Lonny Yarmus

Targeting Nrf2 Signaling Improves Bacterial Clearance by Alveolar Macrophages in Patients with COPD and in a Mouse Model

Bacterial clearance in macrophages from lungs with chronic obstructive pulmonary disease is improved by stimulating the Nrf2 antioxidant signaling pathway. Cleansing Breath With every breath we take, the outside air assaults the lungs. Along with life-sustaining oxygen come dust, dirt, and microbes. A well-functioning lung cleanses itself with broom-like cilia that sweep out debris and with a robust innate immune defense system driven by macrophages that subdue infectious invaders. But constant exposure to cigarette smoke or pollution can interfere with this self-cleaning system and cause the lung ailment COPD (chronic obstructive pulmonary disease). This common disease is characterized by two conditions that cause shortness of breath, wheezing, chronic cough, and tightness in the chest: emphysema—which is associated with progressive destruction of lung tissue—and bronchitis—an inflammation of the airway passages (bronchi). Understanding the mechanistic details of how irritants in the air disable the lung’s defenses can help uncover possible drug targets. Now, Harvey and colleagues have fingered a cigarette smoke–triggered change in a signaling pathway that regulates defense against oxidative stress, which may impair lung macrophage function. In both COPD patients and a mouse model of COPD, a phytochemical found in broccoli can activate this pathway and improve the ability of lung macrophages to sequester and inactivate the bacteria that often causes exacerbations of COPD. Although the mechanism is unclear, lung macrophages from patients with COPD are defective in taking up (phagocytosing) bacteria for eventual destruction. This aberration gives rise to both the persistent presence of bacteria, which promotes inflammation, and frequent bacterial infections often caused by Haemophilus influenzae and Pseudomonas aeruginosa; these conditions aggravate COPD symptoms, and there are no therapies that prevent these bacterially induced exacerbations. It has been suggested that macrophage defects in COPD result from oxidative stress. Studies in mice subjected to secondhand smoke reveal a role for the transcription factor Nrf2 (nuclear erythroid–related factor 2) in protection from emphysema and in the severity of COPD. In response to oxidative stress, Nrf2 moves into the cell’s nucleus, binds to antioxidant response elements in DNA, and activates genes that encode antioxidant proteins. The authors hypothesized that enhancing the synthesis of Nrf2-inducing antioxidants in lung macrophages from COPD patients would reduce oxidative stress and thus restore the cells’ ability to internalize and obliterate bacteria. To this end, Harvey et al. treated these cells with an Nrf2-stimulating phytochemical, sulforaphane, and showed that the macrophages were able to recognize and internalize H. influenzae and P. aeruginosa. The authors then treated mice that had been sucking in smoke for 6 months with the same chemical, which cooled inflammation and enhanced macrophage-driven bacterial clearance in the lungs of wild-type mice but not in Nrf2-deficient mice. Molecular analyses of Nrf-regulated genes revealed that the restorative effects on macrophages required direct transcriptional activation of the gene that encodes MARCO, a scavenger of molecules that cause oxidative stress. These findings suggest that by boosting macrophage function, therapies that regulate Nrf2 or its targets can protect the lungs of COPD patients from serial assaults. Patients with chronic obstructive pulmonary disease (COPD) have innate immune dysfunction in the lung largely due to defective macrophage phagocytosis. This deficiency results in periodic bacterial infections that cause acute exacerbations of COPD, a major source of morbidity and mortality. Recent studies indicate that a decrease in Nrf2 (nuclear erythroid–related factor 2) signaling in patients with COPD may hamper their ability to defend against oxidative stress, although the role of Nrf2 in COPD exacerbations has not been determined. Here, we test whether activation of Nrf2 by the phytochemical sulforaphane restores phagocytosis of clinical isolates of nontypeable Haemophilus influenza (NTHI) and Pseudomonas aeruginosa (PA) by alveolar macrophages from patients with COPD. Sulforaphane treatment restored bacteria recognition and phagocytosis in alveolar macrophages from COPD patients. Furthermore, sulforaphane treatment enhanced pulmonary bacterial clearance by alveolar macrophages and reduced inflammation in wild-type mice but not in Nrf2-deficient mice exposed to cigarette smoke for 6 months. Gene expression and promoter analysis revealed that Nrf2 increased phagocytic ability of macrophages by direct transcriptional up-regulation of the scavenger receptor MARCO. Disruption of Nrf2 or MARCO abrogated sulforaphane-mediated bacterial phagocytosis by COPD alveolar macrophages. Our findings demonstrate the importance of Nrf2 and its downstream target MARCO in improving antibacterial defenses and provide a rationale for targeting this pathway, via pharmacological agents such as sulforaphane, to prevent exacerbations of COPD caused by bacterial infection.

Complications, Consequences, and Practice Patterns of Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration: Results of the AQuIRE Registry

BACKGROUND Few studies of endobronchial ultrasound-guided transbronchial needle aspiration(EBUS-TBNA) have been large enough to identify risk factors for complications. The primary objective of this study was to quantify the incidence of and risk factors for complications in patients undergoing EBUS-TBNA. METHODS Data on prospectively enrolled patients undergoing EBUS-TBNA in the American College of Chest Physicians Quality Improvement Registry, Evaluation, and Education (AQuIRE)database were extracted and analyzed for the incidence, consequences, and predictors of complications. RESULTS We enrolled 1,317 patients at six hospitals. Complications occurred in 19 patients (1.44%;95% CI, 0.87%-2.24%). Transbronchial lung biopsy (TBBx) was the only risk factor for complications,which occurred in 3.21% of patients who underwent the procedure and in 1.15% of those who did not (OR, 2.85; 95% CI, 1.07-7.59; P 5 .04). Pneumothorax occurred in seven patients(0.53%; 95% CI, 0.21%-1.09%). Escalations in level of care occurred in 14 patients (1.06%;95% CI, 0.58%-1.78%); its risk factors were age . 70 years (OR, 4.06; 95% CI, 1.36-12.12; P 5 .012),inpatient status (OR, 4.93; 95% CI, 1.30-18.74; P 5 .019), and undergoing deep sedation or general anesthesia (OR, 4.68; 95% CI, 1.02-21.61; P 5 .048). TBBx was performed in only 12.6% of patients when rapid on site cytologic evaluation (ROSE ) was used and in 19.1% when it was not used ( P 5 .006).Interhospital variation in TBBx use when ROSE was used was significant ( P , .001). CONCLUSIONS TBBx was the only risk factor for complications during EBUS-TBNA procedures.ROSE significantly reduced the use of TBBx.

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.

Clinical Outcomes of Indwelling Pleural Catheter-Related Pleural Infections: An International Multicenter Study

BACKGROUND Indwelling pleural catheters (IPCs) offer effective control of malignant pleural effusions (MPEs). IPC-related infection is uncommon but remains a major concern. Individual IPC centers see few infections, and previous reports lack sufficient numbers and detail. This study combined the experience of 11 centers from North America, Europe, and Australia to describe the incidence, microbiology, management, and clinical outcomes of IPC-related pleural infection. METHODS This was a multicenter retrospective review of 1,021 patients with IPCs. All had confirmed MPE. RESULTS Only 50 patients (4.9%) developed an IPC-related pleural infection; most (94%) were successfully controlled with antibiotics (62% IV). One death (2%) directly resulted from the infection, whereas two patients (4%) had ongoing infectious symptoms when they died of cancer progression. Staphylococcus aureus was the causative organism in 48% of cases. Infections from gram-negative organisms were associated with an increased need for continuous antibiotics or death (60% vs 15% in gram-positive and 25% mixed infections, P = .02). The infections in the majority (54%) of cases were managed successfully without removing the IPC. Postinfection pleurodesis developed in 31 patients (62%), especially those infected with staphylococci (79% vs 45% with nonstaphylococcal infections, P = .04). CONCLUSIONS The incidence of IPC-related pleural infection was low. The overall mortality risk from pleural infection in patients treated with IPC was only 0.29%. Antibiotics should cover S aureus and gram-negative organisms until microbiology is confirmed. Postinfection pleurodesis is common and often allows removal of IPC. Heterogeneity in management is common, and future studies to define the optimal treatment strategies are needed.

Improvement of cellularity on cell block preparations using the so-called tissue coagulum clot method during endobronchial ultrasound-guided transbronchial fine-needle aspiration†

Cell block (CB) preparation during the endobronchial ultrasound‐guided transbronchial fine‐needle aspiration (EBUS‐TBNA) procedure plays an important role in the diagnosis of lung cancer and recovery of cellular material for molecular characterization of the tumor. However, the efficiency of the conventional method of CB preparation is suboptimal.

Technical aspects of endobronchial ultrasound-guided transbronchial needle aspiration CHEST guideline and expert panel report

BACKGROUND Endobronchial ultrasound (EBUS) was introduced in the last decade, enabling real-time guidance of transbronchial needle aspiration (TBNA) of mediastinal and hilar structures and parabronchial lung masses. The many publications produced about EBUS-TBNA have led to a better understanding of the performance characteristics of this procedure. The goal of this document was to examine the current literature on the technical aspects of EBUS-TBNA as they relate to patient, technology, and proceduralist factors to provide evidence-based and expert guidance to clinicians. METHODS Rigorous methodology has been applied to provide a trustworthy evidence-based guideline and expert panel report. A group of approved panelists developed key clinical questions by using the PICO (population, intervention, comparator, and outcome) format that addressed specific topics on the technical aspects of EBUS-TBNA. MEDLINE (via PubMed) and the Cochrane Library were systematically searched for relevant literature, which was supplemented by manual searches. References were screened for inclusion, and well-recognized document evaluation tools were used to assess the quality of included studies, to extract meaningful data, and to grade the level of evidence to support each recommendation or suggestion. RESULTS Our systematic review and critical analysis of the literature on 15 PICO questions related to the technical aspects of EBUS-TBNA resulted in 12 statements: 7 evidence-based graded recommendations and 5 ungraded consensus-based statements. Three questions did not have sufficient evidence to generate a statement. CONCLUSIONS Evidence on the technical aspects of EBUS-TBNA varies in strength but is satisfactory in certain areas to guide clinicians on the best conditions to perform EBUS-guided tissue sampling. Additional research is needed to enhance our knowledge regarding the optimal performance of this effective procedure.

Comparison of 21-Gauge and 22-Gauge Aspiration Needle in Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration: Results of the American College of Chest Physicians Quality Improvement Registry, Education, and Evaluation Registry

BACKGROUND Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive procedure originally performed using a 22-gauge (22G) needle. A recently introduced 21-gauge (21G) needle may improve the diagnostic yield and sample adequacy of EBUS-TBNA, but prior smaller studies have shown conflicting results. To our knowledge, this is the largest study undertaken to date to determine whether the 21G needle adds diagnostic benefit. METHODS We retrospectively evaluated the results of 1,299 patients from the American College of Chest Physicians Quality Improvement Registry, Education, and Evaluation (AQuIRE) Diagnostic Registry who underwent EBUS-TBNA between February 2009 and September 2010 at six centers throughout the United States. Data collection included patient demographics, sample adequacy, and diagnostic yield. Analysis consisted of univariate and multivariate hierarchical logistic regression comparing diagnostic yield and sample adequacy of EBUS-TBNA specimens by needle gauge. RESULTS A total of 1,235 patients met inclusion criteria. Sample adequacy was obtained in 94.9% of the 22G needle group and in 94.6% of the 21G needle group (P = .81). A diagnosis was made in 51.4% of the 22G and 51.3% of the 21G groups (P = .98). Multivariate hierarchical logistic regression showed no statistical difference in sample adequacy or diagnostic yield between the two groups. The presence of rapid onsite cytologic evaluation was associated with significantly fewer needle passes per procedure when using the 21G needle (P < .001). CONCLUSIONS There is no difference in specimen adequacy or diagnostic yield between the 21G and 22G needle groups. EBUS-TBNA in conjunction with rapid onsite cytologic evaluation and a 21G needle is associated with fewer needle passes compared with a 22G needle.

Cryoprobe Transbronchial Lung Biopsy in Patients After Lung Transplantation: A Pilot Safety Study

BACKGROUND Transbronchial biopsies using standard forceps (FTBBxs) are often limited by crush artifact and their small size. To date, there have been no studies aimed at assessing the safety and efficacy of cryoprobe biopsies (CPBxs) in the population of patients who have undergone lung transplants. We present the safety profile and biopsy results from the fi rst 21 procedures in a pilot study comparing CPBx to FTBBx in patients after lung transplantation. METHODS Patients who had undergone lung transplant and who were scheduled for bronchoscopy were sequentially enrolled between November 2011 and September 2012. Inclusion criteria included age . 18 years and bilateral, orthotopic lung transplant. Exclusion criteria were coagulopathy, FEV 1 < 0.8 L, diffuse bullous disease, hemodynamic instability, and severe hypoxemia (Pa(O2) < 55 mm Hg or Sp(O2) < 92% on room air). Twenty-one procedures were performed, 10 using rigid bronchoscopy followed by 11 via flexible bronchoscopy. Patients were monitored for complications including pneumothorax, hemodynamic instability, and/or respiratory distress. Bleeding was categorized on an adapted grading system. RESULTS Twenty-one procedures in 17 patients (median age: 52 years; 12 male patients) were performed. Specimen area and percent open alveoli were significantly greater using CPBx compared with FTBBx ( P < .05). No clinically significant procedural complications occurred and all patients were discharged the day of the procedure. CONCLUSIONS The use of the cryoprobe is a safe, alternative technique to FTBBx during post-lung transplant bronchoscopy. Further studies are needed to determine if larger samples obtained with CPBx translate to an increased diagnostic yield.

Optimizing Endobronchial Ultrasound for Molecular Analysis. How Many Passes Are Needed

BACKGROUND The current oncologic management of non-small cell lung cancer (NSCLC) requires pathologic differentiation between adenocarcinoma and squamous cell carcinoma. Furthermore, novel therapies for adenocarcinoma are clinically available for specific mutation profiles. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been shown to adequately obtain specimens for molecular profiling. However, it remains unclear what quantity of specimens is needed to provide suitable mutational genotyping for adenocarcinoma. The objective of this study was to determine the optimal number of aspirations per EBUS-TBNA procedure required in the presence of rapid on-site cytopathology evaluation (ROSE) for maximal diagnostic yield for molecular mutational analysis. METHODS From March 2010 to February 2012, cytopathologic data were collected from consecutive cases of adenocarcinoma or NSCLC not otherwise specified (NSCLC-NOS), diagnosed by EBUS-TBNA and ROSE. Samples of material obtained were air-dried and wet-fixed. Samples were tested for the KRAS, EGFR, and/or ALK mutations. MEASUREMENTS AND MAIN RESULTS Eighty-five patients who underwent EBUS-TBNA and were diagnosed with adenocarcinoma or NSCLC-NOS were identified. Of the 85 cases identified, 77 (90.6%) were classified as adenocarcinoma with the remaining 8 (9.4%) classified as NSCLC-NOS. Eighty-one of 85 (95.3%) were found to be adequate for molecular profiling. The median number of sites sampled was one. A median of four passes was needed to obtain adequate molecular profiling of 95.3%, using EBUS in conjunction with ROSE. CONCLUSIONS With the use of EBUS-TBNA and ROSE, a minimum of four needle passes may provide an adequate amount of specimen for advanced molecular marker analysis.

Safety, efficiency, and cost-effectiveness of a multidisciplinary percutaneous tracheostomy program.

Objective:The frequency of bedside percutaneous tracheostomies is increasing in intensive care medicine, and both safety and efficiency of care are critical elements in continuing success of this procedure. Prioritizing patient safety, a tracheostomy team was created at our institution to provide bedside expertise in surgery, anesthesiology, respiratory, and technical support. This study was performed to evaluate the metrics of patient outcome, efficiency of care, and cost-benefit analysis of the multidisciplinary Johns Hopkins Percutaneous Tracheostomy Program. Design:A review was performed for patients who received tracheostomies in 2004, the year before the Johns Hopkins Percutaneous Tracheostomy Program was established, and those who received tracheostomies in 2008, the year following the program’s establishment. Comparative outcomes were evaluated, including the efficiency of procedure and intensive care unit length of stay, complication rate including bleeding, hypoxia, loss of airway, and a financial cost-benefit analysis. Setting:Single-center, major university hospital. Patients:The sample consisted of 363 patients who received a tracheostomy in the years 2004 and 2008. Measurements and Main Results:The number of percutaneous procedures increased from 59 of 126 tracheostomy patients in 2004, to 183 of 237 in 2008. There were significant decreases in the prevalence of procedural complications, particularly in the realm of airway injuries and physiologic disturbances. Regarding efficiency, the structured program reduced the time to tracheostomy and overall procedural time. The intensive care unit length of stay in nonpulmonary patients and improvement in intensive care unit and operating room back-fill efficiency contributed to an overall institutional financial benefit. Conclusions:An institutionally subsidized, multi-disciplinary percutaneous tracheostomy program can improve the quality of care in a cost-effective manner by decreasing the incidence of tracheostomy complications and improving both the time to tracheostomy, duration of procedure, and postprocedural intensive care unit stay.