Evaluation of Donor Lungs for Transplantation: The Efficacy of Screening Bronchoscopy for Detecting Donor Aspiration and Its Relationship to the Resulting Allograft Function in Corresponding Recipients.

BACKGROUND: Potential organ donors often have suffered anoxic and/or traumatic brain injury during which they may have experienced aspiration of gastric material (AGM). Evaluation of such donors typically includes a screening bronchoscopic examination during which determinations of aspiration are made. The efficacy of this visual screening and its relationship to post-transplant allograft function are unknown. METHODS: Before procurement, bronchoscopy was performed on donors in which both bronchoalveolar lavage fluid (BALF) was collected and a visual inspection made. As a marker of AGM, BALF specimens were analyzed for the presence of bile salts. Data collected on the corresponding recipients included primary graft dysfunction (PGD) score, post-transplant spirometry, acute rejection scores (ARS), and overall survival. RESULTS: Of 31 donors evaluated, bronchoscopies revealed only 2 with visual evidence of AGM, whereas BALF analysis for bile salts indicated AGM in 14. As such, screening bronchoscopy had a sensitivity of only 7.1%. Visual detection of AGM via bronchoscopy was not associated with any resulting grade of PGD (χ2 = 2.96, P = .23); however, AGM defined by detection of bile salts was associated (χ2 = 7.56, P = .02). Over the first post-transplant year, the corresponding recipients experienced a similar improvement in allograft function (χ2 = 1.63, P = .69), ARS (P = .69), and survival (P = .24). CONCLUSION: Visual inspection during a single bronchoscopic examination of lung donors underestimates the prevalence of AGM. The detection of bile salts in donor BALF is associated with early allograft dysfunction in the corresponding recipients but not with later allograft proficiency, acute rejection responses, or 1-year post-transplant survival.

The profibrotic and senescence phenotype of old lung fibroblasts is reversed or ameliorated by genetic and pharmacological manipulation of Slc7a11 expression.

Increased senescence and expression of profibrotic genes in old lung fibroblasts contribute to disrepair responses. We reported that primary lung fibroblasts from old mice have lower expression and activity of the cystine transporter Slc7a11/xCT than cells from young mice, resulting in changes in both the intracellular and extracellular redox environments. This study examines the hypothesis that low Slc7a11 expression in old lung fibroblasts promotes senescence and profibrotic gene expression. The levels of mRNA and protein of Slc7a11, senescence markers, and profibrotic genes were measured in primary fibroblasts from the lungs of old (24 mo) and young (3 mo) mice. In addition, the effects of genetic and pharmacological manipulation of Slc7a11 were investigated. We found that decreased expression of Slc7a11 in old cells was associated with elevated markers of senescence (p21, p16, p53, and ß-galactosidase) and increased expression of profibrotic genes (Tgfb1, Smad3, Acta2, Fn1, Col1a1, and Col5a1). Silencing of Slc7a11 in young cells replicated the aging phenotype, whereas overexpression of Slc7a11 in old cells decreased expression of senescence and profibrotic genes. Young cells were induced to express the senescence and profibrotic phenotype by sulfasalazine, a Slc7a11 inhibitor, whereas treatment of old cells with sulforaphane, a Slc7a11 inducer, decreased senescence without affecting profibrotic genes. Like aging cells, idiopathic pulmonary fibrosis fibroblasts show decreased Slc7a11 expression and increased profibrotic markers. In short, old lung fibroblasts manifest a profibrotic and senescence phenotype that is modulated by genetic or pharmacological manipulation of Slc7a11.

The Future of Cardiothoracic Surgical Critical Care Medicine as a Medical Science: A Call to Action.

Cardiothoracic surgical critical care medicine (CT-CCM) is a medical discipline centered on the perioperative care of diverse groups of patients. With an aging demographic and an increase in burden of chronic diseases the utilization of cardiothoracic surgical critical care units is likely to escalate in the coming decades. Given these projections, it is important to assess the state of cardiothoracic surgical intensive care, to develop goals and objectives for the future, and to identify knowledge gaps in need of scientific inquiry. This two-part review concentrates on CT-CCM as its own subspeciality of critical care and cardiothoracic surgery and provides aspirational goals for its practitioners and scientists. In part one, a list of guiding principles and a call-to-action agenda geared towards growth and promotion of CT-CCM are offered. In part two, an evaluation of selected scientific data is performed, identifying gaps in CT-CCM knowledge, and recommending direction to future scientific endeavors.

Insights into early postoperative acute kidney injury following lung transplantation.

BACKGROUND: Acute kidney injury (AKI) is a common complication after lung transplantation (LT) and is associated with higher cost and mortality. We sought to evaluate the incidence of postoperative AKI, defined as AKI within 14 days of transplant, and identify associated perioperative factors. METHODS: We conducted a single-center, retrospective review of 153 lung transplant recipients. Postoperative AKI was determined using the RIFLE (Risk, Injury, Failure, Loss, End Stage) criteria. Perioperative covariates and their association with postoperative AKI were analyzed using Cox proportional hazards. Kaplan-Meier survival curves were constructed to evaluate patient survival at 1 year and data finalization. A sub-analysis was performed evaluating factors associated with early AKI (within 48 h of transplant) and late AKI. RESULTS: Postoperative AKI occurred in 36.6% of patients with 51.8% of cases occurring within 48 h of LT. Recipient race, transplant type, cardiopulmonary support, and red blood cell administration were associated with postoperative AKI. Survival was significantly lower in patients with postoperative AKI following LT. CONCLUSIONS: Postoperative AKI within 2 weeks of lung transplant is associated with lower short- and long-term survival. Perioperative factors associated with postoperative AKI may be potential points of intervention to minimize AKI development in the future.

Thoracic transplantation during the COVID-19 pandemic.

The worldwide pandemic caused by COVID-19, resulting from the infection by betacoronarvirus SARS-CoV-2, has dramatically altered healthcare worldwide. Due to the highly contagious nature of SARS-CoV2, coupled with hospitals and intensive care units being overwhelmed, numerous transplant programs either slowed or shut down completely. While there have been isolated reports of COVID-19 in transplant recipients, no study to date has examined how COVID-19 affected actual transplant patterns and outcomes in the United States. Of particular importance is the impact of COVID-19 on mortality in waitlisted patients and transplant recipients. Using the Scientific Registry of Transplant Recipients (SRTR) dataset, we compared waitlist and transplant characteristics from 3/2019-8/2019 to 3/2020-8/2020, as well as COVID-19 associated mortality in patients with prior heart or lung transplant or those active on the waitlist. Overall, there was an initial decrease in transplant volume in April 2020; however, volumes have normalized since then, with comparable outcomes to similar calendar months in 2019. Additionally, there were no significant changes in post-transplant outcomes or waiting list mortality. Given the ongoing COVID-19 pandemic, it would be beneficial to maintain current practices for thoracic transplantation, to continue to provide this life-saving therapy to those in need.

Donor factors and risk of primary graft dysfunction and mortality post lung transplantation: A proposed conceptual framework.

Lung transplantation remains a therapeutic option in end-stage lung disease. However, despite advances in the field, early allograft function can be compromised by the development of primary graft dysfunction (PGD); this being the leading cause of morbidity and mortality immediately following the lung transplant procedure. Several recipient factors have been associated with increased risk of PGD, but less is known about donor factors. Aging, tobacco, and chronic alcohol use are donor factors implicated, but how these factors promote PGD remains unclear. Herein, we discuss the available clinical data that link these donor factors with outcomes after lung transplantation, and how they might render the recipient susceptible to PGD through a two-hit process.

Calcineurin Inhibitor-Based Maintenance Immunosuppression in Lung Transplant Recipients: Optimal Serum Levels for Managing Acute Rejection and Renal Function.

BACKGROUND: Although effective for curtailing alloimmune responses, calcineurin inhibitors (CNIs) have an adverse-effect profile that includes nephrotoxicity. In lung transplant (LTx) recipients, the optimal serum levels of the CNI tacrolimus necessary to control alloimmune responses and minimize nephrotoxicity are unknown. METHODS: This retrospective, single-center study reviewed tacrolimus whole blood trough levels (BTLs), grades of acute cellular rejection (ACR), acute rejection scores, and creatinine clearance (CrCl) obtained in LTx recipients within the first year after their transplant procedure. Comparisons were made between the first 90 days post LTx (when tacrolimus BTLs were maintained >10 µg/L) and the remainder of the post-LTX year (when BTLs were <10 µg/L). RESULTS: Despite tacrolimus mean BTLs being higher during the first 90 days post LTx compared with the remainder of the first post-LTx year (10.4 ± 0.3 µg/L vs 9.5 ± 0.3 µg/L, P < .0001) there was no association with lower grades of ACR (P = .24). The intensity of ACR (as determined by acute rejection scores) did not correlate with tacrolimus mean BTLs at any time during the first posttransplant year (P = .79). During the first 90 days post LTx there was a significant decline in CrCl and a correlation between increasing tacrolimus mean BTLs and declining CrCl (r = -0.26, P = .03); a correlation that was not observed during the remainder of the year (r = -0.09, P = .52). CONCLUSIONS: In LTx recipients, maintaining BTLs of the CNI tacrolimus >10µg/L did not result in superior control of acute rejection responses but was associated with declining renal function.

Early COVID-19 infection after lung transplantation.

COVID-19, the clinical syndrome caused by the novel coronavirus, SARS-CoV-2, continues to rapidly spread, leading to significant stressors on global healthcare infrastructure. The manifestations of COVID-19 in solid organ transplant recipients are only beginning to be understood with cases reported to date in transplant recipients on chronic immunosuppression. Herein, we report the first case of COVID-19 in a lung transplant recipient in the immediate posttransplant period, and we describe the epidemiologic challenges in identifying the source of infection in this unique situation.

Left ventricle and systemic air embolism after percutaneous lung biopsy.

BACKGROUND: Systemic arterial air embolism following a percutaneous transthoracic lung biopsy is a rare but known complication, with current literature reporting an incidence of 0.01-0.45%. A prompt diagnosis of arterial air embolism is important as complications resulting from migration of air to the systemic circulation with correspondent complications. CASE REPORT: A 60-year-old female who presented for an elective percutaneous lung biopsy of an incidentally found pulmonary nodule. The procedure was performed, following the completion of the procedure the patient experiment syncopal symptoms and was diagnosed by CT scan with Left ventricular air embolism, subsequently transferred to Intensive care unit for medical attention, she was placed on right lateral decubitus Trendelenburg for 24 hours and administer 100% oxygen via a nonrebreather mask. Repeat chest CT the following day revealed complete resolution of her intracardiac free air. CONCLUSION: Although systemic arterial air embolism remains a rare complication of percutaneous lung biopsies, recognition prevents potential mortality which can develop due to neurological and cardiac complications. Close vigilance in the intensive care unit is recommended and hyperbaric chamber when appropriate.

Management of the Potential Organ Donor in the ICU: Society of Critical Care Medicine/American College of Chest Physicians/Association of Organ Procurement Organizations Consensus Statement.

This document was developed through the collaborative efforts of the Society of Critical Care Medicine, the American College of Chest Physicians, and the Association of Organ Procurement Organizations. Under the auspices of these societies, a multidisciplinary, multi-institutional task force was convened, incorporating expertise in critical care medicine, organ donor management, and transplantation. Members of the task force were divided into 13 subcommittees, each focused on one of the following general or organ-specific areas: death determination using neurologic criteria, donation after circulatory death determination, authorization process, general contraindications to donation, hemodynamic management, endocrine dysfunction and hormone replacement therapy, pediatric donor management, cardiac donation, lung donation, liver donation, kidney donation, small bowel donation, and pancreas donation. Subcommittees were charged with generating a series of management-related questions related to their topic. For each question, subcommittees provided a summary of relevant literature and specific recommendations. The specific recommendations were approved by all members of the task force and then assembled into a complete document. Because the available literature was overwhelmingly comprised of observational studies and case series, representing low-quality evidence, a decision was made that the document would assume the form of a consensus statement rather than a formally graded guideline. The goal of this document is to provide critical care practitioners with essential information and practical recommendations related to management of the potential organ donor, based on the available literature and expert consensus.

Cigarette smoking following lung transplantation: effects on allograft function and recipient functional performance.

PURPOSE: Despite mandatory tobacco abstinence following lung transplantation (LTX), some recipients resume smoking cigarettes. The effect of smoking on allograft function, exercise performance, and symptomatology is unknown. METHODS: A retrospective review was conducted of LTX recipients who received allografts over an 8-year interval and who were subjected to sequential posttransplant pulmonary function testing (PFT), 6-minute walk (6MW) testing, and assessments of exertional dyspnea (Borg score). Using post-LTX PFT results, recipients were determined to have either bronchiolitis obliterans syndrome (BOS), a manifestation of chronic allograft rejection, or normal pulmonary function (non-BOS). With respect to post-LTX pulmonary function, 6MW distances, and Borg scores, comparisons were made between these recipient groups and those who resumed smoking. RESULTS: Of 34 LTX recipients identified, 13 maintained normal lung function (non-BOS), while 16 demonstrated a decline in their PFT values consistent with BOS. Five recipients began smoking at median postoperative day 365 and smoked 1 pack per day for a mean of 485.6 days. Smokers developed a deterioration of their PFT values that was similar to those with BOS (P = .47) and tended to be worse than those in the non-BOS group (P = .09). All smokers experienced a decline in 6MW distances similar to those with BOS and non-BOS but reported less exertional dyspnea (lower Borg scores) than those with BOS. CONCLUSION: Recipients of LTX who resume cigarette smoking demonstrate a decline in pulmonary function similar to those afflicted with chronic allograft rejection but do not experience a decrement in their functional performance or increased dyspnea.

The role of heat shock protein 27 in bronchiolitis obliterans syndrome after lung transplantation.

BACKGROUND: Heat shock proteins (Hsps) are a family of evolutionary conserved proteins classified according to their size as small and large Hsps. They have a cytoprotective role and have been shown to be immunogenic molecules. In addition, self-reactivity to Hsps has been implicated in various autoimmune diseases and in the development of alloimmunity. This study examined the relationship of large and small Hsps and anti-Hsp antibodies in lung transplant (LTx) recipients who have bronchiolitis obliterans syndrome (BOS). METHODS: Anti-Hsp27 and Hsp70 antibodies, and Hsp27, Hsp60, and Hsp70 protein expression levels were evaluated in serum and bronchoalveolar lavage samples collected from 8 LTx recipients with established BOS and 8 recipients without BOS (controls). Serum from 8 healthy individuals was examined for Hsp levels as a comparison. RESULTS: Elevated serum Hsp27 levels were observed in recipients with BOS compared with controls or healthy individuals, whereas Hsp70 and Hsp60 expression showed no difference. Anti-Hsp27 antibody levels were significantly higher in the BAL of recipients with BOS than in those without BOS. In contrast, anti-Hsp70 antibodies levels in serum or BAL showed no difference between groups. CONCLUSIONS: These results support the novel concept that Hsp27, but not the classic Hsp60 and Hsp70, may be associated with the development BOS. The expression of anti-Hsp27 antibodies found only in the BAL fluid suggests a local response occurring at the level of the alveoli and terminal airways.

The lung allocation score and survival in lung transplant candidates with chronic obstructive pulmonary disease.

The Lung Allocation Score (LAS), devised to prioritize candidates awaiting lung transplantation (LTX), is calculated using the predicted duration of survival on the wait list while also considering the recipient's likelihood of post-transplant survival. This score is generated based, in part, on the severity of the candidate's comorbid illnesses. The actual relationship between the LAS and survival is unknown. The current study was performed to evaluate the relationship between the LAS and both wait-list survival and post-transplant survival in candidates with COPD. The study was a retrospective analysis of 41 LTX candidates with chronic obstructive pulmonary disease (COPD) as well as a cohort of 17 candidates who survived to receive a graft. The study was conducted at a university hospital transplant center. Thirty-six of 41 candidates survived to transplant. The LAS of these survivors was 32.62 +/- 1.06 and was significantly lower than the score of 34.45 +/- 1.19 of the nonsurvivors (P < 0.01). The LAS also exhibited a negative association with survival to transplant (P < 0.05, beta = -1.39). A cohort of 17 LTX recipients was chosen for post-transplant analysis in which 13 survived at least 1 year. In this cohort the LAS did not exhibit significant association with 1-year post-transplant survival (P = 0.58, beta = -0.25). As might be anticipated by virtue of its calculation being based in part on the existence and severity of comorbid conditions, a lower LAS was associated with improved survival to transplantation in LTX candidates with COPD. However, the pretransplant calculation of the LAS was not associated with actual post-transplant survival.

Multidrug-resistant Acinetobacter baumannii pneumonia in lung transplant recipients.

We present 6 cases of multidrug-resistant (MDR) Acinetobacter baumannii pneumonia in lung transplant recipients. All cases were treated with imipenem and/or non-traditional antibiotics, such as tigecycline and colistimethate, and had different microbiologic and clinical outcomes. Prior treatment with broad-spectrum anti-microbial therapy was the single most likely risk factor for the development of infection due to MDR Acinetobacter baumannii. Ideal preventive and therapeutic strategies for this pathogen in lung transplant recipients require further study.

Cardiovascular consequences of pulmonary hypertension.

Pulmonary hypertension occurs when pulmonary vascular pressures are elevated. Pulmonary arterial hypertension is associated with occlusion of the pulmonary arterial tree, while pulmonary venous hypertension is seen when pulmonary vein outflow is impeded. Cardiovascular consequences are common with pulmonary hypertension, regardless of the underlying pathogenesis and whether management is complex. However, there are a number of interventions that may improve quality of life and survival of pulmonary hypertension. This article discusses current recommendations for diagnosis and management.

Activation of Tissue Remodeling Precedes Obliterative Bronchiolitis in Lung Transplant Recipients.

Obliterative bronchiolitis (OB) and Bronchiolitis Obliterans Syndrome (BOS) are frequent complications in the lung transplant recipient, and are the leading cause of mortality after transplantation. The mechanisms responsible for OB remain elusive, but inflammatory and tissue remodeling responses are implicated. We hypothesized that alterations in markers of tissue remodeling in BALF of lung transplant recipients could predict development of OB. To test this, we identified 13 lung transplant recipients who developed both BOS and histologic OB (OB group) at median post-operative day (POD) 485 (range 73-2070). Bronchoalveolar lavage fluid (BALF) was obtained at median POD 387 (range 45-2205), which preceded the onset of OB and BOS by a median of 140 days (range 60-365). As a control, BALF was also obtained from a group of 21 stable recipients without OB (non-OB group) at median POD 335 (range 270-395). BALF was examined for gelatinolytic activity, fibronectin gene transcription, and transforming growth factor-beta1 (TGF-beta1) expression. Gelatin zymography of BALF from the OB group showed increased matrix metalloproteinase-9 (MMP-9) activity over that of the non-OB group (p < 0.005). Similarly, BALF from the OB group induced greater fibronectin expression in fibroblasts compared to the non-OB group (p < 0.03). The induction of fibronectin also correlated with the amount of TGF-beta1 protein in BALF (r = 0.71) from the OB group. We conclude that activation of tissue remodeling precedes the onset of OB, and analysis of gelatinolytic and/or fibronectin-inducing activity in BALF can serve as an early, pre-clinical marker for OB.

Saprophytic fungal infections and complications involving the bronchial anastomosis following human lung transplantation.

STUDY OBJECTIVE: To demonstrate an association between saprophytic fungal infections occurring at the bronchial anastomosis (BA) and the development of additional complications arising at this site. DESIGN: Retrospective review. SETTING: University lung transplant center. MATERIALS AND METHODS: Review of all single-lung and double-lung transplant (LTX) recipients who underwent transplantation between June 1993 and December 2000. All recipients were subjected to surveillance bronchoscopy with biopsy at predetermined intervals and when clinically indicated. Bronchial wash fluid and biopsy material were examined using appropriate fungal stains and culture techniques. An infection was defined when fungal organisms were identified in tissue specimens. RESULTS: Fifteen saprophytic fungal infections involving the BA were identified in 61 LTX recipients (24.6%) who survived a minimum of 75 days post-transplantation. Infections were attributed to Aspergillus sp (n = 9), Candida sp (n = 2), Torulopsis sp (n = 1), and mixed flora (ie, Penicillium + Candida, two patients; and Aspergillus + Candida, one patient). Saprophytic fungal infections occurred by a median of postoperative day 35 (range, 13 to 159 days). Airway complications involving the BA ultimately developed in 11 of 61 recipients (18%). These complications included symptomatic bronchial stenosis (nine patients), bronchomalacia (one patient), and fatal hemorrhage (one patient). Bronchial complications arose in 7 of 15 recipients (46.7%) with saprophytic fungal infections of the BA in contrast to 4 of 46 (8.7%) without infections (p = 0.003, Fisher exact test). Also demonstrated was a positive correlation between anastomotic infections and bronchial complications (Phi coefficient = 0.43; p = 0.001), while logistic regression analysis revealed that the absence of anastomotic infections predicted the absence of such complications (p = 0.002). The risk of developing an additional complication following an anastomotic infection in patients with infections was five times that of those recipients without an infection (relative risk, 5.36; 95% confidence interval [CI], 1.82 to 15.79). The odds in favor of a bronchial complication following an infection were eight times greater than in those recipients without infection (odds ratio, 8.31; 95% CI, 1.96 to 35.16). CONCLUSIONS: Following LTX, saprophytic fungal infections of the BA are associated with serious airway complications.