Unconventional human CD61 pairing with CD103 promotes TCR signaling and antigen-specific T cell cytotoxicity.

Cancer remains one of the leading causes of mortality worldwide, leading to increased interest in utilizing immunotherapy strategies for better cancer treatments. In the past decade, CD103+ T cells have been associated with better clinical prognosis in patients with cancer. However, the specific immune mechanisms contributing toward CD103-mediated protective immunity remain unclear. Here, we show an unexpected and transient CD61 expression, which is paired with CD103 at the synaptic microclusters of T cells. CD61 colocalization with the T cell antigen receptor further modulates downstream T cell antigen receptor signaling, improving antitumor cytotoxicity and promoting physiological control of tumor growth. Clinically, the presence of CD61+ tumor-infiltrating T lymphocytes is associated with improved clinical outcomes, mediated through enhanced effector functions and phenotype with limited evidence of cellular exhaustion. In conclusion, this study identified an unconventional and transient CD61 expression and pairing with CD103 on human immune cells, which potentiates a new target for immune-based cellular therapies.

Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial.

BACKGROUND: The safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population. METHODS: PANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older-or aged 18 years or older with relevant comorbidities-and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (<50 years vs ≥50 years) and vaccination status (yes vs no). COVID-19 outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within 28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN, number 30448031. FINDINGS: Between Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81-1·41]; probability of superiority 0·33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir. INTERPRETATION: Molnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community. FUNDING: UK National Institute for Health and Care Research.

PET-CT-guided versus CT-guided biopsy in suspected malignant pleural thickening: a randomised trial.

BACKGROUND: Pleural biopsy is the gold standard for diagnosis of pleural malignancy but a significant proportion will have an inconclusive biopsy despite ongoing clinical suspicion of malignancy. We investigated whether positron emission tomography-computed tomography (PET-CT) targeted pleural biopsy is superior to standard CT-guided pleural biopsy following an initial non-diagnostic biopsy. METHODS: The TARGET trial was a multicentre, parallel group randomised trial. Patients with a previous inconclusive pleural biopsy but an ongoing suspicion of pleural malignancy were randomised (1:1) to receive either CT-guided biopsy (standard care) or PET-CT followed by a targeted CT biopsy (intervention). The primary outcome was pleural malignancy correctly identified from the trial biopsy. RESULTS: Between September 2015 and September 2018, 59 participants were randomised from eight UK hospital sites: 29 to CT-only followed by targeted biopsy and 30 to PET-CT followed by targeted biopsy. The proportion of pleural malignancy correctly identified was similar between the groups (risk ratio 1.03 (95% CI 0.83-1.29); p=0.77). The sensitivity of the trial biopsy to identify pleural malignancy was 79% (95% CI 54-94%) in the CT-only group versus 81% (95% CI 54-96%) in the PET-CT group. CONCLUSIONS: The results do not support the practice of PET-CT to guide pleural biopsies in patients with a previous non-diagnostic biopsy. The diagnostic sensitivity in the CT-only group was higher than anticipated and supports the practice of repeating a CT-guided biopsy following an inconclusive result if clinical suspicion of malignancy persists.

Malignant pleural effusion: current understanding and therapeutic approach.

Malignant pleural effusion (MPE) is a common complication of thoracic and extrathoracic malignancies and is associated with high mortality and elevated costs to healthcare systems. Over the last decades the understanding of pathophysiology mechanisms, diagnostic techniques and optimal treatment intervention in MPE have been greatly advanced by recent high-quality research, leading to an ever less invasive diagnostic approach and more personalized management. Despite a number of management options, including talc pleurodesis, indwelling pleural catheters and combinations of the two, treatment for MPE remains symptom directed and centered around drainage strategy. In the next future, because of a better understanding of underlying tumor biology together with more sensitive molecular diagnostic techniques, it is likely that combined diagnostic and therapeutic procedures allowing near total outpatient management of MPE will become popular. This article provides a review of the current advances, new discoveries and future directions in the pathophysiology, diagnosis and management of MPE.

Pleural Diseases in Connective Tissue Diseases.

Connective tissue diseases (CTD) are heterogeneous, immune-mediated inflammatory disorders often presenting with multiorgan involvement. With the advent of high-resolution computed tomography, CTD-related pleuritis-pleural thickening and effusion-is now increasingly recognized early in the disease trajectory. The natural history of CTD-related pleural effusions varies from spontaneous resolution to progressive fibrothorax with ventilatory impairment. Treatment of the underlying CTD is necessary to manage the pleural disease. Depending on the degree of symptom burden and physiological insult, specific treatment of pleural disease can include monitoring, repeated aspirations, systemic anti-inflammatory medication, and surgical decortication.

The Biological Role of Pleural Fluid PAI-1 and Sonographic Septations in Pleural Infection: Analysis of a Prospectively Collected Clinical Outcome Study.

Rationale: Sonographic septations are assumed to be important clinical predictors of outcome in pleural infection, but the evidence for this is sparse. The inflammatory and fibrinolysis-associated intrapleural pathway(s) leading to septation formation have not been studied in a large cohort of pleural fluid (PF) samples with confirmed pleural infection matched with ultrasound and clinical outcome data. Objectives: To assess the presence and severity of septations against baseline PF PAI-1 (Plasminogen-Activator Inhibitor-1) and other inflammatory and fibrinolysis-associated proteins as well as to correlate these with clinically important outcomes. Methods: We analyzed 214 pleural fluid samples from PILOT (Pleural Infection Longitudinal Outcome Study), a prospective observational pleural infection study, for inflammatory and fibrinolysis-associated proteins using the Luminex platform. Multivariate regression analyses were used to assess the association of pleural biological markers with septation presence and severity (on ultrasound) and clinical outcomes. Measurements and Main Results: PF PAI-1 was the only protein independently associated with septation presence (P < 0.001) and septation severity (P = 0.003). PF PAI-1 concentrations were associated with increased length of stay (P = 0.048) and increased 12-month mortality (P = 0.003). Sonographic septations alone had no relation to clinical outcomes. Conclusions: In a large and well-characterized cohort, this is the first study to associate pleural biological parameters with a validated sonographic septation outcome in pleural infection. PF PAI-1 is the first biomarker to demonstrate an independent association with mortality. Although PF PAI-1 plays an integral role in driving septation formation, septations themselves are not associated with clinically important outcomes. These novel findings now require prospective validation.

A Multicenter, Single-Arm, Prospective Trial Assessing the Diagnostic Yield of Electromagnetic Bronchoscopic and Transthoracic Navigation for Peripheral Pulmonary Nodules.

Rationale: Strict adherence to procedural protocols and diagnostic definitions is critical to understand the efficacy of new technologies. Electromagnetic navigational bronchoscopy (ENB) for lung nodule biopsy has been used for decades without a solid understanding of its efficacy, but offers the opportunity for simultaneous tissue acquisition via electromagnetic navigational transthoracic biopsy (EMN-TTNA) and staging via endobronchial ultrasound (EBUS). Objective: To evaluate the diagnostic yield of EBUS, ENB, and EMN-TTNA during a single procedure using a strict a priori definition of diagnostic yield with central pathology adjudication. Methods: A prospective, single-arm trial was conducted at eight centers enrolling participants with pulmonary nodules (<3 cm; without computed tomography [CT]- and/or positron emission tomography-positive mediastinal lymph nodes) who underwent a staged procedure with same-day CT, EBUS, ENB, and EMN-TTNA. The procedure was staged such that, when a diagnosis had been achieved via rapid on-site pathologic evaluation, the procedure was ended and subsequent biopsy modalities were not attempted. A study finding was diagnostic if an independent pathology core laboratory confirmed malignancy or a definitive benign finding. The primary endpoint was the diagnostic yield of the combination of CT, EBUS, ENB, and EMN-TTNA. Measurements and Main Results: A total of 160 participants at 8 centers with a mean nodule size of 18 ± 6 mm were enrolled. The diagnostic yield of the combined procedure was 59% (94 of 160; 95% confidence interval [CI], 51-66%). Nodule regression was found on same-day CT in 2.5% of cases (4 of 160; 95% CI, 0.69-6.3%), and EBUS confirmed malignancy in 7.1% of cases (11 of 156; 95% CI, 3.6-12%). The yield of ENB alone was 49% (74 of 150; 95% CI, 41-58%), that of EMN-TTNA alone was 27% (8 of 30; 95% CI, 12-46%), and that of ENB plus EMN-TTNA was 53% (79 of 150; 95% CI, 44-61%). Complications included a pneumothorax rate of 10% and a 2% bleeding rate. When EMN-TTNA was performed, the pneumothorax rate was 30%. Conclusions: The diagnostic yield for ENB is 49%, which increases to 59% with the addition of same-day CT, EBUS, and EMN-TTNA, lower than in prior reports in the literature. The high complication rate and low diagnostic yield of EMN-TTNA does not support its routine use. Clinical trial registered with www.clinicaltrials.gov (NCT03338049).

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).

Brain activity measured by functional brain imaging predicts breathlessness improvement during pulmonary rehabilitation.

BACKGROUND: Chronic breathlessness in chronic obstructive pulmonary disease (COPD) is effectively treated with pulmonary rehabilitation. However, baseline patient characteristics predicting improvements in breathlessness are unknown. This knowledge may provide better understanding of the mechanisms engaged in treating breathlessness and help to individualise therapy. Increasing evidence supports the role of expectation (ie, placebo and nocebo effects) in breathlessness perception. In this study, we tested functional brain imaging markers of breathlessness expectation as predictors of therapeutic response to pulmonary rehabilitation, and asked whether D-cycloserine, a brain-active drug known to influence expectation mechanisms, modulated any predictive model. METHODS: Data from 71 participants with mild-to-moderate COPD recruited to a randomised double-blind controlled experimental medicine study of D-cycloserine given during pulmonary rehabilitation were analysed (ID: NCT01985750). Baseline variables, including brain-activity, self-report questionnaires responses, clinical measures of respiratory function and drug allocation were used to train machine-learning models to predict the outcome, a minimally clinically relevant change in the Dyspnoea-12 score. RESULTS: Only models that included brain imaging markers of breathlessness-expectation successfully predicted improvements in Dyspnoea-12 score (sensitivity 0.88, specificity 0.77). D-cycloserine was independently associated with breathlessness improvement. Models that included only questionnaires and clinical measures did not predict outcome (sensitivity 0.68, specificity 0.2). CONCLUSIONS: Brain activity to breathlessness related cues is a strong predictor of clinical improvement in breathlessness over pulmonary rehabilitation. This implies that expectation is key in breathlessness perception. Manipulation of the brain's expectation pathways (either pharmacological or non-pharmacological) therefore merits further testing in the treatment of chronic breathlessness.

ERS/ESTS statement on the management of pleural infection in adults.

Pleural infection is a common condition encountered by respiratory physicians and thoracic surgeons alike. The European Respiratory Society (ERS) and European Society of Thoracic Surgeons (ESTS) established a multidisciplinary collaboration of clinicians with expertise in managing pleural infection with the aim of producing a comprehensive review of the scientific literature. Six areas of interest were identified: 1) epidemiology of pleural infection, 2) optimal antibiotic strategy, 3) diagnostic parameters for chest tube drainage, 4) status of intrapleural therapies, 5) role of surgery and 6) current place of outcome prediction in management. The literature revealed that recently updated epidemiological data continue to show an overall upwards trend in incidence, but there is an urgent need for a more comprehensive characterisation of the burden of pleural infection in specific populations such as immunocompromised hosts. There is a sparsity of regular analyses and documentation of microbiological patterns at a local level to inform geographical variation, and ongoing research efforts are needed to improve antibiotic stewardship. The evidence remains in favour of a small-bore chest tube optimally placed under image guidance as an appropriate initial intervention for most cases of pleural infection. With a growing body of data suggesting delays to treatment are key contributors to poor outcomes, this suggests that earlier consideration of combination intrapleural enzyme therapy (IET) with concurrent surgical consultation should remain a priority. Since publication of the MIST-2 study, there has been considerable data supporting safety and efficacy of IET, but further studies are needed to optimise dosing using individualised biomarkers of treatment failure. Pending further prospective evaluation, the MIST-2 regimen remains the most evidence based. Several studies have externally validated the RAPID score, but it requires incorporating into prospective intervention studies prior to adopting into clinical practice.

Implementable Deep Learning for Multi-sequence Proton MRI Lung Segmentation: A Multi-center, Multi-vendor, and Multi-disease Study.

BACKGROUND: Recently, deep learning via convolutional neural networks (CNNs) has largely superseded conventional methods for proton (1 H)-MRI lung segmentation. However, previous deep learning studies have utilized single-center data and limited acquisition parameters. PURPOSE: Develop a generalizable CNN for lung segmentation in 1 H-MRI, robust to pathology, acquisition protocol, vendor, and center. STUDY TYPE: Retrospective. POPULATION: A total of 809 1 H-MRI scans from 258 participants with various pulmonary pathologies (median age (range): 57 (6-85); 42% females) and 31 healthy participants (median age (range): 34 (23-76); 34% females) that were split into training (593 scans (74%); 157 participants (55%)), testing (50 scans (6%); 50 participants (17%)) and external validation (164 scans (20%); 82 participants (28%)) sets. FIELD STRENGTH/SEQUENCE: 1.5-T and 3-T/3D spoiled-gradient recalled and ultrashort echo-time 1 H-MRI. ASSESSMENT: 2D and 3D CNNs, trained on single-center, multi-sequence data, and the conventional spatial fuzzy c-means (SFCM) method were compared to manually delineated expert segmentations. Each method was validated on external data originating from several centers. Dice similarity coefficient (DSC), average boundary Hausdorff distance (Average HD), and relative error (XOR) metrics to assess segmentation performance. STATISTICAL TESTS: Kruskal-Wallis tests assessed significances of differences between acquisitions in the testing set. Friedman tests with post hoc multiple comparisons assessed differences between the 2D CNN, 3D CNN, and SFCM. Bland-Altman analyses assessed agreement with manually derived lung volumes. A P value of <0.05 was considered statistically significant. RESULTS: The 3D CNN significantly outperformed its 2D analog and SFCM, yielding a median (range) DSC of 0.961 (0.880-0.987), Average HD of 1.63 mm (0.65-5.45) and XOR of 0.079 (0.025-0.240) on the testing set and a DSC of 0.973 (0.866-0.987), Average HD of 1.11 mm (0.47-8.13) and XOR of 0.054 (0.026-0.255) on external validation data. DATA CONCLUSION: The 3D CNN generated accurate 1 H-MRI lung segmentations on a heterogenous dataset, demonstrating robustness to disease pathology, sequence, vendor, and center. EVIDENCE LEVEL: 4. TECHNICAL EFFICACY: Stage 1.

COVID-19-Related Pleural Diseases.

Coronavirus disease 2019 (COVID-19)-related pleural diseases are now well recognized. Since the beginning of the pandemic, increasing cases of pleural diseases including pneumothorax, pneumomediastinum, and pleural effusion with severe COVID-19 infection have attracted the attention of physicians and are not incidental or due to barotrauma. The complicated course of COVID-19 illness highlights the complex pathophysiological underpinnings of pleural complications. The management of patients with pneumothorax and pneumomediastinum is challenging as the majority require assisted ventilation; physicians therefore appear to have a low threshold to intervene. Conversely, pleural effusion cases, although sharing some similar patient characteristics with pneumothorax and pneumomediastinum, are in general managed more conservatively. The evidence suggests that patients with COVID-19-related pleural diseases, either due to air leak or effusion, have more severe disease with a worse prognosis. This implies that prompt recognition of these complications and targeted management are key to improve outcomes.

Efficacy of Small versus Large-Bore Chest Drain in Pleural Infection: A Systematic Review and Meta-Analysis.

BACKGROUND: Pleural infection represents a significant clinical challenge worldwide. Although prompt drainage of pleural fluid is thought to play a key role in pleural infection management, the optimal size of intrapleural catheter has yet to be defined. OBJECTIVES: The aim of this systematic review and meta-analysis was to summarize data on efficacy and complications of small-bore drain (SBD), defined as ≤14F, in comparison to large-bore drain (LBD) in patients with pleural infection. METHOD: We searched MEDLINE and Embase for all studies reporting outcomes of interest published up to October 2021. Two authors reviewed selected full text to identify studies according to predefined eligibility criteria. Summary estimates were derived using the random-effects model. RESULTS: Twelve original studies were included for qualitative analysis and 7 of these for quantitative analysis. The surgical referral rate of SBD and LBD were, respectively, 0.16 (95% confidence interval [CI], 0.12-0.21) and 0.20 (95% CI, 0.10-0.32), the pooled mortality were 0.12 (95% CI, 0.05-0.21) and 0.20 (95% CI, 0.10-0.32), and the length of hospital stay was 24 days in both groups. Data on complications suggest similar proportions of tube dislodgement. Intensity of pain was evaluated in one study only, reporting higher scores for LBD. CONCLUSIONS: This systematic review and meta-analysis provide the first synthesis of data on performance of SBD and LBD in management of pleural infection, and, overall, clinical outcomes and complications did not substantially differ, although the limited number of studies and the absence of dedicated randomized trials does limit the reliability of results.

Steroid Therapy and Outcome of Parapneumonic Pleural Effusions (STOPPE): A Pilot Randomized Clinical Trial.

Rationale: Pleural effusion commonly complicates community-acquired pneumonia and is associated with intense pleural inflammation. Whether antiinflammatory treatment with corticosteroids improves outcomes is unknown. Objectives: To assess the effects of corticosteroids in an adult population with pneumonia-related pleural effusion. Methods: The STOPPE (Steroid Therapy and Outcome of Parapneumonic Pleural Effusions) trial was a pilot, multicenter, double-blinded, placebo-controlled, randomized trial involving six Australian centers. Patients with community-acquired pneumonia and pleural effusion were randomized (2:1) to intravenous dexamethasone (4 mg twice daily for 48 h) or placebo and followed for 30 days. Given the diverse effects of corticosteroids, a comprehensive range of clinical, serological, and imaging outcomes were assessed in this pilot trial (ACTRN12618000947202). Measurements and Main Results: Eighty patients were randomized (one withdrawn before treatment) and received dexamethasone (n = 51) or placebo (n = 28). This pilot trial found no preliminary evidence of benefits of dexamethasone in improving time to sustained (>12 h) normalization of vital signs (temperature, oxygen saturations, blood pressure, heart, and respiratory rates): median, 41.0 (95% confidence interval, 32.3-54.5) versus 27.8 (15.4-49.5) hours in the placebo arm (hazard ratio, 0.729 [95% confidence interval, 0.453-1.173]; P = 0.193). Similarly, no differences in C-reactive protein or leukocyte counts were observed, except for a higher leukocyte count in the dexamethasone group at Day 3. Pleural drainage procedures were performed in 49.0% of dexamethasone-treated and 42.9% of placebo-treated patients (P = 0.60). Radiographic pleural opacification decreased over time with no consistent intergroup differences. Mean duration of antibiotic therapy (22.4 [SD, 15.4] vs. 20.4 [SD, 13.8] d) and median hospitalization (6.0 [interquartile range, 5.0-10.0] vs. 5.5 [interquartile range, 5.0-8.0] d) were similar between the dexamethasone and placebo groups. Serious adverse events occurred in 25.5% of dexamethasone-treated and 21.4% of placebo-treated patients. Transient hyperglycemia more commonly affected the dexamethasone group (15.6% vs. 7.1%). Conclusions: Systemic corticosteroids showed no preliminary benefits in adults with parapneumonic effusions. Clinical trial registered with www.anzctr.org.au (ACTRN12618000947202).

Cost-effectiveness of ambulatory care management of primary spontaneous pneumothorax: an open-label, randomised controlled trial.

BACKGROUND: Ambulatory management of primary spontaneous pneumothorax has been shown to reduce initial hospitalisation, but at the expense of increase adverse events. As a result, questions remain about the cost-effectiveness of this option. OBJECTIVES: A within-trial economic evaluation alongside a randomised controlled trial was performed to assess the cost-effectiveness of ambulatory care when compared with standard guideline-based management. METHODS: Patients were randomly assigned to treatment with either an ambulatory device or standard guideline-based management (aspiration, standard chest tube insertion or both). Follow-up was 12 months. Outcomes included healthcare resource use and costs, quality of life, quality-adjusted life-years (QALYs) and cost-effectiveness. RESULTS: 236 patients were recruited and randomly assigned to ambulatory care (n=117) and standard care (n=119). After multiple imputation for missing data, patients in the ambulatory care group had significantly lower National Health Service healthcare costs (-£788, 95% CI difference: -1527 to -50; p=0.037) than those in the standard care group. There were no differences in the number of QALYs gained (mean difference: -0.001, 95% CI difference: -0.032 to 0.030; p=0.95). When standard care was compared with ambulatory care, the incremental cost-effectiveness ratio was £799 066 per QALY gained, well above current thresholds of cost-effectiveness. As a result, the probability of ambulatory care being cost-effective was 0.93. CONCLUSION: Outpatient ambulatory management is highly likely to be a cost-effective option in the management of primary pneumothorax. TRIAL REGISTRATION NUMBER: ISRCTN79151659.

Randomised trial of indwelling pleural catheters for refractory transudative pleural effusions.

OBJECTIVE: Refractory 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. METHODS: A 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. RESULTS: 220 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). CONCLUSION: We 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.

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.

Pneumothorax management: current state of practice in the UK.

BACKGROUND AND OBJECTIVE: Spontaneous pneumothorax is a common pathology but optimal initial treatment regime is not well defined. Treatment options including conservative management, needle aspiration (NA) or insertion of a small-bore chest drain. Recent large randomised controlled trials may change the treatment paradigm: comparing conservative and ambulatory management to standard care, but current guidelines need to be updated. The aim of this study was to assess the current "state of play" in the management of pneumothorax in the UK. METHODS: Physicians and respiratory healthcare staff were invited to complete an online survey on the initial and subsequent management of pneumothorax. RESULTS: This study is the first survey of pneumothorax practice across the UK, which highlights variation in practice: 50% would manage a large primary pneumothorax with minimal symptoms conservatively, compared to only 3% if there were significant symptoms; 64% use suction if the pneumothorax had not resolved after > 2 days, 15% always clamp the chest drain prior to removal; whereas 30% never do. NICE guidance recommends the use of digital suction but this has not translated into widespread usage: only 23% use digital suction to check for resolution of air leak). CONCLUSION: Whilst there has always been allowance for individual clinician preference in guidelines, there needs to be consensus on the optimum management strategy. The challenge the new guidelines face is to design a simple and pragmatic approach, using this new evidence base.

Safety and Feasibility of a Sheath Cryoprobe for Bronchoscopic Transbronchial Biopsy: The FROSTBITE Trial.

BACKGROUND: Bronchoscopic lung biopsy is typically performed using transbronchial forceps. However, this method is limited by small sample size and presence of crush artifact. Cryobiopsy offers the potential to overcome these limitations with larger artifact-free samples but has not been widely adopted due to concerns over increased rates of bleeding and pneumothorax. A new, smaller 1.1-mm cryoprobe has been developed that operates in a similar fashion to forceps, though the safety profile of this cryoprobe has not yet been prospectively studied. OBJECTIVE: The aim of this study was to investigate the safety of transbronchial biopsy using a novel 1.1-mm cryoprobe. METHODS: This prospective, single-arm study enrolled patients referred for transbronchial biopsy. All procedures were performed using the 1.1-mm cryoprobe with oversheath. The primary outcome was the composite of significant complications related to the cryobiopsy procedure (bleeding Grade ≥3, pneumothorax Grade ≥2, and respiratory failure). Bleeding and pneumothorax were graded according to previously published scales. RESULTS: Fifty participants from two academic medical centers underwent transbronchial cryobiopsy. Indications for biopsy included evaluation of lung transplant allograft (50%), diffuse lung disease (44%), and pulmonary parenchymal lesion (6%). There were two pneumothoraces (4%), neither of which required aspiration or chest tube placement. There were no Grade 3 or 4 bleeding events. Mild bleeding (Grade ≤2) was observed in 25 cases (50%). No complications occurred that met the a priori primary outcome of bleeding Grade ≥3, pneumothorax Grade ≥2, and respiratory failure. CONCLUSIONS: Transbronchial cryobiopsy using a 1.1-mm cryoprobe is feasible with an acceptable safety profile.

Thoracic ultrasound competence for ultrasound guided pleural procedures: The creation and validation of an assessment tool for use in the certification of basic thoracic ultrasound competence.

OBJECTIVES: Focused thoracic ultrasound (TUS) provides an increased safety profile when undertaking invasive pleural procedures. This has led to the requirement for defined curricula, high quality teaching and robust, validated assessment tools among physicians to ensure patient safety and clinical excellence. Current UK practice is based almost exclusively on expert consensus, but assessment methods employed have been shown to have low reliability and validity and are potentially open to bias. As a result, several assessment tools have been developed, although each has its own limitations. METHODS: This study aimed to develop and validate an assessment tool corresponding to those skills associated with the most basic level of practice, defined recently as an emergency level operator in the British Thoracic Society Training Standards for Thoracic Ultrasound. RESULTS: A total of 27 candidates were enrolled by two examiners based in Belfast and Oxford over a 10-month period between February and November 2019. Mean score of the inexperienced group was 44.3 (95% CI 39.2-49.4, range 28-54) compared with 74.9 (95% CI 72.8-77, range 64-80) in the experienced group providing an estimated mean difference of 30.7 between the two groups (95% CI 24.7-36.7; p < .001). CONCLUSIONS: This tool appears to discriminate between trainees with limited experience of TUS performance and those with no experience. It has the potential to form part of the assessment strategy for trainees in the United Kingdom and beyond, alongside well established assessment tools in postgraduate training.