A Retrospective Analysis of 2-Year Follow-Up of Patients with Incidental Findings of Sarcoidosis.

INTRODUCTION: Sarcoidosis is a multi-system granulomatous disease most commonly involving the lungs. It may be incidentally diagnosed during imaging studies for other conditions or non-specific symptoms. The appropriate follow-up of incidentally diagnosed asymptomatic stage 1 disease has not been well defined. OBJECTIVE: To define the clinical course of incidentally diagnosed asymptomatic stage 1 sarcoidosis and propose an algorithm for the follow-up of these patients. METHODOLOGY: A retrospective case note analysis was performed of all EBUS-TBNA (endobronchial ultrasound-guided transbronchial needle aspiration)-confirmed cases of stage 1 sarcoidosis presenting incidentally to Bristol and Liverpool Interstitial Lung Disease services. Clinical history, serology results, imaging scans, and lung function parameters were examined at baseline, 12, and 24 months. A cost analysis was performed comparing the cost of the current 2-year follow-up guidance to a 1 year follow-up period. RESULTS: Sixty-seven patients were identified as the final cohort. There was no significant change in the pulmonary function tests over the two-year follow-up period. Radiological disease stability was observed in the majority of patients (58%, n = 29), and disease regression was evidenced in 40% (n = 20) at 1 year. Where imaging was performed at 2 years, the majority (69.8%, n = 37) had radiological evidence of disease regression, and 30.2% (n = 16) showed radiological evidence of stability. All patients remained asymptomatic and did not require therapeutic intervention over the study period. CONCLUSIONS: Our results show that asymptomatic patients with incidental findings of thoracic lymph nodal non-caseating granulomas do not progress over a 2-year period. Our results suggest that the prolonged secondary-care follow-up of such patients may not be necessary. We propose that these patients are followed up for 1 year with a further year of patient-initiated follow-up (PIFU) prior to discharge.

ANCA-negative ANCA-associated vasculitis: pitfalls of the 'vasculitis screen'.

Despite its recognition as an 'ANCA-associated vasculitis' (AAV), eosinophilic granulomatosis with polyangiitis (EGPA) is ANCA negative in up to 60% of cases. Herein, we report the case of a young man with a clinical syndrome highly suggestive of EGPA but with repeated negative ANCA serology, ultimately presenting with cardiac arrest before recognition of the primary systemic vasculitis, whereupon he received successful induction therapy with high dose glucocorticoids and cyclophosphamide. The case illustrates the importance of awareness of ANCA negative AAV among general physicians in order to minimise morbidity and mortality.

Suitability of endobronchial ultrasound-guided transbronchial needle aspiration samples for programmed death ligand-1 testing in non-small cell lung cancer, the Bristol experience.

Treatment for non-small cell lung cancer (NSCLC) is now personalised using molecular mutation testing. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) biopsy suitability for anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) mutation testing is established. Less is currently known about EBUS-TBNA suitability for PD-L1 (programmed death ligand-1) testing. To assess EBUS-TBNA biopsy adequacy for ALK, EGFR and PD-L1 testing, we conducted a prospective study of 279 consecutive NSCLC patients referred to a tertiary EBUS-TBNA centre in South West England. One hundred eight-four (62.6%) patients were found to have adenocarcinoma, 83 (28.2%) had squamous cell carcinoma, and 27 (9.2%) were identified as NSCLC-not otherwise specified. EGFR testing was successful in 166 of 168 patients (98.8%), ALK testing in all 115 and PD-L1 testing in 43 of 49 patients (88.2%). Previous EGFR and ALK testing did not affect biopsy PD-L1 testing success. PD-L1 testing failures occurred in three of five (60.0%) of 22G needle biopsies, one of five (20.0%) of 21G needle biopsies and two of 39 (5.1%) of 19G needle biopsies, P = .016. EBUS-TBNA biopsies are mostly suitable for PD-L1 testing. Larger needle size may improve PD-L1 (but not EGFR and ALK) testing success but requires further study in a controlled trial.

Is Systemic Anticancer Therapy Associated With Higher Rates of Malignant Pleural Effusion Control in People With Pharmacologically Sensitive Tumors?: A Retrospective Analysis of Prospectively Collected Data.

BACKGROUND: Malignant pleural effusions (MPEs) often cause symptoms, and guidelines recommend early definitive intervention. However, observational data suggest that systemic anticancer treatment (SACT) may control MPE caused by certain pharmacologically sensitive tumors. RESEARCH QUESTION: Is SACT associated with higher rates of MPE resolution in people with pharmacologically sensitive tumors? STUDY DESIGN AND METHODS: This was a retrospective analysis of prospectively collected data from an observational cohort study of people diagnosed with MPE from lung, breast, ovarian, and hematologic malignancy between May 11, 2008, and August 6, 2017. MPE resolution (defined as radiologic resolution with removal of drain or catheter and cessation of interventions) was compared in pharmacologically sensitive (high-grade lymphoma, small cell or target-mutation-positive lung cancer, and hormone-receptor-positive breast or ovarian cancer) and nonsensitive (remainder of cohort) tumors, with and without SACT. Secondary outcomes included time to resolution, 3-month resolution rates, and total pleural interventions. RESULTS: Of 280 patients, 127 had sensitive and 153 had nonsensitive tumors. One hundred seventy-one received SACT, and 109 did not. More patients with sensitive tumors achieved MPE resolution than those with nonsensitive tumors (53/127 [41.7%] vs 42/153 [27.5%]; P = .01), and this occurred predominantly after receipt of SACT. However, hematologic malignancies were overrepresented in the sensitive group, with high rates of SACT use and MPE resolution. After adjustment for this and other confounders, no relationship was found among pharmacologic sensitivity, SACT, and MPE resolution (adjusted OR, 1.4; 95% CI, 0.5-4.1). The strongest predictor of MPE resolution was administration of chemical pleurodesis (adjusted OR, 6.2; 95% CI, 3.3-11.7). In sensitive tumors, MPE resolution occurred without chemical pleurodesis in 14 of 52 patients (26.9%; 95% CI, 15.6%-41.1%) after SACT and in 5 of 22 patients (22.7%; 95% CI, 8.2%-47.2%) without SACT. INTERPRETATION: In this observational study, SACT was not associated independently on MPE resolution in pharmacologically sensitive tumors. Randomized trials are required, but with current data, patients with symptomatic MPE should receive early definitive pleural intervention regardless of underlying tumor or intended treatment.

The effect of 19-gauge endobronchial ultrasound-guided transbronchial needle aspiration biopsies on characterisation of malignant and benign disease. The Bristol experience.

EBUS-TBNA is a recent mediastinal staging and diagnostic technique. We have previously reported superior characterisation with 21G biopsies over 22G biopsies for benign and malignant mediastinal nodes. A new 19G needle now exists but there are limited studies. We hypothesised 19G biopsies would improve both benign and malignant characterisation due to larger samples. We retrospectively analysed sequential patients referred for EBUS-TBNA with unexplained mediastinal adenopathy performed with 19G, 21G and 22G needles respectively (100 patients each). Contingency table analysis was performed.  There were no complications. Sensitivity for malignancy was highest in the 19G group (95.7% versus 94.7% and 87.5%, respectively). The 19G group had higher mean lymph node size (19.4mm versus 18.6mm and 13.5mm, respectively), the highest proportion of lymphoma (9% versus 5% and 0%, respectively), the lowest proportion of NSCLC-NOS (2% versus 12% and 5%, respectively), the highest proportion of subcharacterised benign disease (89.6% versus 69.8% and 37.9%, respectively). This large single centre retrospective UK study suggests the 19G needle appears safe with the suggestion of better sensitivity for malignancy subcharacterisation of benign disease but this requires further study in adequately powered comparative controlled studies with univariate and multivariate analysis.

A Prospective Study to Evaluate a Diagnostic Algorithm for the Use of Fluid Lymphocyte Subset Analysis in Undiagnosed Unilateral Pleural Effusions.

BACKGROUND: Haematological malignancy is an important cause of pleural effusion. Pleural effusions secondary to haematological malignancy are usually lymphocyte predominant. However, several other conditions such as carcinoma, tuberculosis, and chronic heart failure also cause lymphocytic effusions. Lymphocyte subset (LS) analysis may be a useful test to identify haematological malignancy in patients with lymphocytic effusions. However, research into their utility in pleural effusion diagnostic algorithms has not yet been published. OBJECTIVES: We aimed to determine the clinical utility of pleural fluid LS analysis and whether it can be applied to a diagnostic algorithm to identify effusions secondary to haematological malignancy. The secondary aim was to evaluate the diagnostic value of pleural fluid differential cell count. METHODS: Consecutive consenting patients presenting to our pleural service between 2008 and 2013 underwent thoracentesis and differential cell count analysis. We proposed an algorithm which selected patients with lymphocytic effusions (>50%) to have further fluid sent for LS analysis. Two independent consultants agreed on the cause of the original effusion after a 12-month follow-up period. RESULTS: A total of 60 patients had samples sent for LS analysis. LS analysis had an 80% sensitivity (8/10) and a 100% specificity for the diagnosis of haematological malignancy. The positive and negative predictive values were 100 and 96.1%, respectively. Overall 344 differential cell counts were analysed; 16% of pleural effusions with a malignant aetiology were neutrophilic or eosinophilic at presentation. A higher neutrophil and eosinophil count was associated with benign diagnoses, whereas a higher lymphocyte count was associated with malignant diagnoses. CONCLUSIONS: LS analysis may identify haematological malignancy in a specific cohort of patients with undiagnosed pleural effusions. A pleural fluid differential cell count provides useful additional information to streamline patient pathway decisions.

Relationship between endobronchial ultrasound-guided (EBUS)-transbronchial needle aspiration utility and computed tomography staging, node size at EBUS, and positron emission tomography scan node standard uptake values: A retrospective analysis.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) diagnoses and stages mediastinal lymph node pathology. This retrospective study determined the relationship between EBUS-TBNA utility and non-small cell lung cancer (NSCLC) stage, lymph node size, and positron emission tomography (PET) standard uptake values (SUV), and the utility of neck ultrasound in bulky mediastinal disease. METHODS: Data of 284 consecutive patients who had undergone EBUS-TBNA was collected. Two hundred patients had suspected NSCLC, with 148 confirmed NSCLC cases. The diagnostic utility of EBUS-TBNA was determined according to NSCLC stage, EBUS lymph node size, PET SUV, use in distal metastases, and mutation testing. The utility of neck ultrasound for N3 disease was calculated in patients with bulky mediastinal disease. RESULTS: EBUS-TBNA was well tolerated with 97% sensitivity in distant metastatic disease, avoiding the need for distal metastases biopsy in 81% of cases. It had equivalent diagnostic accuracy in all NSCLC stages and in lymph nodes <10 mm, <20 mm or >20 mm (sensitivity >92% in all cases), with no mutation testing failures. EBUS-TBNA had 33% sensitivity in PET indolent (SUV < 4) nodes and 79% sensitivity in PET active nodes (SUV > 4). EBUS-TBNA diagnosed 12 cases of lymphoma without flow cytometry. CONCLUSIONS: The use of EBUS-TBNA meant that distant metastatic biopsy was avoided in 81% of cases, performing well irrespective of cancer stage, node size, and facilitating mutation testing. Neck ultrasound failed to detect N3 disease in patients with bulky mediastinal disease. EBUS-TBNA had a sensitivity of 33% for metastases in PET negative nodes, highlighting PET limitations.

Endobronchial and transbronchial biopsy experience: A United Kingdom survey.

BACKGROUND: Trainees are performing fewer bronchoscopies as a result of the increased use of endobronchial ultrasound-guided transbronchial needle aspiration. Workforce planning and changes in trainee working patterns may also have compounded this situation. We investigated current trends in endobronchial biopsy (EBB) and transbronchial biopsy (TBB) training and competency in respiratory trainees and consultants across the United Kingdom. METHODS: We performed a national survey and received 131 online responses from 58 consultants and 73 registrars across 13 United Kingdom deaneries. RESULTS: A significant proportion (31%) of consultants, more than half of which were new consultants, had performed <500 bronchoscopies. Bronchoscopic biopsy experience varies widely across trainees and consultants (9.1% of senior trainees and 14.3% of new consultants had performed <100 bronchoscopies). Most trainees and some new consultants reported performing relatively low numbers of EBB (13% <20 and 52% <50 procedures) and TBB (75% of trainees, 36% of new consultants, 12% of established consultants <10 procedures). Significant numbers of trainees do not feel competent in EBB (24%) and TBB (89% of junior trainees, 64% of senior trainees) and some consultants (24% of new and established consultants) wish for support with TBB. CONCLUSIONS: These results have implications for future specialist training, curriculum planning, and service configuration. Training and performance of EBB and TBB may become concentrated in centers with an adequate volume of these procedures. Higher volumes of EBB and TBB may well be more likely to occur paradoxically in centers without endobronchial ultrasound-guided transbronchial needle aspiration; however, this hypothesis requires further study.

Nonmalignant Pleural Effusions: A Prospective Study of 356 Consecutive Unselected Patients.

BACKGROUND: Pleural effusion secondary to a nonmalignant cause can represent significant morbidity and mortality. Nonmalignant pleural effusion (NMPE) is common, with congestive heart failure representing the leading cause. Despite this, there are limited data on mortality risk and associated prognostic factors. METHODS: We recruited 782 consecutive patients presenting to a pleural service between March 2008 and March 2015 with an undiagnosed pleural effusion. Further analysis was conducted in 356 patients with NMPE. Pleural biochemical analysis, cytologic analysis, thoracic ultrasonography, and chest radiography were performed. Echocardiography, CT imaging, radiologically guided biopsy, and medical thoracoscopy were undertaken as clinically indicated. Patients were followed for a minimum duration of 12 months, with the final diagnosis decided through independent review by two respiratory consultants. RESULTS: Of the 782 patients, 356 were diagnosed with NMPE (46%). These patients had a mean age of 68 years (SD, 17 years) with 69% of them being men. Patients with cardiac, renal, and hepatic failure had 1-year mortality rates of 50%, 46%, and 25%, respectively. Bilateral effusions (hazard ratio [HR], 3.55; 95% CI, 2.22-5.68) and transudative effusions (HR, 2.78; 95% CI, 1.81-4.28) were associated with a worse prognosis in patients with NMPE, with a 57% and 43% 1-year mortality rate, respectively. CONCLUSIONS: This is the largest prospectively collected series in patients with NMPE, demonstrating that cases secondary to organ dysfunction have extremely high 1-year mortality. In addition, the presence of bilateral and transudative effusions is an indicator of increased mortality. Clinicians should be aware of these poor prognostic features and guide management accordingly.

Adequacy of endobronchial ultrasound-guided transbronchial needle aspiration samples processed as histopathological samples for genetic mutation analysis in lung adenocarcinoma.

Phenotyping non-small-cell lung cancer is becoming increasingly important with the advent of molecular testing. Tumours harbouring somatic mutations in the gene that encodes for the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) have been found to increase responsiveness to tyrosine kinase inhibitors. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive technique for mediastinal node sampling. The available prospective data on EBUS-TBNA sample suitability for molecular profiling are currently limited. The aim of this prospective study was to evaluate the adequacy of EBUS-TBNA samples for EGFR and anaplastic lymphoma kinase (ALK) genetic mutation analysis in confirmed primary lung adenocarcinomas. We conducted a prospective analysis of 410 consecutive patients referred for EBUS-TBNA between 2010 and 2014. Rapid on-site cytological evaluation was not used. The samples were obtained using 21-gauge (21G) or 22G needles and were prepared as histopathological samples. A total of 91 samples were confirmed as lung adenocarcinomas and 80 of these samples were sent for EGFR mutation analysis. EBUS-TBNA had a diagnostic accuracy of 98.3% for malignancy. EGFR mutation testing was possible in 79/80 cases (98.75%). EGFR mutations were detected in 5/80 (6.3%) samples. ALK gene analysis, which became available during the study period, was requested and successfully performed in 21/21 samples (100%). The total combined genotyping success rate was 100/101 (99.0%). This UK study confirmed the high clinical utility of EBUS-TBNA samples processed as histopathological specimens for EGFR and ALK genotyping in primary lung adenocarcinoma. The needle gauge did not affect genotyping efficacy.

Foamy Macrophage Deposition in Lymph Nodes Mimicking Lung Cancer Recurrence Diagnosed via Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration.

The radiological finding of mediastinal lymph node enlargement following surgery for lung cancer often signifies locoregional recurrence. The use of oxidised cellulose haemostatic agents (OCHAs) during staging mediastinoscopy is common. We report a case of 18-fluorodeoxyglucose-avid subcarinal lymphadenopathy in a patient in whom OCHAs had been used at mediastinoscopy 5 months earlier. Histopathological examination of suspected nodal recurrence is facilitated by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). The technique is particularly useful after previous mediastinoscopy, when repeat surgical exploration can be challenging. EBUS-TBNA samples showed extensive foamy macrophage deposition, with no evidence of malignancy. The association between the use of OCHAs and subsequent intranodal foamy macrophage deposition is new. Clinicians should consider this possibility in the differential diagnosis of mediastinal lymphadenopathy after surgical exploration, where OCHAs have been left in situ; it remains important to resample the lymph nodes before assuming disease recurrence to prevent unnecessary treatment.

Advances in understanding of the pathogenesis of acute respiratory distress syndrome.

The clinical syndrome of acute lung injury (ALI) occurs as a result of an initial acute systemic inflammatory response. This can be consequent to a plethora of insults, either direct to the lung or indirect. The insult results in increased epithelial permeability, leading to alveolar flooding with a protein-rich oedema fluid. The resulting loss of gas exchange leads to acute respiratory failure and typically catastrophic illness, termed acute respiratory distress syndrome (ARDS), requiring ventilatory and critical care support. There remains a significant disease burden, with some estimates showing 200,000 cases each year in the USA with a mortality approaching 50%. In addition, there is a significant burden of morbidity in survivors. There are currently no disease-modifying therapies available, and the most effective advances in caring for these patients have been in changes to ventilator strategy as a result of the ARDS network studies nearly 15 years ago. Here, we will give an overview of more recent advances in the understanding of the cellular biology of ALI and highlight areas that may prove fertile for future disease-modifying therapies.

Pleural irrigation trial (PIT): a randomised controlled trial of pleural irrigation with normal saline versus standard care in patients with pleural infection.

Pleural infection is increasing in incidence. Despite optimal medical management, up to 30% of patients will die or require surgery. Case reports suggest that irrigation of the pleural space with saline may be beneficial.A randomised controlled pilot study in which saline pleural irrigation (three times per day for 3 days) plus best-practice management was compared with best-practice management alone was performed in patients with pleural infection requiring chest-tube drainage. The primary outcome was percentage change in computed tomography pleural fluid volume from day 0 to day 3. Secondary outcomes included surgical referral rate, hospital stay and adverse events.35 patients were randomised. Patients receiving saline irrigation had a significantly greater reduction in pleural collection volume on computed tomography compared to those receiving standard care (median (interquartile range) 32.3% (19.6-43.7%) reduction versus 15.3% (-5.5-28%) reduction) (p<0.04). Significantly fewer patients in the irrigation group were referred for surgery (OR 7.1, 95% CI 1.23-41.0; p=0.03). There was no difference in length of hospital stay, fall in C-reactive protein, white cell count or procalcitonin or adverse events between the treatment groups, and no serious complications were documented.Saline irrigation improves pleural fluid drainage and reduces referrals for surgery in pleural infection. A large multicentre randomised controlled trial is now warranted to evaluate its effects further.

Pleural fluid adenosine deaminase (pfADA) in the diagnosis of tuberculous effusions in a low incidence population.

INTRODUCTION: Previous studies have assessed the diagnostic ability of pleural fluid adenosine deaminase (pfADA) in detecting tuberculous pleural effusions, with good specificity and sensitivity reported. However, in North Western Europe pfADA is not routinely used in the investigation of a patient with an undiagnosed pleural effusion, mainly due to a lack of evidence as to its utility in populations with low mycobacterium tuberculosis (mTB) incidence. METHODS: Patients presenting with an undiagnosed pleural effusion to a tertiary pleural centre in South-West England over a 3 year period, were prospectively recruited to a pleural biomarker study. Pleural fluid from consecutive patients with robust 12-month follow up data and confirmed diagnosis were sent for pfADA analysis. RESULTS: Of 338 patients enrolled, 7 had confirmed tuberculous pleural effusion (2%). All mTB effusions were lymphocyte predominant with a median pfADA of 72.0 IU/L (range- 26.7 to 91.5) compared to a population median of 12.0 IU/L (range- 0.3 to 568.4). The optimal pfADA cut off was 35 IU/L, which had a negative predictive value (NPV) of 99.7% (95% CI; 98.2-99.9%) for the exclusion of mTB, and sensitivity of 85.7% (95% CI; 42.2-97.6%) with an area under the curve of 0.88 (95% CI; 0.732-1.000). DISCUSSION: This is the first study examining the diagnostic utility of pfADA in a low mTB incidence area. The chance of an effusion with a pfADA under 35 IU/L being of tuberculous aetiology was negligible. A pfADA of over 35 IU/L in lymphocyte-predominant pleural fluid gives a strong suspicion of mTB.