Survival after lung transplantation of cystic fibrosis patients infected with Burkholderia dolosa (genomovar VI).

Cystic fibrosis (CF) with severe lung disease is a well-recognized indication for lung transplantation. Colonization with various organisms in CF patients may impact post-transplant morbidity and mortality. Burkholderia cepacia complex (BCC) is made up of distinct genomovars with significant morbidity and mortality associated with B. cenocepacia (genomovar III) following lung transplant. The outcomes of patients infected with genomovar B. dolosa (genomovar VI) have yet to be described in the literature. We performed a retrospective chart review of all cystic fibrosis patients colonized with B. dolosa from our center who underwent lung transplantation (n = 11) at various medical centers across the US between 2000 and 2014. Survival rates were 73%, 53%, and 30% for 1, 3, and 5 years, respectively. Median survival was 44 months (95% CI = 11.1-76.8). CF patients with B. dolosa that have undergone lung transplantation have decreased one-year survival when compared to all patients transplanted with cystic fibrosis. Conditional 5-year survival for B. dolosa-infected patients was 43% in patients that survived the first year post-transplant, suggesting that this first year is crucial in managing the infection. Importantly, the survival of the B. dolosa patients was higher than compared to previously reported survival rates of B. cenocepacia patients post-transplant.

Cyclic AMP-regulated exocytosis of Escherichia coli from infected bladder epithelial cells.

The superficial bladder epithelium is a powerful barrier to urine and also serves as a regulator of bladder volume, which is achieved by apical exocytosis of specialized fusiform vesicles during distension of the bladder. We report that type 1 fimbriated uropathogenic Escherichia coli (UPEC) circumvents the bladder barrier by harboring in these Rab27b/CD63-positive and cAMP-regulatable fusiform vesicles within bladder epithelial cells (BECs). Incorporation of UPEC into BEC fusiform compartments enabled bacteria to escape elimination during voiding and to re-emerge in the urine as the bladder distended. Notably, treatment of UPEC-infected mice with a drug that increases intracellular cAMP and induces exocytosis of fusiform vesicles reduced the number of intracellular E. coli.

An official American Thoracic Society/International Society for Heart and Lung Transplantation/Society of Critical Care Medicine/Association of Organ and Procurement Organizations/United Network of Organ Sharing Statement: ethical and policy considerations in organ donation after circulatory determination of death.

RATIONALE: Donation after circulatory determination of death (DCDD) has the potential to increase the number of organs available for transplantation. Because consent and management of potential donors must occur before death, DCDD raises unique ethical and policy issues. OBJECTIVES: To develop an ethics and health policy statement on adult and pediatric DCDD relevant to critical care and transplantation stakeholders. METHODS: A multidisciplinary panel of stakeholders was convened to develop an ethics and health policy statement. The panel consisted of representatives from the American Thoracic Society, Society of Critical Care Medicine, International Society for Heart and Lung Transplantation, Association of Organ Procurement Organizations, and the United Network of Organ Sharing. The panel reviewed the literature, discussed important ethics and health policy considerations, and developed a guiding framework for decision making by stakeholders. RESULTS: A framework to guide ethics and health policy statement was established, which addressed the consent process, pre- and post mortem interventions, the determination of death, provisions of end-of-life care, and pediatric DCDD. CONCLUSIONS: The information presented in this Statement is based on the current evidence, experience, and clinical rationale. New clinical research and the development and dissemination of new technologies will eventually necessitate an update of this Statement.

Active rehabilitation and physical therapy during extracorporeal membrane oxygenation while awaiting lung transplantation: a practical approach.

OBJECTIVE: Extracorporeal membrane oxygenation as a bridge to lung transplantation has traditionally been associated with substantial morbidity and mortality. A major contributor to these complications may be weakness and overall deconditioning secondary to pretransplant critical illness and immobility. In an attempt to address this issue, we developed a collaborative program to allow for active rehabilitation and physical therapy for patients requiring life support with extracorporeal membrane oxygenation before lung transplantation. DESIGN: An interdisciplinary team responded to an acute need to develop a mechanism for active rehabilitation and physical therapy for patients awaiting lung transplantation while being managed with extracorporeal membrane oxygenation. We describe a series of three patients who benefited from this new approach. SETTING: A quaternary care pediatric intensive care unit in a children's hospital set within an 800-bed university academic hospital with an active lung transplantation program for adolescent and adult patients. PATIENTS, INTERVENTIONS, AND MAIN RESULTS: Three patients (ages 16, 20, and 24 yrs) with end-stage respiratory failure were rehabilitated while on extracorporeal membrane oxygenation awaiting lung transplantation. These patients were involved in active rehabilitation and physical therapy and, ultimately, were ambulatory on extracorporeal membrane oxygenation before successful transplantation. Following lung transplantation, the patients were liberated from mechanical ventilation, weaned to room air, transitioned out of the intensive care unit, and ambulatory less than 1 wk posttransplant. CONCLUSIONS: A comprehensive, multidisciplinary system can be developed to safely allow for active rehabilitation, physical therapy, and ambulation of patients being managed with extracorporeal membrane oxygenation. Such programs may lead to a decreased threshold for the utilization of extracorporeal membrane oxygenation before transplant and have the potential to improve conditioning, decrease resource utilization, and lead to better outcomes in patients who require extracorporeal membrane oxygenation before lung transplantation.

Update on infectious complications following lung transplantation.

PURPOSE OF REVIEW: Lung transplantation is an important therapeutic treatment for many patients with life-threatening pulmonary diseases; however, long-term survival is still relatively limited compared with other solid organ transplants. Over the last year, several articles have been published helping to increase our knowledge of infections in lung transplant recipients. In particular, important new information has been published recently regarding cytomegalovirus (CMV) and fungal infections following lung transplantation. RECENT FINDINGS: Recent studies indicate prolonged (≥12 months) antiviral prophylaxis for CMV after lung transplant may be beneficial in high-risk transplant recipients. Epidemiologic studies show invasive fungal infections are increasingly being recognized following solid organ transplantation, particularly with Aspergillus and Candida species. Pulmonary infections with CMV and Aspergillus are likely contributors to the development of bronchiolitis obliterans syndrome (BOS). SUMMARY: Lung transplantation has many potential posttransplant complications with infection being a major contributor. More information has become available regarding CMV prophylaxis, CMV treatment, pulmonary fungal infection epidemiology, and the role of both CMV and Aspergillus on the development of BOS, which helps toward the goal of increasing long-term survival in lung transplant recipients.

Survival after bronchiolitis obliterans syndrome among bilateral lung transplant recipients.

RATIONALE: Despite the importance of bronchiolitis obliterans syndrome (BOS) in lung transplantation, little is known regarding the factors that influence survival after the onset of this condition, particularly among bilateral transplant recipients. OBJECTIVES: To identify factors that influence survival after the onset of BOS among bilateral lung transplant recipients. METHODS: The effect of demographic or clinical factors, occurring before BOS, upon survival after the onset of BOS was studied in 95 bilateral lung transplant recipient using Cox proportional hazards models. MEASUREMENTS AND MAIN RESULTS: Although many factors, including prior acute rejection or rejection treatments, were not associated with survival after BOS, BOS onset within 2 years of transplantation (early-onset BOS), or BOS onset grade of 2 or 3 (high-grade onset) were predictive of significantly worse survival (early onset P = 0.04; hazard ratio, 1.84; 95% confidence interval, 1.03-3.29; high-grade onset P = 0.003; hazard ratio, 2.40; 95% confidence interval, 1.34-4.32). The effects of both early onset and high-grade onset on survival persisted in multivariable analysis and after adjustment for concurrent treatments. Results suggested an interaction might exist between early onset and high-grade onset. In particular, high-grade onset of BOS, regardless of its timing after transplant, is associated with a very poor prognosis. CONCLUSIONS: The course of BOS after bilateral lung transplantation is variable. Distinct patterns of survival after BOS are evident and related to timing or severity of onset. Further characterization of these subgroups should provide a more rational basis from which to design, stratify, and assess response in future BOS treatment trials.

Complex bacterial infections pre- and posttransplant.

Infections complications following lung transplantation are associated with significant morbidity and mortality. Management of infections is most challenging in patients with cystic fibrosis (CF), but all lung transplant recipients are at heightened risk for opportunistic infections. Particularly in CF, pretransplant infections with PSEUDOMONAS AERUGINOSA, other highly resistant bacteria (e.g., STENOTROPHOMONAS, BURKHOLDERIA), and mycobacteria play a major role in recipient selection and post-lung transplant outcomes. Understanding the clinical impact and management strategies for each of these different pathogens is critical to maximizing the benefit of lung transplantation. In the review, we discuss each of these infections both as pretransplant risk factors as well as posttransplant pathogens and the individual issues that arise with each infection.

Update on medical complications involving the lungs.

PURPOSE OF REVIEW: Lung transplant is now an accepted treatment for end-stage lung disease with improving survival and an increasing number of transplants being performed every year. Recognition of the common medical complications after lung transplant is important for timely diagnosis and treatment. This review will highlight the clinical presentation, diagnosis, and treatment of several noninfectious pulmonary complications that are encountered in lung transplant recipients. RECENT FINDINGS: The review focuses on several broad areas of medical complications after lung transplant, including native lung complications, malignancies, venous thromboembolism, drug toxicity, and pleural disease. Each of these problems is a significant cause of morbidity and mortality after lung transplant. We review the recent publications in these areas that have identified improved ways to diagnose and treat these complications. SUMMARY: Despite its relatively short history, the field of lung transplantation has made significant progress over the past 25 years. The medical advances surrounding lung transplant are not only related to the surgical procedure and immunosuppression, but also to the ability of physicians to diagnose and treat the common complications after transplant. Improvements in the diagnosis and management of these posttransplant medical complications will hopefully lead to even greater survival after lung transplantation in the future.

An unusual case of cardiac amyloidosis.

Cardiac amyloidosis can result from any of the systemic amyloidoses. The disease is often characterized by a restrictive cardiomyopathy although the particular signs and symptoms depend in part on the underlying cause. In addition to managing the symptoms of heart failure, treatment options vary depending on the etiology of amyloid deposition. It is therefore critical to identify the cause of cardiac amyloidosis before initiating definitive therapy. We present a patient with presumed immunoglobulin (AL) amyloidosis who had a circulating lambda monoclonal protein, but a bone marrow biopsy with kappa predominant plasma cells. This unusual finding called into question the diagnosis of AL amyloidosis and highlights the importance and difficulty of determining the cause of cardiac amyloid deposition before initiating treatment. We review the different forms of cardiac amyloidosis and propose a diagnostic algorithm to help identify the etiology of cardiac amyloid deposition before beginning therapy.

The role of lipid rafts in the pathogenesis of bacterial infections.

Numerous pathogens have evolved mechanisms of co-opting normal host endocytic machinery as a means of invading host cells. While numerous pathogens have been known to enter cells via traditional clathrin-coated pit endocytosis, a growing number of viral and bacterial pathogens have been recognized to invade host cells via clustered lipid rafts. This review focuses on several bacterial pathogens that have evolved several different mechanisms of co-opting clustered lipid rafts to invade host cells. Although these bacteria have diverse clinical presentations and many differences in their pathogenesis, they each depend on the integrity of clustered lipid rafts for their intracellular survival. Bacterial invasion via clustered lipid rafts has been recognized as an important virulence factor for a growing number of bacterial pathogens in their battle against host defenses.

Economic Outcomes of Extracorporeal Membrane Oxygenation With and Without Ambulation as a Bridge to Lung Transplantation.

BACKGROUND: An increasing number of centers are using active rehabilitation and ambulation for critically ill patients on extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation. This investigation assessed the economic impact at a single center of ambulatory versus non-ambulatory ECMO strategies as a bridge to lung transplantation. METHODS: We conducted a single-center retrospective cohort analysis of all subjects supported with ECMO as a bridge to lung transplantation (N = 9) from 2007 to 2012. Subjects who were rehabilitated while supported with ECMO before lung transplantation were compared with those who were not rehabilitated during ECMO. Hospital cost data for the month before transplantation through 12 months after the initial post-transplant hospital discharge were compared. RESULTS: The median cost (interquartile range [IQR]) in the 30 d before transplant for the ambulatory cohort was $88,137 (IQR $38,589-$122,111) compared with $52,124 (IQR $23,824-$69,929) for the non-ambulatory cohort (P = .08). The median post-transplant ICU cost for the ambulatory cohort was $38,468 (IQR $23,611-$64,126) compared with $143,407 (IQR $112,199-$168,993) for the non-ambulatory cohort (P = .01). The median total hospital cost for subjects supported with ambulatory ECMO was $213,086 (IQR $166,767-$264,536) compared with $273,291 (IQR $237,299-$374,175) for non-ambulatory ECMO subjects (P = .05). The median total cost for the ambulatory cohort was $268,194 (IQR $219,972-$517,320) compared with $300,307 (IQR $274,262-$394,913) for the non-ambulatory cohort (P = .14). CONCLUSIONS: Subjects supported with ambulatory ECMO had a 22% ($60,204) reduction in total hospital cost, 73% ($104,939) reduction in post-transplant ICU cost, and 11% ($32,133) reduction in total cost compared with non-ambulatory ECMO subjects. This analysis demonstrates the potential economic benefit of rehabilitation and ambulation during ECMO compared with a traditional strategy.

Bacterial penetration of the mucosal barrier by targeting lipid rafts.

Several traditionally extracellular pathogens not known to possess invasive capacity have been shown to invade various mucosal epithelial cells. The mucosal epithelium performs an important barrier function and is not typically amenable to bacterial invasion. Valuable clues to the underlying basis for bacterial invasion have emerged from recent studies examining the invasion of bladder epithelial cells by uropathogenic Escherichia coli and alveolar epithelial cells by Pseudomonas aeruginosa. In both cases, bacterial invasion is achieved through targeting of molecules specifically found within distinct glycosphingolipid- and cholesterol-enriched microdomains called lipid rafts. The importance of lipid rafts in promoting bacterial invasion was shown as disruptors of lipid rafts blocked cellular invasion by both E. coli and P. aeruginosa. In addition, molecular components of lipid rafts were found to be highly enriched in membranes encasing these intracellular bacteria. Furthermore, caveolin proteins, which serve to stabilize and organize lipid raft components, are necessary for bacterial entry. Taken together, targeting of lipid rafts appears to be an effective but poorly recognized mechanism used by pathogenic bacteria to circumvent the mucosal barriers of the host.

Candidacy for lung transplant and lung allocation.

This article provides a summary of the changes in lung transplantation after implementation of the Lung Allocation Score in 2005. Specific issues that are addressed include impact of diagnosis group, age, critical illness, and geographic disparities in transplant.

Ambulatory extracorporeal membrane oxygenation as a bridge to lung transplantation: walking while waiting.

The proportion of critically ill patients awaiting lung transplantation has increased since the implementation of the Lung Allocation Score (LAS) in 2005. Critically ill patients comprise a sizable proportion of wait-list mortality and are known to experience increased posttransplant complications. These critically ill patients have been successfully bridged to lung transplantation with extracorporeal membrane oxygenation (ECMO), but historically these patients have required excessive sedation, been immobile, and have had difficult functional recovery in the posttransplant period and high mortality. One solution to the deconditioning often seen in critically ill patients is the implementation of rehabilitation and ambulation while awaiting transplantation on ECMO. Ambulatory ECMO programs of this nature have been developed in an attempt to provide rehabilitation, physical therapy, and minimization of sedation prior to lung transplantation to improve both surgical and posttransplant outcomes. Favorable outcomes have been reported using this novel approach, but how and where this strategy should be implemented remain unclear. In this commentary, we review the currently available literature for ambulation and rehabilitation during ECMO support as a bridge to lung transplantation, discuss future directions for this technology, and address the important issues of resource allocation and regionalization of care as they relate to ambulatory ECMO.

Cases from the Osler Medical Service at Johns Hopkins University. Scedosporium apiospermum mycetoma of the lung.

PRESENTING FEATURES: A 42-year-old man was admitted with a chief complaint of cough and night sweats of 2 months' duration. The cough produced brown sputum but no blood. He also reported drenching sweats every night for the last several weeks before admission. He attributed his cough to exposure to dust while working on demolishing a funeral home 2 months ago; he denied any history of respiratory symptoms before this recent job. The patient smoked less than one pack of cigarettes per week during the previous year. He had no history of tuberculosis or contact with infected persons. He denied a history of severe lung infection, asthma, sinus disease, or overseas travel, as well as behaviors that are risk factors for human immunodeficiency virus (HIV) infection, such as intravenous drug use or multiple sexual partners.His physical examination was notable for a temperature of 101.4 degrees F and an oxygen saturation of 98% on room air. In general, he was thin, although well in appearance, and not visibly short of breath. His lungs were clear to auscultation. Laboratory studies and urinalysis were normal.A chest radiograph showed a 3-cm by 2-cm mass with a surrounding cavity in the right upper lobe (Figure 1). A subsequent chest computed tomographic scan showed a 5-cm by 4-cm cavity in the right upper lobe, with surrounding infiltrates as well as a mass within the cavity suspicious for a fungus ball (Figure 2). Patchy infiltrates were also seen in the left and right lower lobes. What is the diagnosis?

Cases from the Osler Medical Service at Johns Hopkins University. Antiglomerular basement membrane disease.

A 47-year-old Taiwanese man with no notable medical history was admitted with low-grade fevers and night sweats that had persisted for 5 to 6 weeks. An extensive investigation at another hospital could not determine the cause of the fevers, but documented acute renal failure with a blood urea nitrogen level of 60 mg/dL and a serum creatinine level of 5.6 mg/dL. He was admitted to the Johns Hopkins Hospital for further evaluation.The patient, who had been living in the United States for the past 20 years, reported no recent travel and no behaviors that are associated with transmission of human immunodeficiency virus. He was not taking any medications, and he denied using herbal or nutritional supplements. He had no recent weight loss. There were no specific complaints on review of systems. On physical examination, he was a thin, middle-aged man in no distress. Vital signs included a temperature of 37.5 degrees C, a blood pressure of 166/86 mm Hg, a pulse of 70 beats per minute, a respiratory rate of 16 breaths per minute, and 99% oxygen saturation on room air. Sclera were anicteric, and he had no palpable adenopathy. His lungs were clear, and his heart rate was regular without extra sounds. His abdomen was thin, nontender, and without masses or organomegaly. There was no edema or signs of embolism in the extremities. Laboratory studies revealed a white blood cell count of 14,200/mL(3), a hematocrit of 23.1%, and a platelet count of 456,000/mL(3). Blood chemistries were notable for a blood urea nitrogen level of 61 mg/dL and a serum creatinine level of 7.6 mg/dL. Levels of aminotransferases, total bilirubin, and alkaline phosphatase were within normal limits. Urinalysis revealed large hemoglobin, 1+ protein, numerous red blood cells, and 3 to 5 white blood cells. Numerous red blood cell casts were seen on microscopic examination of the urine sediment. The patient's erythrocyte sedimentation rate was >130 mm/h, and his C-reactive protein level was elevated at 12.6 mg/dL. Serologies were negative for antinuclear antibodies and antineutrophil cytoplasmic antibodies; serum complement levels were normal. What is the diagnosis?

Airway obstruction is common but unsuspected in patients admitted to a general medicine service.

STUDY OBJECTIVES: Obstructive lung disease (OLD) is a worldwide health problem with major impact on health and economics, and can be easily diagnosed by spirometry. Recent expert panels have emphasized the underreporting and underrecognition of this condition. The goal of this study was to measure the prevalence of airway obstruction in patients admitted to an urban teaching hospital and to determine the frequency of a diagnosis of OLD at admission or discharge. METHODS: Prospective study of 153 patients admitted to a medicine service at the Johns Hopkins Hospital in Baltimore, MD. Patients completed bedside spirometry and a questionnaire. RESULTS: Twenty-six percent of patients had airway obstruction (FEV(1)/FVC < 70%), including 6% with a very severe airway obstruction (FEV(1) < 30% predicted). At hospital discharge, a clinical diagnosis of OLD was present in only 33% of patients with mild airway obstruction (FEV(1) > 70% predicted), 30% of patients with moderate airway obstruction (FEV(1) 50 to 69% predicted), 33% of patients with severe airway obstruction (FEV(1) 30 to 49% predicted), and 89% of patients with very severe airway obstruction (FEV(1) < 30% predicted). Only 40% of patients with airway obstruction were receiving bronchodilator medication at hospital admission or discharge. CONCLUSIONS: Airway obstruction is common in hospitalized patients and is usually undiagnosed and untreated. Spirometry may be a useful component of the examination of hospitalized medical patients to identify OLD.

An uncommon mimic of an acute asthma exacerbation.

Foreign body aspiration in adults has a variety of clinical presentations and often goes unrecognized. We describe the case of a patient who experienced crack cocaine aspiration and presented with symptoms of an acute asthma exacerbation requiring mechanical ventilation until the eventual diagnosis and bronchoscopic removal of the foreign body.