Amikacin Liposome Inhalation Suspension for Refractory Mycobacterium avium Complex Lung Disease: Sustainability and Durability of Culture Conversion and Safety of Long-term Exposure.

BACKGROUND: In the CONVERT study, treatment with amikacin liposome inhalation suspension (ALIS) added to guideline-based therapy (GBT) met the primary end point of increased culture conversion by month 6 in patients with treatment-refractory Mycobacterium avium complex lung disease (ALIS plus GBT, 29% [65/224] vs GBT alone, 8.9% [10/112]; P < .0001). RESEARCH QUESTION: In patients who achieved culture conversion by month 6 in the CONVERT study, was conversion sustained (negative sputum culture results for 12 months with treatment) and durable (negative sputum culture results for 3 months after treatment) and were there any additional safety signals associated with a full treatment course of 12 months after conversion? STUDY DESIGN AND METHODS: Adults were randomized 2:1 to receive ALIS plus GBT or GBT alone. Patients achieving culture conversion by month 6 continued therapy for 12 months followed by off-treatment observation. RESULTS: More patients randomized to ALIS plus GBT (intention-to-treat population) achieved conversion that was both sustained and durable 3 months after treatment vs patients randomized to GBT alone (ALIS plus GBT, 16.1% [36/224] vs GBT alone, 0% [0/112]; P < .0001). Of the patients who achieved culture conversion by month 6, 55.4% of converters (36/65) in the ALIS plus GBT treated arm vs no converters (0/10) in the GBT alone arm achieved sustained and durable conversion (P = .0017). Relapse rates through 3 months after treatment were 9.2% (6/65) in the ALIS plus GBT arm and 30.0% (3/10) in the GBT alone arm. Common adverse events among ALIS plus GBT-treated patients (dysphonia, cough, dyspnea, hemoptysis) occurred mainly within the first 8 months of treatment. INTERPRETATION: In a refractory population, conversion was sustained and durable in more patients treated with ALIS plus GBT for 12 months after conversion than in those treated with GBT alone. No new safety signals were associated with 12 months of treatment after conversion. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02344004; URL: www.clinicaltrials.gov.

Amikacin Liposome Inhalation Suspension for Treatment-Refractory Lung Disease Caused by Mycobacterium avium Complex (CONVERT). A Prospective, Open-Label, Randomized Study.

Rationale: Improved therapeutic options are needed for patients with treatment-refractory nontuberculous mycobacterial lung disease caused by Mycobacterium avium complex (MAC). Objectives: To evaluate the efficacy and safety of daily amikacin liposome inhalation suspension (ALIS) added to standard guideline-based therapy (GBT) in patients with refractory MAC lung disease. Methods: Adults with amikacin-susceptible MAC lung disease and MAC-positive sputum cultures despite at least 6 months of stable GBT were randomly assigned (2:1) to receive ALIS with GBT (ALIS + GBT) or GBT alone. Once-daily ALIS was supplied in single-use vials delivering 590 mg amikacin to the nebulizer. The primary endpoint was culture conversion, defined as three consecutive monthly MAC-negative sputum cultures by Month 6. Measurements and Main Results: Enrolled patients (ALIS + GBT, n = 224; GBT-alone, n = 112) were a mean 64.7 years old and 69.3% female. Most had underlying bronchiectasis (62.5%), chronic obstructive pulmonary disease (14.3%), or both (11.9%). Culture conversion was achieved by 65 of 224 patients (29.0%) with ALIS + GBT and 10 of 112 (8.9%) with GBT alone (odds ratio, 4.22; 95% confidence interval, 2.08-8.57; P < 0.001). Patients in the ALIS + GBT arm versus GBT alone were more likely to achieve conversion (hazard ratio, 3.90; 95% confidence interval, 2.00-7.60). Respiratory adverse events (primarily dysphonia, cough, and dyspnea) were reported in 87.4% of patients receiving ALIS + GBT and 50.0% receiving GBT alone; serious treatment-emergent adverse events occurred in 20.2% and 17.9% of patients, respectively. Conclusions: Addition of ALIS to GBT for treatment-refractory MAC lung disease achieved significantly greater culture conversion by Month 6 than GBT alone, with comparable rates of serious adverse events. Clinical trial registered with www.clinicaltrials.gov (NCT02344004).

Management of nontuberculous mycobacterial pulmonary disease.

PURPOSE OF REVIEW: To highlight recent original research and specialty society guidelines regarding the diagnosis and treatment of nontuberculous mycobacterial (NTM) pulmonary disease. RECENT FINDINGS: The prevalence of NTM pulmonary disease has risen in recent years. The prevalence of individual NTM species varies geographically, although Mycobacterium avium complex (MAC) and Mycobacterium abscessus complex (MABC) remain among the most commonly encountered in many regions. Diagnosis and treatment of NTM pulmonary disease can be complex but guideline-based recommendations have been published. However, adherence to guideline recommendations is poor. Drug susceptibility testing plays a role with important caveats for treatment. Alternative therapies are being explored with older antimycobacterial drugs like clofazimine, which has demonstrated efficacy and tolerability for treatment-refractory NTM infections, and a novel formulation of amikacin for inhalation which may be better tolerated than parenteral administration. Several studies have shown that patients will have recurrences as high as 48%, and that these are not solely relapses but many cases are reinfections with a new organism. United States and European research registries of patients with non-cystic fibrosis bronchiectasis are expected to provide needed data on clinical characteristics of patients at risk for NTM pulmonary disease. SUMMARY: The evidence base for optimal management of NTM pulmonary disease is expanding but notable gaps in the literature remain.

Randomized Trial of Liposomal Amikacin for Inhalation in Nontuberculous Mycobacterial Lung Disease.

RATIONALE: Lengthy, multidrug, toxic, and low-efficacy regimens limit management of pulmonary nontuberculous mycobacterial disease. OBJECTIVES: In this phase II study, we investigated the efficacy and safety of liposomal amikacin for inhalation (LAI) in treatment-refractory pulmonary nontuberculous mycobacterial (Mycobacterium avium complex [MAC] or Mycobacterium abscessus) disease. METHODS: During the double-blind phase, patients were randomly assigned to LAI (590 mg) or placebo once daily added to their multidrug regimen for 84 days. Both groups could receive open-label LAI for 84 additional days. The primary endpoint was change from baseline to Day 84 on a semiquantitative mycobacterial growth scale. Other endpoints included sputum conversion, 6-minute-walk distance, and adverse events. MEASUREMENTS AND MAIN RESULTS: The modified intention-to-treat population included 89 (LAI = 44; placebo = 45) patients. The average age of the sample was 59 years; 88% were female; 92% were white; and 80 and 59 patients completed study drug dosing during the double-blind and open-label phases, respectively. The primary endpoint was not achieved (P = 0.072); however, a greater proportion of the LAI group demonstrated at least one negative sputum culture (14 [32%] of 44 vs. 4 [9%] of 45; P = 0.006) and improvement in 6-minute-walk test (+20.6 m vs. -25.0 m; P = 0.017) at Day 84. A treatment effect was seen predominantly in patients without cystic fibrosis with MAC and was sustained 1 year after LAI. Most adverse events were respiratory, and in some patients it led to drug discontinuation. CONCLUSIONS: Although the primary endpoint was not reached, LAI added to a multidrug regimen produced improvements in sputum conversion and 6-minute-walk distance versus placebo with limited systemic toxicity in patients with refractory MAC lung disease. Further research in this area is needed. Clinical trial registered with www.clinicaltrials.gov (NCT01315236).

Pulmonary and Critical Care In-Service Training Examination Score as a Predictor of Board Certification Examination Performance.

RATIONALE: Most trainees in combined pulmonary and critical care medicine fellowship programs complete in-service training examinations (ITEs) that test knowledge in both disciplines. Whether ITE scores predict performance on the American Board of Internal Medicine Pulmonary Disease Certification Examination and Critical Care Medicine Certification Examination is unknown. OBJECTIVES: To determine whether pulmonary and critical care medicine ITE scores predict performance on subspecialty board certification examinations independently of trainee demographics, program director competency ratings, fellowship program characteristics, and prior medical knowledge assessments. METHODS: First- and second-year fellows who were enrolled in the study between 2008 and 2012 completed a questionnaire encompassing demographics and fellowship training characteristics. These data and ITE scores were matched to fellows' subsequent scores on subspecialty certification examinations, program director ratings, and previous scores on their American Board of Internal Medicine Internal Medicine Certification Examination. Multiple linear regression and logistic regression were used to identify independent predictors of subspecialty certification examination scores and likelihood of passing the examinations, respectively. MEASUREMENTS AND MAIN RESULTS: Of eligible fellows, 82.4% enrolled in the study. The ITE score for second-year fellows was matched to their certification examination scores, which yielded 1,484 physicians for pulmonary disease and 1,331 for critical care medicine. Second-year fellows' ITE scores (ß = 0.24, P < 0.001) and Internal Medicine Certification Examination scores (ß = 0.49, P < 0.001) were the strongest predictors of Pulmonary Disease Certification Examination scores, and were the only significant predictors of passing the examination (ITE odds ratio, 1.12 [95% confidence interval, 1.07-1.16]; Internal Medicine Certification Examination odds ratio, 1.01 [95% confidence interval, 1.01-1.02]). Similar results were obtained for predicting Critical Care Medicine Certification Examination scores and for passing the examination. The predictive value of ITE scores among first-year fellows on the subspecialty certification examinations was comparable to second-year fellows' ITE scores. CONCLUSIONS: The Pulmonary and Critical Care Medicine ITE score is an independent, and stronger, predictor of subspecialty certification examination performance than fellow demographics, program director competency ratings, and fellowship characteristics. These findings support the use of the ITE to identify the learning needs of fellows as they work toward subspecialty board certification.

Adult Bronchoscopy Training: Current State and Suggestions for the Future: CHEST Expert Panel Report.

BACKGROUND: The determination of competency of trainees in programs performing bronchoscopy is quite variable. Some programs provide didactic lectures with hands-on supervision, other programs incorporate advanced simulation centers, whereas others have a checklist approach. Although no single method has been proven best, the variability alone suggests that outcomes are variable. Program directors and certifying bodies need guidance to create standards for training programs. Little well-developed literature on the topic exists. METHODS: To provide credible and trustworthy guidance, rigorous methodology has been applied to create this bronchoscopy consensus training statement. All panelists were vetted and approved by the CHEST Guidelines Oversight Committee. Each topic group drafted questions in a PICO (population, intervention, comparator, outcome) format. MEDLINE data through PubMed and the Cochrane Library were systematically searched. Manual searches also supplemented the searches. All gathered references were screened for consideration based on inclusion criteria, and all statements were designated as an Ungraded Consensus-Based Statement. RESULTS: We suggest that professional societies move from a volume-based certification system to skill acquisition and knowledge-based competency assessment for trainees. Bronchoscopy training programs should incorporate multiple tools, including simulation. We suggest that ongoing quality and process improvement systems be introduced and that certifying agencies move from a volume-based certification system to skill acquisition and knowledge-based competency assessment for trainees. We also suggest that assessment of skill maintenance and improvement in practice be evaluated regularly with ongoing quality and process improvement systems after initial skill acquisition. CONCLUSIONS: The current methods used for bronchoscopy competency in training programs are variable. We suggest that professional societies and certifying agencies move from a volume- based certification system to a standardized skill acquisition and knowledge-based competency assessment for pulmonary and thoracic surgery trainees.

Methodology for development of guidelines for lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.

BACKGROUND: The objective was to develop high-quality and comprehensive evidence-based guidelines on the diagnosis and management of lung cancer. METHODS: A carefully crafted panel of lung cancer experts, methodologists, and other specialists was assembled and reviewed for relevant conflicts of interest. The American College of Chest Physicians guideline methodology was used. Population, intervention, comparator, outcome (PICO)-based key questions and defined criteria for eligible studies were developed to inform the search strategies, subsequent evidence summaries, and recommendations. Research studies, systematic reviews, and meta-analyses, where they existed, were assessed for quality and summarized to inform the recommendations. RESULTS: Each recommendation was developed with supporting evidence and the consensus of the writing committees. Controversial recommendations were identified for further consultation by the entire panel, with anonymous voting to achieve consensus. CONCLUSIONS: The final recommendations can be trusted by health-care providers, patients, and other stakeholders since they are based on the current evidence in these areas and were developed with trustworthy processes for guideline development.

Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.

BACKGROUND: This section of the guidelines is intended to provide an evidence-based approach to the preoperative physiologic assessment of a patient being considered for surgical resection of lung cancer. METHODS: The current guidelines and medical literature applicable to this issue were identified by computerized search and were evaluated using standardized methods. Recommendations were framed using the approach described by the Guidelines Oversight Committee. RESULTS: The preoperative physiologic assessment should begin with a cardiovascular evaluation and spirometry to measure the FEV1 and the diffusing capacity for carbon monoxide (Dlco). Predicted postoperative (PPO) lung functions should be calculated. If the % PPO FEV1 and % PPO Dlco values are both > 60%, the patient is considered at low risk of anatomic lung resection, and no further tests are indicated. If either the % PPO FEV1 or % PPO Dlco are within 60% and 30% predicted, a low technology exercise test should be performed as a screening test. If performance on the low technology exercise test is satisfactory (stair climbing altitude > 22 m or shuttle walk distance > 400 m), patients are regarded as at low risk of anatomic resection. A cardiopulmonary exercise test is indicated when the PPO FEV1 or PPO Dlco (or both) are < 30% or when the performance of the stair-climbing test or the shuttle walk test is not satisfactory. A peak oxygen consumption (V˙O2 peak) < 10 mL/kg/min or 35% predicted indicates a high risk of mortality and long-term disability for major anatomic resection. Conversely, a V˙O2 peak > 20 mL/kg/min or 75% predicted indicates a low risk. CONCLUSIONS: A careful preoperative physiologic assessment is useful for identifying those patients at increased risk with standard lung cancer resection and for enabling an informed decision by the patient about the appropriate therapeutic approach to treating his or her lung cancer. This preoperative risk assessment must be placed in the context that surgery for early-stage lung cancer is the most effective currently available treatment of this disease.

Multisociety task force recommendations of competencies in Pulmonary and Critical Care Medicine.

RATIONALE: Numerous accrediting organizations are calling for competency-based medical education that would help define specific specialties and serve as a foundation for ongoing assessment throughout a practitioner's career. Pulmonary Medicine and Critical Care Medicine are two distinct subspecialties, yet many individual physicians have expertise in both because of overlapping content. Establishing specific competencies for these subspecialties identifies educational goals for trainees and guides practitioners through their lifelong learning. OBJECTIVES: To define specific competencies for graduates of fellowships in Pulmonary Medicine and Internal Medicine-based Critical Care. METHODS: A Task Force composed of representatives from key stakeholder societies convened to identify and define specific competencies for both disciplines. Beginning with a detailed list of existing competencies from diverse sources, the Task Force categorized each item into one of six core competency headings. Each individual item was reviewed by committee members individually, in group meetings, and conference calls. Nominal group methods were used for most items to retain the views and opinions of the minority perspective. Controversial items underwent additional whole group discussions with iterative modified-Delphi techniques. Consensus was ultimately determined by a simple majority vote. MEASUREMENTS AND MAIN RESULTS: The Task Force identified and defined 327 specific competencies for Internal Medicine-based Critical Care and 276 for Pulmonary Medicine, each with a designation as either: (1) relevant, but competency is not essential or (2) competency essential to the specialty. CONCLUSIONS: Specific competencies in Pulmonary and Critical Care Medicine can be identified and defined using a multisociety collaborative approach. These recommendations serve as a starting point and set the stage for future modification to facilitate maximum quality of care as the specialties evolve.

Continuing medical education effect on physician knowledge application and psychomotor skills: effectiveness of continuing medical education: American College of Chest Physicians Evidence-Based Educational Guidelines.

BACKGROUND: Recommendations for optimizing continuing medical education (CME) effectiveness in improving physician application of knowledge and psychomotor skills are needed to guide the development of processes that effect physician change and improve patient care. METHODS: The guideline panel reviewed evidence tables and a comprehensive review of the effectiveness of CME developed by The Johns Hopkins Evidence-based Practice Center for the Agency for Healthcare Research and Quality (AHRQ Evidence Report). The panel considered studies relevant to the effect of CME on physician knowledge application and psychomotor skill development. From the 136 studies identified in the systematic review, 15 articles, 12 addressing physician application of knowledge and 3 addressing psychomotor skills, were identified and reviewed. Recommendations for optimizing CME were developed using the American College of Chest Physicians guideline grading system. RESULTS: The preponderance of evidence demonstrated improvement in physician application of knowledge with CME. The quality of evidence did not allow specific recommendations regarding optimal media or educational techniques or the effectiveness of CME in improving psychomotor skills. CONCLUSIONS: CME is effective in improving physician application of knowledge. Multiple exposures and longer durations of CME are recommended to optimize educational outcomes.

Clinical correlation of asbestos bodies in BAL fluid.

BACKGROUND: Asbestos bodies (AB) in BAL cells are specific markers of asbestos exposure. METHODS: We retrospectively reviewed BAL cytocentrifuge slides of 30 utility workers with a history of asbestos exposure and 30 normal volunteers. BAL cytocentrifuge slides were blinded and scanned under 40 x light microscope. RESULTS: AB were found more frequently in subjects with a history of asbestos exposure compared to normal volunteers (10 of 30 subjects, 33%, vs 0 of 30 subjects). The mean number of AB seen in the AB-positive group was 2.7 per slide. Demographic data were comparable including age, gender, and smoking. Exposure histories were also similar: duration > 20 years, onset > 30 years ago, and time since last exposure > 7 years. More AB-positive patients reported respiratory symptoms (70% vs 26%, p < 0.05). High-resolution CT scans of AB-positive patients revealed a higher prevalence of parenchymal disease (70% vs 26%, p < 0.05). AB-positive subjects had reduced pulmonary function compared to AB-negative subjects: FVC (86% vs 97% predicted), FEV(1) (77% vs 92% predicted, p < 0.05), and diffusion capacity of the lung for carbon monoxide (76% vs 104% predicted, p < 0.01). CONCLUSION: In individuals with a history of asbestos exposure, the presence of AB in BAL cells is associated with higher prevalence of parenchymal abnormalities, respiratory symptoms, and reduced pulmonary function.

Clinical presentation of pulmonary mycetoma in HIV-infected patients.

STUDY OBJECTIVE: s: Although pulmonary mycetoma has been well-described in immunocompetent hosts, the only description in HIV-infected patients has been of 10 patients from our institution, from 1992 to 1995. To further investigate the impact of HIV status on the presentation and course of pulmonary mycetoma, we conducted a follow-up study. DESIGN: Retrospective review of all cases of pulmonary mycetoma at Bellevue Hospital from 1992 to 1999. SETTING: Patients were evaluated on the inpatient chest service and in the outpatient chest and HIV clinics of Bellevue Hospital in New York City. PATIENTS: We identified 74 patients with pulmonary mycetoma; 20 of them were HIV-infected (27%). INTERVENTIONS: The 20 HIV-infected patients were treated with antiretroviral and/or antifungal therapy. MEASUREMENTS AND RESULTS: Predisposing diseases were pulmonary tuberculosis (TB), Pneumocystis carinii pneumonia (PCP), or both TB and PCP. Seventeen patients had a CD4+ cell count of < 100 cells/ micro L at presentation. Hemoptysis was present in 13 patients, but was massive in only 1 patient. Cough was common. Of the 18 patients for whom follow-up was available, 11 received antifungal treatment and 7 were observed without therapy. Six patients received both antiretroviral and antifungal therapy. Disease progression occurred in 50%. Only five patients exhibited radiographic or clinical improvement. All five were treated with both antiretroviral and antifungal therapy. CONCLUSIONS: PCP is a risk factor for pulmonary mycetoma in the HIV-infected individual. HIV-infected patients with mycetomas have a significant rate of disease progression, although they rarely have life-threatening hemoptysis. A combination of antifungal and antiretroviral therapy may improve the clinical outcome in HIV-infected patients with pulmonary mycetoma.