are urgently needed to plan follow-up services.MethodsConsecutive patients hospitalised with COVID-19 were prospectively recruited to this observational study with outcomes recorded at 28-days. All were invited to a systematic follow up at 8-12 weeks, including chest radiograph, spirometry, exercise test, bloods, and health-related quality of life (HRQoL) questionnaires.FindingsBetween 30th March and 3rd June 2020, 163 patients with COVID-19 were recruited. Median hospital length of stay was 5 days (IQR 2-8) and 19 patients died. At 8-12 weeks post admission, 134 patients were available for follow up and 110 attended. Most (74%) had persistent symptoms (notably breathlessness and excessive fatigue) with reduced HRQoL.Only patients who required oxygen therapy in hospital had abnormal radiology, clinical examination or spirometry at follow up. Thirteen (12%) patients had an abnormal chest X-ray with improvement in all but 2 from admission. Eleven (10%) had restrictive spirometry. Blood test abnormalities had returned to baseline in the majority (104/110).InterpretationPatients with COVID-19 remain highly symptomatic at 8-12 weeks, however, clinical abnormalities requiring action are infrequent, especially in those without a supplementary oxygen requirement during their acute illness. This has significant implications for physicians assessing patients with persistent symptoms, suggesting that a more holistic approach focussing on rehabilitation and general wellbeing is paramount.FundingSouthmead Hospital Charity

Here we describe the case of a COVID-19 patient who developed recurring ventilator-associated pneumonia caused by Pseudomonas aeruginosa that acquired increasing levels of antimicrobial resistance (AMR) in response to treatment. Metagenomic analysis revealed the AMR genotype, while immunological analysis revealed massive and escalating levels of T-cell activation. These were both SARS-CoV-2 and P. aeruginosa specific, and bystander activated, which may have contributed to this patient’s persistent symptoms and radiological changes.

BackgroundIschaemic stroke and myocardial infarction (MI) are common after pneumonia and are associated with long-term mortality. Aspirin may attenuate this risk and should be explored as a therapeutic option.MethodsWe extracted all patients with pneumonia (aged over 50 years) from the Clinical Practice Research Datalink (CPRD), a large UK primary care database, from inception until January 2019. We then performed a prior event rate ratio (PERR) analysis with propensity score matching (PSM), an approach that allows for control of measured and unmeasured confounding, with aspirin usage as the exposure and ischaemic events as the outcome. The primary outcome was the combined outcome of ischaemic stroke and MI. Secondary outcomes were ischaemic stroke and MI individually. Relevant confounders (smoking, comorbidities, age and gender) were included in the analysis.Findings48 743 patients were eligible for matching. Of these, 9864 were aspirin users who were matched to 9864 non-users. Aspirin users had a reduced risk of the primary outcome (adjusted hazard ratio 0.64, 95% CI 0.52–0.79) in the PERR analysis. For both secondary outcomes, aspirin use was also associated with a reduced risk for MI (hazard ratio 0.46, 95% CI 0.30–0.72) and stroke (hazard ratio 0.70, 95% CI 0.55–0.91), respectively.InterpretationThis study provides supporting evidence that aspirin use is associated with reduced ischaemic events after pneumonia in a primary care setting. This drug may have a future clinical role in preventing this important complication.

ObjectivesTo assess the performance (sensitivity and specificity) of the Abbott Architect SARS-CoV-2 IgG antibody assay across three clinical settings.MethodsAntibody testing was performed on three clinical cohorts of COVID-19 disease: hospitalised patients with PCR confirmation, hospitalized patients with a clinical diagnosis but negative PCR, and symptomatic healthcare workers (HCW’s). Pre-pandemic respiratory infection sera were tested as negative controls. The sensitivity of the assay was calculated at different time points (20 days, >42 days), and compared between cohorts.ResultsPerformance of the Abbot Architect SARS-CoV-2 assay varied significantly between cohorts. For PCR confirmed hospitalised patients (n = 114), early sensitivity was low: In contrast, 17 out of 114 symptomatic healthcare workers tested at >20 days had negative results, generating a sensitivity of 85.1% (95%CI, 77.4% - 90.5%). All pre-pandemic sera were negative, a specificity of 100%. Seroconversion rates were similar for PCR positive and PCR negative hospitalised cases.ConclusionsThe sensitivity of the Abbot Architect SARS-CoV-2 IgG assay increases over time, with sensitivity not peaking until 20 days post symptoms. Performance varied markedly by setting, with sensitivity significantly worse in symptomatic healthcare workers than in the hospitalised cohort. Clinicians, policymakers, and patients should be aware of the reduced sensitivity in this setting.

IntroductionCOVID-19 has an unpredictable clinical course so prognostic biomarkers would be invaluable when triaging patients on admission to hospital. Many biomarkers have been suggested using large observational datasets but sample timing is crucial to ensure prognostic relevance. The DISCOVER study prospectively recruited patients with COVID-19 admitted to a UK hospital and analysed a panel of putative prognostic biomarkers on the admission blood sample to identify markers of poor outcome.MethodsConsecutive patients admitted to hospital with proven or clinicoradiological suspected COVID-19 were recruited. Admission bloods were extracted from the clinical laboratory. A panel of biomarkers (IL-6, suPAR, KL-6, Troponin, Ferritin, LDH, BNP, Procalcitonin) were performed in addition to routinely performed markers (CRP, neutrophils, lymphocytes, neutrophil:lymphocyte ratio). Age, NEWS score and CURB-65 were included as comparators. All biomarkers were tested in logistic regression against a composite outcome of non-invasive ventilation, intensive care admission, or death, with Area Under the Curve (AUC) figures calculated.Results155 patients had 28-day outcomes at the time of analysis. CRP (AUC 0.51, CI:0.40-0.62), lymphocyte count (AUC 0.62, CI:0.51-0.72), and other routine markers did not predict the primary outcome. IL-6 (AUC: 0.78,0.65-0.89) and suPAR (AUC 0.77, CI: 0.66-0.85) showed some promise, but simple clinical features alone such as NEWS score (AUC: 0.74, 0.64-0.83) or age (AUC: 0.70, 0.61-0.78) performed nearly as well.DiscussionAdmission blood biomarkers have only moderate predictive value for predicting COVID-19 outcomes, while simple clinical features such as age and NEWS score outperform many biomarkers. IL-6 and suPAR had the best performance, and further studies should validate these biomarkers in a prospective fashion.

Background: Risk stratification tools (RSTs) are used in healthcare settings to identify patients at risk of sepsis and subsequent adverse outcomes. In practice RSTs are used on admission and thereafter as ‘trigger’ tools prompting sepsis management. However, studies investigating their performance report scores at a single timepoint which varies in relation to admission. The aim of this meta-analysis was to determine if the predictive performance of RSTs is altered by the timing of their use. Methods: We conducted a systematic review and meta-regression analysis of studies published from inception to 31 October 2018, using EMBASE and PubMed databases. Any cohort studies investigating the ability of an RST to predict mortality in adult sepsis patients admitted to hospital, from which a 2x2 table was available or could be constructed, were included. The diagnostic performance of RSTs in predicting mortality was the primary outcome. Sensitivity, specificity, positive predictive value, negative predictive value and area under the receiver-operating curve (AUROC) were the primary measures, enabling further meta-regression analysis. Results: 47 studies were included, comprising 430,427 patients. Results of bivariate meta-regression analysis found tools using a first-recorded score were less sensitive than those using worst-recorded score (REML regression coefficient 0.57, 95% CI 0.07-1.08). Using worst-recorded score led to a large increase in sensitivity (summary sensitivity 0.76, 95% CI 0.67-0.83, for worst-recorded scores vs. 0.64 (0.57-0.71) for first-recorded scores). Scoring system type did not have a significant relationship with studies’ predictive ability. The most analysed RSTs were qSOFA (n=37) and EWS (n=14). Further analysis of these RSTs also found timing of their use to be associated with predictive performance. Conclusion: The timing of any RST is paramount to their predictive performance. This must be reflected in their use in practice, and lead to prospective studies in future.

RATIONALE: Parapneumonic effusions have a wide clinical spectrum. The majority settle with conservative management but some progress to complex collections requiring intervention. For decades, physicians have relied on pleural fluid pH to determine the need for chest tube drainage despite a lack of prospective validation and no ability to predict the requirement for fibrinolytics or thoracic surgery.OBJECTIVES: To study the ability of soluble urokinase Plasminogen Activator Receptor (suPAR), a potential biomarker of pleural fluid loculation, to predict the need for invasive management compared to conventional fluid biomarkers (pH, glucose, LDH) in parapneumonic effusions.METHODS: Patients presenting with pleural effusions were prospectively recruited to an observational study with biological samples stored at presentation. Pleural fluid and serum suPAR levels were measured using the suPARnosticTM double-monoclonal antibody sandwich ELISA on 93 patients with parapneumonic effusions and 47 controls (benign and malignant effusions).MEASUREMENTS AND MAIN RESULTS: Pleural suPAR levels were significantly higher in effusions that loculated versus non-loculated parapneumonic effusions (median 132ng/ml vs 22ng/ml, pCONCLUSIONS: Raised pleural suPAR was predictive of patients receiving more invasive management of parapneumonic effusions and added value to conventional biomarkers. These results need validation in a prospective multicenter trial.

Introduction For decades the management of parapneumonic effusions has relied on pleural fluid pH measurement. However, the eventual requirement for fibrinolytics or surgery is more often dictated by the development of loculations. soluble urokinase Plasminogen Activating Receptor (suPAR) is a novel biomarker released by pleural mesothelial cells in response to infection as part of the fibrinolysis cascade. This study assessed levels of suPAR in the pleural fluid (PF) and serum of patients with parapneumonic effusions. Methods We analysed stored serum and PF from a prospectively collected cohort of patients with effusions due to infection. Cases with frank pus on thoracentesis were excluded. Baseline pleural ultrasounds were performed to assess loculations, with routine bloods and pleural fluid analysis. Clinical outcomes and final diagnoses were confirmed at 12 months by two respiratory consultants. suPAR levels were analysed in duplicate using the suPARnostic® double monoclonal antibody sandwich ELISA assay. Binomial logistic regression was used to compare clinical outcomes to biochemical markers. Mann Whitney test was used to compare suPAR levels between groups. Results Between 2008 and 2016 there were 93 patients with parapneumonic effusions recruited (49 non-loculated and 44 loculated effusions). Median PF suPAR was 88ng/ml (9–614ng/ml). PF suPAR was significantly higher in loculated effusions (median 162ng/ml versus 22ng/ml, p The sensitivity and specificity of PF suPAR >35ng/ml to predict loculations was 100% and 91% respectively. 94% of patients (45/48) with a pf suPAR over 35ng/ml were managed with a chest tube. Using stepwise logistic regression (in a model that included PF pH) PF suPAR was an independent predictor of need for fibrinolytics and surgery (p Conclusion The development of loculations is an important differentiator in the management of parapneumonic effusions. suPAR is a novel biomarker and is part of the fibrinolysis cascade. This is the first study to assess the potential role of suPAR in parapneumonic effusions. PF suPAR was superior to PF pH and serum CRP at predicting loculations as well as requirement for fibrinolytics or surgery. Its true utility needs assessing in a larger prospective study.

Background The BTS pleural disease guidelines recommend all patients with an undiagnosed unilateral pleural undergo computed tomography (CT) of the thorax with contrast.1 However, there is no consensus on whether to include the abdomen and pelvis in the initial examination, with the BTS mesothelioma guidelines recommending this as an area that requires further research.2 Methods We performed a cross-sectional study using prospectively collected data between March 2008 and September 2018 of patients presenting with an undiagnosed pleural effusion. All patients consented for this study, underwent CT thorax, abdomen and pelvis as part of their standard work up and were followed for 12 months or until death, to ensure a robust diagnosis. Results 249 patients were included; mean age 72 (IQR 66–80), 167 (67%) male, WHO PS 0–1 (62%), 2–3 (37%), 190 (76%) out-patients, 147 (59%) right sided, 87 (35%) previous asbestos exposure. The final diagnosis was malignancy in 159 (64%). The CT thorax alone was consistent with the final diagnosis in 171 (69%). There were clinically significant findings below the costophrenic recesses in 59 patients (23.6%). Including the abdomen increased the diagnostic yield of clinically significant findings by 11.6% (n=29). Within the malignant group additional findings were of a primary tumour (6), upstaging of disease (19) and alternative biopsy sites (2). Including the pelvis resulted in 30 additional findings (12%), primary tumours (11), upstaging of disease (13) and alternative biopsy sites (3). 14 (5.6%) had an underlying ovarian cancer – 86% would have been missed if only CT chest and abdomen was performed. In females the pelvic CT revealed additional findings in 18 (22%). Conclusion CT thorax, abdomen and pelvis has a considerably higher diagnostic yield than more limited sequences in the work up of unilateral pleural effusions and this paper lends support to its inclusion for standard of care.

The use of thoracic CT for patients presenting with a unilateral pleural effusion is well established. However, there is no consensus with regard to the inclusion of the entire abdomen and pelvis in the initial imaging protocol. In this prospective UK-based study, 249 patients presenting with a unilateral effusion had a CT thorax/abdomen/pelvis performed. The prevalence of malignancy on thoracic CT was 56% (140/249). Clinically significant findings below the diaphragm were identified in 59 patients (24%). Integrating this approach into standard practice allows more rapid identification of the primary malignancy, upstaging lesions or alternative sites for biopsy.

Introduction: Several factors imply a viral role in the development of pleural infection including low yield on bacterial culture and seasonal variation. The relationship between respiratory viruses and pneumococcal pneumonia is well known but no studies have tested the association with pleural infection. Additionally, Epstein-Barr virus (EBV) has been implicated as a possible cause of ‘undiagnosed effusions’ without being validated. Methods: We analysed serum and pleural fluid (pf) from a prospective cohort of patients with effusions due to infection and biopsy-proven inflammatory pleuritis (IP). Nucleic acids were extracted from pf using the QIAsymphony DSP Virus/Pathogen Kit. Real-time PCR was performed using TaqMan array with 48 pathogen targets. Serum complement fixation testing using influenza and RSV antigen was performed alongside EBV serological tests. Results: From 193 patients including 60 empyema, 50 parapneumonic, 28 IP and 55 cardiac transudates (controls) there were no significant respiratory viral titres in pf. In patients with infective effusions, 21% had serological evidence of recent viral infection (Influenzas A&B or RSV). EBV was present at low levels in 22 pf samples (11%). There was no evidence of acute or re-activated EBV infection in the sera of patients with EBV DNA in pf. Conclusion: This is the first prospective study to test for the presence of viruses in pleural infection. We found no evidence of respiratory viruses within the effusions of either infection or control groups. However, there was serological evidence of recent flu/RSV infection in patients with pleural infection indicating a precedent illness. Results from pf EBV analysis demonstrated latent infection in 11% but no causative role.

Introduction: Increasingly, research is performed on routinely recorded clinical data, such as hospital episode statistics (HES). In uncommon diseases like pleural empyema, this data would be useful in assessing epidemiology. Also, empyema has a significant healthcare tariff and accurate coding ensures appropriate reimbursement. We aimed to assess the accuracy of coding for empyema across three separate UK hospitals. Methods: HES data (J86 code) was extracted for 1 year (Aug 2017 to Aug 2018) from 3 UK hospitals. Cases were verified to assess accuracy using medical notes, radiology, and microbiology. Empyema was defined using BTS criteria. To assess coding sensitivity, data from screened participants in the Pleural Infection Longitudinal Outcome (PILOT) study, for which our hospital was a recruitment centre, was extracted. The coding of these ‘confirmed cases’ was cross checked with hospital data from the same period. Results: Overall, 182 patients with a coded diagnosis of empyema were identified: 124 from a surgical centre. This coding was accurate in 158 cases (86%). Limiting the codes to exclude elective admissions increased the accuracy of coding (to 93%). This also excluded the vast majority (14/21) of empyema secondary to cardiothoracic or upper GI surgery. In patients with a confirmed empyema from the PILOT study, coding was 72% sensitive (18/25). The most common replacement code was ‘effusion otherwise unspecified’. Conclusion: Empyema coding was specific, with >85% of HES codes recorded accurately. However, in a prospectively collected cohort of patients, known clinically to have empyema, coding was around 70% sensitive. Excluding codes for elective admissions removed 2/3 of post-surgical cases.

Summary Background Transbronchial lung cryobiopsy (TBLC) is a novel technique for sampling lung tissue for interstitial lung disease diagnosis. The aim of this study was to establish the diagnostic accuracy of TBLC compared with surgical lung biopsy (SLB), in the context of increasing use of TBLC in clinical practice as a less invasive biopsy technique. Methods COLDICE was a prospective, multicentre, diagnostic accuracy study investigating diagnostic agreement between TBLC and SLB, across nine Australian tertiary hospitals. Patients with interstitial lung disease aged between 18 and 80 years were eligible for inclusion if they required histopathological evaluation to aid diagnosis, after detailed baseline evaluation. After screening at a centralised multidisciplinary discussion (MDD), patients with interstitial lung disease referred for lung biopsy underwent sequential TBLC and SLB under one anaesthetic. Each tissue sample was assigned a number between 1 and 130, allocated in a computer-generated random sequence. Encoded biopsy samples were then analysed by masked pathologists. At subsequent MDD, de-identified cases were discussed twice with either TBLC or SLB along with clinical and radiological data, in random non-consecutive order. Co-primary endpoints were agreement of histopathological features in TBLC and SLB for patterns of definite or probable usual interstitial pneumonia, indeterminate for usual interstitial pneumonia, and alternative diagnosis; and for agreement of consensus clinical diagnosis using TBLC and SLB at MDD. Concordance and κ values were calculated for each primary endpoint. This study is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12615000718549. Findings Between March 15, 2016, and April 15, 2019, we enrolled 65 patients (31 [48%] men, 34 [52%] women; mean age 66·1 years [SD 9·3]; forced vital capacity 83·7% [SD 14·2]; diffusing capacity for carbon monoxide 63·4% [SD 12·8]). TBLC (7·1 mm, SD 1·9) and SLB (46·5 mm, 14·9) samples were each taken from two separate ipsilateral lobes. Histopathological agreement between TBLC and SLB was 70·8% (weighted κ 0·70, 95% CI 0·55–0·86); diagnostic agreement at MDD was 76·9% (κ 0·62, 0·47–0·78). For TBLC with high or definite diagnostic confidence at MDD (39 [60%] of 65 cases), 37 (95%) were concordant with SLB diagnoses. In the 26 (40%) of 65 cases with low-confidence or unclassifiable TBLC diagnoses, SLB reclassified six (23%) to alternative high-confidence or definite MDD diagnoses. Mild-moderate airway bleeding occurred in 14 (22%) patients due to TBLC. The 90-day mortality was 2% (one of 65 patients), following acute exacerbation of idiopathic pulmonary fibrosis. Interpretation High levels of agreement between TBLC and SLB for both histopathological interpretation and MDD diagnoses were shown. The TBLC MDD diagnoses made with high confidence were particularly reliable, showing excellent concordance with SLB MDD diagnoses. These data support the clinical utility of TBLC in interstitial lung disease diagnostic algorithms. Further studies investigating the safety profile of TBLC are needed. Funding University of Sydney, Hunter Medical Research Institute, Erbe Elektromedizin, Medtronic, Cook Medical, Rymed, Karl-Storz, Zeiss, and Olympus.

Unilateral pleural effusions are a common diagnostic challenge for the respiratory physician. In the majority a diagnosis can be made after medical history, computerised tomography (CT) and pleural fluid analysis [1]. A proportion of patients will require a pleural biopsy but following this a minority will remain undiagnosed and are defined as idiopathic/inflammatory pleuritis (IP) [2]. These patients often require extended follow up to ensure effusion resolution and exclude malignancy. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Arnold has nothing to disclose. Conflict of interest: Dr. Suri has nothing to disclose. Conflict of interest: Dr. Hamilton has nothing to disclose. Conflict of interest: Dr. Morley has nothing to disclose. Conflict of interest: Dr. Medford has nothing to disclose. Conflict of interest: Dr. Vipond has nothing to disclose. Conflict of interest: Dr. Muir has nothing to disclose. Conflict of interest: Dr. Maskell has nothing to disclose.

Malignant pleural effusions (MPEs) are a common diagnostic challenge for the respiratory physician. Their incidence is increasing with an estimated 150,000 new cases in the USA annually (1). As well as an increasing incidence, patients with MPE are presenting older due to ageing population and improved survival from primary cancer. The survival from diagnosis of all-cause MPEs is poor at around 5 months (2). Therefore, a clear and minimally invasive pathway for investigating these patients is essential. Currently, the mainstay of early investigation is computed tomography (CT) scanning and pleural fluid sampling for cytological analysis.