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).

A randomised controlled trial of intrapleural balloon intercostal chest drains to prevent drain displacement.

BACKGROUND: Chest drain displacement is a common clinical problem that occurs in 9-42% of cases and results in treatment failure or additional pleural procedures conferring unnecessary risk. A novel chest drain with an integrated intrapleural balloon may reduce the risk of displacement. METHODS: A prospective randomised controlled trial comparing the balloon drain to standard care (12 F chest drain with no balloon) with the primary outcome of objectively defined unintentional or accidental chest drain displacement. RESULTS: 267 patients were randomised (primary outcome data available in 257, 96.2%). Displacement occurred less frequently using the balloon drain (displacement 5 of 128, 3.9%; standard care displacement 13 of 129, 10.1%) but this was not statistically significant (OR for drain displacement 0.36, 95% CI 0.13-1.0, Chi-squared 1 degree of freedom (df)=2.87, p=0.09). Adjusted analysis to account for minimisation factors and use of drain sutures demonstrated balloon drains were independently associated with reduced drain fall-out rate (adjusted OR 0.27, 95% CI 0.08-0.87, p=0.028). Adverse events were higher in the balloon arm than the standard care arm (balloon drain 59 of 131, 45.0%; standard care 18 of 132, 13.6%; Chi-squared 1 df=31.3, p<0.0001). CONCLUSION: Balloon drains reduce displacement compared with standard drains independent of the use of sutures but are associated with increased adverse events specifically during drain removal. The potential benefits of the novel drain should be weighed against the risks, but may be considered in practices where sutures are not routinely used.

Bio-prospecting the future in perspective of amidohydrolase L-glutaminase from marine habitats.

In the current scenario, considerable attention is being given to the enzyme L-glutaminase (EC 3.5.1.2). It belongs to the amidohydrolase class adherent to the family of serine-reliant ß-lactamases and the penicillin-binding proteins due to its higher affinity to polymerize and modify peptidoglycan synthesis. However, based on the catalytic proficiency, L-glutaminase is characterized as a proteolytic endopeptidase that cleaves peptide linkage and emancipates various byproducts, viz. ammonia along with glutamate. L-glutamine is considered the key amino acid reportedly involved in multiple metabolic pathways such as nitrogen metabolism. The present review is focused on the recent development and aspects concomitant to the biotechnological applicability of L-glutaminase predominantly from the marine habitat. Additionally, a majority of L-glutaminases finds application in cancer therapy as therapeutic agents, especially for acute lymphocytic leukaemia. The in vitro studies have been effective against various human cancer cell lines. L-glutaminase enhances the growth of probiotic bacteria. Apart from all these applications, it is suitably applicable in fermented foods as a flavour enhancer especially the umami flavour and content. Marine habitats have largely been exploited for their bio-catalytic potential but very scarcely for therapeutic enzymes. Some of the reports of such marine bacterial isolates from Bacillus sp., Pseudomonas sp. and Vibrio sp. are in the domain, but none highlights the therapeutic applications predominantly as anticancer and anti-proliferative agents. KEY POINTS: The exploration of marine habitats along the Gujarat coasts mainly for bacteria secreting L-glutaminase is scarcely reported, and even more scarce are the amidohydrolases from these marine niches as compared to their terrestrial counterparts. Microbial sourced amidohydrolase has wide bio-applicability that includes food, cosmetics and therapeutics especially as anticancer/anti-proliferative agent making it of immense biotechnological significance.

'Pleural Triage' facilitates effective management of a pleural service in the COVID-19 era.

The COVID-19 pandemic has created new challenges for management of pleural diseases. As resources and staff have been redirected to manage acutely unwell COVID-19 patients, routine medical practice and service provision for pleural diseases have been severely disrupted. We recognised the impact this had for patients with pleural diseases, who can be highly vulnerable to infection and often have conditions for which treatment cannot be safely delayed. The pleural service was reviewed in a tertiary centre, focusing on the changes that allowed maintenance of a service whilst maximising patient and staff safety, with the aim that these service transformations can be adopted elsewhere to improve care for pleural patients during and beyond COVID-19.

The effectiveness of primary care based risk stratification for targeted latent tuberculosis infection screening in recent immigrants to the UK: a retrospective cohort study.

BACKGROUND: Most UK tuberculosis (TB) cases occur in immigrants from high TB incidence areas, implicating reactivation of imported latent TB infection (LTBI). Strategies to identify and treat immigrant LTBI in primary care at the time of first registration (coded Flag-4) may be effective. METHODS: This was an 11-year retrospective cohort study to evaluate effectiveness of LTBI screening in recent immigrants to Leicestershire at their time of primary care registration. We examined the temporal relationship between dates of Flag-4 primary care registration (n=59 007) and foreign-born TB (FB-TB) cases (n=857), for immigrants arriving to the UK after 1999. TB diagnosed >6 months after registration was considered potentially preventable with screening. Primary outcomes were the potentially preventable proportion of FB-TB and the number needed to screen (NNS) of immigrants to identify one potentially preventable case, stratified by age and region of origin. RESULTS: 250 cases (29%) were potentially preventable in Flag-4-registered immigrants. Overall, 511 cases (60%) were potentially preventable among primary-care registered immigrants, implying a significant proportion without Flag-4 status. Prospective TB incidence (95% CI) after Flag-4 registration was 183 (163 to 205) cases/100 000 person-years, with a NNS (95% CI) of 145 (130 to 162). Targeted screening was most effective for 16-35 year olds from TB incidence regions 150-499/100 000 (NNS (95% CI)=65 (57 to 74), preventing 159 (18.7%) cases). Unpreventable TB risk increased with delayed primary care registration after UK entry (p<0.001) and was associated with HIV seropositivity (relative risk (95% CI)=1.89 (1.25 to 2.84), p=0.003). CONCLUSIONS: LTBI screening at primary care registration offers an effective strategy for potentially identifying immigrants at high risk of developing TB.

Cardiac related pleural effusions: a narrative review.

Background and Objective: Pleural effusions (PEs) are commonly seen in various pathologies and have a significant impact on patient health and quality of life. Unlike for malignant PEs, non-malignant PEs (NMPEs) do not have well-established guidelines. Much of the evidence base in this field is from a handful of randomised controlled trials (RCTs) and the majority are from retrospective cohort analyses and cases series. Cardiac related PEs fall within the entity of NMPEs and the aim of this narrative review is to gather the existing evidence in the field of congestive heart failure (CHF), pericarditis and post-cardiac injury syndrome (PCIS). This narrative review investigates the pathophysiology, diagnostic criteria and treatment options for the various cause of cardiac related PEs. Methods: This narrative review is based on a comprehensive literature search analysing RCTs, prospective and retrospective cohort analyses and published case series. Key Content and Findings: CHF related PEs have a substantial mortality rate and carry a worse prognosis if the PEs are bilateral and transudative in nature. Light's criteria have often shown to misclassify transudative effusions in CHF (pseudo-exudates) and hence measuring serum-pleural albumin gradient is an invaluable tool to accurately identify transudates. Elevated serum and pleural N-terminal pro-B type natriuretic peptide (NT-proBNP) has shown increasing evidence of correctly identifying PEs secondary to CHF. However, they should be considered with the pre-test probability of CHF. Therapeutic thoracentesis and indwelling pleural catheter (IPC) placement may be necessary if medical management has failed. PEs can also occur secondary to pericarditis and are often small, bilateral and exudative. PCIS also results in PEs and are commonly seen in post-coronary artery bypass graft (CABG) surgery. Both entities need management of the underlying cause first, but in cases where PEs are refractory, individualised pleural interventions may be necessary. Conclusions: This comprehensive narrative review provides valuable insights into the aetiology, diagnosis and management of PEs secondary to CHF, pericarditis and PCIS. The aim is to enhance the clinicians' knowledge of this complex and controversial topic to improve patient care of cardiac-related PEs. Ongoing trials in this field will be able to provide valuable insights.

The Role of Multilevel Intercostal Nerve Block in Local Anesthetic Thoracoscopy.

BACKGROUND: Intercostal nerve block (ICNB) has long been used in thoracic surgery. Local anesthetic thoracoscopy (LAT) is performed under conscious sedation with local anesthesia at the port insertion site. This alone, however, does not anesthetize the parietal pleura from where biopsies are taken and patients can experience pain. OBJECTIVES: To compare LAT with multilevel ICNB versus standard care to determine whether it reduces pain during and post-LAT, its effect on analgesia use, the hospital length of stay (LOS), and related complications. METHODS: Prospective analysis of patients undergoing LAT between January and June 2021. In the ICNB group, levobupivacaine/xylocaine is administered at the angle of the rib immediately before LAT (up to 5 rib spaces). Visual Analog Score for pain (0 to 100 mm) was measured at 1 and 2 hours post-LAT and daily including analgesia use. RESULTS: Twenty patients (10 ICNB vs. 10 standard care group). The mean age is 68 years with 70% males. Visual Analog Score for pain in the ICNB group reduced by 55 mm at 1 and 2 hours post-LAT and 45 mm at day 1 ( P <0.05) (minimal clinically important difference >16 mm]. Median LOS was reduced by 50% in the ICNB group ( P <0.05). Paracetamol use reduced by 56% ( P <0.05). CONCLUSION: ICNB not only significantly reduces postprocedure pain but also reduces LOS.

Aetiology of Pleural Effusions in a Large Multicentre Cohort: Variation Between Outpatients and Inpatients.

INTRODUCTION: This multi-centre retrospective cohort study aimed to determine whether the cause of an undiagnosed pleural effusion differed depending on if a patient presented as an outpatient or inpatient. METHODS: A total of 1080 adult patients (556 inpatients and 524 outpatients) presenting primarily with an undiagnosed pleural effusion from 1 January 2021 to 31 December 2022 from four UK hospitals were included. RESULTS: We found malignant effusions were more common in outpatients compared to inpatients (48.3% vs. 36.0% p < 0.0001). Infection was common in inpatients but uncommon in outpatients (36.2% vs. 5.0% p < 0.0001). Other causes in all patients included heart and/or renal failure (13.1%) and non-specific pleuritis (5.6%). No diagnosis was possible in 11.8% of patients referred. CONCLUSION: Investigative pathways should vary depending on whether patients present as an inpatient or outpatient.

Implementation of facemask sampling for the detection of infectious individuals with SARS-CoV-2 in high stakes clinical examinations - a feasibility study.

Introduction: SARS-CoV-2 may transmit across vaccinated cohorts during practical clinical examinations. We sought to assess the feasibility of facemask sampling (FMS) to identify individuals emitting SARS-CoV-2 during a mock PACES exam. Methods: In May 2022 we recruited participants from a mock PACES examination in Leicester, UK. Following a negative lateral flow test assay, all participants wore modified facemasks able to capture exhaled virus during the assessment (FMS). A concomitant upper respiratory tract sample (URTS) was provided prior to FMS. Exposed facemasks were processed by removal and dissolution of sampling matrices fixed within the mask and cycle thresholds values quantified by RT-qPCR. Participants were asked to grade statements regarding the comfort, effort, ethics and communication when providing FMS; laboratory technicians were asked to grade key statements surrounding suitability of samples for processing. Results: 34 participants provided concomitant URTS and FMS during the examination. One participant was positive for SARS-CoV-2, with a cycle threshold value of 22.5 on URTS, but negative (no viral RNA detected) on FMS; no transmission to others was identified from this individual. Participants responded positively to statements regarding FMS describing all four domains; however, 69% of participants felt that a positive result from FMS alone was insufficient for diagnosis and that further tests were required. All but one FMS sample was suitable for processing. Discussion: FMS during PACES exams are acceptable among participants and samples provided are suitable for processing. Our results demonstrate feasibility of FMS within practical examination settings and support the further assessment of FMS as a scalable tool that can be compared with URTS to identify those who are infectious.

Subcutaneous Emphysema Risk Following Indwelling Pleural Catheter Insertion During Rigid Local Anesthetic Thoracoscopy: Via Thoracoscopy Port Versus Separate Incision Site.

BACKGROUND: Local anesthetic thoracoscopy (LAT) is important in the diagnosis of unilateral pleural effusions. Indwelling pleural catheters (IPC) can be inserted during LAT if a nonexpandable lung is suspected. Subcutaneous emphysema (SCE) is a known complication and is associated with increased morbidity and length of stay. It is unclear however if the incidence of SCE is affected if IPC is inserted through a separate incision to the LAT port. We aim to establish the incidence and grading of SCE when IPC is inserted during LAT and to determine if the site of IPC placement influences this. METHODS: Retrospective analysis of LAT electronic records and radiology images over 8 years in a University Hospital. The incidence of SCE was assessed during admission and follow-up with the severity of SCE graded 0 to 4 (0 none; 1 at IPC site; 2 ipsilateral chest wall; 3 ipsilateral neck; 4 contralateral chest wall). RESULTS: 55 combined LAT and IPC procedures were performed. In 28 patients the IPC was inserted through the LAT port and in 27 the IPC was inserted in a separate intercostal space (ICS) to the LAT port. On day zero, the incidence of any SCE was lower if the IPC was inserted using a separate ICS to the LAT port compared with the same site as the LAT port( P =0.01). This was similarly reduced on discharge chest radiographs and subsequent follow-up. CONCLUSION: IPC insertion at LAT using a separate ICS to the LAT port is associated with a reduction in the incidence of SCE during admission and follow-up.

Local Anaesthetic Thoracoscopy for Pleural Effusion-A Narrative Review.

The incidence of pleural disease is increasing, and interventions are crucial in this subspecialist area of respiratory medicine. One of the cornerstones of pleural effusion investigation and management is medical, which is also known as local anaesthetic thoracoscopy. This allows fluid drainage, biopsy for diagnosis and preventative measures for further fluid potential build-up. This article summarises the evidence around this procedure through a narrative review of the available evidence.

The impact of the COVID-19 pandemic on pleural infection incidence: a UK multicentre retrospective analysis.

There was a significant reduction in pleural infection incidence, by almost a third, in the year following the start of the #COVID19 pandemic. Public health measures enforced during this period are likely to have played a significant role. https://bit.ly/3QAPPR9.

Cerebral air embolism after indwelling pleural catheter insertion in a chronic hydropneumothorax secondary to epithelioid mesothelioma.

A 75-year-old man with a history of epithelioid mesothelioma and a right-sided indwelling pleural catheter (IPC) presented with a history of a purulent fluid drainage via the IPC. The pleural fluid cultured Klebsiella oxytoca and Enterococcus faecalis He was treated with a course of oral fluoroquinolone followed by uneventful IPC replacement. One and half hours postprocedure, the patient had a witnessed drop in conscious level accompanied by seizure like activity. Acute stroke was suspected and a CT head was performed. CT head revealed multiple serpiginous pockets of air along the cerebral fissure, with features that were highly suggestive of cerebral air embolism and multiple wedge-shaped areas of infarction involving the cerebral hemispheres. Further imaging revealed satisfactory position of the replaced IPC. The patient was admitted to the intensive care unit for high flow oxygen therapy and head down ventilation. However, his condition deteriorated and he died later.

Modern day management of a unilateral pleural effusion.

Over 50 systemic conditions may affect the pleura and, thus, unilateral pleural effusions may present for a variety of reasons. Investigating the cause is essential to providing appropriate management. Various pleural interventions are available in current practice, but have varying diagnostic sensitivity. It is, therefore, vital to consider the intervention with the highest diagnostic yield appropriate to the particular clinical situation. The diagnostic pathway in unilateral pleural effusion is increasingly outpatient based, avoiding hospitalisation, which is particularly relevant with the recent COVID-19 pandemic.

Serum Proteomics and Plasma Fibulin-3 in Differentiation of Mesothelioma From Asbestos-Exposed Controls and Patients With Other Pleural Diseases.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is difficult to diagnose. An accurate blood biomarker could prompt specialist referral or be deployed in future screening. In earlier retrospective studies, SOMAscan proteomics (Somalogic, Boulder, CO) and fibulin-3 seemed highly accurate, but SOMAscan has not been validated prospectively and subsequent fibulin-3 data have been contradictory. METHODS: A multicenter prospective observational study was performed in 22 centers, generating a large intention-to-diagnose cohort. Blood sampling, processing, and diagnostic assessment were standardized, including a 1-year follow-up. Plasma fibulin-3 was measured using two enzyme-linked immunosorbent assays (CloudClone [used in previous studies] and BosterBio, Pleasanton, CA). Serum proteomics was measured using the SOMAscan assay. Diagnostic performance (sensitivity at 95% specificity, area under the curve [AUC]) was benchmarked against serum mesothelin (Mesomark, Fujirebio Diagnostics, Malvern, PA). Biomarkers were correlated against primary tumor volume, inflammatory markers, and asbestos exposure. RESULTS: A total of 638 patients with suspected pleural malignancy (SPM) and 110 asbestos-exposed controls (AECs) were recruited. SOMAscan reliably differentiated MPM from AECs (75% sensitivity, 88.2% specificity, validation cohort AUC 0.855) but was not useful in patients with differentiating non-MPM SPM. Fibulin-3 (by BosterBio after failed CloudClone validation) revealed 7.4% and 11.9% sensitivity at 95% specificity in MPM versus non-MPM SPM and AECs, respectively (associated AUCs 0.611 [0.557-0.664], p = 0.0015) and 0.516 [0.443-0.589], p = 0.671), both inferior to mesothelin. SOMAscan proteins correlated with inflammatory markers but not with asbestos exposure. Neither biomarker correlated with tumor volume. CONCLUSIONS: SOMAscan may prove useful as a future screening test for MPM in asbestos-exposed persons. Neither fibulin-3 nor SOMAscan should be used for diagnosis or pathway stratification.

Chylothorax in a patient with HIV-related Kaposi's sarcoma.

We present a case of a 33-year-old man with a background of HIV and Kaposi's sarcoma (KS), who presented with a right sided chylothorax. He was managed with percutaneous chest drainage and talc pleurodesis, in addition to his chemotherapy and antiretroviral therapy for KS and HIV, respectively. Good clinical control of the chylothorax remained 4 months post drainage. This case report summarises the approach to investigating and managing pleural effusion, and in particular chylothorax, in HIV patients.