Impaired immune responses in the airways are associated with poor outcome in critically ill COVID-19 patients.

Introduction: Mounting evidence indicates that an individual's humoral adaptive immune response plays a critical role in the setting of SARS-CoV-2 infection, and that the efficiency of the response correlates with disease severity. The relationship between the adaptive immune dynamics in the lower airways with those in the systemic circulation, and how these relate to an individual's clinical response to SARS-CoV-2 infection, are less understood and are the focus of this study. Material and methods: We investigated the adaptive immune response to SARS-CoV-2 in paired samples from the lower airways and blood from 27 critically ill patients during the first wave of the pandemic (median time from symptom onset to intubation 11 days). Measurements included clinical outcomes (mortality), bronchoalveolar lavage fluid (BALF) and blood specimen antibody levels, and BALF viral load. Results: While there was heterogeneity in the levels of the SARS-CoV-2-specific antibodies, we unexpectedly found that some BALF specimens displayed higher levels than the paired concurrent plasma samples, despite the known dilutional effects common in BALF samples. We found that survivors had higher levels of anti-spike, anti-spike-N-terminal domain and anti-spike-receptor-binding domain IgG antibodies in their BALF (p<0.05), while there was no such association with antibody levels in the systemic circulation. Discussion: Our data highlight the critical role of local adaptive immunity in the airways as a key defence mechanism against primary SARS-CoV-2 infection.

Pleural fluid microbiota as a biomarker for malignancy and prognosis.

Malignant pleural effusions (MPE) complicate malignancies and portend worse outcomes. MPE is comprised of various components, including immune cells, cancer cells, and cell-free DNA/RNA. There have been investigations into using these components to diagnose and prognosticate MPE. We hypothesize that the microbiome of MPE is unique and may be associated with diagnosis and prognosis. We compared the microbiota of MPE against microbiota of pleural effusions from non-malignant and paramalignant states. We collected a total of 165 pleural fluid samples from 165 subjects; Benign (n = 16), Paramalignant (n = 21), MPE-Lung (n = 57), MPE-Other (n = 22), and Mesothelioma (n = 49). We performed high throughput 16S rRNA gene sequencing on pleural fluid samples and controls. We showed that there are compositional differences among pleural effusions related to non-malignant, paramalignant, and malignant disease. Furthermore, we showed differential enrichment of bacterial taxa within MPE depending on the site of primary malignancy. Pleural fluid of MPE-Lung and Mesothelioma were associated with enrichment with oral and gut bacteria that are commonly thought to be commensals, including Rickettsiella, Ruminococcus, Enterococcus, and Lactobacillales. Mortality in MPE-Lung is associated with enrichment in Methylobacterium, Blattabacterium, and Deinococcus. These observations lay the groundwork for future studies that explore host-microbiome interactions and their influence on carcinogenesis.

Microbial signatures in the lower airways of mechanically ventilated COVID-19 patients associated with poor clinical outcome.

Respiratory failure is associated with increased mortality in COVID-19 patients. There are no validated lower airway biomarkers to predict clinical outcome. We investigated whether bacterial respiratory infections were associated with poor clinical outcome of COVID-19 in a prospective, observational cohort of 589 critically ill adults, all of whom required mechanical ventilation. For a subset of 142 patients who underwent bronchoscopy, we quantified SARS-CoV-2 viral load, analysed the lower respiratory tract microbiome using metagenomics and metatranscriptomics and profiled the host immune response. Acquisition of a hospital-acquired respiratory pathogen was not associated with fatal outcome. Poor clinical outcome was associated with lower airway enrichment with an oral commensal (Mycoplasma salivarium). Increased SARS-CoV-2 abundance, low anti-SARS-CoV-2 antibody response and a distinct host transcriptome profile of the lower airways were most predictive of mortality. Our data provide evidence that secondary respiratory infections do not drive mortality in COVID-19 and clinical management strategies should prioritize reducing viral replication and maximizing host responses to SARS-CoV-2.

Microbial signatures in the lower airways of mechanically ventilated COVID19 patients associated with poor clinical outcome.

Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal ( Mycoplasma salivarium ), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized.

Percutaneous Dilational Tracheostomy for Coronavirus Disease 2019 Patients Requiring Mechanical Ventilation.

OBJECTIVES: To assess the impact of percutaneous dilational tracheostomy in coronavirus disease 2019 patients requiring mechanical ventilation and the risk for healthcare providers. DESIGN: Prospective cohort study; patients were enrolled between March 11, and April 29, 2020. The date of final follow-up was July 30, 2020. We used a propensity score matching approach to compare outcomes. Study outcomes were formulated before data collection and analysis. SETTING: Critical care units at two large metropolitan hospitals in New York City. PATIENTS: Five-hundred forty-one patients with confirmed severe coronavirus disease 2019 respiratory failure requiring mechanical ventilation. INTERVENTIONS: Bedside percutaneous dilational tracheostomy with modified visualization and ventilation. MEASUREMENTS AND MAIN RESULTS: Required time for discontinuation off mechanical ventilation, total length of hospitalization, and overall patient survival. Of the 541 patients, 394 patients were eligible for a tracheostomy. One-hundred sixteen were early percutaneous dilational tracheostomies with median time of 9 days after initiation of mechanical ventilation (interquartile range, 7-12 d), whereas 89 were late percutaneous dilational tracheostomies with a median time of 19 days after initiation of mechanical ventilation (interquartile range, 16-24 d). Compared with patients with no tracheostomy, patients with an early percutaneous dilational tracheostomy had a higher probability of discontinuation from mechanical ventilation (absolute difference, 30%; p < 0.001; hazard ratio for successful discontinuation, 2.8; 95% CI, 1.34-5.84; p = 0.006) and a lower mortality (absolute difference, 34%, p < 0.001; hazard ratio for death, 0.11; 95% CI, 0.06-0.22; p < 0.001). Compared with patients with late percutaneous dilational tracheostomy, patients with early percutaneous dilational tracheostomy had higher discontinuation rates from mechanical ventilation (absolute difference 7%; p < 0.35; hazard ratio for successful discontinuation, 1.53; 95% CI, 1.01-2.3; p = 0.04) and had a shorter median duration of mechanical ventilation in survivors (absolute difference, -15 d; p < 0.001). None of the healthcare providers who performed all the percutaneous dilational tracheostomies procedures had clinical symptoms or any positive laboratory test for severe acute respiratory syndrome coronavirus 2 infection. CONCLUSIONS: In coronavirus disease 2019 patients on mechanical ventilation, an early modified percutaneous dilational tracheostomy was safe for patients and healthcare providers and associated with improved clinical outcomes.

Microbial signatures in the lower airways of mechanically ventilated COVID19 patients associated with poor clinical outcome.

Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal ( Mycoplasma salivarium ), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized.

Multi-institutional retrospective analysis of adverse events following rigid tracheobronchoscopy.

BACKGROUND AND OBJECTIVE: Rigid tracheobronchoscopy (RTB) has seen an increasing interest over the last decades with the development of the field of IPM but no benchmark exists for complication rates in RTB. We aimed to establish benchmarks for complication rates in RTB. METHODS: A multicentric retrospective analysis of RTB performed between 2009 and 2015 in eight participating centres was performed. RESULTS: A total of 1546 RTB were performed over the study period. One hundred and thirty-one non-lethal complications occurred in 103 procedures (6.7%, 95% CI: 5.5-8.0%). The periprocedural mortality rate was 1.2% (95% CI: 0.6-1.8%). The 30-day mortality rate was 5.6% (95% CI: 4.5-6.8%). Complication rate increases further when procedures were performed in an emergency setting. Procedures in patients with MAO are associated with a higher 30-day mortality (8.1% vs 2.7%, P < 0.01) and a different complication profile when compared to procedures performed for BAS. CONCLUSION: RTB is associated with a 6.7% non-lethal complication rate, a 1.2% periprocedural mortality rate and a 5.6% 30-day mortality in a large multicentre cohort of patients with benign and malignant airway disease.

Early Outcomes From Early Tracheostomy for Patients With COVID-19.

Importance: Decision-making in the timing of tracheostomy in patients with coronavirus disease 2019 (COVID-19) has centered on the intersection of long-standing debates on the benefits of early vs late tracheostomy, assumptions about timelines of infectivity of the novel coronavirus, and concern over risk to surgeons performing tracheostomy. Multiple consensus guidelines recommend avoiding or delaying tracheostomy, without evidence to indicate anticipated improvement in outcomes as a result. Objective: To assess outcomes from early tracheostomy in the airway management of patients with COVID-19 requiring mechanical ventilation. Design, Setting, and Participants: A retrospective medical record review was completed of 148 patients with reverse transcriptase-polymerase chain reaction-confirmed COVID-19 requiring mechanical ventilation at a single tertiary-care medical center in New York City from March 1 to May 7, 2020. Interventions: Open or percutaneous tracheostomy. Main Outcomes and Measures: The primary outcomes were time from symptom onset to (1) endotracheal intubation, (2) tracheostomy; time from endotracheal intubation to tracheostomy; time from tracheostomy to (1) tracheostomy tube downsizing, (2) decannulation; total time on mechanical ventilation; and total length of stay. Results: Participants included 148 patients, 120 men and 28 women, with an overall mean (SD) age of 58.1 (15.8) years. Mean (SD; median) time from symptom onset to intubation was 10.57 (6.58; 9) days; from symptom onset to tracheostomy, 22.76 (8.84; 21) days; and from endotracheal intubation to tracheostomy, 12.23 (6.82; 12) days. The mean (SD; median) time to discontinuation of mechanical ventilation was 33.49 (18.82; 27) days; from tracheostomy to first downsize, 23.02 (13.76; 19) days; and from tracheostomy to decannulation, 30.16 (16.00; 26) days. The mean (SD; median) length of stay for all patients was 51.29 (23.66; 45) days. Timing of tracheostomy was significantly associated with length of stay: median length of stay was 40 days in those who underwent early tracheostomy (within 10 days of endotracheal intubation) and 49 days in those who underwent late tracheostomy (median difference, -8; 95% CI, -15 to -1). In a competing risks model with death as the competing risk, the late tracheostomy group was 16% less likely to discontinue mechanical ventilation (hazard ratio, 0.84; 95% CI, 0.55 to 1.28). Conclusions and Relevance: This cohort study from the first 2 months of the pandemic in New York City provides an opportunity to reconsider guidelines for tracheostomy for patients with COVID-19. Findings demonstrated noninferiority of early tracheostomy and challenges recommendations to categorically delay or avoid tracheostomy in this patient population. When aligned with emerging evidence about the timeline of infectivity of the novel coronavirus, this approach may optimize outcomes from tracheostomy while keeping clinicians safe.

Lower Airway Dysbiosis Affects Lung Cancer Progression.

In lung cancer, enrichment of the lower airway microbiota with oral commensals commonly occurs, and ex vivo models support that some of these bacteria can trigger host transcriptomic signatures associated with carcinogenesis. Here, we show that this lower airway dysbiotic signature was more prevalent in the stage IIIB-IV tumor-node-metastasis lung cancer group and is associated with poor prognosis, as shown by decreased survival among subjects with early-stage disease (I-IIIA) and worse tumor progression as measured by RECIST scores among subjects with stage IIIB-IV disease. In addition, this lower airway microbiota signature was associated with upregulation of the IL17, PI3K, MAPK, and ERK pathways in airway transcriptome, and we identified Veillonella parvula as the most abundant taxon driving this association. In a KP lung cancer model, lower airway dysbiosis with V. parvula led to decreased survival, increased tumor burden, IL17 inflammatory phenotype, and activation of checkpoint inhibitor markers. SIGNIFICANCE: Multiple lines of investigation have shown that the gut microbiota affects host immune response to immunotherapy in cancer. Here, we support that the local airway microbiota modulates the host immune tone in lung cancer, affecting tumor progression and prognosis.See related commentary by Zitvogel and Kroemer, p. 224.This article is highlighted in the In This Issue feature, p. 211.

Novel Percutaneous Tracheostomy for Critically Ill Patients With COVID-19.

BACKGROUND: Coronavirus 2019 (COVID-19) is a worldwide pandemic, with many patients requiring prolonged mechanical ventilation. Tracheostomy is not recommended by current guidelines as it is considered a superspreading event owing to aerosolization that unduly risks health care workers. METHODS: Patients with severe COVID-19 who were on mechanical ventilation for 5 days or longer were evaluated for percutaneous dilational tracheostomy. We developed a novel percutaneous tracheostomy technique that placed the bronchoscope alongside the endotracheal tube, not inside it. That improved visualization during the procedure and continued standard mechanical ventilation after positioning the inflated endotracheal tube cuff in the distal trachea. This technique offers a significant mitigation for the risk of virus aerosolization during the procedure. RESULTS: From March 10 to April 15, 2020, 270 patients with COVID-19 required invasive mechanical ventilation at New York University Langone Health Manhattan's campus; of those, 98 patients underwent percutaneous dilational tracheostomy. The mean time from intubation to the procedure was 10.6 ± 5 days. Currently, 32 patients (33%) do not require mechanical ventilatory support, 19 (19%) have their tracheostomy tube downsized, and 8 (8%) were decannulated. Forty patients (41%) remain on full ventilator support, and 19 (19%) are weaning from mechanical ventilation. Seven patients (7%) died as a result of respiratory and multiorgan failure. Tracheostomy-related bleeding was the most common complication (5 patients). None of health care providers has had symptoms or tested positive for COVID-19. CONCLUSIONS: Our percutaneous tracheostomy technique appears to be safe and effective for COVID-19 patients and safe for health care workers.

ATS Core Curriculum 2020. Adult Pulmonary Medicine.

The American Thoracic Society Core Curriculum updates clinicians annually in adult and pediatric pulmonary disease, medical critical care, and sleep medicine in a 3- to 4-year recurring cycle of topics. The topics of the 2020 Pulmonary Core Curriculum include pulmonary vascular disease (submassive pulmonary embolism, chronic thromboembolic pulmonary hypertension, and pulmonary hypertension) and pulmonary infections (community-acquired pneumonia, pulmonary nontuberculous mycobacteria, opportunistic infections in immunocompromised hosts, and coronavirus disease [COVID-19]).

Tumor-draining lymph nodes demonstrate a suppressive immunophenotype in patients with non-small cell lung cancer assessed by endobronchial ultrasound-guided transbronchial needle aspiration: A pilot study.

OBJECTIVES: Tumor draining lymph nodes (TDLN) are key sites of early immunoediting in patients with non-small cell lung cancer (NSCLC) and play an important role in generating anti-tumor immunity. Immune suppression in the tumor microenvironment has prognostic implications and may predict therapeutic response. T cell composition of draining lymph nodes may reflect an immunophenotype with similar prognostic potential which could be measured during standard-of-care bronchoscopic assessment. In this study, we compared the immunophenotype from different sites within individuals to primary tumor characteristics in patients with NSCLC to see whether there were tumor-regional differences in immunophenotype which could be evaluated from transbronchial needle aspirates. MATERIALS AND METHODS: Twenty patients were enrolled in this study and had tissue (lymph node aspirates and/or peripheral blood) obtained during standard of care bronchoscopy with endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for diagnosis or staging of known or suspected NSCLC. Aspirates and blood underwent flow-assisted cell sorting and a subset of sorted effector T cells underwent RNA quantitation to determine feasibility of this approach. Immunophenotypic patterns from twelve patients with paired data from tumor-draining and non-tumor draining lymph nodes (NDLN) were compared relative to one another and based on PD-L1 immunohistochemistry and primary tumor histology. RESULTS: TDLN had significantly fewer CD4+ T cells (12.68% vs 27%, p = 0.002) and significantly more regulatory T cells (Treg, 12.03% vs 9.52%, p = 0.03) relative to paired NDLN suggesting tumor-regional immunosuppression. There were significantly more Treg in NDLN relative to paired PBMC (9.52% vs 5.6%, p = 0.016). Patients with PD-L1 expression ≥50% had significantly greater tumor-regional CD4+ T cell depletion compared to patients with PD-L1 expression <50% (-35.98% vs -1.89%, p = 0.0357; negative values represent absolute difference between paired TDLN and NDLN). CONCLUSIONS: In patients with NSCLC, TDLN have a suppressive immunophenotype correlating with tumor PD-L1 status and can be assessed during routine EBUS-TBNA.

Evaluation of the airway microbiome in nontuberculous mycobacteria disease.

Aspiration is associated with nontuberculous mycobacterial (NTM) pulmonary disease and airway dysbiosis is associated with increased inflammation. We examined whether NTM disease was associated with a distinct airway microbiota and immune profile.297 oral wash and induced sputum samples were collected from 106 participants with respiratory symptoms and imaging abnormalities compatible with NTM. Lower airway samples were obtained in 20 participants undergoing bronchoscopy. 16S rRNA gene and nested mycobacteriome sequencing approaches characterised microbiota composition. In addition, inflammatory profiles of lower airway samples were examined.The prevalence of NTM+ cultures was 58%. Few changes were noted in microbiota characteristics or composition in oral wash and sputum samples among groups. Among NTM+ samples, 27% of the lower airway samples were enriched with Mycobacterium A mycobacteriome approach identified Mycobacterium in a greater percentage of samples, including some nonpathogenic strains. In NTM+ lower airway samples, taxa identified as oral commensals were associated with increased inflammatory biomarkers.The 16S rRNA gene sequencing approach is not sensitive in identifying NTM among airway samples that are culture-positive. However, associations between lower airway inflammation and microbiota signatures suggest a potential role for these microbes in the inflammatory process in NTM disease.

Pharmacokinetics and safety of paclitaxel delivery into porcine airway walls by a new endobronchial drug delivery catheter.

BACKGROUND AND OBJECTIVE: Intratumoral administration of chemotherapeutic agents is a treatment modality that has proven efficacious in reducing the recurrence of tumours and increases specificity of treatment while minimizing systemic side effects. Direct intratumoral injection of malignant airway obstruction has potential therapeutic benefits but tissue drug concentrations and side-effect profiles are poorly understood. METHODS: Bronchial wall injection of generic paclitaxel (PTX) (102 injections of 0.05, 0.5, 1.5 or 2.5 mg/mL in 10 healthy pigs), saline (14 injections in 2 healthy pigs) or Abraxane (ABX) (24 injections of 0.5 mg/mL in 4 healthy pigs) was performed with a microneedle infusion catheter. Local histopathology, plasma and tissue PTX concentrations were evaluated at 7, 20 or 28 days post-injection. RESULTS: Injection of generic PTX directly into the bronchial wall at doses up to 1.5 mg/mL only caused minimal tissue injury. Dose-limiting tissue reaction was observed at 2.5 mg/mL. Plasma PTX was detectable for up to 5 days but not at 28 days, with area under the curve (AUC)(0-5d) 20- to 50-fold lower than the AUC(0-∞) of 6300 ng h/mL for the approved intravenous dose. At 7 and 28 days post-injection, bronchial PTX tissue concentrations were above a 10-nmol/L cancer therapeutic level. PTX was not found in peripheral tissues. Similar results were observed between ABX and generic PTX. CONCLUSION: Results of these studies confirm the administration of PTX directly into the bronchial wall is safe and feasible. PTX was detectable in plasma for <7 days but tissue concentrations remained therapeutic throughout the follow-up period.

Randomized Trial of Pleural Fluid Drainage Frequency in Patients with Malignant Pleural Effusions. The ASAP Trial.

RATIONALE: Patients with malignant pleural effusions have significant dyspnea and shortened life expectancy. Indwelling pleural catheters allow patients to drain pleural fluid at home and can lead to autopleurodesis. The optimal drainage frequency to achieve autopleurodesis and freedom from catheter has not been determined. OBJECTIVES: To determine whether an aggressive daily drainage strategy is superior to the current standard every other day drainage of pleural fluid in achieving autopleurodesis. METHODS: Patients were randomized to either an aggressive drainage (daily drainage; n = 73) or standard drainage (every other day drainage; n = 76) of pleural fluid via a tunneled pleural catheter. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the incidence of autopleurodesis following the placement of the indwelling pleural catheters. The rate of autopleurodesis, defined as complete or partial response based on symptomatic and radiographic changes, was greater in the aggressive drainage arm than the standard drainage arm (47% vs. 24%, respectively; P = 0.003). Median time to autopleurodesis was shorter in the aggressive arm (54 d; 95% confidence interval, 34-83) as compared with the standard arm (90 d; 95% confidence interval, 70 to nonestimable). Rate of adverse events, quality of life, and patient satisfaction were not significantly different between the two arms. CONCLUSIONS: Among patients with malignant pleural effusion, daily drainage of pleural fluid via an indwelling pleural catheter led to a higher rate of autopleurodesis and faster time to liberty from catheter. Clinical trial registered with www.clinicaltrials.gov (NCT 00978939).

Diagnostic Yield and Complications of Bronchoscopy for Peripheral Lung Lesions. Results of the AQuIRE Registry.

RATIONALE: Advanced bronchoscopy techniques such as electromagnetic navigation (EMN) have been studied in clinical trials, but there are no randomized studies comparing EMN with standard bronchoscopy. OBJECTIVES: To measure and identify the determinants of diagnostic yield for bronchoscopy in patients with peripheral lung lesions. Secondary outcomes included diagnostic yield of different sampling techniques, complications, and practice pattern variations. METHODS: We used the AQuIRE (ACCP Quality Improvement Registry, Evaluation, and Education) registry to conduct a multicenter study of consecutive patients who underwent transbronchial biopsy (TBBx) for evaluation of peripheral lesions. MEASUREMENTS AND MAIN RESULTS: Fifteen centers with 22 physicians enrolled 581 patients. Of the 581 patients, 312 (53.7%) had a diagnostic bronchoscopy. Unadjusted for other factors, the diagnostic yield was 63.7% when no radial endobronchial ultrasound (r-EBUS) and no EMN were used, 57.0% with r-EBUS alone, 38.5% with EMN alone, and 47.1% with EMN combined with r-EBUS. In multivariate analysis, peripheral transbronchial needle aspiration (TBNA), larger lesion size, nonupper lobe location, and tobacco use were associated with increased diagnostic yield, whereas EMN was associated with lower diagnostic yield. Peripheral TBNA was used in 16.4% of cases. TBNA was diagnostic, whereas TBBx was nondiagnostic in 9.5% of cases in which both were performed. Complications occurred in 13 (2.2%) patients, and pneumothorax occurred in 10 (1.7%) patients. There were significant differences between centers and physicians in terms of case selection, sampling methods, and anesthesia. Medical center diagnostic yields ranged from 33 to 73% (P = 0.16). CONCLUSIONS: Peripheral TBNA improved diagnostic yield for peripheral lesions but was underused. The diagnostic yields of EMN and r-EBUS were lower than expected, even after adjustment.

Experimental Pilot Study of a Novel Endobronchial Drug Delivery Catheter.

BACKGROUND: An endobronchial infusion catheter introduced through a flexible bronchoscope channel has not been previously described. The aim of this study was to evaluate the technical feasibility of a new device. METHODS: Four porcine models underwent bronchoscopy with the infusion catheter. In the first experiment, methylene blue was injected into airway in volumes of 0.1, 0.3, or 1.0 mL into 2 animals. One animal was killed at 1 hour and the other at 24 hours after the procedure and gross dye diffusion was visually assessed. In the second experiment, a mixture of 80% sterile normal saline and 20% contrast media was injected into the airway in volumes of 0.3, 1.0, and 3.0 mL into 2 animals. One animal was killed at 7 days and the other at 20 days. Histologic evaluations were performed according to a bronchial damage scoring system. RESULTS: There was no perioperative morbidity. In the first experiment, infusion volumes of 0.1, 0.3, and 1.0 mL resulted in dye surrounding 67%±29%, 55%±17%, and 80%±20% of the infusion-site circumference, and longitudinal distribution of 4.0±1.7, 8.1±4.1, and 18.0±3.0 mm each, respectively. In the second experiment, infusion of 0.3 to 3.0 mL resulted in mild injury, inflammation, and hemorrhage/fibrin/thrombus at 7 and 20 days after surgery. CONCLUSIONS: Endobronchial infusion of dye and contrast media by the endobronchial drug delivery catheter showed that the media spread in a dose-dependent manner macroscopically and histologically. Further investigation will be required to assess the catheter as a new tool for localized drug delivery into the airway.

A randomised trial of lung sealant versus medical therapy for advanced emphysema.

Uncontrolled pilot studies demonstrated promising results of endoscopic lung volume reduction using emphysematous lung sealant (ELS) in patients with advanced, upper lobe predominant emphysema. We aimed to evaluate the safety and efficacy of ELS in a randomised controlled setting.Patients were randomised to ELS plus medical treatment or medical treatment alone. Despite early termination for business reasons and inability to assess the primary 12-month end-point, 95 out of 300 patients were successfully randomised, providing sufficient data for 3- and 6-month analysis.57 patients (34 treatment and 23 control) had efficacy results at 3 months; 34 (21 treatment and 13 control) at 6 months. In the treatment group, 3-month lung function, dyspnoea, and quality of life improved significantly from baseline when compared to control. Improvements persisted at 6 months with >50% of treated patients experiencing clinically important improvements, including some whose lung function improved by >100%. 44% of treated patients experienced adverse events requiring hospitalisation (2.5-fold more than control, p=0.01), with two deaths in the treated cohort. Treatment responders tended to be those experiencing respiratory adverse events.Despite early termination, results show that minimally invasive ELS may be efficacious, yet significant risks (probably inflammatory) limit its current utility.