Regulation of ICAM-1 in human neutrophils.

Intercellular cell adhesion molecule 1 (ICAM-1) is a cell surface glycoprotein with a vital role in the immune response to pathogens. The expression pattern of ICAM-1 is wide-ranging, encompassing endothelial cells, epithelial cells and neutrophils. Recent work has characterized the role of ICAM-1 in murine neutrophils, but the function of human neutrophil ICAM-1 is incompletely understood. Herein, we investigated the expression and role of ICAMs in human neutrophils in vitro and in vivo. Our findings show clear expression of ICAM-1, -3 and -4 on peripheral blood-derived neutrophils and demonstrate that the pathogen-associated molecular pattern (PAMP) lipoteichoic acid (LTA) is an inducer of ICAM-1 expression in vitro. In vivo, neutrophils obtained from the pleural cavity of patients with a parapneumonic effusion display enhanced expression of ICAM-1 compared to peripheral blood- and oral cavity-derived neutrophils. Moreover, migration of peripheral blood-derived neutrophils across endothelial cells can upregulate neutrophil ICAM-1 expression. These findings indicate that PAMPs and/or cytokines, alongside transmigration, enhance neutrophil ICAM-1 expression at sites of inflammation. Mechanistically we observed that ICAM-1high neutrophils display elevated S. aureus phagocytic capacity. However, unlike murine neutrophils, ICAM-1 intracellular signaling in human neutrophils was not essential for phagocytosis of S. aureus and reactive oxygen species (ROS) generation. Taken together, these results have important implications for the regulation of neutrophil-mediated pathogen clearance.

Delayed identification of compound heterozygous (Phe508del/Arg117His) cystic fibrosis variants in a patient awaiting liver transplantation.

A man in his 60s undergoing liver transplant assessment was referred to the respiratory team after a thoracic CT scan revealed diffuse tree-in-bud changes. He had a history of infertility, chronic pancreatitis and liver cirrhosis with portal hypertension. Broncho-alveolar lavage was positive for Pseudomonas aeruginosa Genetic screening found two cystic fibrosis transmembrane conductance regulator variants: Phe508del and Arg117His-7T. The patient was referred to the regional cystic fibrosis (CF) centre for follow-up but died from hepatobiliary complications. The atypical presentation with relatively late onset of pulmonary disease and hepatobiliary disease predominance created a diagnostic challenge. This case is a reminder that while CF is a monogenic disorder, its manifestation, natural history and extent can be highly variable. Taking a thorough medical history of any chronic illness is essential, and patients with the appropriate clinical presentation, regardless of age, should be investigated for CF.

Corrigendum: Service evaluation of the impact of capnography on the safety of procedural sedation.

[This corrects the article DOI: 10.3389/fmed.2022.867536.].

Service Evaluation of the Impact of Capnography on the Safety of Procedural Sedation.

Background: Capnography has been associated with a reduced incidence of events related to respiratory compromise during procedural sedation. Methods: A prospective service evaluation was conducted at a large United Kingdom (UK) teaching hospital to assess the impact of capnography on patient safety within four speciality services: bronchoscopy, endoscopy, interventional cardiology, and interventional radiology. Events were defined as provided by the World Society of Intravenous Anaesthesia. One thousand four hundred one patients were enrolled in the evaluation, with 666 patients before and 735 after implementation of capnography. Data was entered as a convenience sample on site in an offline data-collection tool. Results were assessed for the relative reduction in the incidence and resulting adjusted odds ratio for the combined incidence of oxygen desaturation (75-90% for <60s), severe oxygen desaturation (<75% at any time) or prolonged oxygen desaturation (<90% for >60s), bradycardia (>25% from baseline) and tachycardia (>25% from baseline). The adjusted odds ratio was controlled for both procedure and patient characteristics. Results: After implementation of capnography, a significant reduction (43.2%, p ≤ 0.05) in adverse events was observed: 147 adverse events occurred during 666 procedures without capnography compared with 93 adverse events that occurred during 735 procedures with capnography. The adjusted odds ratio for the occurrence of the target adverse events was 0.57 (95% CI: 0.42-0.77). Multivariable linear regression indicated that capnography was a significant predictor (p 0.001) of reduced adverse events. Conclusion: These results suggest improved patient safety following capnography implementation.

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.

Combining clinical, radiological and genetic approaches to pneumothorax management.

Familial spontaneous pneumothorax (FSP) accounts for 10% of primary spontaneous pneumothoraces. Appropriate investigation of FSP enables early diagnosis of serious monogenic diseases and the practice of precision medicine. Here, we show that a pneumothorax genetics multidisciplinary team (MDT) can efficiently diagnose a range of syndromic causes of FSP. A sizeable group (73.6%) of clinically unclassifiable FSPs remains. Using whole genome sequencing we demonstrate that most of these cases are not known monogenic disorders. Therefore, clinico-radiological assessment by an MDT has high sensitivity for currently known clinically important monogenic causes of FSP, which has relevance for the design of efficient pneumothorax services.

Intrapleural Hyaluronidase in Viscous Malignant Mesothelioma Pleural Effusion.

Malignant pleural effusion is common in mesothelioma. We report a case of viscous recurrent malignant mesothelioma pleural effusion. The viscosity was due to the presence of hyaluronic acid and resulted in prolonged drainage time. The use of intrapleural hyaluronidase significantly reduced fluid viscosity and drainage duration. No adverse reactions were noted. This novel case highlights the feasibility and safety of the use of intrapleural hyaluronidase in the management of hyaluronic acid-rich viscous malignant pleural effusion.

Ambulatory Thoracoscopic Pleurodesis Combined With Indwelling Pleural Catheter in Malignant Pleural Effusion.

Background and Objective: Malignant pleural effusion (MPE) often results in debilitating symptoms. Relief of dyspnoea and improvement in quality of life can be achieved with either talc pleurodesis or insertion of an indwelling tunneled pleural catheter (IPC). The former requires a lengthy hospital stay and the latter is associated with lower pleurodesis rates. In response to limited hospital bed capacity, we developed a pragmatic approach in managing MPE by combining thoracoscopic talc poudrage and insertion of IPC into a single day case procedure. We present data on the safety and efficacy of this approach. Methods: Patients who had undergone the abovementioned procedure between 2017 and 2020 were analyzed. Demographic data, hospital length of stay (LOS), histological diagnosis, rates of pleurodesis success and procedural related complications were collated. Patients were followed-up for 6 months. Results: Forty-five patients underwent the procedure. Mean age was 68.5 ± 10.4 years and 56% were male. Histological diagnosis was achieved in all cases. 86.7% of patients were discharged on the day of the procedure. Median LOS was 0 (IQR 0-0) days. Successful pleurodesis was attained in 77.8% at 6-month follow-up. No procedure related deaths or IPC related infections were recorded. Conclusion: Ambulatory thoracoscopic poudrage and IPC insertion is a safe and effective option in the management of MPE. All patients received a definitive pleural intervention with 77.8% pleurodesis success at 6-months and majority of them discharged on the same day. Future randomized trials are required to confirm these findings.

Case Report: Indwelling Pleural Catheter Based Management of Refractory Hepatic Hydrothorax as a Bridge to Liver Transplantation.

Introduction: Liver transplantation is the treatment of choice for decompensated liver disease, and by extension for hepatic hydrothorax. Persistent pleural effusions make it challenging for patients to maintain physiological fitness for transplantation. Indwelling pleural catheters (IPCs) provide controlled pleural fluid removal, including peri-operatively. The immune dysfunction of cirrhosis heightens susceptibility to bacterial infection and concerns exist regarding the sepsis potential from a tunnelled drain. Method: Six patients were identified who underwent IPC insertion for hepatic hydrothorax before successful liver transplantation, between November 2016 and November 2017. Results: All patients had recurrent transudative right sided pleural effusions. Mean age was 49 years (range 24-64) and mean United Kingdom Model for End-Stage Liver Disease score was 58. Four patients required correction of coagulopathy before insertion. There were no complications secondary to bleeding. Three patients were taught self-drainage at home of up to 1 litre (L) daily. A protocol was developed to ensure weekly review, pleural fluid culture and drainage of larger volumes in hospital. For every 2-3 L of pleural fluid drained, 100 mls of 20% Human Albumin Solution (HAS) was administered. On average an IPC was in situ for 58 days before surgery and drained 19 L of fluid in hospital. There was a small increase in average BMI (0.2) and serum albumin (2.1 g/L) at transplantation. There was one episode of stage one acute kidney injury secondary to high volume drainage. No further ascitic or pleural procedures were needed while an IPC was in situ. One thoracentesis was required after IPC removal. On average IPCs remained in situ for 7 days post transplantation and drained a further 2 L of fluid. Pleural fluid sampling was acquired on 92% of drainages in hospital. Of 44 fluid cultures, 2 cultured bacteria. Two patients had their IPCs and all other lines removed post transplantation due to suspected infection. Conclusion: Our case series describes a novel protocol and successful use of IPCs in the management of refractory hepatic hydrothorax as a bridge to liver transplantation. The protocol includes albumin replacement during pleural drainage, regular clinical review and culture of pleural fluid, with the option of self-drainage at home.

Use of Intrapleural Fibrinolytic Therapy in a Trapped Lung following Acute Traumatic Haemothorax.

Retained haemothorax is a common sequela of traumatic haemothorax and refers to blood that cannot be drained from the pleural cavity. We report a case of trapped lung secondary to retained haemothorax in a patient who sustained a penetrating chest injury. Initial chest computed tomography (CT) showed a large haemothorax that was managed with an intercostal drain insertion (ICD). Repeat chest CT and thoracic ultrasonography performed after ICD removal showed an organized pleural space resembling haematoma. ICD was reinserted with administration of intrapleural fibrinolytic therapy (IPFT). Subsequent chest CT showed the development of a pleural rind and trapped lung. A second ICD was inserted, and further IPFT were administered together with aggressive negative pressure suction. Haemoglobin remained stable. The patient made a full recovery and imaging performed two weeks later showed minor blunting of the costophrenic angle. This case highlights the feasibility and safety of IPFT in the management of trapped lung associated with traumatic retained haemothorax as an alternative to surgery.

Unusual case of malignant pleural mesothelioma.

We present the case of a 65-year-old woman who presented with progressive dysphagia and was diagnosed with achalasia. She subsequently developed bilateral chylous pleural effusions, with no cause identified despite extensive investigations (including computed tomography (CT) scans, gastroscopy and medical thoracoscopy (MT)) and review at a dedicated pleural multidisciplinary team meeting.Despite optimal supportive management she deteriorated and was admitted to the intensive care unit, where she passed away due to sepsis and respiratory failure 10 months after initial presentation. A postmortem returned a diagnosis of epithelioid mesothelioma, encasing the carina, distal oesophagus and coeliac axis.Mesothelioma only very rarely presents with either chylous effusions or achalasia. Additionally while MT normally conveys excellent sensitivity for pleural malignancy, it was insufficient here. This case highlights how an unusually located mesothelioma can produce an unusual clinical picture. It also suggests a role for early video-assisted thoracoscopy to aid diagnosis.

Ambulatory Intrapleural Fibrinolytic Therapy in Highly Viscous Recurrent Malignant Pleural Effusion.

Malignant pleural effusion (MPE) is common in lung cancer. We report a case of highly viscous recurrent MPE associated with lung cancer. The viscosity prohibited gravity-dependent drainage initially with a 6-Fr aspiration catheter and subsequently with a 12-Fr intercostal drain. The effusion was eventually evacuated after a single dose of intrapleural fibrinolytic therapy. This process was repeated a total of 13 times over a 12-month period in an ambulatory setting. No bleeding complications were observed. This case highlights the feasibility and safety of repeated intrapleural fibrinolysis in the management of highly viscous recurrent MPE in an ambulatory setting.

Intrapleural fibrinolysis in acute non-traumatic retained haemothorax.

Haemothorax is an accumulation of blood in the pleural space. Retained haemothorax refers to blood that cannot be drained from the pleural cavity and is associated with an increased risk of empyema and fibrothorax often necessitating surgical evacuation. We describe our experience of using intrapleural fibrinolytic therapy in three patients with different bleeding risk and acute non-traumatic retained haemothorax. The first was a 41-year-old female with disseminated Candida guilliermondii sepsis and an iatrogenic haemothorax, second was a 48-year-old female with transfusion-dependent acute myeloid leukaemia and spontaneous haemothorax, and the third was a 72-year-old female with spontaneous haemothorax from newly diagnosed lung cancer. All patients received one to two doses of intrapleural alteplase without any bleeding complications and resolution of retained haemothorax. This case series demonstrates the successful application and safety of this approach as an alternative to surgery in a well-resourced environment with close monitoring and ready access to blood transfusion.

Development and implementation of a customised rapid syndromic diagnostic test for severe pneumonia.

Background: The diagnosis of pneumonia has been hampered by a reliance on bacterial cultures which take several days to return a result, and are frequently negative. In critically ill patients this leads to the use of empiric, broad-spectrum antimicrobials and compromises good antimicrobial stewardship. The objective of this study was to establish the performance of a syndromic molecular diagnostic approach, using a custom TaqMan array card (TAC) covering 52 respiratory pathogens, and assess its impact on antimicrobial prescribing. Methods: The TAC was validated against a retrospective multi-centre cohort of broncho-alveolar lavage samples. The TAC was assessed prospectively in patients undergoing investigation for suspected pneumonia, with a comparator cohort formed of patients investigated when the TAC laboratory team were unavailable. Co-primary outcomes were sensitivity compared to conventional microbiology and, for the prospective study, time to result. Metagenomic sequencing was performed to validate findings in prospective samples. Antibiotic free days (AFD) were compared between the study cohort and comparator group. Results: 128 stored samples were tested, with sensitivity of 97% (95% confidence interval (CI) 88-100%). Prospectively, 95 patients were tested by TAC, with 71 forming the comparator group. TAC returned results 51 hours (interquartile range 41-69 hours) faster than culture and with sensitivity of 92% (95% CI 83-98%) compared to conventional microbiology. 94% of organisms identified by sequencing were detected by TAC. There was a significant difference in the distribution of AFDs with more AFDs in the TAC group (p=0.02). TAC group were more likely to experience antimicrobial de-escalation (odds ratio 2.9 (95%1.5-5.5)). Conclusions: Implementation of a syndromic molecular diagnostic approach to pneumonia led to faster results, with high sensitivity and impact on antibiotic prescribing.

Food for Thought: Dietary Intervention in a Rare Cause of Severe Ventilatory Failure.

Plastic bronchitis is a rare condition characterised by endobronchial cast formation. We report the case of a 53-year-old women who deteriorated following an elective bronchoscopy procedure. She developed refractory ventilatory failure and required repeated bronchoscopy, which identified thick tenacious casts as the cause of her airway compromise. She did not respond to conventional therapies including endoscopic clearance, mucolytic therapy and nebulised tissue plasminogen activator (TPA). Total parenteral nutrition and a fat-free enteral diet were instituted while the patient was on extracorporeal membrane oxygenation (ECMO), which led to substantial improvement in her condition and demonstrated the importance of dietary strategies in this case. LEARNING POINTS: Plastic bronchitis can rarely present in adults with acute ventilatory failure and life-threatening airway obstruction.Although there are no established guidelines on management, dietary intervention (e.g., a fat-free diet) should be strongly considered as a therapeutic option.Extracorporeal membrane oxygenation (ECMO) is feasible and should be considered in plastic bronchitis with airway compromise.

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.

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 .).

The relationship between basic audio quality and overall listening experience.

Basic audio quality (BAQ) is a well-known perceptual attribute, which is rated in various listening test methods to measure the performance of audio systems. Unfortunately, when it comes to purchasing audio systems, BAQ might not have a significant influence on the customers' buying decisions since other factors, like brand loyalty, might be more important. In contrast to BAQ, overall listening experience (OLE) is an affective attribute which incorporates all aspects that are important to an individual assessor, including his or her preference for music genre and audio quality. In this work, the relationship between BAQ and OLE is investigated in more detail. To this end, an experiment was carried out, in which participants rated the BAQ and the OLE of music excerpts with different timbral and spatial degradations. In a between-group-design procedure, participants were assigned into two groups, in each of which a different set of stimuli was rated. The results indicate that rating of both attributes, BAQ and OLE, leads to similar rankings, even if a different set of stimuli is rated. In contrast to the BAQ ratings, which were more influenced by timbral than spatial degradations, the OLE ratings were almost equally influenced by timbral and spatial degradations.

Acute Respiratory Distress Syndrome Neutrophils Have a Distinct Phenotype and Are Resistant to Phosphoinositide 3-Kinase Inhibition.

RATIONALE: Acute respiratory distress syndrome is refractory to pharmacological intervention. Inappropriate activation of alveolar neutrophils is believed to underpin this disease's complex pathophysiology, yet these cells have been little studied. OBJECTIVES: To examine the functional and transcriptional profiles of patient blood and alveolar neutrophils compared with healthy volunteer cells, and to define their sensitivity to phosphoinositide 3-kinase inhibition. METHODS: Twenty-three ventilated patients underwent bronchoalveolar lavage. Alveolar and blood neutrophil apoptosis, phagocytosis, and adhesion molecules were quantified by flow cytometry, and oxidase responses were quantified by chemiluminescence. Cytokine and transcriptional profiling were used in multiplex and GeneChip arrays. MEASUREMENTS AND MAIN RESULTS: Patient blood and alveolar neutrophils were distinct from healthy circulating cells, with increased CD11b and reduced CD62L expression, delayed constitutive apoptosis, and primed oxidase responses. Incubating control cells with disease bronchoalveolar lavage recapitulated the aberrant functional phenotype, and this could be reversed by phosphoinositide 3-kinase inhibitors. In contrast, the prosurvival phenotype of patient cells was resistant to phosphoinositide 3-kinase inhibition. RNA transcriptomic analysis revealed modified immune, cytoskeletal, and cell death pathways in patient cells, aligning closely to sepsis and burns datasets but not to phosphoinositide 3-kinase signatures. CONCLUSIONS: Acute respiratory distress syndrome blood and alveolar neutrophils display a distinct primed prosurvival profile and transcriptional signature. The enhanced respiratory burst was phosphoinositide 3-kinase-dependent but delayed apoptosis and the altered transcriptional profile were not. These unexpected findings cast doubt over the utility of phosphoinositide 3-kinase inhibition in acute respiratory distress syndrome and highlight the importance of evaluating novel therapeutic strategies in patient-derived cells.