Safety and utility of indwelling pleural catheters in lung transplant recipients.

INTRODUCTION: The safety and efficacy of indwelling pleural catheters (IPCs) in lung allograft recipients is under-reported. METHODS: We performed a multicenter, retrospective analysis between 1/1/2010 and 6/1/2022 of consecutive IPCs placed in lung transplant recipients. Outcomes included incidence of infectious and non-infectious complications and rate of auto-pleurodesis. RESULTS: Seventy-one IPCs placed in 61 lung transplant patients at eight centers were included. The most common indication for IPC placement was recurrent post-operative effusion. IPCs were placed at a median of 59 days (IQR 40-203) post-transplant and remained for 43 days (IQR 25-88). There was a total of eight (11%) complications. Infection occurred in five patients (7%); four had empyema and one had a catheter tract infection. IPCs did not cause death or critical illness in our cohort. Auto-pleurodesis leading to the removal of the IPC occurred in 63 (89%) instances. None of the patients in this cohort required subsequent surgical decortication. CONCLUSIONS: The use of IPCs in lung transplant patients was associated with an infectious complication rate comparable to other populations previously studied. A high rate of auto-pleurodesis was observed. This work suggests that IPCs may be considered for the management of recurrent pleural effusions in lung allograft recipients.

The Impact of Bronchial Thermoplasty on Asthma-Related Quality of Life and Controller Medication Use.

BACKGROUND: Despite an improved understanding of the pathophysiology of asthma, severe asthma sufferers continue to experience a poor quality of life (QOL). Bronchial thermoplasty (BT) utilizes thermal energy to reduce airway smooth muscle. In industry-sponsored trials, BT improves QOL and reduces severe exacerbations; however, the impact of BT on asthma-related QOL and medication use in non-industry-sponsored trials is less clear. OBJECTIVE: The aim of this study was to determine the impact of BT on asthma QOL measures (mini-AQLQ) and asthma controller medication use during the year following treatment with BT. METHODS: We performed a prospective study of the impact of BT in 25 patients with severe persistent asthma. Our primary outcome was change in asthma-related QOL score (mini-AQLQ) 1 year after BT treatment. Our secondary outcome was change in asthma medication use 1 year after BT. RESULTS: BT led to an improvement in mini-AQLQ score from a baseline of 3.6 ± 0.3 before therapy to 5.6 ± 0.3 1 year after the final BT procedure. Overall, 88% percent of patients showed a clinically significant improvement in mini-AQLQ at 1 year. Patients treated with BT showed a reduction in the use of montelukast and omalizumab 1 year after BT. CONCLUSION: In patients with severe persistent asthma and low asthma-related QOL scores, BT leads to an improvement in asthma-related QOL and a decrease in asthma medication use when measured 1 year after the final BT treatment.

Adipose Tissue-Derived Mesenchymal Stem Cells Attenuate Pulmonary Infection Caused by Pseudomonas aeruginosa via Inhibiting Overproduction of Prostaglandin E2.

RATIONALE: New strategies for treating Pseudomonas aeruginosa pulmonary infection are urgently needed. Adipose tissue-derived mesenchymal stem cells (ASCs) may have a potential therapeutic role in P. aeruginosa-induced pulmonary infection. METHODS: The therapeutic and mechanistic effects of ASCs on P. aeruginosa pulmonary infection were evaluated in a murine model of P. aeruginosa pneumonia. RESULTS: ASCs exhibited protective effects against P. aeruginosa pulmonary infection, evidenced by reduced bacterial burdens, inhibition of alveolar neutrophil accumulation, decreased levels of myeloperoxidase, macrophage inflammatory protein-2 and total proteins in broncho-alveolar lavage fluid (BALF), and attenuated severity of lung injury. ASCs had no effects on BALF and serum levels of keratinocyte growth factor or Ang-1. ASCs had no effects on the levels of insulin growth factor 1 (IGF-1) in BALF, but increased IGF-1 levels in serum. ASCs inhibited the overproduction of prostaglandin E2 (PGE2 ) by decreasing the expression of cyclooxygenase-2 (COX2) and enhancing the expression of 15-PGDH. In addition, the addition of exogenous PGE2 with ASCs abolished many of the protective effects of ASCs, and administrating PGE2 alone exacerbated lung infection. By inhibiting production of PGE2 , ASCs improved phagocytosis and the bactericidal properties of macrophages. Furthermore suppressing PGE2 signaling by COX2 inhibition or EP2 inhibition exhibited protective effects against pulmonary infection as well. CONCLUSIONS: In a murine model of P. aeruginosa pneumonia, ASCs exhibited protective effects by inhibiting production of PGE2 , which subsequently improved phagocytosis and the bactericidal properties of macrophages. ASCs may provide a new strategy for managing pulmonary infection caused by P. aeruginosa.

Increased expression of neutrophil-related genes in patients with early sepsis-induced ARDS.

The early sequence of events leading to the development of the acute respiratory distress syndrome (ARDS) in patients with sepsis remains inadequately understood. The purpose of this study was to identify changes in gene expression early in the course of illness, when mechanisms of injury may provide the most relevant treatment and prognostic targets. We collected whole blood RNA in critically ill patients admitted from the Emergency Department to the intensive care unit within 24 h of admission at a tertiary care center. Whole genome expression was compared in patients with sepsis and ARDS to patients with sepsis alone. We selected genes with >1 log2 fold change and false discovery rate <0.25, determined their significance in the literature, and performed pathway analysis. Several genes were upregulated in 29 patients with sepsis with ARDS compared with 28 patients with sepsis alone. The most differentially expressed genes included key mediators of the initial neutrophil response to infection: olfactomedin 4, lipocalin 2, CD24, and bactericidal/permeability-increasing protein. These gene expression differences withstood adjustment for age, sex, study batch, white blood cell count, and presence of pneumonia or aspiration. Pathway analysis demonstrated overrepresentation of genes involved in known respiratory and infection pathways. These data indicate that several neutrophil-related pathways may be involved in the early pathogenesis of sepsis-related ARDS. In addition, identifiable gene expression differences occurring early in the course of sepsis-related ARDS may further elucidate understanding of the neutrophil-related mechanisms in progression to ARDS.

Development and Validation of a Mortality Prediction Model for Patients Receiving 14 Days of Mechanical Ventilation.

OBJECTIVES: The existing risk prediction model for patients requiring prolonged mechanical ventilation is not applicable until after 21 days of mechanical ventilation. We sought to develop and validate a mortality prediction model for patients earlier in the ICU course using data from day 14 of mechanical ventilation. DESIGN: Multicenter retrospective cohort study. SETTING: Forty medical centers across the United States. PATIENTS: Adult patients receiving at least 14 days of mechanical ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Predictor variables were measured on day 14 of mechanical ventilation in the development cohort and included in a logistic regression model with 1-year mortality as the outcome. Variables were sequentially eliminated to develop the ProVent 14 model. This model was then generated in the validation cohort. A simplified prognostic scoring rule (ProVent 14 Score) using categorical variables was created in the development cohort and then tested in the validation cohort. Model discrimination was assessed by the area under the receiver operator characteristic curve. Four hundred ninety-one patients and 245 patients were included in the development and validation cohorts, respectively. The most parsimonious model included age, platelet count, requirement for vasopressors, requirement for hemodialysis, and nontrauma admission. The area under the receiver operator characteristic curve for the ProVent 14 model using continuous variables was 0.80 (95% CI, 0.76-0.83) in the development cohort and 0.78 (95% CI, 0.72-0.83) in the validation cohort. The ProVent 14 Score categorized age at 50 and 65 years old and platelet count at 100×10(9)/L and had similar discrimination as the ProVent 14 model in both cohorts. CONCLUSION: Using clinical variables available on day 14 of mechanical ventilation, the ProVent 14 model can identify patients receiving prolonged mechanical ventilation with a high risk of mortality within 1 year.

Noradrenergic neurons regulate monocyte trafficking and mortality during gram-negative peritonitis in mice.

Effective host defense requires a robust, yet self-limited response to pathogens. A poorly calibrated response can lead to either bacterial dissemination due to insufficient inflammation or organ injury due to excessive inflammation. Recent evidence suggests that the cholinergic anti-inflammatory reflex helps calibrate the immune response. However, the influence of peripheral noradrenergic neurons, which are primarily sympathetic neurons, in regulating immunity remains incompletely characterized. Using a model of 6-hydroxydopamine-mediated noradrenergic nerve ablation, we show that elimination of noradrenergic neurons improves survival during Klebsiella pneumoniae peritonitis (67 versus 23%, p < 0.005) in mice. The survival benefit results from enhanced MCP-1-dependent monocyte recruitment and a subsequent decrease in bacterial loads. Splenectomy eliminated both the survival benefit of 6-hydroxydopamine and monocyte recruitment, suggesting that monocytes recruited to the peritoneum originate in the spleen. These results suggest that noradrenergic neurons regulate the immune response through two pathways. First, sympathetic nerve-derived norepinephrine directly restrains MCP-1 production by peritoneal macrophages during infection. Second, norepinephrine derived from the vagally innervated splenic nerve regulates splenic monocyte egress. Removal of these two modulators of the immune response enhances antibacterial immunity and improves survival. These results may have implications for how states of catecholamine excess influence the host response to bacterial infections.

Increased susceptibility to Klebsiella pneumonia and mortality in GSNOR-deficient mice.

S-nitrosoglutathione reductase (GSNOR) is a key denitrosylase and critically important for protecting immune and other cells from nitrosative stress. Pharmacological inhibition of GSNOR is being actively pursued as a therapeutic approach to increase S-nitrosoglutathione levels for the treatment of asthma and cystic fibrosis. In the present study, we employed GSNOR-deficient (GSNOR(-/-)) mice to investigate whether inactivation of GSNOR may increase susceptibility to pulmonary infection by Klebsiella pneumoniae, a common cause of nosocomial pneumonia. We found that compared to wild-type mice, bacterial colony forming units 48 h after intranasal infection with K. pneumoniae were increased over 4-folds in lung and spleen and strikingly, over a 1000-folds in blood of GSNOR(-/-) mice. Lung injury was comparable between infected wild-type and GSNOR(-/-) mice, but inflammation and injury was significantly elevated in spleen of GSNOR(-/-) mice. Whereas all wild-type mice survived 48 h after infection, 10 of 23 GSNOR(-/-) mice died. Thus, GSNOR appears to play a crucial role in controlling pulmonary and systemic infection by K. pneumoniae. Our results suggest that patients treated in clinical trials with inhibitors of GSNOR should be carefully monitored for signs of infection.

Impact of a Dedicated Pleural Clinic on Indwelling Pleural Catheter Related Outcomes: A Retrospective Single Center Experience.

BACKGROUND: Recurrent pleural effusions are a major cause of morbidity and frequently lead to hospitalization. Indwelling pleural catheters (IPCs) are tunneled catheters that allow ambulatory intermittent drainage of pleural fluid without repeated thoracentesis. Despite the efficacy and safety of IPCs, data supporting postplacement follow-up is limited and variable. Our study aims to characterize the impact of a dedicated pleural clinic (PC) on patient outcomes as they relate to IPCs. METHODS: Patients who underwent IPC placement between 2015 and 2021 were included in this retrospective study. Differences in outcomes were analyzed between patients with an IPC placed and managed by Interventional Pulmonology (IP) through the PC and those placed by non-IP services (non-PC providers) before and after the PC implementation. RESULTS: In total, 371 patients received IPCs. Since the implementation of the PC, there was an increase in ambulatory IPC placement (31/133 pre-PC vs. 96/238 post-PC; P =0.001). There were fewer admissions before IPC placement (18/103 vs. 43/133; P =0.01), and fewer thoracenteses per patient (2.7±2.5 in PC cohort vs. 4±5.1 in non-PC cohort; P <0.01). The frequency of pleurodesis was higher in the PC cohort (40/103 vs. 41/268; P <0.001). A Fine and Gray competing risks model indicated higher likelihood of pleurodesis in the PC cohort (adjusted subhazard ratio 3.8, 95% CI: 2.5-5.87). CONCLUSION: Our experience suggests that the implementation of a dedicated PC can lead to improved patient outcomes including fewer procedures and admissions before IPC placement, and increased rates of pleurodesis with IPC removal.

Inflection points in sepsis biology: from local defense to systemic organ injury.

Sepsis and septic shock lead to considerable morbidity and mortality in developed and developing countries. Despite advances in understanding the innate immune events that lead to septic shock, molecular therapies based on these advances have failed to improve sepsis mortality. The clinical failure of laboratory-derived therapies may be, in part, due to the pleiotropic consequences of the acute inflammatory response, which is the focus of this review. A brisk response to infecting organism is essential for pathogen containment and eradication. However, systemic spread of inflammation beyond a single focus leads to organ injury and higher mortality. The primary goal of this article is to discuss recent animal- and human-based scientific advances in understanding the host response to infection and to highlight how these defense mechanisms can be locally beneficial but systemically detrimental. There are other factors that determine the severity of sepsis that are beyond the scope of this review, including the virulence of the pathogen and regulation by Toll-like receptors. Specifically, this review focuses on how the effector mechanisms of platelets, mast cells, neutrophil extracellular traps (NETs), and the endothelium participate in combating local infections yet can induce organ injury during systemic infection.

A multicenter mortality prediction model for patients receiving prolonged mechanical ventilation.

OBJECTIVE: Significant deficiencies exist in the communication of prognosis for patients requiring prolonged mechanical ventilation after acute illness, in part because of clinician uncertainty about long-term outcomes. We sought to refine a mortality prediction model for patients requiring prolonged ventilation using a multicentered study design. DESIGN: Cohort study. SETTING: Five geographically diverse tertiary care medical centers in the United States (California, Colorado, North Carolina, Pennsylvania, and Washington). PATIENTS: Two hundred sixty adult patients who received at least 21 days of mechanical ventilation after acute illness. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: For the probability model, we included age, platelet count, and requirement for vasopressors and/or hemodialysis, each measured on day 21 of mechanical ventilation, in a logistic regression model with 1-yr mortality as the outcome variable. We subsequently modified a simplified prognostic scoring rule (ProVent score) by categorizing the risk variables (age 18-49, 50-64, and ≥65 yrs; platelet count 0-150 and >150; vasopressors; hemodialysis) in another logistic regression model and assigning points to variables according to ß coefficient values. Overall mortality at 1 yr was 48%. The area under the curve of the receiver operator characteristic curve for the primary ProVent probability model was 0.79 (95% confidence interval 0.75-0.81), and the p value for the Hosmer-Lemeshow goodness-of-fit statistic was .89. The area under the curve for the categorical model was 0.77, and the p value for the goodness-of-fit statistic was .34. The area under the curve for the ProVent score was 0.76, and the p value for the Hosmer-Lemeshow goodness-of-fit statistic was .60. For the 50 patients with a ProVent score >2, only one patient was able to be discharged directly home, and 1-yr mortality was 86%. CONCLUSION: The ProVent probability model is a simple and reproducible model that can accurately identify patients requiring prolonged mechanical ventilation who are at high risk of 1-yr mortality.

Decreased respiratory system compliance on the sixth day of mechanical ventilation is a predictor of death in patients with established acute lung injury.

BACKGROUND: Multiple studies have identified single variables or composite scores that help risk stratify patients at the time of acute lung injury (ALI) diagnosis. However, few studies have addressed the important question of how changes in pulmonary physiologic variables might predict mortality in patients during the subacute or chronic phases of ALI. We studied pulmonary physiologic variables, including respiratory system compliance, P/F ratio and oxygenation index, in a cohort of patients with ALI who survived more than 6 days of mechanical ventilation to see if changes in these variables were predictive of death and whether they are informative about the pathophysiology of subacute ALI. METHODS: Ninety-three patients with ALI who were mechanically ventilated for more than 6 days were enrolled in this prospective cohort study. Patients were enrolled at two medical centers in the US, a county hospital and a large academic center. Bivariate analyses were used to identify pulmonary physiologic predictors of death during the first 6 days of mechanical ventilation. Predictors on day 1, day 6 and the changes between day 1 and day 6 were compared in a multivariate logistic regression model. RESULTS: The overall mortality was 35%. In multivariate analysis, the PaO2/FiO2 (OR 2.09, p < 0.04) and respiratory system compliance (OR 3.61, p < 0.01) were predictive of death on the 6th day of acute lung injury. In addition, a decrease in respiratory system compliance between days 1 and days 6 (OR 2.14, p < 0.01) was independently associated with mortality. CONCLUSIONS: A low respiratory system compliance on day 6 or a decrease in the respiratory system compliance between the 1st and 6th day of mechanical ventilation were associated with increased mortality in multivariate analysis of this cohort of patients with ALI. We suggest that decreased respiratory system compliance may identify a subset of patients who have persistent pulmonary edema, atelectasis or the fibroproliferative sequelae of ALI and thus are less likely to survive their hospitalization.

Molecular cytopathology diagnosis of a lung neoplasm: Case report of an unusual non-small cell carcinoma with MET exon 14 skipping mutation.

Here we report the combined cytological and molecular diagnosis of a lung mass. The cytology and extensive immunohistochemistry on an endobronchial ultrasound-guided fine needle aspiration biopsy were inconclusive. By genomic profiling of the cell block material, we identified a MET exon 14 skipping mutation that indicated a lung origin and made the patient eligible for the tyrosine kinase inhibitor, crizotinib. This case is a prime example of complementing adequate aspiration and cell block processing techniques with molecular testing. Such an approach would augment the usability of fine needle aspiration biopsy, both as a diagnostic modality and as the first line to find therapeutic targets in the era of precision medicine.

A retrospective observational study of benign anthracotic lymphadenitis and its association with PET avid lymph nodes in patients undergoing cancer evaluation.

BACKGROUND: Accurate staging of newly diagnosed or recurrent malignancy is essential for effective treatment. An important first step in staging involves the use of PET/CT to identify areas of FDG avidity. PET/CT however has limitations, including false positive FDG uptake from benign causes. In this paper we characterize an uncommon yet clinically important cause of false positive PET/CTs, that of benign anthracotic lymphadenitis (BAL). We examine the clinical, radiographic and histologic characteristics of BAL in patients referred for endobronchial ultrasound (EBUS) guided biopsies and discuss its context in relation to existing literature. METHODS: We performed a retrospective observational case series of 20 patients who were referred for EBUS guided biopsies of PET positive mediastinal and hilar lymph nodes during the work-up or treatment of suspected malignancy. RESULTS: To be included, all patients received PET imaging as well as an EBUS guided biopsy of FDG avid lymph nodes which demonstrated anthracotic pigment as the only histologic abnormality. The key findings were that 90% of patients in this cohort were born outside of the US, 90% had bilateral FDG avid lymph nodes with an average standardized uptake value (SUV) of 7.9±2.2. Most patients, based on their history, had a likely exposure to biomass fuel or urban pollution. CONCLUSIONS: BAL may be an underrecognized cause for PET positive lymph nodes in patients undergoing work-up for malignancy. These findings support the importance of sampling mediastinal and hilar lymph nodes even when SUVs are highly suggestive of malignancy.

A mass that has no (EBUS) echo.

We report findings for a patient that underwent endobronchial ultrasound (EBUS) guided transbronchial needle aspiration (TBNA) for diagnostic purposes after an abnormal chest CT. The patient initially presented with cough and shortness of breath. Chest CT revealed a 6 cm soft tissue mass with mildly enlarged right hilar lymph nodes (LNs) and a small right sided pleural effusion. Based on these radiologic findings, the patient underwent an EBUS guided FNA of the mass. To our surprise, the mass was hypoechoic by EBUS and on aspiration, the syringe filled with yellow fluid. This finding in combination with a re-review of the CT scans with a special focus on the Hounsfield Units of the lesion confirmed the diagnosis of a mediastinal bronchogenic cyst. This case demonstrates the role of Hounsfield units in analyzing mediastinal masses and highlights the effectiveness of EBUS guided TBNA in diagnosis and treatment of bronchogenic cysts.

Central Airway Obstruction Due to Tracheal Glomus Tumor.

Background Tracheal glomus tumors are rare mesenchymal neoplasms that have the potential to cause malignant, central airway obstruction. They require a thoughtful approach to safely secure the airway and definitively resect the tumor. Case Description We report the clinical course of a 25-year-old man in severe respiratory distress secondary to tracheal glomus tumor and the subsequent surgical management. Conclusion Due to their hypervascular nature, greater familiarity with tracheal glomus tumors is needed to ensure appropriate preoperative planning and intervention.