Antibiotic pharmacokinetics in infected pleural effusions.

Pleural infection is usually treated with empirical broad-spectrum antibiotics, but limited data exist on their penetrance into the infected pleural space. We performed a pharmacokinetic study analysing the concentration of five intravenous antibiotics across 146 separate time points in 35 patients (amoxicillin, metronidazole, piperacillin-tazobactam, clindamycin and cotrimoxazole). All antibiotics tested, apart from co-trimoxazole, reach pleural fluid levels equivalent to levels within the blood and well above the relevant minimum inhibitory concentrations. The results demonstrate that concerns about the penetration of commonly used antibiotics, apart from co-trimoxazole, into the infected pleural space are unfounded.

Trial Protocol: Reaccumulation rate of pleural effusions after therapeutic aspiration: An observational cohort study to determine baseline factors associated with rate of pleural fluid reaccumulation following therapeutic aspiration in patients with malignant pleural effusion attending a pleural clinic (REPEAT).

Background: Malignant pleural effusion (MPE) is the build-up of pleural fluid in the space between the lung and chest wall due to advanced cancer. It is treated initially by large volume drainage (therapeutic aspiration). If the fluid reaccumulates, a definitive procedure is performed. There is wide variation in rate of reaccumulation. Patients with rapid reaccumulation often attend hospital as an emergency. Conversely, patients with slow reaccumulation do not need a definitive procedure and may experience cancelled or unnecessary procedures. This study aims to create and validate a multivariable prediction model to predict how quickly pleural fluid will reaccumulate in patients with MPE following therapeutic aspiration. Research question: Can we predict how quickly pleural fluid will reaccumulate in patients with MPEs? Methods: A total of 200 patients with known or suspected MPE attending for therapeutic aspiration will be recruited from 5-10 UK hospitals over 20 months. Patients will be enrolled prior to undergoing aspiration. Following this, they will undergo chest X-ray, which will be repeated one week later (treatment as usual). Rate of reaccumulation will be calculated based on change of size of the effusion seen on X-ray. Data will be collected on common clinical biomarkers e.g., size of effusion on pre-aspiration chest X-ray, volume of fluid drained. This data will be analysed to create a clinical score.A further validation cohort of 40 patients will be enrolled in parallel with creation of the score. Anticipated impact: The ability to predict rate of reaccumulation of MPE will enable patients and clinicians to make better informed treatment decisions. For patients with predicted rapid reaccumulation, a definitive procedure could be offered as first-line treatment, rather than a therapeutic aspiration. This will prevent emergency hospital admissions and decrease number of procedures. By contrast, patients whose effusions will recur slowly may avoid an unnecessary procedure.

People with incurable cancer commonly feel breathless due to buildup of fluid around the lung. We treat this by draining fluid off, but it often comes back. When this happens, we offer the patient a permanent implanted drain, so they can drain the fluid off at home. However, sometimes the fluid builds up very quickly. The patient becomes very breathless and needs an emergency hospital admission. In other people, the fluid builds up slowly and they may never need another drain. The aim of this study is to improve treatment by finding a way to predict how quickly fluid will come back. It will be run in five hospitals across England and involve 240 patients over three years. When patients first come to have fluid drained, we will record information about them and their disease. We will measure how quickly the fluid comes back and record hospital admissions and need for fluid drainage over the following three months. We will use this information to create a clinical score. We will then test this score in a second group of patients to make sure it works. The idea for this study came from one of our patients who had just had fluid drained and asked, 'when will it come back?' We couldn't answer his question and therefore developed this study. Our patients and the public have been involved in the design of this study and will continue to be involved. This score will be used to inform patients so they can choose the best treatment for them. If we know the fluid will build up quickly, we can offer patients a permanent drain straight away. If patients know their fluid will build up slowly, they may choose to have the fluid drained when needed without a permanent drain.

Are aerosols generated during lung function testing in patients and healthy volunteers? Results from the AERATOR study.

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.

Aerosol emission from the respiratory tract: an analysis of aerosol generation from oxygen delivery systems.

INTRODUCTION: continuous positive airway pressure (CPAP) and high-flow nasal oxygen (HFNO) provide enhanced oxygen delivery and respiratory support for patients with severe COVID-19. CPAP and HFNO are currently designated as aerosol-generating procedures despite limited high-quality experimental data. We aimed to characterise aerosol emission from HFNO and CPAP and compare with breathing, speaking and coughing. MATERIALS AND METHODS: Healthy volunteers were recruited to breathe, speak and cough in ultra-clean, laminar flow theatres followed by using CPAP and HFNO. Aerosol emission was measured using two discrete methodologies, simultaneously. Hospitalised patients with COVID-19 had cough recorded using the same methodology on the infectious diseases ward. RESULTS: In healthy volunteers (n=25 subjects; 531 measures), CPAP (with exhalation port filter) produced less aerosol than breathing, speaking and coughing (even with large >50 L/min face mask leaks). Coughing was associated with the highest aerosol emissions of any recorded activity. HFNO was associated with aerosol emission, however, this was from the machine. Generated particles were small (<1 µm), passing from the machine through the patient and to the detector without coalescence with respiratory aerosol, thereby unlikely to carry viral particles. More aerosol was generated in cough from patients with COVID-19 (n=8) than volunteers. CONCLUSIONS: In healthy volunteers, standard non-humidified 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 be the main aerosol-generating risk out of all measured activities.

Patient outcomes after hospitalisation with COVID-19 and implications for follow-up: results from a prospective UK cohort.

The longer-term consequences of SARS-CoV-2 infection are uncertain. Consecutive patients hospitalised with COVID-19 were prospectively recruited to this observational study (n=163). At 8-12 weeks postadmission, survivors were invited to a systematic clinical follow-up. Of 131 participants, 110 attended the follow-up clinic. Most (74%) had persistent symptoms (notably breathlessness and excessive fatigue) and limitations in reported physical ability. However, clinically significant abnormalities in chest radiograph, exercise tests, blood tests and spirometry were less frequent (35%), especially in patients not requiring supplementary oxygen during their acute infection (7%). Results suggest that a holistic approach focusing on rehabilitation and general well-being is paramount.

Investigation of a unilateral pleural effusion: What CT scan coverage is optimal?

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.

Novel pleural-bladder pump in malignant pleural effusions: from animal model to man.

Malignant pleural effusion is common and causes disabling symptoms such as breathlessness. Treatments are palliative and centred around improving symptoms and quality of life but an optimal management strategy is yet to be universally agreed. A novel pump system, allowing fluid to be moved from the pleural space to the urinary bladder, may have a role for the management of recurrent malignant pleural effusion. We hereby describe the first animal study using this device and the results of the first application in patients.

Pleural Fluid suPAR Levels Predict the Need for Invasive Management in Parapneumonic Effusions.

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 suPAR (soluble urokinase plasminogen activator receptor), a potential biomarker of pleural fluid loculation, to predict the need for invasive management compared with conventional fluid biomarkers (pH, glucose, and lactate dehydrogenase) 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 suPARnostic double-monoclonal antibody sandwich ELISA on 93 patients with parapneumonic effusions and 47 control subjects (benign and malignant effusions).Measurements and Main Results: Pleural suPAR levels were significantly higher in effusions that were loculated versus nonloculated parapneumonic effusions (median, 132 ng/ml vs. 22 ng/ml; P < 0.001). Pleural suPAR could more accurately predict the subsequent insertion of a chest tube with an area under the curve (AUC) of 0.93 (95% confidence interval, 0.89-0.98) compared with pleural pH (AUC 0.82; 95% confidence interval, 0.73-0.90). suPAR was superior to the combination of conventional pleural biomarkers (pH, glucose, and lactate dehydrogenase) when predicting the referral for intrapleural fibrinolysis or thoracic surgery (AUC 0.92 vs. 0.76).Conclusions: 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.

MesoTRAP: a feasibility study that includes a pilot clinical trial comparing video-assisted thoracoscopic partial pleurectomy decortication with indwelling pleural catheter in patients with trapped lung due to malignant pleural mesothelioma designed to address recruitment and randomisation uncertainties and sample size requirements for a phase III trial.

Introduction: One of the most debilitating symptoms of malignant pleural mesothelioma (MPM) is dyspnoea caused by pleural effusion. MPM can be complicated by the presence of tumour on the visceral pleura preventing the lung from re-expanding, known as trapped lung (TL). There is currently no consensus on the best way to manage TL. One approach is insertion of an indwelling pleural catheter (IPC) under local anaesthesia. Another is video-assisted thoracoscopic partial pleurectomy/decortication (VAT-PD). Performed under general anaesthesia, VAT-PD permits surgical removal of the rind of tumour from the visceral pleura thereby allowing the lung to fully re-expand. Methods and analysis: MesoTRAP is a feasibility study that includes a pilot multicentre, randomised controlled clinical trial comparing VAT-PD with IPC in patients with TL and pleural effusion due to MPM. The primary objective is to measure the SD of visual analogue scale scores for dyspnoea following randomisation and examine the patterns of change over time in each treatment group. Secondary objectives include documenting survival and adverse events, estimating the incidence and prevalence of TL in patients with MPM, examining completion of alternative forms of data capture for economic evaluation and determining the ability to randomise 38 patients in 18 months. Ethics and dissemination: This study was approved by the East of England-Cambridge Central Research Ethics Committee and the Health Research Authority (reference number 16/EE/0370). We aim to publish the outputs of this work in international peer-reviewed journals compliant with an Open Access policy. Trial registration: NCT03412357.

Early specialist palliative care on quality of life for malignant pleural mesothelioma: a randomised controlled trial.

PURPOSE: Malignant pleural mesothelioma (MPM) has a high symptom burden and poor survival. Evidence from other cancer types suggests some benefit in health-related quality of life (HRQoL) with early specialist palliative care (SPC) integrated with oncological services, but the certainty of evidence is low. METHODS: We performed a multicentre, randomised, parallel group controlled trial comparing early referral to SPC versus standard care across 19 hospital sites in the UK and one large site in Western Australia. Participants had newly diagnosed MPM; main carers were additionally recruited. INTERVENTION: review by SPC within 3 weeks of allocation and every 4 weeks throughout the study. HRQoL was assessed at baseline and every 4 weeks with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30. PRIMARY OUTCOME: change in EORTC C30 Global Health Status 12 weeks after randomisation. RESULTS: Between April 2014 and October 2016, 174 participants were randomised. There was no significant between group difference in HRQoL score at 12 weeks (mean difference 1.8 (95% CI -4.9 to 8.5; p=0.59)). HRQoL did not differ at 24 weeks (mean difference -2.0 (95% CI -8.6 to 4.6; p=0.54)). There was no difference in depression/anxiety scores at 12 weeks or 24 weeks. In carers, there was no difference in HRQoL or mood at 12 weeks or 24 weeks, although there was a consistent preference for care, favouring the intervention arm. CONCLUSION: There is no role for routine referral to SPC soon after diagnosis of MPM for patients who are cared for in centres with good access to SPC when required. TRIAL REGISTRATION NUMBER: ISRCTN18955704.

Defining the minimal important difference for the visual analogue scale assessing dyspnea in patients with malignant pleural effusions.

BACKGROUND: The minimal important difference (MID) is essential for interpreting the results of randomised controlled trials (RCTs). Despite a number of RCTs in patients with malignant pleural effusions (MPEs) which use the visual analogue scale for dyspnea (VASD) as an outcome measure, the MID has not been established. METHODS: Patients with suspected MPE undergoing a pleural procedure recorded their baseline VASD and their post-procedure VASD (24 hours after the pleural drainage), and in parallel assessed their breathlessness on a 7 point Likert scale. FINDINGS: The mean decrease in VASD in patients with a MPE reporting a 'small but just worthwhile decrease' in their dyspnea (i.e. equivalent to the MID) was 19mm (95% CI 14-24mm). The mean drainage volume required to produce a change in VASD of 19mm was 760ml. INTERPRETATION: The mean MID for the VASD in patients with a MPE undergoing a pleural procedure is 19mm (95% CI 14-24mm). Thus choosing an improvement of 19mm in the VASD would be justifiable in the design and analysis of future MPE studies.

Pleural fluid adenosine deaminase (pfADA) in the diagnosis of tuberculous effusions in a low incidence population.

INTRODUCTION: Previous studies have assessed the diagnostic ability of pleural fluid adenosine deaminase (pfADA) in detecting tuberculous pleural effusions, with good specificity and sensitivity reported. However, in North Western Europe pfADA is not routinely used in the investigation of a patient with an undiagnosed pleural effusion, mainly due to a lack of evidence as to its utility in populations with low mycobacterium tuberculosis (mTB) incidence. METHODS: Patients presenting with an undiagnosed pleural effusion to a tertiary pleural centre in South-West England over a 3 year period, were prospectively recruited to a pleural biomarker study. Pleural fluid from consecutive patients with robust 12-month follow up data and confirmed diagnosis were sent for pfADA analysis. RESULTS: Of 338 patients enrolled, 7 had confirmed tuberculous pleural effusion (2%). All mTB effusions were lymphocyte predominant with a median pfADA of 72.0 IU/L (range- 26.7 to 91.5) compared to a population median of 12.0 IU/L (range- 0.3 to 568.4). The optimal pfADA cut off was 35 IU/L, which had a negative predictive value (NPV) of 99.7% (95% CI; 98.2-99.9%) for the exclusion of mTB, and sensitivity of 85.7% (95% CI; 42.2-97.6%) with an area under the curve of 0.88 (95% CI; 0.732-1.000). DISCUSSION: This is the first study examining the diagnostic utility of pfADA in a low mTB incidence area. The chance of an effusion with a pfADA under 35 IU/L being of tuberculous aetiology was negligible. A pfADA of over 35 IU/L in lymphocyte-predominant pleural fluid gives a strong suspicion of mTB.

Testing mapping algorithms of the cancer-specific EORTC QLQ-C30 onto EQ-5D in malignant mesothelioma.

BACKGROUND: In order to estimate utilities for cancer studies where the EQ-5D was not used, the EORTC QLQ-C30 can be used to estimate EQ-5D using existing mapping algorithms. Several mapping algorithms exist for this transformation, however, algorithms tend to lose accuracy in patients in poor health states. The aim of this study was to test all existing mapping algorithms of QLQ-C30 onto EQ-5D, in a dataset of patients with malignant pleural mesothelioma, an invariably fatal malignancy where no previous mapping estimation has been published. METHODS: Health related quality of life (HRQoL) data where both the EQ-5D and QLQ-C30 were used simultaneously was obtained from the UK-based prospective observational SWAMP (South West Area Mesothelioma and Pemetrexed) trial. In the original trial 73 patients with pleural mesothelioma were offered palliative chemotherapy and their HRQoL was assessed across five time points. This data was used to test the nine available mapping algorithms found in the literature, comparing predicted against observed EQ-5D values. The ability of algorithms to predict the mean, minimise error and detect clinically significant differences was assessed. RESULTS: The dataset had a total of 250 observations across 5 timepoints. The linear regression mapping algorithms tested generally performed poorly, over-estimating the predicted compared to observed EQ-5D values, especially when observed EQ-5D was below 0.5. The best performing algorithm used a response mapping method and predicted the mean EQ-5D with accuracy with an average root mean squared error of 0.17 (Standard Deviation; 0.22). This algorithm reliably discriminated between clinically distinct subgroups seen in the primary dataset. CONCLUSIONS: This study tested mapping algorithms in a population with poor health states, where they have been previously shown to perform poorly. Further research into EQ-5D estimation should be directed at response mapping methods given its superior performance in this study.

A clinical score (RAPID) to identify those at risk for poor outcome at presentation in patients with pleural infection.

BACKGROUND: Pleural infection is associated with a high morbidity and mortality. Development of a validated clinical risk score at presentation to identify those at high risk of dying would enable patient triage and may help formulate early management strategies. METHODS: A clinical risk score was derived based on data from patients entering the multicenter UK pleural infection trial (first Multicenter Intrapleural Sepsis Trial [MIST1], n=411). From 22 baseline clinical characteristics, model selection was undertaken to find variables predictive of poor clinical outcome. Outcomes were mortality at 3 months (primary), need for surgical intervention at 3 months, and time from randomization to discharge. The derived scoring system RAPID (renal, age, purulence, infection source, and dietary factors) was validated using patients enrolled in the subsequent MIST2 trial (n=191). RESULTS: Age, urea, albumin, hospital-acquired infection, and nonpurulence predicted poor outcome. Patients were stratified into low-risk (0-2), medium-risk (3-4), and high-risk (5-7) groups. Using the low-risk group as a reference, a RAPID score of 3 to 4 and >4 was associated with an OR of 24.4 (95% CI, 3.1-186.7; P=.002) and 192.4 (95% CI, 25.0-1480.4; P<.001), respectively, for death at 3 months. In the validation cohort (MIST2), a medium-risk RAPID score was nonsignificantly associated with mortality (OR, 3.2; 95% CI, 0.8-13.2; P=.11), and a high-risk score was associated with increased mortality (OR, 14.1; 95% CI, 3.5-56.8; P<.001). Hospitalization duration was associated with increasing RAPID score (score 0-2: median duration=7, interquartile range 6-13; score>5: median duration=15, interquartile range 9-28, P=.08). CONCLUSIONS: The RAPID score may permit risk stratification of patients with pleural infection at presentation.

Intrapleural use of tissue plasminogen activator and DNase in pleural infection.

BACKGROUND: More than 30% of patients with pleural infection either die or require surgery. Drainage of infected fluid is key to successful treatment, but intrapleural fibrinolytic therapy did not improve outcomes in an earlier, large, randomized trial. METHODS: We conducted a blinded, 2-by-2 factorial trial in which 210 patients with pleural infection were randomly assigned to receive one of four study treatments for 3 days: double placebo, intrapleural tissue plasminogen activator (t-PA) and DNase, t-PA and placebo, or DNase and placebo. The primary outcome was the change in pleural opacity, measured as the percentage of the hemithorax occupied by effusion, on chest radiography on day 7 as compared with day 1. Secondary outcomes included referral for surgery, duration of hospital stay, and adverse events. RESULTS: The mean (±SD) change in pleural opacity was greater in the t-PA-DNase group than in the placebo group (-29.5±23.3% vs. -17.2±19.6%; difference, -7.9%; 95% confidence interval [CI], -13.4 to -2.4; P=0.005); the change observed with t-PA alone and with DNase alone (-17.2±24.3 and -14.7±16.4%, respectively) was not significantly different from that observed with placebo. The frequency of surgical referral at 3 months was lower in the t-PA-DNase group than in the placebo group (2 of 48 patients [4%] vs. 8 of 51 patients [16%]; odds ratio for surgical referral, 0.17; 95% CI, 0.03 to 0.87; P=0.03) but was greater in the DNase group (18 of 46 patients [39%]) than in the placebo group (odds ratio, 3.56; 95% CI, 1.30 to 9.75; P=0.01). Combined t-PA-DNase therapy was associated with a reduction in the hospital stay, as compared with placebo (difference, -6.7 days; 95% CI, -12.0 to -1.9; P=0.006); the hospital stay with either agent alone was not significantly different from that with placebo. The frequency of adverse events did not differ significantly among the groups. CONCLUSIONS: Intrapleural t-PA-DNase therapy improved fluid drainage in patients with pleural infection and reduced the frequency of surgical referral and the duration of the hospital stay. Treatment with DNase alone or t-PA alone was ineffective. (Funded by an unrestricted educational grant to the University of Oxford from Roche UK and by others; Current Controlled Trials number, ISRCTN57454527.).