A Multicenter, Single-Arm, Prospective Trial Assessing the Diagnostic Yield of Electromagnetic Bronchoscopic and Transthoracic Navigation for Peripheral Pulmonary Nodules.

Rationale: Strict adherence to procedural protocols and diagnostic definitions is critical to understand the efficacy of new technologies. Electromagnetic navigational bronchoscopy (ENB) for lung nodule biopsy has been used for decades without a solid understanding of its efficacy, but offers the opportunity for simultaneous tissue acquisition via electromagnetic navigational transthoracic biopsy (EMN-TTNA) and staging via endobronchial ultrasound (EBUS). Objective: To evaluate the diagnostic yield of EBUS, ENB, and EMN-TTNA during a single procedure using a strict a priori definition of diagnostic yield with central pathology adjudication. Methods: A prospective, single-arm trial was conducted at eight centers enrolling participants with pulmonary nodules (<3 cm; without computed tomography [CT]- and/or positron emission tomography-positive mediastinal lymph nodes) who underwent a staged procedure with same-day CT, EBUS, ENB, and EMN-TTNA. The procedure was staged such that, when a diagnosis had been achieved via rapid on-site pathologic evaluation, the procedure was ended and subsequent biopsy modalities were not attempted. A study finding was diagnostic if an independent pathology core laboratory confirmed malignancy or a definitive benign finding. The primary endpoint was the diagnostic yield of the combination of CT, EBUS, ENB, and EMN-TTNA. Measurements and Main Results: A total of 160 participants at 8 centers with a mean nodule size of 18 ± 6 mm were enrolled. The diagnostic yield of the combined procedure was 59% (94 of 160; 95% confidence interval [CI], 51-66%). Nodule regression was found on same-day CT in 2.5% of cases (4 of 160; 95% CI, 0.69-6.3%), and EBUS confirmed malignancy in 7.1% of cases (11 of 156; 95% CI, 3.6-12%). The yield of ENB alone was 49% (74 of 150; 95% CI, 41-58%), that of EMN-TTNA alone was 27% (8 of 30; 95% CI, 12-46%), and that of ENB plus EMN-TTNA was 53% (79 of 150; 95% CI, 44-61%). Complications included a pneumothorax rate of 10% and a 2% bleeding rate. When EMN-TTNA was performed, the pneumothorax rate was 30%. Conclusions: The diagnostic yield for ENB is 49%, which increases to 59% with the addition of same-day CT, EBUS, and EMN-TTNA, lower than in prior reports in the literature. The high complication rate and low diagnostic yield of EMN-TTNA does not support its routine use. Clinical trial registered with www.clinicaltrials.gov (NCT03338049).

Making of a Successful Early Mobilization Program for a Medical Intensive Care Unit.

OBJECTIVES: To provide a guideline for intensive care unit (ICU) early mobilization program development and implementation and to describe the patient characteristics and endpoints for those who participated in our hospital's early mobilization program. METHODS: An ICU early mobilization program was developed with five guiding principles: analgesia/sedation optimization, sedation minimization, protocol of progressive mobility, physical therapy and occupational therapy recruitment, and nursing education. This program began in April 2014, and the initial 32 patients who ambulated while receiving mechanical ventilation were retrospectively assessed and their characteristics described. RESULTS: After program implementation, more than 50 mechanically ventilated patients ambulated in the first year following early mobilization initiation. Patients with an FiO2 as high as 1.0 and on nonconventional modes of mechanical ventilation successfully ambulated without adverse events. The mean ambulation distance was 102 ± 152 f. and usually required three ICU staff members with 5 to 10 minutes of preparation before ambulation. After implementation, a retrospective analysis revealed a decrease in the average length of ICU stay, from 4.8 to 4.1 days. CONCLUSIONS: Addressing analgesia and sedation practices, along with instituting a progressive mobility protocol and recruiting physical and occupational therapy, may serve as a guide to the creation of a successful early mobilization program. This study provides additional supportive evidence that early mobilization in the ICU is safe and effective.

Optimizing clinical outcomes for bronchoscopic lung volume reduction with Zephyr® valves.

Bronchoscopic lung volume reduction treatment with Zephyr one-way valves is an effective guideline-based treatment option for patients with severe emphysema and hyperinflation. However, in some cases the treatment response is less than anticipated or there might be a loss of initial treatment effect. Reasons for the lack of response can include incorrect assessment of collateral ventilation, improper valve placement, or patient related factors. Loss of initial benefit can be due to granulation tissue formation and subsequent valve dysfunction, or there may be side effects such as excessive coughing or infectious problems. Careful follow-up after treatment with valves is important and evaluation with a CT scan and/or bronchoscopy is helpful if there is no improvement after treatment or loss of initial benefit. This paper aims to describe the most important causes and provide a strategy of how to approach and manage these patients.

Cell-free DNA methylation analysis as a marker of malignancy in pleural fluid.

Diagnosis of malignant pleural effusion (MPE) is made by cytological examination of pleural fluid or histological examination of pleural tissue from biopsy. Unfortunately, detection of malignancy using cytology has an overall sensitivity of 50%, and is dependent upon tumor load, volume of fluid assessed, and cytopathologist experience. The diagnostic yield of pleural fluid cytology is also compromised by low abundance of tumor cells or when morphology is obscured by inflammation or reactive mesothelial cells. A reliable molecular marker that may complement fluid cytology for the diagnosis of malignant pleural effusion is needed. The purpose of this study was to establish a molecular diagnostic approach based on pleural effusion cell-free DNA methylation analysis for the differential diagnosis of malignant pleural effusion and benign pleural effusion. This was a blind, prospective case-control biomarker study. We recruited 104 patients with pleural effusion for the study. We collected pleural fluid from patients with: MPE (n = 48), indeterminate pleural effusion in subjects with known malignancy or IPE (n = 28), and benign PE (n = 28), and performed the Sentinel-MPE liquid biopsy assay. The methylation level of Sentinel-MPE was markedly higher in the MPE samples compared to BPE control samples (p < 0.0001) and the same tendency was observed relative to IPE (p = 0.004). We also noted that the methylation signal was significantly higher in IPE relative to BPE (p < 0.001). We also assessed the diagnostic efficiency of the Sentinel-MPE test by performing receiver operating characteristic analysis (ROC). For the ROC analysis we combined the malignant and indeterminate pleural effusion groups (n = 76) and compared against the benign group (n = 28). The detection sensitivity and specificity of the Sentinel-MPE test was high (AUC = 0.912). The Sentinel-MPE appears to have better performance characteristics than cytology analysis. However, combining Sentinel-MPE with cytology analysis could be an even more effective approach for the diagnosis of MPE. The Sentinel-MPE test can discriminate between BPE and MPE. The Sentinel-MPE liquid biopsy test can detect aberrant DNA in several different tumor types. The Sentinel-MPE test can be a complementary tool to cytology in the diagnosis of MPE.

Cell-Free DNA Methylation Analysis as a Marker of Malignancy in Pleural Fluid.

Background: Diagnosis of malignant pleural effusion (MPE) is made by cytological examination of pleural fluid or histological examination of pleural tissue from biopsy. Unfortunately, detection of malignancy using cytology has an overall sensitivity of 50%, and is dependent upon tumor load, volume of fluid assessed, and cytopathologist experience. The diagnostic yield of pleural fluid cytology is also compromised by low abundance of tumor cells or when morphology is obscured by inflammation or reactive mesothelial cells. A reliable molecular marker that may complement fluid cytology malignant pleural effusion diagnosis is needed. The purpose of this study was to establish a molecular diagnostic approach based on pleural effusion cell-free DNA methylation analysis for the differential diagnosis of malignant pleural effusion and benign pleural effusion. Results: This was a blind, prospective case-control biomarker study. We recruited 104 patients with pleural effusion for the study. We collected pleural fluid from patients with: MPE (n = 48), PPE (n = 28), and benign PE (n = 28), and performed the Sentinel-MPE liquid biopsy assay. The methylation level of Sentinel-MPE was markedly higher in the MPE samples compared to BPE control samples (p < 0.0001) and the same tendency was observed relative to PPE (p = 0.004). We also noted that the methylation signal was significantly higher in PPE relative to BPE (p < 0.001). We also assessed the diagnostic efficiency of the Sentinel-MPE test by performing receiver operating characteristic analysis (ROC). For the ROC analysis we combined the malignant and paramalignant groups (n = 76) and compared against the benign group (n = 28). The detection sensitivity and specificity of the Sentinel-MPE test was high (AUC = 0.912). The Sentinel-MPE appears to have better performance characteristics than cytology analysis. However, combining Sentinel-MPE with cytology analysis could be an even more effective approach for the diagnosis of MPE. Conclusions: The Sentinel-MPE test can discriminate between BPE and MPE. The Sentinel-MPE liquid biopsy test can detect aberrant DNA in several different tumor types. The Sentinel-MPE test can be a complementary tool to cytology in the diagnosis of MPE.

The Use of Bronchoscopy During the Coronavirus Disease 2019 Pandemic: CHEST/AABIP Guideline and Expert Panel Report.

BACKGROUND: The coronavirus disease 2019 (COVID-19) has swept the globe and is causing significant morbidity and mortality. Given that the virus is transmitted via droplets, open airway procedures such as bronchoscopy pose a significant risk to health-care workers (HCWs). The goal of this guideline was to examine the current evidence on the role of bronchoscopy during the COVID-19 pandemic and the optimal protection of patients and HCWs. STUDY DESIGN AND METHODS: A group of approved panelists developed key clinical questions by using the Population, Intervention, Comparator, and Outcome (PICO) format that addressed specific topics on bronchoscopy related to COVID-19 infection and transmission. MEDLINE (via PubMed) was systematically searched for relevant literature and references were screened for inclusion. Validated evaluation tools were used to assess the quality of studies and to grade the level of evidence to support each recommendation. When evidence did not exist, suggestions were developed based on consensus using the modified Delphi process. RESULTS: The systematic review and critical analysis of the literature based on six PICO questions resulted in six statements: one evidence-based graded recommendation and 5 ungraded consensus-based statements. INTERPRETATION: The evidence on the role of bronchoscopy during the COVID-19 pandemic is sparse. To maximize protection of patients and HCWs, bronchoscopy should be used sparingly in the evaluation and management of patients with suspected or confirmed COVID-19 infections. In an area where community transmission of COVID-19 infection is present, bronchoscopy should be deferred for nonurgent indications, and if necessary to perform, HCWs should wear personal protective equipment while performing the procedure even on asymptomatic patients.

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]).

Micronodular radiographic pulmonary pattern in metastatic medullary thyroid carcinoma.

Medullary carcinoma of the thyroid is a rare form of all thyroid malignancies, thereby limiting the clinical nature and the ability to optimize diagnostic tools. We present two cases of a micronodular radiographic pulmonary pattern in metastatic medullary thyroid cancer to enhance awareness of the disease process. We reviewed the literature to examine the ideal methods to establish a diagnosis.

Novel antigens in non-small cell lung cancer: SP17, AKAP4, and PTTG1 are potential immunotherapeutic targets.

Lung cancer is the leading cause of cancer deaths in both genders worldwide, with an incidence only second to prostate cancer in men and breast cancer in women. The lethality of the disease highlights the urgent need for innovative therapeutic options. Immunotherapy can afford efficient and specific targeting of tumor cells, improving efficacy and reducing the side effects of current therapies. We have previously reported the aberrant expression of cancer/testis antigens (CTAs) in tumors of unrelated histological origin. In this study we investigated the expression and immunogenicity of the CTAs, Sperm Protein 17 (SP17), A-kinase anchor protein 4 (AKAP4) and Pituitary Tumor Transforming Gene 1 (PTTG1) in human non-small cell lung cancer (NSCLC) cell lines and primary tumors. We found that SP17, AKAP4 and PTTG1 are aberrantly expressed in cancer samples, compared to normal lung cell lines and tissues. We established the immunogenicity of these CTAs by measuring CTA-specific autoantibodies in patients' sera and generating CTA-specific autologous cytotoxic lymphocytes from patients' peripheral blood mononuclear cells. Our results provide proof of principle that the CTAs SP17/AKAP4/PTTG1 are expressed in both human NSCLC cell lines and primary tumors and can elicit an immunogenic response in lung cancer patients.

Use of a hemoglobin-based oxygen carrier in the treatment of severe anemia.

BACKGROUND: Hemoglobin-based oxygen carriers hold promise for the treatment of acute anemia. CASE: We report a patient with severe dysfunctional uterine bleeding. During her hospitalization, her lowest hemoglobin level was 3.1 g/dL, with a hematocrit of 9.3%. An investigational product, o-raffinose cross-linked human hemoglobin solution (hemoglobin raffimer), was infused along with ongoing high-dose recombinant human erythropoietin and estrogen. The time until the patient's own hematopoiesis provided sufficient red blood cell mass was successfully managed by reducing oxygen demand and providing multiple hemoglobin-based oxygen carrier infusions. After hemoglobin-based oxygen carrier administration, transient pulmonary hypertension and fever were noted. She was discharged after corrective surgery 7 days after hemoglobin-based oxygen carrier administration with a hemoglobin level of 7.8 g/dL. CONCLUSION: The hemoglobin level-based oxygen carrier improved oxygen delivery and permitted uterine corrective surgery.

Selective expression and immunogenicity of the cancer/testis antigens SP17, AKAP4 and PTTG1 in non-small cell lung cancer: new candidates for active immunotherapy.

ABSTRACT BACKGROUND. Lung cancer is the leading cause of cancer deaths in both genders worldwide, with an incidence only second to prostate cancer in men and breast cancer in women. The lethality of the disease highlights the urgent need for innovative therapeutic options. Immunotherapy can afford efficient and specific targeting of tumor cells, improving efficacy and reducing the side effects of current therapies. We have previously reported the aberrant expression of cancer/testis antigens (CTAs) in tumors of unrelated histological origin. In this study we investigated the expression and immunogenicity of the cancer/testis antigens (CTAs) Sperm Protein 17 (SP17), A-kinase anchor protein 4 (AKAP4) and Pituitary Tumor Transforming Gene 1 (PTTG1) in human non-small cell lung cancer (NSCLC) cell lines and primary tumors. METHODS. We used RT-PCR, immunofluorescence, flow cytometry, ELISA and cytotoxicity assays to determine the expression levels and immunogenicity of SP17, AKAP4 and PTTG1 in human NSCLC cell lines and primary tumors. RESULTS. We found that SP17, AKAP4 and PTTG1 are aberrantly expressed in NSCLC cancer cell lines and primary tumor tissues from patients, compared to normal lung cell lines and tissues. We established the immunogenicity of these CTAs by measuring CTA-specific autoantibodies in patients' sera and generating CTA-specific autologous cytotoxic lymphocytes (CTLs) from patients' peripheral blood mononuclear cells (PBMCs). CONCLUSIONS. Our results provide proof of principle that the CTAs SP17/AKAP4/PTTG1 are expressed in both human NSCLC cell lines and primary tumors and can elicit an immunogenic response in NSCLC patients. Based on our findings, further studies are warranted to explore the feasibility of developing CTA-specific immunotherapeutic strategies for NSCLC patients.

Acute effect of sildenafil on central hemodynamics in mechanically ventilated patients with WHO group III pulmonary hypertension and right ventricular failure necessitating administration of dobutamine.

BACKGROUND/OBJECTIVES: Sildenafil decreases pulmonary vascular resistance index (PVRI), in patients with pulmonary hypertension (PH). We investigated sildenafil's effects on central hemodynamics of mechanically ventilated patients with WHO group-III PH and RV failure necessitating dobutamine administration. METHODS: Prospective non-controlled study involving 12 (9 males, 59 ± 4 years old), patients with the above characteristics. All patients in phase-1 (days 1-2) received dobutamine (5 µg/kg/min IV). During phase-2 (days 3-6), sildenafil was started via nasogastric tube (80 mg/day) and dobutamine discontinuation was attempted. Patients were designated responders or non-responders based on whether dobutamine could be stopped or not. Phase-3 lasted from day 7 to day of weaning from mechanical ventilation; or if weaning failed, until day 20 following admission (end-of-study). Invasive and echocardiographic parameters were repeatedly recorded throughout the study. RESULTS: Significantly changed parameters (P<0.025) from baseline to phase-1, -2 and -3 (%change of mean ratios), in responders (n=7) included among others PVRI (-40%, -51%, -42%), RV stroke work index (RVSWI: 43%, 79%, 41%) and cardiac index (49%, 54%, 48%), which also differed significantly from non-responders (N=5). In phases-1 and -3 non-responders had not significant changes, in phase-2 PVRI (27%) and RVSWI (-22%) changed significantly. In contrast to non-responders, all responders were weaned from mechanical ventilation until the end-of-study (P<0.025). CONCLUSIONS: Sildenafil may improve central hemodynamics and RV function indices in ventilated patients with WHO group-III PH and RV failure requiring dobutamine infusion, when they respond favorably to the latter. Accordingly, an adequate RV systolic reserve may be mandatory for sildenafil to exert its actions.

Hyperthyroidism and pulmonary hypertension: an important association.

Pulmonary hypertension is a complex disorder with multiple etiologies. The World Health Organization Group 5 (unclear multifactorial mechanisms) includes patients with thyroid disorders. The authors reviewed the literature on the association between hyperthyroidism and pulmonary hypertension and identified 20 publications reporting 164 patients with treatment outcomes. The systolic pulmonary artery (PA) pressures in these patients ranged from 28 to 78 mm Hg. They were treated with antithyroid medications, radioactive iodine and surgery. The mean pretherapy PA systolic pressure was 39 mm Hg; the mean posttreatment pressure was 30 mm Hg. Pulmonary hypertension should be considered in hyperthyroid patients with dyspnea. All patients with pulmonary hypertension should be screened for hyperthyroidism, because the treatment of hyperthyroidism can reduce PA pressures, potentially avoid the side-effects and costs with current therapies for pulmonary hypertension and limit the consequences of untreated hyperthyroidism. However, the long-term outcome in these patients is uncertain, and this issue needs more study. Changes in the pulmonary circulation and molecular regulators of vascular remodeling likely explain this association.

Prolonged acute care in a 52-year-old man with respiratory failure: lessons learned from 70-day intensive care unit hospitalization.

PURPOSE: This study was undertaken to record the experiences of a patient who survived prolonged intensive care unit (ICU) care secondary to acute respiratory failure. MATERIALS AND METHODS: The patient's medical record was summarized, and the patient was interviewed with audio recording and transcription. He completed several surveys, including the ICU memory tool, the 14-question Posttraumatic Stress Syndrome Questionnaire, the Impact of Event Scale-Revised Questionnaire, and the Hospital Anxiety and Depression Scale Questionnaire. RESULTS: The patient had little factual recall of his prolonged ICU care but had multiple delusional memories from this period. The Impact of Event Scale-Revised results indicate that this hospitalization had significant impact. However, his scores on the 14-question Posttraumatic Stress Syndrome and Hospital Anxiety and Depression Scale questionnaires indicate that his risk for posttraumatic stress disorder, anxiety, and depression is low. These outcomes were attributed, in part, to his willingness to discuss his ICU care and experiences with health care workers, family, and friends. CONCLUSIONS: Patient debriefing may improve outcomes after prolonged acute care. Current survey instruments provide a good estimate of a patient's mental status. Patients themselves can provide important information about hospital care and areas needing improvement.

Amiodarone-induced loculated pleural effusion: case report and review of the literature.

Pleural effusion is an uncommon manifestation of amiodarone toxicity and is usually associated with amiodarone-induced interstitial pneumonitis. We describe a 70-year-old woman who came to the emergency department with bilateral pleuritic chest pain and malaise 4 weeks after her amiodarone dose was increased from 200 mg/day to 600 mg/day. She had bilateral exudative pleural effusions without associated pneumonitis. She was diagnosed with amiodarone-induced pleural effusions after a thorough workup during her hospitalization excluded other causes for the effusions. Due to intractable arrhythmias, the patient's amiodarone was not discontinued, and she was discharged home. Four days later at a follow-up visit at the pulmonary clinic, the patient complained of worsening chest pain as well as dyspnea and cough. A computed tomography scan showed left-sided pleural effusion with multiple loculations. She underwent a pulmonary vein isolation procedure, and amiodarone was discontinued. She was treated with prednisone 40 mg/day, tapered over the next 2 weeks. Three weeks after the amiodarone was stopped, the patient was asymptomatic, and a chest radiograph showed complete resolution of the effusions. Review of the patient's medical records revealed that she had experienced similar symptoms and exudative pleural effusions 2 years earlier after a similar dose escalation of amiodarone; the symptoms and pleural effusions resolved after the amiodarone dosage was reduced. Use of the Naranjo adverse drug reaction probability scale indicated that the association between the pleural effusions and amiodarone was highly probable (score of 9). This case report emphasizes that amiodarone should be considered in the differential diagnosis of patients with exudative effusions after a thorough workup has excluded other causes. Amiodarone should be replaced with alternative antiarrhythmic therapy if clinically feasible, and corticosteroids may be beneficial.

Severe reversible myocardial depression in a patient with Pseudomonas aeruginosa sepsis suggesting tako-tsubo cardiomyopathy.

Acute coronary syndromes are not uncommon in medical intensive care units. Multiple molecular, pharmacologic, and hemodynamic mechanisms may contribute to the pathogenesis resulting in increased mortality in this setting. Tako-tsubo cardiomyopathy is a recently defined uncommon cardiac syndrome with characteristic features often encountered in patients with hyperadrenergic situations such as emotional stress. Although myocardial depression in sepsis can be expected in previously healthy individuals; tako-tsubo cardiomyopathy is rarely reported in septic patients. In this case report we present a 52 year-old man with sepsis secondary to Pseudomonas pneumonia who developed significant segmental wall motion abnormalities during the disease course. The patient's myocardial function recovered completely soon after the sepsis resolved. Clinical, echocardiographic, and coronary angiographic findings suggested the diagnosis of tako-tsubo cardiomyopathy in this patient.

One hundred-foot walk test for functional assessment of clinic patients.

BACKGROUND: Gait velocity measurements provide functional assessment of patients with diverse diseases and allow predictions about future adverse events. The optimal distance for patient classification is uncertain. METHODS: Participants were identified in internal medicine clinics and had to be independently ambulatory. Study investigators collected medical information, used a qualitative test to assess gait and balance (G and B score), and measured gait velocity with a timed 100-foot walk. RESULTS: One hundred eighty-four patients participated in this study. The mean age was 57.8 +/- 12.7 years; 50% of the participants were men. The mean gait speed was 3.33 +/- 0.71 ft/sec. Gait speed decreased with age and with body mass index (BMI) and increased with height and male sex. Patients with more comorbidities had decreased speed (P < 0.01). There were significant correlations between gait speed and grip strength (P < 0.01) and between lower G and B scores and slower gait speeds (P < 0.01). G and B scores were negatively correlated with age, BMI, and certain diagnoses. They also predicted risk for past falls. The mean heart rate change during the test was 8 beats per minute. Patients in the highest quartile for heart rate change had lower gait speeds than patients in the other 3 quartiles, suggesting physiologic impairment. CONCLUSIONS: A 100-foot walk test in clinic patients provides a practical functional assessment. Gait speed was slower in patients with multiple comorbidities and poor balance. Patients with increased heart rate responses during this test seem to have physiologic impairment. This test has the potential to predict adverse events and to quantitatively determine responses to therapeutic interventions but needs prospective evaluation in clinical studies.

Lung transplantation and interstitial lung disease.

PURPOSE OF REVIEW: Interstitial lung disease includes a heterogeneous group of disorders that leads to respiratory insufficiency and death in a significant number of patients. Lung transplantation is a therapeutic option in select candidates. RECENT FINDINGS: The indications, transplant procedure options, and outcomes continue to evolve. Various recipient comorbidities influence the choice of procedure in patients with interstitial lung disease. Single lung transplants are used as the procedure of choice and bilateral transplants are reserved for patients with suppurative lung disease and patients with pulmonary hypertension. Issues unique to patients with interstitial lung disease affect the morbidity, mortality and recurrence of the disease. SUMMARY: Lung transplantation is an effective therapy for respiratory failure in interstitial lung disease with survival following transplant being similar to that achieved in transplant recipients with other diseases.