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Background: Allografts from donation after circulatory death (DCD) or brain death donors may be evaluated by ex vivo lung perfusion (EVLP) to assess quality for transplantation. We sought to determine the association of donor type with transplantation outcomes at a national level., Methods: The United Network for Organ Sharing database was queried for lung transplant recipients, who were stratified into DCD EVLP, brain death EVLP, standard DCD, and standard brain death, followed by an unadjusted analysis. A 1:1 propensity score match based on donor and recipient characteristics was used to compare DCD vs DCD EVLP, brain death vs brain death EVLP, and brain death vs DCD EVLP. The cohorts were assessed with comparative statistics. Finally, static EVLP and portable EVLP were compared to determine independent association with increased death., Results: The unadjusted DCD EVLP group had significantly higher incidence of postoperative morbidity and mortality. The 3-year survival was significantly lower in the DCD EVLP group, 65.3% (P = .026). After matching, the EVLP groups had significantly higher morbidity and in-hospital mortality (DCD EVLP vs brain death), but midterm survival was no longer significantly different. However, the DCD EVLP group had about ∼6% lower survival than the DCD group (P = .05) and about ∼7% lower survival than the brain death group (P = .12). Within the EVLP groups, static EVLP and portable EVLP were not independently associated with increased death., Conclusions: Expansion of DCD EVLP allografts increases organ access, although providers should be aware of potential increases in complications and death compared with DCD alone., Competing Interests: Disclosures Asvin M. Ganapathi reports a relationship with AbbVie Inc that includes: consulting or advisory. Nahush A. Mokadam reports a relationship with Abbott Laboratories that includes: consulting or advisory; with Medtronic Inc that includes: consulting or advisory; with Carmat that includes: consulting or advisory; with XyloCor Therapeutics Inc that includes: consulting or advisory; and with SynCardia Systems LLC that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: Primary graft dysfunction (PGD) has detrimental effects on recipients following lung transplantation. Here, we determined the contemporary trends of PGD in a national database, factors associated with the development of PGD grade 3 (PGD3) and ex vivo lung perfusion's (EVLP) effect on this harmful postoperative complication. Methods: The United Network for Organ Sharing database was queried from 2015 to 2023, and recipients were stratified into No-PGD, PGD1/2, or PGD3. The groups were analyzed with comparative statistics, and survival was determined with Kaplan-Meier methods. Multivariable Cox regression was used to determine factors associated with increased mortality. PGD3 recipients were then stratified based on EVLP use prior to transplantation, and a 3:1 propensity match was performed to determine outcomes following transplantation. Finally, logistic regression models based on select criteria were used to determine risk factors associated with the development of PGD3 and mortality within 1 year. Results: A total of 21.4% of patients were identified as having PGD3 following lung transplant. Those with PGD3 suffered significantly worse perioperative morbidity, mortality, and had worse long-term survival. PGD3 was also independently associated with increased mortality. Matched EVLP PGD3 recipients had significantly higher use of ECMO postoperatively; however, they did not suffer other significant morbidity or mortality as compared to PGD3 recipients without EVLP use. Importantly, EVLP use prior to transplantation was significantly associated with decreased likelihood of PGD3 development, while having no significant association with early mortality. Conclusions: EVLP is associated with decreased PGD3 development, and further optimization of this technology is necessary to expand the donor pool.

Introduction: Early extubation has been adopted in many settings within cardiothoracic surgery, with several advantages for patients. We sought to determine the association of timing of extubation in lung transplant recipients' short- and long-term outcomes., Methods: Adult, primary lung transplants were identified from the United Network for Organ Sharing database. Recipients were stratified based on the duration of postoperative ventilation: 1) None (NV); 2) <5 Days (<5D); and 3) 5+ Days (5+D). Comparative statistics were performed, and both unadjusted and adjusted survival were analyzed with Kaplan-Meier Methods and a Cox proportional hazard model. A multivariable model including recipient, donor, and transplant characteristics was created to examine factors associated with NV., Results: 28,575 recipients were identified (NV = 960, <5D = 21,959, 5+D = 5656). The NV group had shorter median length of stay (P < 0.01) and lower incidence of postoperative dialysis (P < 0.01). The NV and <5D groups had similar survival, while 5+D recipients had decreased survival (P < 0.01). The multivariable model demonstrated increased donor BMI, center volume, ischemic time, single lung transplant, and transplantation between 2011 and 2015 were associated with NV (P < 0.01 for all). Use of donation after cardiac death donors and transplantation between 2016 and 2021 was associated with postoperative ventilator use., Conclusions: Patients extubated early after lung transplantation have a shorter median length of stay without an associated increase in mortality. While not all patients are appropriate for earlier extubation, it is possible to extubate patients early following lung transplant. Further efforts are necessary to help expand this practice and ensure its' success for recipients., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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 (χ 2  = 2.96, P = .23); however, AGM defined by detection of bile salts was associated (χ 2  = 7.56, P = .02). Over the first post-transplant year, the corresponding recipients experienced a similar improvement in allograft function (χ 2  = 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., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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.

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., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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 β-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.

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., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Gastroesophageal reflux (GER) in recipients of lung transplant (LTX) is associated with chronic allograft rejection, presumably via microaspiration that damages airway epithelium. Most LTX programs perform a single post-LTX esophageal study to evaluate for GER; the efficacy of this test is unclear., Methods: Patients with 1 year of post-LTX follow-up, including routine bronchoscopies with bronchoalveolar lavage fluid (BALF) samples as well as high-resolution esophageal manometry and pH probe monitoring (HREMpH), were evaluated. BALF samples were analyzed with competitive enzyme-linked immunosorbent assay to detect bile salts, which are indicative of aspiration. These results were compared to results of HREMpH studies post LTX., Results: Ninety BALF samples were analyzed for bile salts and acted as disease positive for this evaluation. Of the 13 HREMpH cases, 8 were positive for GER, but only 3 were positive for bile salts via assay. Of the 5 HREMpH-negative cases, 2 experienced aspiration. A solitary HREMpH study had 60.0% sensitivity and 37.5% specificity with positive and negative likelihood ratios: 0.96 and 1.07, respectively., Conclusion: Microaspiration appears to be an intermittent phenomenon, and HREMpH screening poorly correlates with BALF evidence of aspiration; which may not be adequate. As aspiration detection is crucial in this population, further analysis is warranted., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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.

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.

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.

Lung transplantation (LTX) requires continual systemic immunosuppression, which can result in infections that may compromise recipient survival. A recent outbreak of Acinetobacter baumannii at our institution resulted in infections experienced in both LTX recipients and nontransplant patients. A retrospective review was conducted of patients who had A. baumannii recovered from blood, other normally sterile body fluids, and/or respiratory secretions and who had clinical follow-up extending to 1 year postinfection. A. baumannii was considered "multidrug-resistant" when its growth was not inhibited by minimum inhibitory concentrations of multiple antibiotics. Despite the resistance profile, patients were treated with a combination of antibiotics, which included tigecycline, colistimethate, and when susceptible, imipenem. Once infection was diagnosed, immunosuppression was reduced in all LTX recipients. Six LTX recipients became infected with A. baumannii and were contrasted to infections identified in 14 non-LTX, nonimmunosuppressed patients. A. baumannii was persistently recovered in 4 of 6 LTX recipients (66.7%) compared with only 1 of 14 (7.1%) non-LTX patients (χ(2) = 9.9, p = 0.005). LTX recipients received antibiotic therapy for an average of 76 ± 18.4 days compared with 16.0 ± 6.8 days for the non-LTX patients (p = 0.025, Mann-Whitney U test). All 4 of the 6 (66.7%) LTX recipients died as a consequence of their infection compared with 1 of 14 (7.1%) of the non-LTX patients (χ(2) = 9.9, p = 0.005). Despite receiving more antibiotic therapy, LTX recipients who were infected with multidrug-resistant A. baumannii were less likely to clear their infection and experienced greater mortality compared with non-LTX patients.

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 (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.

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.

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.

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.

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.

Neutrophils are sequestered in the newly transplanted lung after reperfusion or with infection, rejection, and chronic graft dysfunction. Because unopposed (free) neutrophil elastase (NE) released into bronchoalveolar secretions may injure the lung allograft and impair bacterial clearance, we assessed total neutrophil numbers, myeloperoxidase activity as an index of neutrophil influx and degranulation, alpha1-antiprotease (alpha1-AP) concentrations, and unopposed NE activity in bronchoalveolar secretions from lung transplant recipients. Unopposed NE activity was present in bronchoalveolar lavage fluid (BALF) from recipients transplanted for emphysema associated with alpha1-AP deficiency as well as recipients without such deficiency (171 of 2,137 BALF; 8%). Ten of 17 (59%) recipients with alpha1-AP deficiency who were followed for at least 1 yr after transplant with multiple surveillance and diagnostic bronchoscopies had at least one BALF containing unopposed NE, usually associated with the presence of > or = 10(5) colony forming units/ml BALF of aerobic bacteria. In contrast, 19 of 58 (33%) with emphysema not associated with alpha1-AP deficiency, 8 of 32 (25%) recipients with cystic fibrosis (CF), 6 of 16 (38%) with idiopathic pulmonary fibrosis (IPF), and 11 of 36 (31%) with other indications for transplant had unopposed NE in BALF. alpha1-AP levels were significantly elevated in the early posttransplant time period and could be augmented considerably in alpha1-AP-deficient recipients with episodes of infection or rejection. Our findings indicate that unopposed NE activity can be found in both alpha1-AP-deficient and alpha1-AP-sufficient recipients after transplantation, usually in association with endobronchial bacterial infection.

Objective: To assess the prevalence and etiology of empyema complicating successful lung transplantation., Design: Retrospective review., Setting: University medical center transplant service., Patients: All recipients (n = 392) of single-lung, double-lung, and heart-lung transplantation between May 1984 and April 1997., Results: Of the 392 transplant recipients, empyema was documented in 14 patients (3.6%) at a mean time (+/- SD) of 46 days after transplantation (range, 14 to 167 days). Of these 14 recipients with empyema, 4 recipients (28.6%) died of infectious complications related to empyema. Empyema was seen secondary to Gram-positive, Gram-negative, and saprophytic organisms; however, there was no predominance of a particular organism recovered from the empyemic fluid (chi2 = 0.53; p = 0.75). The development of empyema was not related to whether the transplant was performed secondary to a septic or nonseptic lung disorder (chi2 = 1.06; p = 0.67), nor was it related to the type of transplant procedure performed (ie, single-lung, double-lung, or heart-lung allografts; chi2 = 4.39; p = 0.30)., Conclusion: Empyema, a relatively uncommon complication of lung transplantation, is not related to the type of allograft received or to whether the recipient had a septic or a nonseptic lung disorder. If empyema does occur, the mortality associated with this infection is substantial.

Background: Sarcoidosis is a multi-system granulomatous disease which can cause significant pulmonary morbidity and occasionally be fatal. The long term benefit of lung transplantation for this disorder are unknown., Methods: A retrospective review was made of nine single lung transplant procedures performed at the University of Pittsburgh between March 1991 and March 1995 in patients with end-stage lung disease secondary to sarcoidosis. Two contemporaneous groups of recipients receiving transplants for COPD (n = 30) and inflammatory lung disease (n = 13) served as control groups. Surviving recipients underwent sequential surveillance bronchoscopy with transbronchial biopsy., Results: All recipients survived beyond post-operative day (POD) 30, with 5 recipients currently alive. One year survival for this group was 6/9 (67%). Eight of the 9 sarcoidosis recipients had sequential lung biopsy procedures. Five of these 8 recipients (62.5%) had recurrence of granulomata in the lung allograft with the mean time to diagnosis of recurrent sarcoidosis being POD 224.2 +/- 291.3 (range POD 21-719). None of these 5 recipients had radiographic evidence or clinical symptoms related to granulomatous inflammation in the allograft. Pre-operative and post-operative spirometric values were available on 8 recipients. Vital capacity significantly improved in all recipients from 1.54 +/- 0.43 litres to 2.55 +/- 0.63 litres by POD 180 and was maintained through the fourth postoperative year (p < 0.05 Wilcoxon Signed Rank). Spirometric values were also compared before and after transplantation in the 5 recipients with granulomata in the allograft. Vital capacity significantly improved in these 5 recipients from 1.53 +/- 0.48 litres to 2.71 +/- 0.71 litres by POD 180 and was maintained throughout the first postoperative year (p < 0.05, Wilcoxon Signed Rank). The prevalence of high grade acute cellular rejection [ACR (histologic grades III and IV)] did not differ from that seen in a contemporaneous group of 30 single lung recipients who received allografts for COPD (p < 0.05 Mann-Whitney U), nor when compared to a group of 13 single lung recipients who received allografts for immunologically mediated lung disease (p < 0.05 Mann-Whitney U). The prevalence of chronic rejection (histologic obliterative bronchiolitis [OB]) in the sarcoidosis recipients was 4/8 (50%). In the controls with COPD recipients the prevalence of OB was 10/30 (33.3%), and in the 13 controls with immunologic disease it was 6/13 (46.2%). There was no significant difference in the prevalence of OB between the sarcoidosis recipients and controls. When analyzed to the fifth year after transplantation, freedom from the development of OB also failed to differ between these 3 groups (p = 0.25, Logrank, Mantel-Cox)., Conclusions: Although granulomatous inflammation in the lung allograft is common following transplantation for sarcoidosis, it is not clinically or radiographically relevant. In addition, the prevalence of high grade ACR and histologic OB is no different when compared to other single lung recipients. For these reasons lung transplantation is a viable alternative for end-stage lung disease secondary to sarcoidosis.

Study Objective: To define the prevalence of colonization and infection of the lower respiratory tract (LRT) with Aspergillus in lung transplant recipients with and without cystic fibrosis (CF)., Design: Retrospective review., Setting: Large university lung transplant center., Materials and Methods: The postoperative course of 31 CF and 53 non-CF double lung or double lobar transplant recipients receiving allografts from April 1991 to February 1996 was reviewed. All recipients were subjected to surveillance bronchoscopy and biopsy at predetermined intervals and when clinically indicated. BAL fluid (BALF) and biopsy material were examined by appropriate fungal culture and staining techniques. Infection was defined by the finding of tissue-invasive disease on biopsy specimens., Results: Seven of the 31 CF recipients (22%) had Aspergillus isolated from cultures of sputum prior to transplantation. Following transplantation, 15 CF recipients (48%) had Aspergillus isolated from either sputum or BALF, including 4 of the 7 recipients identified with the fungus prior to transplantation. By contrast, 21 of the 53 non-CF recipients (40%) had Aspergillus isolated from the LRT following transplantation, none having had the fungus isolated prior to transplantation. The prevalence of Aspergillus did not differ between these groups (p = 0.51). Infections with Aspergillus occurred in 4 of the CF recipients (27%) and did not differ from the 3 infections (14%) identified in the non-CF recipients (p = 0.36). However, three of the four infections in the CF recipients involved the healing bronchial anastomosis and occurred prior to postoperative day 60. All three of these recipients had Aspergillus preoperatively. Postoperative infection was more common in the CF recipients having Aspergillus preoperatively than in those CF recipients without preoperative Aspergillus (p = 0.02)., Conclusions: Isolation of Aspergillus from the LRT following double lung transplantation is common and generally not associated with tissue-invasive disease. Those CF recipients with Aspergillus isolated in cultures of sputum preoperatively are at risk for postoperative infections with this agent. The healing bronchial anastomosis is particularly vulnerable.

Objective: To assess the incidence of pseudomonal infection, colonization, and inflammation in the allograft of lung transplant recipients with cystic fibrosis (CF) as compared with recipients with other end-stage lung disease., Design: Retrospective review., Setting: University medical center transplant service., Patients: All patients with CF and chronic pseudomonal infection (n=62) and patients with nonseptic end-stage lung disease (n=52) receiving a double lung transplant between October 1983 and March 1996., Results: Fifty lung transplant recipients with CF survived beyond postoperative day (POD) 15 and were subject to sequential bronchoscopy with BAL. Forty-four CF lung transplant recipients had Pseudomonas isolated from the allograft by median POD 15 as compared with 21 non-CF lung transplant recipients (p<0.001) with isolation at median POD 158 (p<0.0001). Thirteen CF lung transplant recipients had histologic evidence of infection when Pseudomonas was isolated as compared with only three of the non-CF lung transplant recipients (p<0.01). These infections occurred earlier in the CF lung transplant recipients (median POD 10 vs 261) (p<0.01). When compared with non-CF lung transplant recipients, CF lung transplant recipients with Pseudomonas isolated but without concomitant histologic infection (colonized) were demonstrated to have increased number of polymorphonuclear cells (PMNs) in the BAL fluid recovered from the allograft (17.66+/-24.94 x 10(6) cells vs 3.46+/-4.73 x 10(6)) (p<0.05). Non-CF lung transplant recipients who became colonized with Pseudomonas also had a greater number of PMNs recovered when compared with non-CF lung transplant recipients who did not have Pseudomonas (22.32+/-34.00 x 10(6) cells vs 0.21+/-0.18 x 10(6)) (p<0.01). Nine of 32 (28%) lung transplant recipients with CF have died from pseudomonal allograft infections, but this is no greater than 4 of 21 (19%) deaths related to Pseudomonas infection in recipients without CF (p=0.34)., Conclusions: Isolation of Pseudomonas from the lung allograft occurs more frequently and earlier after transplantation in recipients with CF. While infections related to Pseudomonas also occur more frequently in recipients with CF, there is no increase in mortality. There is an intense inflammatory response in the lung allograft associated with the isolation of Pseudomonas in recipients with and without CF.

Background: In patients with cystic fibrosis (CF) who are awaiting lung transplant, prolonged exposure to systemic antibiotics has frequently led to airway colonization with resistant isolates of Pseudomonas. This resistance limits the arsenal of effective antimicrobials available for infections after the initiation of immunosuppression and has been considered a theoretical deterrent to lung transplantation., Methods: Twenty CF transplant candidates with "pan-resistant" Pseudomonas received maintenance antibiotic therapy with aerosolized colistin sodium (75 mg b.i.d.), and intravenous antibiotics were eliminated. Ten other CF candidates did not use colistin sodium. Sputum cultures and antibiotic sensitivities were followed every 3-6 weeks., Results: All 20 candidates (100%) who used aerosolized colistin sodium became colonized with sensitive isolates of Pseudomonas in an average of 45.1+/-20.2 days. In contrast, only 3 of 10 CF transplant candidates (30%) who did not use colistin sodium later became colonized with sensitive isolates. The mean time to spontaneous emergence of sensitive organisms was 144.6+/-48.0 days in candidates who did not use colistin sodium and was significantly longer than in the candidates who used colistin sodium (P=0.007). The occurrence of redeveloping sensitive isolates of Pseudomonas was significantly greater in the candidates who used colistin sodium (P<0.05). Of the candidates who used colistin sodium, six have been transplanted at our institution. In five of these six recipients (83.3%) bacterial cultures taken from the explanted lungs continued to demonstrate sensitive organisms., Conclusion: Aerosolized colistin sodium may be a useful therapy to promote emergence of sensitive microbes in CF candidates with pan-resistant isolates of Pseudomonas.

To clarify the usefulness of spirometry to assess the function of the lung allograft post-transplant, we retrospectively reviewed 351 sequential spirometry measurements performed by 65 healthy recipients after the 80th postoperative day when the clinical evaluation and fiberoptic bronchoscopy with transbronchial biopsies and bronchoalveolar lavage excluded significant rejection or infection in the allograft. The mean coefficients of variation (CV) and significant values for change (SC) for the FVC, FEV1, and FEF25-75% were calculated according to the type of transplant procedure (heart-lung and double-lung [HL-DL] versus single-lung [SL]), and to the time after transplant when the spirometry measurements were obtained < or = 1 yr versus > 1 yr). The SC for the FVC decreased with time after transplantation for both HL-DL (< or = 1 yr: 17% versus > 1 yr: 7%) and SL recipients (< or = 1 yr: 13% versus > 1 yr: 8%). The higher degree of variability within the first year was primarily due to increasing values especially in the HL-DL recipients. The SC for the FEV1 also decreased over time for HL-DL recipients (< or = 1 yr: 18% versus > 1 yr: 9%) but was similar for SL recipients at both intervals (13%). Our results suggest that decreases of > or = 11% in FVC or 12% in FEV1 in HL-DL recipients and > or = 12% in FVC or 13% in FEV1 for SL recipients indicate a significant decrease in allograft function that may be due to infection or rejection.

The modern era of lung transplantation was ushered in on the wings of discoveries in new immunosuppressive agents and surgical technique. It has allowed those with end-stage organ disease to have a second chance at life. Even though still in its youth relative to other solid organ transplants, it is gaining momentum and promises to be a continuing area of growth and development. Although over 2,700 lung transplants have been done in the last 13 years worldwide, the lack of availability of donor organs is the major factor slowing the rapid expansion of this field of endeavor. Primary care physicians may have an impact on this problem by raising the awareness for organ donation in their patients and patients' families. Although initially performed almost exclusively for those with pulmonary vascular disease, indications have now expanded to include interstitial disease, septic lung disease, and emphysema, with the latter being the major reason for transplantation today. Unfortunately, at experienced institutions with long waiting lists, 20% or more of candidates do not survive to transplantation. With proper care and selection of transplant candidates it is hoped that more will survive to benefit from this treatment. The primary care physician will likely be assuming a greater role in the management of transplant candidates as their numbers increase. The care of transplant recipients, although often complex, is frequently rewarding. For the most part it is performed at transplant centers, but a role for the recipient's local physician in this process is also growing in the era of managed care. This chapter has also highlighted how the recipient's local physician can participate in postoperative care. Strict attention needs to be paid to any and all signs of organ rejection or infection because both can have devastating consequences. Awareness of the medications used in this population, their side effects, and drug interactions is essential. Despite the recent advances in pharmacologic therapy, organ rejection continues to be problematic. This is especially the case with the entity of chronic rejection because it frequently fails to respond long-term to therapy and accounts for a significant percentage of late mortality. Although infections continue to be the primary cause of both early and late mortality in these recipients, proper care and postoperative prophylaxis can lessen the incidence. Likewise, early and aggressive treatment of infections in recipients can be lifesaving. Despite all the potential problems, patients receiving lung transplants are living longer and return to productive lives. Between 50% and 60% are now living between 3 and 4 years, and one can only anticipate that this will continue to climb as our understanding of infections, medications, and the body's immunoregulatory system improves. As techniques for donor organ allocation and organ preservation improve, it is hoped that all those with end-stage lung disorders may have the opportunity to benefit from this expanding technology.

Background: A prospective clinical trial was undertaken to compare the efficacy of tacrolimus (FK 506) versus cyclosporine as the primary immunosuppressive agent after lung transplantation., Methods: Between October 1991 and May 1994, 133 single-lung and bilateral-lung recipients were randomized to receive either cyclosporine (n = 67) or tacrolimus (n = 66). The two groups were similar in age, sex, and underlying disease., Results: One-year and 2-year survival rates were similar in the two groups, although the trend was toward increased survival with tacrolimus. Acute rejection episodes per 100 patient-days were fewer (p = 0.07) in the tacrolimus group (0.85) than in the cyclosporine group (1.09). Obliterative bronchiolitis developed in significantly fewer patients in the tacrolimus group (21.7%) compared with the cyclosporine group (38%) (p = 0.025), and there was greater freedom from obliterative bronchiolitis over time for patients receiving tacrolimus (p < 0.03). Significantly more cyclosporine-treated patients (n = 13) required crossover to tacrolimus than tacrolimus-treated patients to cyclosporine (n = 2) (p = 0.02). The switch to tacrolimus controlled persistent acute rejection in 6 of 9 patients. The overall incidence of infections was similar in the two groups, although bacterial infections were more common with cyclosporine (p = 0.0375), whereas the risk of fungal infection was higher with tacrolimus (p < 0.05)., Conclusions: This trial demonstrates the advantage of tacrolimus in reducing the risk of obliterative bronchiolitis, the most important cause of long-term morbidity and mortality after lung transplantation.