Host and pathogen response to bacteriophage engineered against Mycobacterium abscessus lung infection.

Two mycobacteriophages were administered intravenously to a male with treatment-refractory Mycobacterium abscessus pulmonary infection and severe cystic fibrosis lung disease. The phages were engineered to enhance their capacity to lyse M. abscessus and were selected specifically as the most effective against the subject's bacterial isolate. In the setting of compassionate use, the evidence of phage-induced lysis was observed using molecular and metabolic assays combined with clinical assessments. M. abscessus isolates pre and post-phage treatment demonstrated genetic stability, with a general decline in diversity and no increased resistance to phage or antibiotics. The anti-phage neutralizing antibody titers to one phage increased with time but did not prevent clinical improvement throughout the course of treatment. The subject received lung transplantation on day 379, and systematic culturing of the explanted lung did not detect M. abscessus. This study describes the course and associated markers of a successful phage treatment of M. abscessus in advanced lung disease.

Addressing sex-based disparities in solid organ transplantation in the United States - a conference report.

Solid organ transplantation provides the best treatment for end-stage organ failure, but significant sex-based disparities in transplant access exist. On June 25, 2021, a virtual multidisciplinary conference was convened to address sex-based disparities in transplantation. Common themes contributing to sex-based disparities were noted across kidney, liver, heart, and lung transplantation, specifically the existence of barriers to referral and wait listing for women, the pitfalls of using serum creatinine, the issue of donor/recipient size mismatch, approaches to frailty and a higher prevalence of allosensitization among women. In addition, actionable solutions to improve access to transplantation were identified, including alterations to the current allocation system, surgical interventions on donor organs, and the incorporation of objective frailty metrics into the evaluation process. Key knowledge gaps and high-priority areas for future investigation were also discussed.

Social and biologic determinants in lung transplant allocation.

PURPOSE OF REVIEW: Lung transplant is a life-saving intervention for many with end-stage lung disease. As usable donor lungs are a limited resource and the risk of death on the waitlist is not uniform among candidates, organ allocation must consider many variables in order to be equitable. RECENT FINDINGS: The lung allocation score (LAS) system, implemented in 2005, accounted for disease severity, risk of death without transplant, and 1-year survival estimates; however, recipient size, allosensitization, and blood type, biologic features that influence donor pool for a given recipient, do not impact allocation priority. Additionally, social determinants such as geography, socioeconomic status, race, and ethnicity can impact the likelihood of receiving a transplant. This has resulted in certain groups being transplanted at lower rates and at higher risk of dying on the waitlist. In order to address these disparities, lung organ allocation in the United States transitioned to a continuous distribution system using the composite allocation score (CAS) on 9 March 2023. SUMMARY: In this article, we will review some of the data demonstrating the impact that biologic and social determinants have had on lung allocation in order to provide background as to why these have been incorporated into the CAS.

Split-Bolus, Single-Acquisition, Dual-Phase Abdominopelvic CT Angiography for the Evaluation of Lung Transplant Candidates: Image Quality and Resource Utilization.

OBJECTIVE. The purpose of this study was to assess the image quality and resource utilization of single-injection, split-bolus, dual-enhancement abdominopelvic CT angiography (hereafter referred to as dual-enhancement CTA) performed for combined vascular and solid organ assessment compared with those of single-injection, single-enhancement abdominopelvic CT angiography (hereafter referred to as single-enhancement CTA) for vascular assessment in combination with additional examinations (CT, MRI, and US) performed to assess for malignancy in lung transplant candidates. MATERIALS AND METHODS. We retrospectively reviewed 100 patients who underwent abdominopelvic CTA examinations before lung transplant. Cohort A (n = 50) underwent dual-enhancement CTA and cohort B (n = 50) underwent single-enhancement CTA. Contrast opacification of the vasculature was assessed along the abdominal aorta through the right femoral artery. Solid organ enhancement was assessed in the right lobe of the liver and the right renal cortex. Measurements of mean radiation dose, contrast exposure, and cost of the studies (in U.S. dollars) were compared. RESULTS. Mean (± SD) vascular enhancement on dual-enhancement CTA and single-enhancement CTA was 334.2 ± 26.5 HU (coefficient of variation, 8.3%) and 340.0 ± 21.6 HU (coefficient of variation, 6.5%) (p = 0.23), respectively. For dual-enhancement CTA and single-enhancement CTA, mean liver enhancement was 125.8 ± 30.5 HU and 60.4 ± 6.9 HU (p < 0.01), respectively, whereas mean renal cortical enhancement was 260.3 ± 62.2 HU and 133.4 ± 38.6 HU (p < 0.01), respectively. The mean IV contrast volume was 150 mL for dual-enhancement CTA and 75 mL for single-enhancement CTA. Cohort A underwent six additional imaging studies (one of which was a CT colonography study with an effective dose of 19.0 mSv) at a total cost of $9840 per patient. Cohort B underwent 44 additional imaging studies (mean effective dose, 12.7 ± 6.5 mSv) at a total cost of $12,846 per patient (resulting in a 30.6% reduction in cost for dual-enhancement CTA studies; p < 0.0001). CONCLUSION. Dual-enhancement abdominopelvic CTA allows combined vascular and abdominopelvic solid organ assessment with improved image quality and a lower cost compared with traditional imaging pathways.

Depression, Immunosuppressant Levels, and Clinical Outcomes in Postlung Transplant Recipients.

OBJECTIVE: Posttransplant depression has been linked to increased risk for adverse outcomes in lung transplant patients. Maintaining target serum immunosuppressant levels is also essential for optimal lung transplant clinical outcome and may be a crucial predictor of outcomes. Because depression could affect medication nonadherence, resulting in out-of-range immunosuppressant levels, we examined the relationship between posttransplant depression, immunosuppressant medication trough level variability, indexed by out-of-range values on clinical outcomes and coefficient of variability, and clinical outcomes. METHOD: A consecutive series of 236 lung transplant recipients completed the Center for Epidemiological Studies-Depression two-month posttransplant. Immunosuppressant trough levels (i.e., tacrolimus or cyclosporine) within the range of individualized immunosuppressant targets were obtained at three-, six-, nine-month follow-up clinic visits. Clinical outcomes including hospitalizations and mortality were obtained from medical records. RESULTS: Fourteen percent of patients were classified as depressed (Center for Epidemiological Studies-Depression ≥16), 144 (61%) of patients had at least 25% out-of-range immunosuppressant values, and the average coefficient of variability was 36%. Over a median of 2.6 years (interquartile range = 1.2), 32 participants died (14%) and 144 (61%) had at least one unplanned, transplant-related hospitalization. Both depression (hazard ratio = 1.45 (1.19, 1.76), p < . 01) and immunosuppressant variation (immunosuppressant out-of-range: hazard ratio = 1.41 (1.10, 1.81), p < .01) independently predicted more frequent hospitalizations and higher mortality. CONCLUSIONS: Early posttransplant depression was associated with significantly worse clinical outcomes. While immunosuppressant level variability is also related to adverse outcomes, such variability does not account for increased risk observed with depression.

Parenteral administration of oral medications in lung transplant recipients: An underrecognized problem.

Microcrystalline cellulose (MCC) is an insoluble material commonly used as a binder and filler in oral medications. Identification of pulmonary intravascular deposition of MCC in transbronchial biopsies from lung transplant (LT) recipients following parenteral injection of oral medications has only been reported once. A search of our surgical pathology electronic database was performed from January 1, 2000 to November 1, 2017 using the text "transplant transbronchial." The diagnosis field for all cases retrieved was then searched for the text "cellulose." These cases were queried for patient demographics and outcomes. Between January 1, 2000 and November 1, 2017, 1558 lung transplants were performed in 1476 individual patients at our institution; 12 were identified to have MCC in their lung tissue. Patients with MCC identified on biopsies were more likely to be transplanted for cystic fibrosis versus other indications and younger versus older. MCC identified in 2 of our cases was favored to be donor derived. Of the 12 patients, 6 (50%) are deceased. MCC within the pulmonary vasculature may be an indicator of increased complications, mortality, or shortened survival in LT recipients. Detecting intravascular MCC and distinguishing it from aspirated foreign material can be challenging. Awareness of the differential diagnosis for pulmonary foreign material is of paramount importance for the pathologist.

Initial skin cancer screening for solid organ transplant recipients in the United States: Delphi method development of expert consensus guidelines.

Skin cancer is the most common malignancy affecting solid organ transplant recipients (SOTR), and SOTR experience increased skin cancer-associated morbidity and mortality. There are no formal multidisciplinary guidelines for skin cancer screening after transplant, and current practices are widely variable. We conducted three rounds of Delphi method surveys with a panel of 84 U.S. dermatologists and transplant physicians to establish skin cancer screening recommendations for SOTR. The transplant team should risk stratify SOTR for screening, and dermatologists should perform skin cancer screening by full-body skin examination. SOTR with a history of skin cancer should continue regular follow-up with dermatology for skin cancer surveillance. High-risk transplant patients include thoracic organ recipients, SOTR age 50 and above, and male SOTR. High-risk Caucasian patients should be screened within 2 years after transplant, all Caucasian, Asian, Hispanic, and high-risk African American patients should be screened within 5 years after transplant. No consensus was reached regarding screening for low-risk African American SOTR. We propose a standardized approach to skin cancer screening in SOTR based on multidisciplinary expert consensus. These guidelines prioritize and emphasize the need for screening for SOTR at greatest risk for skin cancer.

Expectations and outcomes of prolonged mechanical ventilation.

OBJECTIVE: To compare prolonged mechanical ventilation decision-makers' expectations for long-term patient outcomes with prospectively observed outcomes and to characterize important elements of the surrogate-physician interaction surrounding prolonged mechanical ventilation provision. Prolonged mechanical ventilation provision is increasing markedly despite poor patient outcomes. Misunderstanding prognosis in the prolonged mechanical ventilation decision-making process could provide an explanation for this phenomenon. DESIGN: Prospective observational cohort study. SETTING: Academic medical center. PATIENTS: A total of 126 patients receiving prolonged mechanical ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Participants were interviewed at the time of tracheostomy placement about their expectations for 1-yr patient survival, functional status, and quality of life. These expectations were then compared with observed 1-yr outcomes measured with validated questionnaires. The 1-yr follow-up was 100%, with the exception of patient death or cognitive inability to complete interviews. At 1 yr, only 11 patients (9%) were alive and independent of major functional status limitations. Most surrogates reported high baseline expectations for 1-yr patient survival (n = 117, 93%), functional status (n = 90, 71%), and quality of life (n = 105, 83%). In contrast, fewer physicians described high expectations for survival (n = 54, 43%), functional status (n = 7, 6%), and quality of life (n = 5, 4%). Surrogate-physician pair concordance in expectations was poor (all kappa = <0.08), as was their accuracy in outcome prediction (range = 23%-44%). Just 33 surrogates (26%) reported that physicians discussed what to expect for patients' likely future survival, general health, and caregiving needs. CONCLUSIONS: One-year patient outcomes for prolonged mechanical ventilation patients were significantly worse than expected by patients' surrogates and physicians. Lack of prognostication about outcomes, discordance between surrogates and physicians about potential outcomes, and surrogates' unreasonably optimistic expectations seem to be potentially modifiable deficiencies in surrogate-physician interactions.

An interesting case of positional hypoxia: the effect of multiple synergistic pathological conditions.

This report describes an elderly patient evaluated for generalized fatigue, dyspnea, presyncopal episodes, and positional hypoxemia. Workup revealed posturally related oxygen desaturation, a patent foramen ovale (PFO), an atrial septal aneurysm, and primary adrenal insufficiency. Normal intracardiac pressures and a right-to-left PFO shunt were present only while the patient was in the upright position. Numerous etiologies of positional right-to-left shunting associated with platypnea-orthodeoxia have been described. Despite advancements in diagnostic and treatment modalities, the pathophysiology of right-to-left shunting with normal intracardiac pressure remains elusive. This report highlights the complexity of positional right-to-left shunting in hypoxemic patients with normal intracardiac pressures and multiple synergistic medical conditions.

Lung transplant referral for individuals with cystic fibrosis: Cystic Fibrosis Foundation consensus guidelines.

OBJECTIVE: Provide recommendations to the cystic fibrosis (CF) community to facilitate timely referral for lung transplantation for individuals with CF. METHODS: The CF Foundation organized a multidisciplinary committee to develop CF Lung Transplant Referral Consensus Guidelines. Three workgroups were formed: timing for transplant referral; modifiable barriers to transplant; and transition to transplant care. A focus group of lung transplant recipients with CF and spouses of CF recipients informed guideline development. RESULTS: The committee formulated 21 recommendation statements based on literature review, committee member practices, focus group insights, and in response to public comment. Critical approaches to optimizing access to lung transplant include early discussion of this treatment option, assessment for modifiable barriers to transplant, and open communication between the CF and lung transplant centers. CONCLUSIONS: These guidelines will help CF providers counsel their patients and may reduce the number of individuals with CF who die without consideration for lung transplant.

Patterns and predictors of pain following lung transplantation.

OBJECTIVE: Our objective was to examine variability in pain levels following lung transplantation, and examine individual biopsychosocial factors influencing changes in pain. METHOD: We performed a retrospective study of a cohort of 150 patients transplanted and discharged from Duke University Hospital between January 2015 and September 2016. During hospitalization and at clinic visits up to two months after discharge, subjective pain ratings were obtained using a 0-10 Numeric Rating Scale. Psychiatric diagnoses of anxiety and depression and Center for Epidemiological Studies - Depression (CES-D) scores collected after hospital discharge were examined as predictors of post-surgery pain. Medical and surgical variables were examined as covariates. RESULTS: During hospitalization, pain ratings decreased over time (p<0.001). Predictors of higher pain levels included pre-transplant history of depression (p=0.001) and anxiety (p=0.04), bilateral lung transplant (p=0.03), and lower six-minute walk distance (p=0.02). Two months after discharge, 18% of patients reported continued pain and 34% remained on opioid pain medications. Two months after discharge, more frequent post-operative complications predicted higher pain levels in a univariate analysis (p=0.02) although this relationship was attenuated after adjustment for depression. In a multivariate analysis, elevated CES-D scores (p=0.002), and greater opioid use (p=0.031) predicted higher pain levels 2-months post-discharge. CONCLUSION: We conclude that patients with psychiatric comorbidities may be at risk for greater pain, and may require additional strategies for more effective pain management.

Correlation between sinus and lung cultures in lung transplant patients with cystic fibrosis.

BACKGROUND: Lung transplantation has revolutionized the treatment of end-stage pulmonary disease due to cystic fibrosis. However, infection of the transplanted lungs can lead to serious complications, including graft failure and death. Although many of these patients have concurrent sinusitis, it is unclear whether bacteria from the sinuses can infect the allograft. METHODS: This is a single-institution retrospective study of all patients who underwent lung transplantation for cystic fibrosis from 2005 to 2015 at Duke University Hospital. Pre- and posttransplant nasal and pulmonary cultures obtained via nasal endoscopy and bronchoalveolar lavage (BAL), respectively, were analyzed. RESULTS: A total of 141 patients underwent 144 lung transplants. Sinus cultures were available for 76 patients (12 pretransplant, 42 posttransplant, 22 both pre- and posttransplant). Pretransplant BAL cultures were available for 139 patients, and posttransplant BAL cultures were available for all patients. Pseudomonas aeruginosa (PsA) and methicillin-resistant Staphylococcus aureus (MRSA) were the most common organisms cultured. There was a significant correlation between pretransplant sinus and posttransplant BAL cultures for PsA (p = 0.003), MRSA (p = 0.013), and Burkholderia cepacia (p = 0.001). CONCLUSION: There was a high correlation between pretransplant sinus cultures and posttransplant BAL cultures for PsA, MRSA, and Burkholderia sp. This suggests that the paranasal sinuses may act as a reservoir for allograft colonization in patients with cystic fibrosis. Further studies are needed to determine whether treatment of sinusitis affects allograft colonization and transplant outcomes.

Management of dofetilide overdose in a patient with known cocaine abuse.

Dofetilide, a class III antiarrhythmic agent, is prescribed for conversion to and maintenance of normal sinus rhythm in patients with persistent atrial fibrillation or atrial flutter. Most antiarrhythmics have significant toxicities such as torsade de pointes, and patients should be closely monitored while receiving antiarrhythmic therapy. However, we know of no reports concerning management of intentional overdose of dofetilide that have been published. We report the case of a 33-year-old man who was treated for ingestion of approximately 5 mg of dofetilide as a suicide attempt. In addition, he had a known history of cocaine abuse. He came to the emergency department approximately 45 minutes after the ingestion; examination revealed a QTc interval of approximately 570 msec. He was treated with activated charcoal and sorbitol by nasogastric tube and received aggressive supplementation with potassium and magnesium. The patient was monitored by telemetry for several days and responded well. Cardiac toxicity is the utmost concern when treating dofetilide overdose. The mainstay of treatment focuses on supportive care and prevention of drug absorption. Ventricular dysrhythmias or torsade de pointes should be treated according to advanced cardiac life support guidelines.

Strengthening care teams to improve adherence in cystic fibrosis: a qualitative practice assessment and quality improvement initiative.

BACKGROUND: Treatment regimens for patients with cystic fibrosis (CF) are complex, time consuming, and burdensome, and adherence to CF treatment is suboptimal. CF care teams play a critical role in supporting patients' chronic self-management skills, but there is no uniform method for assessing patients' adherence to treatment or standard interventions to help patients improve when necessary. METHODS: Between May 2015 and March 2016, care team members from 10 CF centers in the USA participated in a practice assessment and quality improvement (QI) initiative. The intervention included a baseline practice assessment survey, personalized continuing medical education (CME)-certified Webconferences with expert study faculty, targeted reinforcement of key practice points, and follow-up online survey and telephone interviews to evaluate the benefits and limitations of the intervention. RESULTS: Responses to the baseline practice assessment survey were received from 50 multidisciplinary care team members representing 10 CF centers. Primary barriers to adherence-related aspects of care in their clinics were motivating patients and caregivers to improve adherence and obtaining accurate information about adherence from patients. At the conclusion of the initiative, participants reported improvements in communication within their care team, implementation of new approaches to asking about adherence, and a renewed commitment to asking patients and caregivers about adherence at each clinic visit. CONCLUSION: Structured QI interventions that bring multidisciplinary care teams together to reflect on clinic processes and elicit objective insights from outside faculty have the potential to improve practice patterns related to the assessment and improvement of patient adherence in CF.

Lung transplantation at Duke.

Lung transplantation represents the gold-standard therapy for patients with end-stage lung disease. Utilization of this therapy continues to rise. The Lung Transplant Program at Duke University Medical Center was established in 1992, and since that time has grown to one of the highest volume centers in the world. The program to date has performed over 1,600 lung transplants. This report represents an up-to-date review of the practice and management strategies employed for safe and effective lung transplantation at our center. Specific attention is paid to the evaluation of candidacy for lung transplantation, donor selection, surgical approach, and postoperative management. These evidence-based strategies form the foundation of the clinical transplantation program at Duke.