Early Video-assisted Thoracoscopic Surgery or Intrapleural Enzyme Therapy in Pleural Infection: A Feasibility Randomized Controlled Trial. The Third Multicenter Intrapleural Sepsis Trial-MIST-3.

Rationale: Assessing the early use of video-assisted thoracoscopic surgery (VATS) or intrapleural enzyme therapy (IET) in pleural infection requires a phase III randomized controlled trial (RCT). Objectives: To establish the feasibility of randomization in a surgery-versus-nonsurgery trial as well as the key outcome measures that are important to identify relevant patient-centered outcomes in a subsequent RCT. Methods: The MIST-3 (third Multicenter Intrapleural Sepsis Trial) was a prospective multicenter RCT involving eight U.K. centers combining on-site and off-site surgical services. The study enrolled all patients with a confirmed diagnosis of pleural infection and randomized those with ongoing pleural sepsis after an initial period (as long as 24 h) of standard care to one of three treatment arms: continued standard care, early IET, or a surgical opinion with regard to early VATS. The primary outcome was feasibility based on >50% of eligible patients being successfully randomized, >95% of randomized participants retained to discharge, and >80% of randomized participants retained to 2 weeks of follow-up. The analysis was performed per intention to treat. Measurements and Main Results: Of 97 eligible patients, 60 (62%) were randomized, with 100% retained to discharge and 84% retained to 2 weeks. Baseline demographic, clinical, and microbiological characteristics of the patients were similar across groups. Median times to intervention were 1.0 and 3.5 days in the IET and surgery groups, respectively (P = 0.02). Despite the difference in time to intervention, length of stay (from randomization to discharge) was similar in both intervention arms (7 d) compared with standard care (10 d) (P = 0.70). There were no significant intergroup differences in 2-month readmission and further intervention, although the study was not adequately powered for this outcome. Compared with VATS, IET demonstrated a larger improvement in mean EuroQol five-dimension health utility index (five-level edition) from baseline (0.35) to 2 months (0.83) (P = 0.023). One serious adverse event was reported in the VATS arm. Conclusions: This is the first multicenter RCT of early IET versus early surgery in pleural infection. Despite the logistical challenges posed by the coronavirus disease (COVID-19) pandemic, the study met its predefined feasibility criteria, demonstrated potential shortening of length of stay with early surgery, and signals toward earlier resolution of pain and a shortened recovery with IET. The study findings suggest that a definitive phase III study is feasible but highlights important considerations and significant modifications to the design that would be required to adequately assess optimal initial management in pleural infection.The trial was registered on ISRCTN (number 18,192,121).

Clinical characteristics of chylothorax: results from the International Collaborative Effusion database.

Background: Chylothorax is an uncommon medical condition for which limited data are available regarding the contemporary aetiology, management and outcomes. The goal of this study was to better define these poorly characterised features. Methods: The medical records of adult patients diagnosed with chylothorax at 12 centres across Europe, America and South Africa from 2009-2021 were retrospectively reviewed. Descriptive and inferential statistics were performed. Results: 77 patients (median age 69 years, male to female ratio 1.5) were included. Subacute dyspnoea was the most typical presenting symptom (66%). The commonest cause of chylothorax was malignancy (68.8%), with lymphoma accounting for 62% of these cases. Other aetiologies were trauma (13%), inflammatory/miscellaneous conditions (11.7%) and idiopathic cases (6.5%). At the initial thoracentesis, the pleural fluid appeared milky in 73%, was exudative in 89% and exhibited triglyceride concentrations >100 mg·dL-1 in 88%. Lymphangiography/lymphoscintigraphy were rarely ordered (3%), and demonstration of chylomicrons in pleural fluid was never ascertained. 67% of patients required interventional pleural procedures. Dietary measures were infrequently followed (36%). No patient underwent thoracic duct ligation or embolisation. Morbidity included infections (18%), and thrombosis in malignant aetiologies (16%). The 1-year mortality was 47%. Pleural fluid protein >3.5 mg·dL-1 (sub-distribution hazard ratio (SHR) 4.346) or lactate dehydrogenase <500 U·L-1 (SHR 10.21) increased the likelihood of effusion resolution. Pleural fluid protein ≤3.5 mg·dL-1 (HR 4.047), bilateral effusions (HR 2.749) and a history of respiratory disease (HR 2.428) negatively influenced survival. Conclusion: Chylothoraces have a poor prognosis and most require pleural interventions. Despite the standard recommendations, lymphatic imaging is seldom used, nor are dietary restrictions followed.

Evidence-based training and certification: the ERS thoracic ultrasound training programme.

Thoracic ultrasound has developed into an integral part of the respiratory physician's diagnostic and therapeutic toolbox, with high diagnostic accuracy for many diseases causing acute or chronic respiratory symptoms. However, it is vitally important that the operator has received the appropriate education and training to ensure a systematic and thorough examination, correct image interpretation, and that they then have the appropriate skills to integrate all the findings for patient benefit. In this review, we present the new European Respiratory Society thoracic ultrasound training programme, including a discussion of curriculum development, its implementation, and trainee evaluation. This programme enables participants to gain competence in thoracic ultrasound through structured, evidence-based training with robustly validated assessments and certification. The training programme consists of three components: an online, theoretical part (part 1), which is accessible all year; a practical course (part 2), with four courses held each year (two online courses and two on-site courses); and an examination (part 3) comprising an objective structured clinical examination (OSCE), which is hosted each year at the European Respiratory Society Congress.

Achieving Molecular Profiling in Pleural Biopsies: A Multicenter, Retrospective Cohort Study.

BACKGROUND: Pleural biopsy findings offer greater diagnostic sensitivity in malignant pleural effusions compared with pleural fluid. The adequacy of pleural biopsy techniques in achieving molecular marker status has not been studied, and such information (termed "actionable" histology) is critical in providing a rational, efficient, and evidence-based approach to diagnostic investigation. RESEARCH QUESTION: What is the adequacy of various pleural biopsy techniques at providing adequate molecular diagnostic information to guide treatment in malignant pleural effusions? STUDY DESIGN AND METHODS: This study analyzed anonymized data on 183 patients from four sites across three countries in whom pleural biopsy results had confirmed a malignant diagnosis and molecular profiling was relevant for the diagnosed cancer type. The primary outcome measure was adequacy of pleural biopsy for achieving molecular marker status. Secondary outcomes included clinical factors predictive of achieving a molecular diagnosis. RESULTS: The median age of patients was 71 years (interquartile range, 63-78 years), with 92 of 183 (50%) male. Of the 183 procedures, 105 (57%) were local anesthetic thoracoscopies (LAT), 12 (7%) were CT scan guided, and 66 (36%) were ultrasound guided. Successful molecular marker analysis was associated with mode of biopsy, with LAT having the highest yield and ultrasound-guided biopsy the lowest (LAT vs CT scan guided vs ultrasound guided: LAT yield, 95%; CT scan guided, 86%; and ultrasound guided, 77% [P = .004]). Biopsy technique and size of biopsy sample were independently associated with successful molecular marker analysis. LAT had an adjusted OR for successful diagnosis of 30.16 (95% CI, 3.15-288.56; P = .003) and biopsy sample size an OR of 1.18 (95% CI, 1.02-1.37) per millimeter increase in tissue sample size (P < .03). INTERPRETATION: Although previous studies have shown comparable overall diagnostic yields, in the modern era of targeted therapies, this study found that LAT offers far superior results to image-guided techniques at achieving molecular profiling and remains the optimal diagnostic tool.

The bacteriology of pleural infection (TORPIDS): an exploratory metagenomics analysis through next generation sequencing.

BACKGROUND: Pleural infection is a common and severe disease with high morbidity and mortality worldwide. The knowledge of pleural infection bacteriology remains incomplete, as pathogen detection methods based on culture have insufficient sensitivity and are biased to selected microbes. We designed a study with the aim to discover and investigate the total microbiome of pleural infection and assess the correlation between bacterial patterns and 1-year survival of patients. METHODS: We assessed 243 pleural fluid samples from the PILOT study, a prospective observational study on pleural infection, with 16S rRNA next generation sequencing. 20 pleural fluid samples from patients with pleural effusion due to a non-infectious cause and ten PCR-grade water samples were used as controls. Downstream analysis was done with the DADA2 pipeline. We applied multivariate Cox regression analyses to investigate the association between bacterial patterns and 1-year survival of patients with pleural infection. FINDINGS: Pleural infection was predominately polymicrobial (192 [79%] of 243 samples), with diverse bacterial frequencies observed in monomicrobial and polymicrobial disease and in both community-acquired and hospital-acquired infection. Mixed anaerobes and other Gram-negative bacteria predominated in community-acquired polymicrobial infection whereas Streptococcus pneumoniae prevailed in monomicrobial cases. The presence of anaerobes (hazard ratio 0·46, 95% CI 0·24-0·86, p=0·015) or bacteria of the Streptococcus anginosus group (0·43, 0·19-0·97, p=0·043) was associated with better patient survival, whereas the presence (5·80, 2·37-14·21, p<0·0001) or dominance (3·97, 1·20-13·08, p=0·024) of Staphylococcus aureus was linked with lower survival. Moreover, dominance of Enterobacteriaceae was associated with higher risk of death (2·26, 1·03-4·93, p=0·041). INTERPRETATION: Pleural infection is a predominantly polymicrobial infection, explaining the requirement for broad spectrum antibiotic cover in most individuals. High mortality infection associated with S aureus and Enterobacteriaceae favours more aggressive, with a narrower spectrum, antibiotic strategies. FUNDING: UK Medical Research Council, National Institute for Health Research Oxford Biomedical Research Centre, Wellcome Trust, Oxfordshire Health Services Research Committee, Chinese Academy of Medical Sciences, and John Fell Fund.

Successful awake proning is associated with improved clinical outcomes in patients with COVID-19: single-centre high-dependency unit experience.

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

Intercostal vessel screening prior to pleural interventions by the respiratory physician: a prospective study of real world practice.

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

Biological effect of tissue plasminogen activator (t-PA) and DNase intrapleural delivery in pleural infection patients.

Background: Pleural infection (PI) is a major global disease with an increasing incidence, and pleural fluid (PF) drainage is essential for the successful treatment. The MIST2 study demonstrated that intrapleural administration of tissue plasminogen activator (t-PA) and DNase, or t-PA alone increased the volume of drained PF. Mouse model studies have suggested that the volume increase is due to the interaction of the pleura with the t-PA via the monocyte chemoattractant protein 1 (MCP-1) pathway. We designed a study to determine the time frame of drained PF volume induction on intrapleural delivery of t-PA±DNase in humans, and to test the hypothesis that the induction is mediated by the MCP-1 pathway. Methods: Data and samples from the MIST2 study were used (210 PI patients randomised to receive for 3 days either: t-PA and DNase, t-PA and placebo, DNase and placebo or double placebo). PF MCP-1 levels were measured by ELISA. One-way and two-way analysis of variance (ANOVA) with Tukey's post hoc tests were used to estimate statistical significance. Pearson's correlation coefficient was used to assess linear correlation. Results: Intrapleural administration of t-PA±DNase stimulated a statistically significant rise in the volume of drained PF during the treatment period (days 1-3). No significant difference was detected between any groups during the post-treatment period (days 5-7). Intrapleural administration of t-PA increased MCP-1 PF levels during treatment; however, no statistically significant difference was detected between patients who received t-PA and those who did not. PF MCP-1 expression was not correlated to the drug given nor the volume of drained PF. Conclusions: We conclude that the PF volume drainage increment seen with the administration of t-PA does not appear to act solely via activation of the MCP-1 pathway.

Prospective Analysis of the Predictive Value of Sonographic Pleural Fluid Echogenicity for the Diagnosis of Exudative Effusion.

BACKGROUND: Pleural effusion echogenicity on ultrasound has previously been suggested to allow identification of exudates. A case series suggested that homogenously echogenic effusions are always exudates. With modern imaging techniques and more advanced ultrasound technology, this may no longer be true. OBJECTIVES: This study aims to prospectively assess the predictive value of echogenicity in the identification of exudates. METHOD: Patients undergoing thoracic ultrasound before pleural fluid sampling were analysed prospectively (n = 140). Pleural fluid was classified as an exudate if both fluid total protein (TP) > 29 g/L and fluid lactate dehydrogenase (LDH) > 2/3 upper limit of normal serum LDH (which is 255 IU/L in females and 235 IU/L in males) were present. If only one of these criteria was met, the effusion was considered to have discordant biochemistry. RESULTS: Fifty-five (39%) patients had non-echogenic and 85 (61%) had echogenic effusions. Six (7.1%) patients with echogenic effusions had transudates; the median fluid TP for this group was 18.5 g/L (IQR 9.75) and median LDH 63.0 IU/L (IQR 40.3). The specificity of echogenicity identifying exudates from transudates, excluding patients with discordant biochemistry, was 57.1%, positive predictive value (PPV) 90.3%, sensitivity 65.1%, and negative predictive value (NPV) 21.0%. The specificity of echogenicity identifying exudates (including discordant biochemistry) from transudates was 57.1%, PPV 92.9%, sensitivity 62.7%, and NPV 14.5%. CONCLUSIONS: Echogenicity of a pleural effusion has a low specificity for identifying an underlying exudate, and the echogenic qualities of the fluid should not influence clinical decision-making.

Does attempting talc pleurodesis affect subsequent indwelling pleural catheter (IPC)-related non-draining septated pleural effusion and IPC-related spontaneous pleurodesis?

Prior talc pleurodesis does not result in worsened outcomes from subsequent indwelling pleural catheter use, and patients should not be dissuaded from choosing talc as a primary treatment for recurrent pleural effusion. http://ow.ly/qAAC30mYmr3.

The Hospital and Patient Burden of Indwelling Pleural Catheters: A Retrospective Case Series of 210 Indwelling Pleural Catheter Insertions.

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

Randomized Controlled Trial of Urokinase versus Placebo for Nondraining Malignant Pleural Effusion.

RATIONALE: Patients with malignant pleural effusion experience breathlessness, which is treated by drainage and pleurodesis. Incomplete drainage results in residual dyspnea and pleurodesis failure. Intrapleural fibrinolytics lyse septations within pleural fluid, improving drainage. OBJECTIVES: To assess the effects of intrapleural urokinase on dyspnea and pleurodesis success in patients with nondraining malignant effusion. METHODS: We conducted a prospective, double-blind, randomized trial. Patients with nondraining effusion were randomly allocated in a 1:1 ratio to intrapleural urokinase (100,000 IU, three doses, 12-hourly) or matched placebo. MEASUREMENTS AND MAIN RESULTS: Co-primary outcome measures were dyspnea (average daily 100-mm visual analog scale scores over 28 d) and time to pleurodesis failure to 12 months. Secondary outcomes were survival, hospital length of stay, and radiographic change. A total of 71 subjects were randomized (36 received urokinase, 35 placebo) from 12 U.K. centers. The baseline characteristics were similar between the groups. There was no difference in mean dyspnea between groups (mean difference, 3.8 mm; 95% confidence interval [CI], -12 to 4.4 mm; P = 0.36). Pleurodesis failure rates were similar (urokinase, 13 of 35 [37%]; placebo, 11 of 34 [32%]; adjusted hazard ratio, 1.2; P = 0.65). Urokinase was associated with decreased effusion size visualized by chest radiography (adjusted relative improvement, -19%; 95% CI, -28 to -11%; P < 0.001), reduced hospital stay (1.6 d; 95% CI, 1.0 to 2.6; P = 0.049), and improved survival (69 vs. 48 d; P = 0.026). CONCLUSIONS: Use of intrapleural urokinase does not reduce dyspnea or improve pleurodesis success compared with placebo and cannot be recommended as an adjunct to pleurodesis. Other palliative treatments should be used. Improvements in hospital stay, radiographic appearance, and survival associated with urokinase require further evaluation. Clinical trial registered with ISRCTN (12852177) and EudraCT (2008-000586-26).

Increasing burden of community-acquired pneumonia leading to hospitalisation, 1998-2014.

BACKGROUND: Community-acquired pneumonia (CAP) is a major cause of mortality and morbidity in many countries but few recent large-scale studies have examined trends in its incidence. METHODS: Incidence of CAP leading to hospitalisation in one UK region (Oxfordshire) was calculated over calendar time using routinely collected diagnostic codes, and modelled using piecewise-linear Poisson regression. Further models considered other related diagnoses, typical administrative outcomes, and blood and microbiology test results at admission to determine whether CAP trends could be explained by changes in case-mix, coding practices or admission procedures. RESULTS: CAP increased by 4.2%/year (95% CI 3.6 to 4.8) from 1998 to 2008, and subsequently much faster at 8.8%/year (95% CI 7.8 to 9.7) from 2009 to 2014. Pneumonia-related conditions also increased significantly over this period. Length of stay and 30-day mortality decreased slightly in later years, but the proportions with abnormal neutrophils, urea and C reactive protein (CRP) did not change (p>0.2). The proportion with severely abnormal CRP (>100 mg/L) decreased slightly in later years. Trends were similar in all age groups. Streptococcus pneumoniae was the most common causative organism found; however other organisms, particularly Enterobacteriaceae, increased in incidence over the study period (p<0.001). CONCLUSIONS: Hospitalisations for CAP have been increasing rapidly in Oxfordshire, particularly since 2008. There is little evidence that this is due only to changes in pneumonia coding, an ageing population or patients with substantially less severe disease being admitted more frequently. Healthcare planning to address potential further increases in admissions and consequent antibiotic prescribing should be a priority.

Diagnostic value of radiological imaging pre- and post-drainage of pleural effusions.

Patients with an unexplained pleural effusion often require urgent investigation. Clinical practice varies due to uncertainty as to whether an effusion should be drained completely before diagnostic imaging. We performed a retrospective study of patients undergoing medical thoracoscopy for an unexplained effusion. In 110 patients with paired (pre- and post-drainage) chest X-rays and 32 patients with paired computed tomography scans, post-drainage imaging did not provide additional information that would have influenced the clinical decision-making process.