Rachel M. Mercer

A Pilot Feasibility Study in Establishing the Role of Ultrasound-Guided Pleural Biopsies in Pleural Infection (The AUDIO Study)

Background Pleural infection is a common complication of pneumonia associated with high mortality and poor clinical outcome. Treatment of pleural infection relies on the use of broad‐spectrum antibiotics because reliable pathogen identification occurs infrequently. We performed a feasibility interventional clinical study assessing the safety and significance of ultrasound (US)‐guided pleural biopsy culture to increase microbiological yield. In an exploratory investigation, the 16S ribosomal RNA technique was applied to assess its utility on increasing speed and accuracy vs standard microbiological diagnosis. Methods Twenty patients with clinically established pleural infection were recruited. Participants underwent a detailed US scan and US‐guided pleural biopsies before chest drain insertion, alongside standard clinical management. Pleural biopsies and routine clinical samples (pleural fluid and blood) were submitted for microbiological analysis. Results US‐guided pleural biopsies were safe with no adverse events. US‐guided pleural biopsies increased microbiological yield by 25% in addition to pleural fluid and blood samples. The technique provided a substantially higher microbiological yield compared with pleural fluid and blood culture samples (45% compared with 20% and 10%, respectively). The 16S ribosomal RNA technique was successfully applied to pleural biopsy samples, demonstrating high sensitivity (93%) and specificity (89.5%). Conclusions Our findings demonstrate the safety of US‐guided pleural biopsies in patients with pleural infection and a substantial increase in microbiological diagnosis, suggesting potential niche of infection in this disease. Quantitative polymerase chain reaction primer assessment of pleural fluid and biopsy appears to have excellent sensitivity and specificity.

Ultrasound in the management of pleural disease

ABSTRACT Introduction: Pleural disease encompasses a large range of conditions, is a common presentation to the acute medical take and often requires comprehensive investigation and treatment. Ultrasound is well recognised as a useful investigative tool in pleural disease especially in the field of pleural effusion, pleural thickening and interventional procedures. Thoracic ultrasound (TUS) has gained widespread use by physicians as evidence has shown a reduced rate of complications when performing pleural procedures with ultrasound guidance. Areas covered: This article will review studies assessing the role of TUS in the management of pleural disease and examine ongoing research into how TUS could advance our knowledge and understanding over the next decade. Expert commentary: Physician lead thoracic ultrasound has become commonplace over the last decade, and now represents a minimum standard of safety in conducting the majority of ‘bedside’ pleural procedures. The current evidence points to important diagnostic and procedural roles of the use of bedside thoracic ultrasound. In the future, research developments are likely to lead to the use of thoracic ultrasound in prognostication, targeted treatment and understanding pathogenesis in pleural disease.

Development and validation of response markers to predict survival and pleurodesis success in patients with malignant pleural effusion (PROMISE): a multicohort analysis

BACKGROUND The prevalence of malignant pleural effusion is increasing worldwide, but prognostic biomarkers to plan treatment and to understand the underlying mechanisms of disease progression remain unidentified. The PROMISE study was designed with the objectives to discover, validate, and prospectively assess biomarkers of survival and pleurodesis response in malignant pleural effusion and build a score that predicts survival. METHODS In this multicohort study, we used five separate and independent datasets from randomised controlled trials to investigate potential biomarkers of survival and pleurodesis. Mass spectrometry-based discovery was used to investigate pleural fluid samples for differential protein expression in patients from the discovery group with different survival and pleurodesis outcomes. Clinical, radiological, and biological variables were entered into least absolute shrinkage and selection operator regression to build a model that predicts 3-month mortality. We evaluated the model using internal and external validation. FINDINGS 17 biomarker candidates of survival and seven of pleurodesis were identified in the discovery dataset. Three independent datasets (n=502) were used for biomarker validation. All pleurodesis biomarkers failed, and gelsolin, macrophage migration inhibitory factor, versican, and tissue inhibitor of metalloproteinases 1 (TIMP1) emerged as accurate predictors of survival. Eight variables (haemoglobin, C-reactive protein, white blood cell count, Eastern Cooperative Oncology Group performance status, cancer type, pleural fluid TIMP1 concentrations, and previous chemotherapy or radiotherapy) were validated and used to develop a survival score. Internal validation with bootstrap resampling and external validation with 162 patients from two independent datasets showed good discrimination (C statistic values of 0·78 [95% CI 0·72-0·83] for internal validation and 0·89 [0·84-0·93] for external validation of the clinical PROMISE score). INTERPRETATION To our knowledge, the PROMISE score is the first prospectively validated prognostic model for malignant pleural effusion that combines biological and clinical parameters to accurately estimate 3-month mortality. It is a robust, clinically relevant prognostic score that can be applied immediately, provide important information on patient prognosis, and guide the selection of appropriate management strategies. FUNDING European Respiratory Society, Medical Research Funding-University of Oxford, Slater & Gordon Research Fund, and Oxfordshire Health Services Research Committee Research Grants.

S129 Does inflammation predict successful pleurodesis? a post hoc analysis from the time 1 trial

Introduction Malignant pleural effusions are a common complication of advanced malignancy, have a poor prognosis and have a significant impact on quality of life. Treatment strategies include chest drain and pleurodesis, or insertion of an indwelling pleural catheter. Successful pleurodesis is thought to be due to the body’s inflammatory response resulting in pleural symphysis. This post hoc analysis of data from the TIME 1 was conducted to address assess whether there is a correlation between the pleurodesis and a systemic inflammatory response. Methods A total of 282 patients from the TIME 1 trial had data on pleurodesis success, which was defined as no further pleural procedures for up to 3 months after pleurodesis. Patients who had undergone thoracosopy and poudrage as well as those who had undergone chest drain with pleurodesis were included. Sterile talc was used in all patients. The difference in the white cell count (WCC) and C-reactive protein (CRP) levels was calculated between the day of pleurodesis (Day 0) and Day 1. The data are normally distributed thus independent t test was used for analysis. The CRP Day 0 and 1 data were not normally distributed, and therefore were log transformed to produce a normal distribution. Results Two hundred and eighty two patients were included in the analysis with a mean age of 71 in both groups. 229 had a successful pleurodesis and 53 patients required a further pleural procedure on the ipsilateral side signifying failed pleurodesis. 193 patients had CRP levels and 220 patients had WCC levels recorded on both Day 0 and Day 1. Patients who had a successful pleurodesis had a significantly greater rise in CRP than those who failed pleurodesis. There was no significant difference in the change in WCC between the groups. There was also no significant difference in Day 0 and Day 1 WCC or CRP levels between the two groups. Conclusions This analysis demonstrates that systemic rise in CRP as an indicator of inflammation is a better predictor of pleurodesis success than the WCC. These data support the hypothesis that higher levels of inflammation are associated with pleurodesis success. Abstract S129 Table 1 Pleurodesis Success Pleurodesis Failure Significance WCC Day 0 8.84 (SD 4.00, n=213) 9.12 (SD – 3.14, n=46) p=0.582 WCC Day 1 11.14 (SD 3.78, n=191) 10.71 (SD 4.01, n=42) p=0.525 WCC Change 2.30 (SD 3.07, n=180) 1.55 (SD 2.82, n=40) p=0.140 CRP Day 0 (log) 1.46 (SD 0.58, n=181) 1.45 (SD 0.58, n=42) p=0.900 CRP Day 1 (log) 1.92 (SD 0.34, n=179) 1.83 (SD 0.33, n=41) p=0.123 CRP Change 47.81 (SD 52.08, n=154) 27.05 (SD 32.47, n=39) p=0.003 SD=Standard Deviation and n=number of patients

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.

Chest Drain Fall-Out Rate According to Suturing Practices: A Retrospective Direct Comparison

Background: Chest drains often become displaced and require replacement, adding unnecessary risks to patients. Simple measures such as suturing of the drain may reduce fall-out rates; however, there is no direct data to demonstrate this and no standardized recommended practice that is evidence based. Objectives: The study aimed to analyze the rate of chest drain fall out according to suturing practice. Methods: Retrospective analysis of all chest drain insertions (radiology and pleural teams) in 2015–2016. Details of chest drain fall out were collected from patient electronic records. Drain “fall out” was pre-hoc defined as the drain tip becoming dislodged outside the pleural cavity unintentionally before a clinical decision was taken to remove the drain. Results: A total of 369 chest drains were inserted: sutured (n = 106, 28.7%; 44 male [41.5%], median age 74 [interquartile range (IQR) 21] years), and unsutured (n = 263, 71.3%; 139 male [52.9%], median age 68 [IQR 21] years). Of the sutured drains, 7 (6.6%) fell out after a mean of 3.3 days (SD 2.6) compared to 39 (14.8%; p = 0.04) unsutured drains falling out after a mean of 2.7 days (SD 2.0; p = 0.8). Conclusions: Within the limits of this retrospective analysis, these results suggest that suturing of drains is associated with lower fall-out rates.

The role of pleurodesis in respiratory diseases

ABSTRACT Introduction: Pleurodesis is used to obliterate the pleural space, most commonly in patients with symptomatic malignant pleural effusions but also in patients with benign effusions or pneumothorax. Areas covered: Traditionally, chemical pleurodesis has been undertaken at thoracoscopy or using instillation of a slurry through a chest drain. The optimum method of achieving pleurodesis, whether surgical or medical, has yet to be proven. Evidence in the different disease areas will be reviewed, along with ongoing trial evidence, which may change practice. Expert commentary: Newer methods of achieving pleurodesis are being introduced. Studies have shown that instilling sclerosing agents via an indwelling pleural catheter or introducing drug-eluting catheters are safe and effective ways of inducing pleurodesis. There is evidence that pleurodesis might increase in survival, especially after pleural infection, possibly due to activation of the immune system. Multiple studies are currently underway to answer some of these questions and the future landscape may be very different from the present.

Advances in Interventional Pulmonology

Much has changed since the last review of interventional pulmonology (IP) published in this Clinics series. The rate of development of new techniques and their complexities require IP physicians to be constantly maintaining and updating their skill set. International agreed training pathways help ensure that the interventionalists of the present and future have the required knowledge of anatomy, manual dexterity, and clinical judgment to keep up with the continuing advances that are constantly expanding IPs diagnostic and therapeutic boundaries. IP remains one of the most desirable subspecialities in pulmonology, and the technologic advances make the future an exciting one.

Thoracic Ultrasound as an Early Predictor of Pleurodesis Success in Malignant Pleural Effusion

BACKGROUND: Malignant pleural effusion (MPE) is common and imposes a significant burden on patients and health‐care providers. Most patients require definitive treatment, usually drainage and chemical pleurodesis, to relieve symptoms and prevent fluid recurrence. Thoracic ultrasound (TUS) can identify the presence of pleural adhesions in other clinical scenarios, and could therefore have a role in predicting long‐term pleurodesis success or failure in MPE. METHODS: Patients undergoing chest tube drainage and talc slurry pleurodesis for symptomatic MPE were recruited to a prospective observational cohort pilot study assessing whether TUS findings pre‐talc and post‐talc instillation predicted treatment outcome. Participants underwent TUS examination immediately before, and 24 h after talc slurry administration to derive pleural adherence scores for the affected hemithorax. The recorded TUS scans were additionally scored by two independent assessors blinded to the patients clinical status. The primary outcome was pleurodesis success at 1‐month and 3‐month follow‐up. RESULTS: Eighteen participants were recruited to the pilot study. Participants who suffered pleurodesis failure had a lower pleural adherence score at 24 h post‐talc instillation than those who were successful (difference of 6.27; 95% CI, 3.94‐8.59). TUS examination was acceptable to patients, while TUS scoring was highly consistent across all assessors (intraclass correlation coefficient, 0.762; 95% CI, 0.605‐0.872). CONCLUSION: A TUS‐derived pleural adherence score may facilitate early prediction of long‐term outcomes following chemical pleurodesis, with implications for personalized care and decision making in MPE. Further research is needed to evaluate this novel finding. TRIAL REGISTRY: ClinicalTrials.gov; No. NCT02625675; URL: www.clinicaltrials.gov.

P233 Thoracic ultrasonography as a predictor of pleurodesis success in malignant pleural effusion

Background Over 50 000 patients with malignant pleural effusion (MPE) are seen annually in the UK. The majority develop recurrent symptomatic disease requiring definitive treatment. MPE is most frequently managed with talc slurry pleurodesis via intercostal chest drain. This involves a lengthy inpatient stay and has a success rate of around 70%, with no means of predicting which patients will suffer pleurodesis failure. Thoracic ultrasound (TUS) is widely used by respiratory physicians, and data from animal and human studies suggest it can identify pleural adhesions (through the absence of normal lung sliding) in a range of conditions. By extension, TUS may allow clinicians to diagnose the presence or absence of adhesions post-pleurodesis in MPE, identifying patients suitable for discharge or needing further intervention. Abstract P233 Table 1 Ultrasonographic pleurodesis score at day 0 (pre-pleurodesis) and day 1 (24 hours post-pleurodesis) in patients being treated for malignant pleural effusion Successful pleurodesis n=11/15 (73.3%) patients Failed pleurodesis n=4/15 (26.7%) patients p value unpaired t-test Day 0 pleurodesis score (mean±SD, total out of 18) 10.89±3.98 6.50±1.29 0.054 Difference=4.39 (95% CI −0.09 to 8.86) Day 1 pleurodesis score (mean±SD, total out of 18) 13.45±2.63 6.75±2.94 0.002 Difference=6.70 (95% CI 3.08 to 10.33) Change from day 0 to 1 (mean±SD) 2.57±3.98 0.25±3.59 0.326 Difference=2.32 (95% CI −2.59 to 7.23) Method We recruited 18 adult patients with MPE undergoing drainage and talc slurry pleurodesis to a prospective single-centre cohort study. Patients underwent standardised TUS assessment pre- and post-pleurodesis, evaluating pleural sliding and adhesions at nine points (three anterior, three lateral, three posterior) across the affected hemithorax. Lung sliding was graded as per Zhu et al.,1 creating a total pleurodesis score out of 18. Pleurodesis failure was defined as radiological and symptomatic fluid recurrence in the same hemithorax requiring further intervention at any point up to 3 months post-pleurodesis. Patients also completed a questionnaire addressing satisfaction with TUS assessment. Results 3/18 patients (16.7%) died before 1 month follow-up. Of 15 patients seen at one month, 11 (73.3%) had successful pleurodesis and 4 (26.7%) had failed. No patient had delayed pleurodesis failure between 1 and 3 month follow-up. There was a significant difference observed in the day 1 TUS pleurodesis score between patients who went on to have successful pleurodesis and those who failed during follow-up (table 1). TUS assessment was acceptable to patients, with none considering it either time-consuming or unwilling to have it again if needed. Conclusion Our data suggest TUS assessment 24 hours post-pleurodesis for MPE predicts success or failure of this intervention, with significant implications for clinical care. A larger randomised study is now underway to further evaluate this hypothesis. Reference Chest2005;128(2):934–9.