Evaluation of Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration (EBUS-TBNA) Samples from Advanced Non-Small Cell Lung Cancer for Whole Genome, Whole Exome and Comprehensive Panel Sequencing.

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is often the only source of tumor tissue from patients with advanced, inoperable lung cancer. EBUS-TBNA aspirates are used for the diagnosis, staging, and genomic testing to inform therapy options. Here we extracted DNA and RNA from 220 EBUS-TBNA aspirates to evaluate their suitability for whole genome (WGS), whole exome (WES), and comprehensive panel sequencing. For a subset of 40 cases, the same nucleic acid extraction was sequenced using WGS, WES, and the TruSight Oncology 500 assay. Genomic features were compared between sequencing platforms and compared with those reported by clinical testing. A total of 204 aspirates (92.7%) had sufficient DNA (100 ng) for comprehensive panel sequencing, and 109 aspirates (49.5%) had sufficient material for WGS. Comprehensive sequencing platforms detected all seven clinically reported tier 1 actionable mutations, an additional three (7%) tier 1 mutations, six (15%) tier 2-3 mutations, and biomarkers of potential immunotherapy benefit (tumor mutation burden and microsatellite instability). As expected, WGS was more suited for the detection and discovery of emerging novel biomarkers of treatment response. WGS could be performed in half of all EBUS-TBNA aspirates, which points to the enormous potential of EBUS-TBNA as source material for large, well-curated discovery-based studies for novel and more effective predictors of treatment response. Comprehensive panel sequencing is possible in the vast majority of fresh EBUS-TBNA aspirates and enhances the detection of actionable mutations over current clinical testing.

Hospital-treated deliberate self-poisoning patients: Drug-induced delirium and clinical outcomes.

OBJECTIVE: Drug-induced delirium has been attributed to opioid, benzodiazepine, antipsychotic, antihistaminic and anticholinergic drug groups at therapeutic doses. Delirium also occurs in hospital-treated self-poisoning (at supra-therapeutic doses), although the causative drug classes are not well established and co-ingestion is common. We tested the magnitude and direction of association of five major drug groups with incident cases of delirium. METHODS: A retrospective longitudinal cohort (n = 5131) study was undertaken of deliberate and recreational/chronic misuse poisoning cases from a regional sentinel toxicology unit. We described ingestion and co-ingestion patterns and estimated the unadjusted and adjusted odds for developing a drug-induced delirium. We also estimated the odds of drug-induced delirium being associated with three outcomes: intensive care unit admission, general hospital length of stay and discharge to home. RESULTS: Drug-induced delirium occurred in 3.9% of cases (n = 200). The unadjusted odds ratios for development of delirium were increased for anticholinergics 10.79 (5.43-21.48), antihistamines 6.10 (4.20-8.84) and antipsychotics 2.99 (2.20-4.06); non-significant for opioids 1.31 (95% confidence interval = [0.81, 2.13]); and reduced for benzodiazepines 0.37 (0.24-0.58); with little change after adjustment for age, gender and co-ingestion. Delirium was associated with intensive care unit admission, longer length of stay and discharge destination. CONCLUSION: Drug-induced delirium was uncommon in this population. Co-ingestion was common but did not alter the risk. In contrast to drug-induced delirium at therapeutic doses in older populations, opioids were not associated with delirium and benzodiazepines were protective. Drug-induced delirium required increased clinical services. Clinical services should be funded and prepared to provide additional supportive care for these deliriogenic drug group ingestions.

Parapneumonic Effusions Are Characterized by Elevated Levels of Neutrophil Extracellular Traps.

BACKGROUND: Neutrophil extracellular traps (NETs) increasingly are implicated in acute and chronic conditions involving multiple organ systems. RESEARCH QUESTION: Are NET concentrations higher in parapneumonic effusions compared with effusions of other origin and does this reflect the inflammatory nature of these effusions? STUDY DESIGN AND METHODS: Patients (N = 101) seeking hospital treatment for undifferentiated pleural effusion underwent pleural fluid classification based on cytologic analysis results, biochemical findings, microbiological characteristics, and clinical judgement. Concentrations of NET markers (extracellular DNA [eDNA], citrullinated histone H3 [citH3]), neutrophils (α-defensins), and inflammation (IL-1ß)-related proteins were quantified by enzyme-linked immunosorbent assay. Differences between groups were analyzed using the Kruskal-Wallis one-way analysis of variance. Correlations used Spearman coefficient. Receiver operating characteristic (ROC) curves were calculated. RESULTS: Effusions were classified into four groups: parapneumonic (n = 18), malignant (n = 35), transudative (n = 22), and unclassifiable (n = 26). Concentrations of NETs markers were significantly higher in the parapneumonic group compared with malignant, transudative, and unclassifiable groups (median eDNA, 12.8 ng/mL vs 0.77 ng/mL, 0.44 ng/mL, and 0.86 ng/mL [P < .001]; and median citH3, 127.1 ng/mL vs 0.44 ng/mL, 0.34 ng/mL, and 0.49 ng/mL [P < .001]). citH3 and eDNA were correlated highly with lactate dehydrogenase (LDH; Spearman r = 0.66 and r = 0.73, respectively; P < .001) and moderately negatively correlated with pH (r = -0.55 and r = -0.62, respectively; P < .001). α-Defensins and IL-1ß were higher in the parapneumonic group than in other groups (median α-defensins, 124.4 ng/mL vs 4.7 ng/mL,7 ng/mL, and 6.9 ng/mL [P < .001]; and median IL-1ß, 145 pg/mL vs 1.87 pg/mL, 1.39 pg/mL, and 2.6 pg/mL [P < .001]) and moderately correlated with LDH (r = 0.60 and r = 0.57; P < .001). ROC curves showed high sensitivity and specificity for NET markers for prediction of parapneumonic effusion. INTERPRETATION: High levels of some NET-related mediators in parapneumonic effusions correlate with inflammation. Effusions of other causes do not show high levels of NETs. These results may have treatment implications because NETs may be an important contributor to the inflammation and viscosity of parapneumonic effusions and may help us to understand the therapeutic benefit of deoxyribonuclease in empyema.

The Emerging Role of Neutrophil Extracellular Traps in Respiratory Disease.

Neutrophil extracellular traps (NETs) are extrusions of intracellular DNA and attached granular material that enable bacterial killing. NETs are increasingly recognized for their role in the pathogenesis of respiratory disease. NETs are composed of a complex mix of intracellularly derived material that neutrophils organize within the cytoplasm and then expel in a nondirected manner in the vicinity of invading organisms. Combined, these trap and destroy multiple genera of microbes including bacteria, fungi, viruses, and protozoans, limiting infection especially where phagocytosis is not possible. At first, NET formation was thought to be a terminal event for neutrophils; however, it is now apparent that some neutrophils survive this process, becoming anuclear, and may drive ongoing tissue damage. NETs are now known to be directly cytotoxic to lung epithelium and endothelium, and their excessive production is seen in pneumonia and acute lung injury as well as several chronic diseases, including COPD, asthma, and cystic fibrosis. NETs also appear to play a role in both tumor defense and dissemination, depending on the local microenvironment and the specific tumor subtype. It is becoming increasingly apparent that NET formation can exert a positive or negative influence on multiple respiratory pathologies and that simply globally reducing or increasing NET formation is unlikely to be a therapeutic success. Rather, as our understanding grows, it is likely that targeted NET up- or downregulation along with destruction or protection of already formed NETs may become an additional point of intervention for respiratory physicians.

Pulmonary hypertension in patients with a history of intravenous drug use.

OBJECTIVE: Pulmonary hypertension may be a consequence of intrinsic elevation in pulmonary vasculature resistance or complicate numerous other conditions affecting the cardiac and respiratory systems. In this review we sought to explore the relationship between pulmonary hypertension and intravenous drug use. METHODS: A narrative review was conducted using PubMed MeSH search with further papers identified using a standard PubMed search with relevant key terms and various synonyms. RESULTS: HIV infection may be associated with pulmonary hypertension due to indirect consequences of viral infection, venous thromboembolism or its therapies. Anti-retroviral infection may also influence plasma concentrations of commonly used treatments for pulmonary hypertension. Intravenous drug use is acknowledged as an important portal for the acquisition of hepatitis virus C infection, with portopulmonary hypertension a potential complication associated with poor prognosis. Interferon based therapy, used in treatment of chronic hepatitis C infection, may also play a causal role in the development of pulmonary hypertension. More recently, sofosbuvir has been linked to development or exacerbation of pulmonary arterial hypertension. Certain drugs of abuse may cause pulmonary hypertension due to properties that result in direct injury to the pulmonary vasculature. The potential for embolic phenomena, complicating venous thromboembolism, recurrent embolization of particulate matter or because of right-sided endocarditis, resulting in pulmonary hypertension is an important contributing factor in the pathophysiology in this unique cohort. CONCLUSIONS: Eliciting a history of intravenous drug use is important and may be associated with a number of less common etiologies, each with specific diagnostic and therapeutic implications.

Thoracic Ultrasound: What Non-radiologists Need to Know.

PURPOSE OF REVIEW: The aim of this review is to provide the theoretical and practical knowledge essential for non-radiologists to develop the skills necessary to apply thoracic ultrasound as an extension of clinical assessment and intervention. RECENT FINDINGS: Issues relating to training and competence are discussed and a library of thoracic ultrasound videos is provided to illustrate artefacts, pleural, parenchymal and pneumothorax pathology as well as important pitfalls to consider. Novel and future diagnostic applications of thoracic ultrasound in the setting of acute cardiorespiratory pathology including consolidation, acute interstitial syndromes and pulmonary embolism are explored. SUMMARY: Thoracic ultrasound requires an understanding of imaging artefact specific to lung and pleura and a working knowledge of machine knobology for image optimisation and interpretation. Ultrasound is a valuable tool for the practicing chest clinician providing diagnostic information for the assessment of pleural and parenchymal disease and increased safety and cost effectiveness of thoracic interventions.

Thoracic ultrasound recognition of competence: A position paper of the Thoracic Society of Australia and New Zealand.

The ability to perform bedside thoracic ultrasound is increasingly recognized as an essential skill for thoracic clinicians, extending the clinical examination and aiding diagnostic and therapeutic procedures. Thoracic ultrasound reduces complications and increases success rates when used prior to thoracentesis or intercostal chest tube insertion. It is increasingly difficult to defend performing these procedures without real or near-real time image guidance. To assist thoracic physicians and others achieve and demonstrate thoracic ultrasound competence, the Interventional Pulmonology Special Interest Group (IP-SIG) of the Thoracic Society of Australia and New Zealand (TSANZ) has developed a new pathway with four components: (i) completion of an approved thoracic ultrasound theory and hands-on teaching course. (ii) A log of at least 40 relevant scans. (iii) Two formative assessments (following 5-10 scans and again after 20 scans) using the Ultrasound-Guided Thoracentesis Skills and Tasks Assessment Tool (UG-STAT). (iv) A barrier assessment (UG-STAT, pass score of 90%) by an accredited assessor not directly involved in the candidate's training. Upon completion of these requirements a candidate may apply to the TSANZ for recognition of competence. This pathway is intended to provide a regional standard for thoracic ultrasound training.