Outpatient Talc Administration by Indwelling Pleural Catheter for Malignant Effusion.

BACKGROUND: Malignant pleural effusion affects more than 750,000 persons each year across Europe and the United States. Pleurodesis with the administration of talc in hospitalized patients is the most common treatment, but indwelling pleural catheters placed for drainage offer an ambulatory alternative. We examined whether talc administered through an indwelling pleural catheter was more effective at inducing pleurodesis than the use of an indwelling pleural catheter alone. METHODS: Over a period of 4 years, we recruited patients with malignant pleural effusion at 18 centers in the United Kingdom. After the insertion of an indwelling pleural catheter, patients underwent drainage regularly on an outpatient basis. If there was no evidence of substantial lung entrapment (nonexpandable lung, in which lung expansion and pleural apposition are not possible because of visceral fibrosis or bronchial obstruction) at 10 days, patients were randomly assigned to receive either 4 g of talc slurry or placebo through the indwelling pleural catheter on an outpatient basis. Talc or placebo was administered on a single-blind basis. Follow-up lasted for 70 days. The primary outcome was successful pleurodesis at day 35 after randomization. RESULTS: The target of 154 patients undergoing randomization was reached after 584 patients were approached. At day 35, a total of 30 of 69 patients (43%) in the talc group had successful pleurodesis, as compared with 16 of 70 (23%) in the placebo group (hazard ratio, 2.20; 95% confidence interval, 1.23 to 3.92; P=0.008). No significant between-group differences in effusion size and complexity, number of inpatient days, mortality, or number of adverse events were identified. No significant excess of blockages of the indwelling pleural catheter was noted in the talc group. CONCLUSIONS: Among patients without substantial lung entrapment, the outpatient administration of talc through an indwelling pleural catheter for the treatment of malignant pleural effusion resulted in a significantly higher chance of pleurodesis at 35 days than an indwelling catheter alone, with no deleterious effects. (Funded by Becton Dickinson; EudraCT number, 2012-000599-40 .).

Effect of Thoracoscopic Talc Poudrage vs Talc Slurry via Chest Tube on Pleurodesis Failure Rate Among Patients With Malignant Pleural Effusions: A Randomized Clinical Trial.

Importance: Malignant pleural effusion (MPE) is challenging to manage. Talc pleurodesis is a common and effective treatment. There are no reliable data, however, regarding the optimal method for talc delivery, leading to differences in practice and recommendations. Objective: To test the hypothesis that administration of talc poudrage during thoracoscopy with local anesthesia is more effective than talc slurry delivered via chest tube in successfully inducing pleurodesis. Design, Setting, and Participants: Open-label, randomized clinical trial conducted at 17 UK hospitals. A total of 330 participants were enrolled from August 2012 to April 2018 and followed up until October 2018. Patients were eligible if they were older than 18 years, had a confirmed diagnosis of MPE, and could undergo thoracoscopy with local anesthesia. Patients were excluded if they required a thoracoscopy for diagnostic purposes or had evidence of nonexpandable lung. Interventions: Patients randomized to the talc poudrage group (n = 166) received 4 g of talc poudrage during thoracoscopy while under moderate sedation, while patients randomized to the control group (n = 164) underwent bedside chest tube insertion with local anesthesia followed by administration of 4 g of sterile talc slurry. Main Outcomes and Measures: The primary outcome was pleurodesis failure up to 90 days after randomization. Secondary outcomes included pleurodesis failure at 30 and 180 days; time to pleurodesis failure; number of nights spent in the hospital over 90 days; patient-reported thoracic pain and dyspnea at 7, 30, 90, and 180 days; health-related quality of life at 30, 90, and 180 days; all-cause mortality; and percentage of opacification on chest radiograph at drain removal and at 30, 90, and 180 days. Results: Among 330 patients who were randomized (mean age, 68 years; 181 [55%] women), 320 (97%) were included in the primary outcome analysis. At 90 days, the pleurodesis failure rate was 36 of 161 patients (22%) in the talc poudrage group and 38 of 159 (24%) in the talc slurry group (adjusted odds ratio, 0.91 [95% CI, 0.54-1.55]; P = .74; difference, -1.8% [95% CI, -10.7% to 7.2%]). No statistically significant differences were noted in any of the 24 prespecified secondary outcomes. Conclusions and Relevance: Among patients with malignant pleural effusion, thoracoscopic talc poudrage, compared with talc slurry delivered via chest tube, resulted in no significant difference in the rate of pleurodesis failure at 90 days. However, the study may have been underpowered to detect small but potentially important differences. Trial Registration: ISRCTN Identifier: ISRCTN47845793.

Respiratory manifestations of eosinophilic granulomatosis with polyangiitis (Churg-Strauss).

The respiratory manifestations of eosinophilic granulomatosis with polyangiitis (EGPA) have not been studied in detail.In this retrospective multicentre study, EGPA was defined by asthma, eosinophilia and at least one new onset extra-bronchopulmonary organ manifestation of disease.The study population included 157 patients (mean±sd age 49.4±14.1 years), with a mean±sd blood eosinophil count of 7.4±6.4×109 L-1 at diagnosis. There was a mean±sd of 11.8±18.2 years from the onset of asthma to the diagnosis of EGPA, of 1.4±8.4 years from the first onset of peripheral eosinophilia to the diagnosis of EGPA, and of 7.4±6.4 years from EGPA diagnosis to the final visit. Despite inhaled and oral corticosteroid treatment, the severity of asthma increased 3-6 months before the onset of the systemic manifestations. Asthma was severe in 57%, 48%, and 56% of patients at diagnosis, at 3 years, and at the final visit, respectively. Persistent airflow obstruction was present in 38%, 30%, and 46% at diagnosis, at 3 years, and at the final visit, respectively.In EGPA, asthma is severe, antedates systemic manifestations by a mean of 12 years, and progresses to long-term persistent airflow obstruction despite corticosteroids in a large proportion of patients, which affects long-term management and morbidity.

Indwelling pleural catheters for non-malignant effusions: a multicentre review of practice.

Indwelling pleural catheters (IPCs) are commonly used in the management of malignant pleural effusion (MPE). There is little data on their use in non-malignant conditions. All IPC insertions for non-malignant cases from five large UK centres were found using prospectively maintained databases. Data were collected on 57 IPC insertions. The commonest indications were hepatic hydrothorax (33%) and inflammatory pleuritis (26%). The mean weekly fluid output was 2.8 L (SD 2.52). 48/57 (84%) patients had no complications. Suspected pleural infection was documented in 2 (3.5%) cases. 33% (19/57) of patients underwent 'spontaneous' pleurodesis at a median time of 71 days. Patients with hepatic disease achieved pleurodesis significantly less often than those with non-hepatic disease (p=0.03). These data support the use of IPCs in select cases of non-malignant disease when maximal medical therapy has failed.

Manometry performed at indwelling pleural catheter insertion to predict unexpandable lung.

BACKGROUND: The finding of unexpandable lung (UL) at an early timepoint is of increasing importance in guiding treatment decisions in patients with malignant pleural effusion (MPE). Pleural manometry is the most common technique to delineate UL, however it has never been measured via an indwelling pleural catheter (IPC). To further the evidence base we analysed all patients in the IPC-PLUS study who had manometry performed during IPC insertion for the ability to predict substantial UL using manometry. METHODS: All patients enrolled in IPC-PLUS who had manometry performed at IPC insertion and radiographic assessment of UL at day 10 were included. Elastance curves were visually inspected for each patient. Initial pleural pressure, closing pleural pressure, and terminal elastance were analysed for their differences and predictive ability in those with substantial UL, defined as ≥25% entrapment on chest radiography. RESULTS: A total of 89 patients had manometry performed at IPC insertion with subsequent radiographic assessment of UL and interpretable elastance curves. Those with substantial UL had a significantly lower median closing pleural pressure (-15.00 vs. 0.00 cmH2O, P=0.012) and higher terminal elastance (12.03 vs. 8.59 cmH2O/L, P=0.021) compared to a combined group with no or partial UL. However, the predictive ability of these factors to discriminate substantial UL was poor, with areas under the receiver operating characteristic curves of 0.695 and 0.680 for closing pleural pressure and elastance respectively. CONCLUSIONS: Our results suggest that manometry is not useful in accurately predicting substantial UL when used via an IPC at the time of insertion.

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

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

Providing safe and effective pleural medicine services in the UK: an aspirational statement from UK pleural physicians.

Physicians face considerable challenges in ensuring safe and effective care for patients admitted to hospital with pleural disease. While subspecialty development has driven up standards of care, this has been tempered by the resulting loss of procedural experience in general medical teams tasked with managing acute pleural disease. This review aims to define a framework though which a minimum standard of care might be implemented. This review has been written by pleural clinicians from across the UK representing all types of secondary care hospital. Its content has been formed on the basis of literature review, national guidelines, National Health Service England policy and consensus opinion following a round table discussion. Recommendations have been provided in the broad themes of procedural training, out-of-hours management and pleural service specification. Procedural competences have been defined into descriptive categories: emergency, basic, intermediate and advanced. Provision of emergency level operators at all times in all trusts is the cornerstone of out-of-hours recommendations, alongside readily available escalation pathways. A proposal for minimum standards to ensure the safe delivery of pleural medicine have been described with the aim of driving local conversations and providing a framework for service development, review and risk assessment.

Pulmonary Involvement in Antineutrophil Cytoplasmic Antibodies (ANCA)-associated Vasculitis: The Influence of ANCA Subtype.

OBJECTIVE: To describe pulmonary involvement at time of diagnosis in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), as defined by computed tomography (CT). METHODS: Patients with thoracic CT performed on or after the onset of AAV (n = 140; 75 women; granulomatosis with polyangiitis, n = 79; microscopic polyangiitis MPA, n = 61) followed at a tertiary referral center vasculitis clinic were studied. Radiological patterns of pulmonary involvement were evaluated from the CT studies using a predefined protocol, and compared to proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA specificity. RESULTS: Of the patients, 77% had an abnormal thoracic CT study. The most common abnormality was nodular disease (24%), of which the majority were peribronchial nodules, followed by bronchiectasis and pleural effusion (19%, each), pulmonary hemorrhage and lymph node enlargement (14%, each), emphysema (13%), and cavitating lesions (11%). Central airways disease and a nodular pattern of pulmonary involvement were more common in PR3-ANCA-positive patients (p < 0.05). Usual interstitial pneumonitis (UIP) and bronchiectasis were more prevalent in MPO-ANCA-positive patients (p < 0.05). Alveolar hemorrhage, pleural effusion, lymph node enlargement, and pulmonary venous congestion were more frequent in MPO-ANCA-positive patients. CONCLUSION: Pulmonary involvement is frequent and among 140 patients with AAV who underwent a thoracic CT study, almost 80% have pulmonary abnormalities on thoracic CT. Central airway disease occurs exclusively among patients with PR3-ANCA while UIP were mainly seen in those with MPO-ANCA. These findings may have important implications for the investigation, management, and pathogenesis of AAV.

Revisiting the systemic vasculitis in eosinophilic granulomatosis with polyangiitis (Churg-Strauss): A study of 157 patients by the Groupe d'Etudes et de Recherche sur les Maladies Orphelines Pulmonaires and the European Respiratory Society Taskforce on eosinophilic granulomatosis with polyangiitis (Churg-Strauss).

OBJECTIVE: To guide nosology and classification of patients with eosinophilic granulomatosis with polyangiitis (EGPA) based on phenotype and presence or absence of ANCA. METHODS: Organ manifestations and ANCA status were retrospectively analyzed based on the presence or not of predefined definite vasculitis features or surrogates of vasculitis in patients asthma, eosinophilia, and at least one systemic organ manifestation attributable to systemic disease. RESULTS: The study population included 157 patients (mean age 49.4±14.1), with a follow-up of 7.4±6.4years. Patients with ANCA (31%) more frequently had weight loss, myalgias, arthralgias, biopsy-proven vasculitis, glomerulonephritis on biopsy, hematuria, leukocytoclastic capillaritis and/or eosinophilic infiltration of arterial wall on biopsy, and other renal disease. A total of 41% of patients had definite vasculitis manifestations (37%) or strong surrogates of vasculitis (4%), of whom only 53% had ANCA. Mononeuritis multiplex was associated with systemic vasculitis (p=0.005) and with the presence of ANCA (p<0.001). Overall, 59% of patients had polyangiitis as defined by definite vasculitis, strong surrogate of vasculitis, mononeuritis multiplex, and/or ANCA with at least one systemic manifestation other than ENT or respiratory. Patients with polyangiitis had more systemic manifestations including arthralgias (p=0.02) and renal disease (p=0.024), had higher peripheral eosinophilia (p=0.027), and a trend towards less myocarditis (p=0.057). Using predefined criteria of vasculitis and surrogates of vasculitis, ANCA alone were found to be insufficient to categorise patients with vasculitis features. CONCLUSION: We suggest a revised nomenclature and definition for EGPA and a new proposed entity referred to as hypereosinophilic asthma with systemic (non vasculitic) manifestations.

How small peptides block and reverse serpin polymerisation.

Many of the late-onset dementias, including Alzheimer's disease and the prion encephalopathies, arise from the aberrant aggregation of individual proteins. The serpin family of serine protease inhibitors provides a well-defined structural example of such pathological aggregation, as its mutant variants readily form long-chain polymers, resulting in diseases ranging from thrombosis to dementia. The intermolecular linkages result from the insertion of the reactive site loop of one serpin molecule into the middle strand (s4A) position of the A beta-sheet of another molecule. We define here the structural requirements for small peptides to competitively bind to and block the s4A position to prevent this intermolecular linkage and polymerisation. The entry and anchoring of blocking-peptides is facilitated by the presence of a threonine which inserts into the site equivalent to P8 of s4A. But the critical requirement for small blocking-peptides is demonstrated in crystallographic structures of the complexes formed with selected tri- and tetrapeptides. These structures indicate that the binding is primarily due to the insertion of peptide hydrophobic side-chains into the P4 and P6 sites of s4A. The findings allow the rational design of synthetic blocking-peptides small enough to be suitable for mimetic design. This is demonstrated here with a tetrapeptide that preferentially blocks the polymerisation of a pathologically unstable serpin commonly present in people of European descent.

Long-term outcome of airway stenosis in granulomatosis with polyangiitis (Wegener granulomatosis): an observational study.

IMPORTANCE: Airway stenosis occurs in patients with granulomatosis with polyangiitis (GPA or Wegener granulomatosis). It produces significant morbidity and contributes to mortality. OBJECTIVE: To investigate the frequency and distribution of airway stenoses in GPA and evaluate the efficacy of local interventions in maintaining airway patency. DESIGN, SETTING, AND PARTICIPANTS: A retrospective single-center study of 44 patients with GPA and airway stenosis assessed and treated as needed by a multidisciplinary team at a university medical center between 1997 and 2012. The median duration of observation for each patient from the time of diagnosis was 146 months. INTERVENTIONS: Patients who had critical stenoses underwent either dilatation or laser radial cuts to the lesion. In some cases, intralesional administration of steroids or topical mitomycin C was used. MAIN OUTCOMES AND MEASURES: The main outcome measure was airway patency for at least 12 months and the number of interventions required to achieve this end point. Details of patients and interventions were recorded at baseline and at each treatment. RESULTS: The median age at diagnosis was 37.6 years; 73% of patients were women (n = 34). The median follow-up after the initial intervention was 62.5 months. Subglottic stenosis was found in 36 patients, lower airway stenosis in 30. There were 213 interventions in 39 patients, including balloon and bougie dilatation and laser treatment. Adjuvant local treatment was used in 71 interventions. A 12-month period of airway stability was achieved in 34 of 36 cases (97%) (5 had no procedures and 3 had follow-up shorter than 12 months). The median interval between procedures was 4.9 months, and after the last intervention recorded, patients had at least 27 months of airway stability. Fourteen adverse events were recorded (6.6%). CONCLUSIONS AND RELEVANCE: The frequency and distribution of airway stenoses in 44 patients with GPA has been described. In the 39 patients who required intervention, multiple procedures were required, but 97% then achieved a prolonged period of airway patency. The procedures and adjuvant treatments were found to be safe. Our experience with a variety of techniques in this rare presentation has permitted design of a structured approach and an algorithm to manage and evaluate airway stenosis in GPA.

Clinical demonstration of efficiency and reversibility of hypoxic pulmonary vasoconstriction in a patient presenting with unilateral incomplete bronchial occlusion.

Although hypoxic pulmonary vasoconstriction is a well-recognized physiological phenomenon it is unusual to observe and assess its efficiency in clinical practice. Here, we report the case of a 50-year-old female who presented with unilateral incomplete bronchial occlusion due to a carcinoid tumor involving the left main bronchus in the absence of atelectasis. Ventilation-perfusion imaging revealed absent ventilation and perfusion to the left lung. She underwent bronchotomy and removal of the tumor. One month after the operation a further ventilation-perfusion lung scan revealed complete restoration of ventilation to the left lung and almost complete recovery of the perfusion. This unusual case demonstrates the marked efficiency of hypoxic pulmonary vasoconstriction at the level of a single lung and its reversible nature following relief of regional hypoxia.

Isolated large vessel pulmonary vasculitis as a cause of chronic obstruction of the pulmonary arteries.

Isolated pulmonary artery involvement by large vessel vasculitis is rare. This case report describes two patients with large vessel pulmonary vasculitis initially thought to have chronic thromboembolic pulmonary hypertension who had their diagnosis revised following pulmonary endarterectomy surgery. Advances in imaging techniques such as positron emission tomography and magnetic resonance imaging have permitted complementary radiological methods of diagnosis and follow up of large vessel disease and these are discussed in conjunction with the immunosuppressive and operative management of these patients.