Evaluation of Bivalirudin as the Primary Anticoagulant in Patients Receiving Extracorporeal Membrane Oxygenation for SARS-CoV-2-Associated Acute Respiratory Failure.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a potential option for the management of severe acute respiratory failure secondary to COVID-19. Conflicting the use of this therapy is the known coagulopathy within COVID-19, leading to an incidence of venous thrombotic events of 25% to 49%. To date, limited guidance is available on optimal anticoagulation strategies in this population. OBJECTIVE: The purpose of this study was to evaluate the utilization of a pharmacist-driven bivalirudin dosing protocol for anticoagulation in the setting of ECMO for COVID-19-associated respiratory failure. METHODS: This was a single-center retrospective chart review over a 9-month period of patients receiving bivalirudin while on ECMO. All patients with acute respiratory failure requiring ECMO with a positive SARS-CoV-2 polymerase chain reaction were included. Bivalirudin was dosed via aPTT monitoring after a starting dose of 0.2 or 0.3 mg/kg/h. RESULTS: There were 33 patients included in this study, all receiving mechanical ventilation. The most common starting dose of bivalirudin was 0.2 mg/kg/h, with an average time to therapeutic range of 20 hours. Compared to previous reports, rates of bleeding were low at 15.1%, and 6.1% of patients developed a new venous thromboembolic event while on ECMO. ECMO survival was 51.5%, with an ICU mortality rate of 48.5%. CONCLUSION AND RELEVANCE: In the first published report of its use within this population, bivalirudin was found to be a viable choice for anticoagulation in those patients on ECMO for severe respiratory failure secondary to COVID-19.

Impact of donor lung pathogenic bacteria on patient outcomes in the immediate post-transplant period.

BACKGROUND: Patient outcomes post-lung transplant remain inferior to other types of solid organ transplantation. We investigated whether the presence of potentially pathogenic bacteria (PPB) in donor lung bronchial cultures was associated with adverse outcomes postoperatively. METHODS: All patients who underwent lung transplantation between August 2015 and April 2017 at the University of Kentucky Medical Center were retrospectively reviewed. Retransplants, patients with bronchiectasis (including cystic fibrosis), and individuals who received organs from donation after cardiac death (DCD) donors were excluded. The remaining subjects were separated into two groups: individuals whose donor bronchial cultures grew PPB, and those whose cultures either returned negative for PPB or were sterile. 30-day mortality rates as well as the incidence of grade 3 primary graft dysfunction (PGD) and acute kidney injury (AKI) at both 24 and 72 hours post-transplant were calculated. The duration of mechanical ventilation postoperatively was also recorded. RESULTS: Thirty two subjects comprised the study population. 20 patients (63%) had growth of PPB on donor cultures, while 12 (37%) did not. Patients with PPB had a significantly greater number of days on the ventilator postoperatively compared to those with no PPB (mean = 11.3 and median = 5.0 vs mean = 5.8 and median = 3.0, respectively, P = 0.0232). Subsequent regression analysis revealed this association to not be influenced by recipient lung allocation score (LAS), donor age, donor smoking history, recipient mean pulmonary artery pressure (mPAP) value, and/or use of cardiopulmonary bypass at the time of transplantation. Neither 30-day survival nor incidence of Grade 3 PGD and AKI at 24 or 72 hours post-transplant differed between the two groups (P > 0.05). CONCLUSION: The recovery of PPB in donor lung cultures was associated with a longer duration of mechanical ventilation postoperatively in lung transplant recipients.

Comparison of sirolimus with azathioprine in a tacrolimus-based immunosuppressive regimen in lung transplantation.

RATIONALE: Lung transplantation has evolved into a life-saving therapy for select patients with end-stage lung diseases. However, long-term survival remains limited because of chronic rejection. Sirolimus is beneficial in preventing cardiac rejection and may decrease rejection after lung transplantation. OBJECTIVES: To determine the potential benefit versus risk of sirolimus in lung transplantation. METHODS: We conducted a multicenter randomized, open label controlled trial comparing sirolimus (SIR) with azathioprine (AZA) in a tacrolimus-based immunosuppressive regimen in lung transplantation. The primary end point was the incidence of acute rejection at 1 year after transplantation between the two study groups. MEASUREMENTS AND MAIN RESULTS: One hundred eighty-one patients were randomized to be included in this study. At 1 year after transplantation, there was no significant difference in the incidence of grade A acute rejection between the two study groups. Similarly, the incidence of chronic rejection and graft survival was no different between the two study groups. Cytomegalovirus infection was decreased in the SIR arm compared with the AZA arm (relative risk, 0.67 [95% confidence interval, 0.55, 0.82]; P < 0.01). There was a higher rate of adverse events leading to early discontinuation of SIR (64%) compared with AZA (49%) during the course of this study. CONCLUSIONS: Sirolimus, an mTOR inhibitor, did not decrease the incidence of acute rejection at 1 year compared with azathioprine in lung transplantation. These results differ from previous results in cardiac and renal transplantation and emphasize the need for multicenter randomized controlled trials in lung transplantation. Clinical trial registered with www.clinicaltrials.gov (NCT 00321906).

Technical pearls for swine lung transplantation.

BACKGROUND: Since the advent of ex vivo lung perfusion (EVLP), there has been increased focus on swine models of lung transplantation; however, the anatomic differences between human and swine lungs and the technical challenges in performing porcine lung transplantation are not well described in the surgical literature. METHODS: Surgically important anatomic variations are described, and the technical measures taken to address them during harvest and transplantation are introduced. RESULTS: There are three surgically important anatomic variations in pigs. First, the right cranial lobe bronchus arises directly from the trachea, which makes right lung transplantation technically challenging if not prohibitive. Second, the left hemi-azygos vein is fully developed and courses upward through the posterior mediastinum, where it crosses the left pulmonary hilum and drains directly into the coronary sinus. During transplantation, this vein is ligated and dissected away to expose the underlying left pulmonary hilar structures. Third, the right inferior pulmonary vein crosses the midline to drain into the left atrium immediately adjacent to the left inferior pulmonary vein. During donor lung preparation, the right inferior pulmonary vein is ligated distally from the left atrium, which leaves an adequate atrial cuff around the left sided pulmonary veins for later anastomosis. CONCLUSION: Experimental porcine lung transplantation is technically demanding. We have found recognition of the above described anatomical differences and technical nuances facilitate transplantation and provide reproducible results.

Lung Transplantation in a Patient With COVID-19-Associated Acute Respiratory Failure.

Coronavirus disease 2019 (COVID-19) is currently a significant cause of acute respiratory failure worldwide, leading to irreversible fibrotic lung disease. In patients with persistent respiratory failure after acute COVID-19 infection, lung transplant is an emerging option. Here, we have presented a case where the patient required venovenous extracorporeal membrane oxygenation (VV-ECMO) support for 33 days until a bilateral lung transplant was performed on day 71 after the initial COVID-19 infection. The early outcomes have been favorable. Currently, no guidelines exist for an acceptable time period after initial COVID-19 infection, duration of negative COVID polymerase chain reaction (PCR) testing, or negative Vero cell culture in the setting of persistent positive COVID PCR testing before listing for a lung transplant. Due to a lack of standardized guidelines, this patient was not listed for a lung transplant until the COVID-19 PCRs came negative on days 47 and 49 after the infection.

Discrepancies between clinical and autopsy diagnoses in lung transplant recipients.

We sought to investigate the role of autopsy diagnoses in lung transplantation by comparing the clinically derived cause of death with autopsy deduced cause of death in a cohort of lung transplant recipients. We retrospectively reviewed all consecutive autopsy findings on lung transplant recipients transplanted between March 1994 and March 2007. We reviewed medical records and our lung transplant database to determine the clinical diagnosis of cause of death based on the clinical assessment and discharge summary at the time of death. Our study showed that 21% of the autopsies performed on lung transplant recipients at our institution revealed findings unsuspected at the time of death. Myocardial infarction, pulmonary embolism, high grade acute cellular rejection and infections were the most frequently missed diagnoses. The autopsy remains a useful tool in confirming diagnostic accuracy in lung transplant recipients.

Pleural mesothelial cell transformation into myofibroblasts and haptotactic migration in response to TGF-beta1 in vitro.

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology characterized by the development of subpleural foci of myofibroblasts that contribute to the exuberant fibrosis noted in the pulmonary parenchyma. Pleural mesothelial cells (PMC) are metabolically dynamic cells that cover the lung and chest wall as a monolayer and are in intimate proximity to the underlying lung parenchyma. The precise role of PMC in the pathogenesis of pulmonary parenchymal fibrosis remains to be identified. Transforming growth factor (TGF)-beta1, a cytokine known for its capacity to induce proliferative and transformative changes in lung cells, is found in significantly higher quantities in the lungs of patients with IPF. High levels of TGF-beta1 in the subpleural milieu may play a key role in the transition of normal PMC to myofibroblasts. Here we demonstrate that PMC activated by TGF-beta1 undergo epithelial-mesenchymal transition (EMT) and respond with haptotactic migration to a gradient of TGF-beta1 and that the transition of PMC to myofibroblasts is dependent on smad-2 signaling. The EMT of PMC was marked by upregulation of alpha-smooth muscle actin (alpha-SMA), fibroblast specific protein-1 (FSP-1), and collagen type I expression. Cytokeratin-8 and E-cadherin expression decreased whereas vimentin remained unchanged over time in transforming PMC. Knockdown of smad-2 gene by silencing small interfering RNA significantly suppressed the transition of PMC to myofibroblasts and significantly inhibited the PMC haptotaxis. We conclude that PMC undergo EMT when exposed to TGF-beta1, involving smad-2 signaling, and PMC may be a possible source of myofibroblasts in IPF.

Effects of administration of intravenous naloxone on gas exchange in brain-dead lung donors.

OBJECTIVE: To observe the effect of naloxone on the lung function of potential lung transplant donors with neurogenic pulmonary edema. DESIGN AND INTERVENTIONS: Donors aged 16 to 55 years without any factors to contraindicate lung donation (pneumonia, pulmonary contusion, etc) were included. Ventilator settings were standardized to a tidal volume of 10 to 12 mL/kg, an FIO2 of 0.40, and a respiratory rate that kept PCO2 between 35 and 45 mm Hg. Chest physiotherapy, nebulizer treatments, and frequent suctioning were undertaken. Baseline arterial blood gas analysis and an oxygen challenge were performed. The patients were then given 8 to 10 mg of naloxone. Oxygen challenges and arterial blood gas analyses were repeated every 4 to 6 hours. The data were analyzed by using a paired t test, and each patient served as his or her own control. SETTING: These interventions were performed on the 19 LifeQuest donors who met the set criteria from July 2002 to July 2004. RESULTS: The PaO2 on the oxygen challenge immediately after administration of naloxone increased from 329 (SD 177) to 363 (SD 191) mm Hg, although the increase from baseline was not significant. The PaO2 from the second oxygen challenge (median time, 7 hours after administration of naloxone) increased to 413 (SD 177) mm Hg (P<.01).

Simultaneous fundoplication and gastric stimulation in a lung transplant recipient with gastroparesis and reflux.

BACKGROUND: Gastroparesis following lung transplantation can complicate medical management leading to malnutrition, weight loss, and erratic absorption of immunosuppressive medications, which are all important factors in the success of grafts. Gastric electrical stimulation has been shown to reduce the frequency of nausea and vomiting and lead to weight gain in patients with gastroparesis refractory to standard medical treatment; however, it has not yet been reported as being used for the treatment of gastroparesis in lung transplant recipients. METHODS: We report the case of a female bilateral lung transplant recipient suffering from severe gastric reflux and severe gastroparesis, who was successfully treated with simultaneous creation of a laparoscopic Nissen fundoplication and placement of a gastric stimulator. RESULTS: The patient noted an immediate and sustained decrease in her symptoms of nausea and vomiting, and an increased appetite, and less variability in the serum levels of her immunosuppressive medication. CONCLUSION: Lung transplant recipients with severe gastroparesis and reflux may benefit from Nissen fundoplication and gastric electrical stimulation.

Two Decades of Lung Retransplantation: A Single-Center Experience.

BACKGROUND: Lung retransplantation (ReTx) comprises an increasing share of lung transplants and recently has shown improved outcomes. The aim of this study was to identify risk factors affecting overall survival after pulmonary ReTx. METHODS: The United Network for Organ Sharing database was used to identify patients undergoing lung transplantation at our institution from 1995 to 2014. Of the total 542 lung transplants performed, 87 (16.1%) were ReTxs. The primary outcome was overall survival. Multivariate Cox regression models were used to assess the effect of recipient and donor characteristics on survival. RESULTS: Of the patients who underwent ReTx, median survival was 2 years. Predictors of worse survival include recipient age between 50 and 60 years (relative risk, 4.3; p = 0.02) or older than 60 years (relative risk, 10.2; p < 0.001), and time to ReTx of less than 2 years (relative risk, 3.8; p = 0.01). ReTx for bronchiolitis obliterans syndrome had longer median survival than for restrictive chronic lung allograft dysfunction (2.7 years vs 0.9 years; p = 0.055). Overall survival of ReTx patients after initiation of the lung allocation score was not significantly different (p = 0.21). CONCLUSIONS: Lung ReTx outcomes are significantly worse than for primary transplantation but may be appropriate in well-selected patients with certain diagnoses. Lung ReTx in patients older than 50 years or within 2 years of primary lung transplantation was associated with decreased survival. Further work is warranted to identify patients who benefit most from ReTx.

Caregivers of lung transplant candidates: do they benefit when the patient is receiving psychological services?

BACKGROUND: We recently demonstrated that a targeted psychological intervention has quality of life, mood, and social intimacy benefits for patients awaiting lung transplantation. OBJECTIVE: To evaluate the impact of the patient's participation in treatment on caregiver functioning. DESIGN AND INTERVENTION: Caregivers of patients participating in a randomized clinical trial designed to compare 2 telephone-based psychological interventions completed outcome measures at baseline and at 1 and 3 months after patients completed treatment. Patients were randomized to receive either supportive therapy (emotional and educational support) or quality-of-life therapy (a cognitive-behavioral intervention that provided specific intervention strategies to boost happiness and satisfaction in life domains that compromise overall quality of life). Caregivers did not participate directly in the interventions. Setting and Participants-Participants were 28 caregivers from a large lung transplant center in the southeastern United States. MAIN OUTCOME MEASURES: Quality of life (Quality of Life Inventory), mood disturbance (Profile of Mood States-Short Form), and social intimacy (Miller Social Intimacy Scale). RESULTS AND CONCLUSIONS: Caregivers reported higher quality of life and lower mood disturbance scores, and comparable social intimacy scores relative to the patients for whom they were caring. Caregivers whose patients received quality-of-life therapy reported vicarious gains in quality of life, mood disturbance, and social intimacy, relative to those whose patients received support therapy. Finally, the degree of change in patients' quality of life, mood disturbance, and social intimacy contributed significantly to predicting caregivers' functioning at the 3-month follow-up assessment. These findings suggest that telephone-based quality-of-life therapy has beneficial effects that extend beyond patients to their caregivers.

Bone marrow-derived stem-cell repopulation contributes minimally to the Type II pneumocyte pool in transplanted human lungs.

BACKGROUND: Lung transplant recipients are vulnerable to immunologic, infectious, ischemic, and toxic pulmonary injuries. The authors investigated whether type II pneumocytes in the lungs of cross-gender lung transplant patients show genotypic evidence to support repopulation of the lung by stem cells of bone marrow origin, and whether the degree of repopulation was related to rejection history. METHODS: Recut sections were obtained from lung biopsy specimens from seven male recipients of transplanted lungs from female donors. Sequential immunohistochemistry and fluorescence in situ hybridization was performed on each section to evaluate for Y-chromosome-containing type II pneumocytes. RESULTS: Y-chromosome-containing type II pneumocytes were found in 9 of 25 biopsy specimens from 5 of 7 gender-mismatched male lung transplant recipients, and accounted for 0% to 0.553% of type II pneumocytes. There was no evidence of polyploidy to suggest cell-cell fusion. The number of type II pneumocytes of male karyotype showed a statistically significant relationship to the cumulative number of episodes of acute cellular rejection. CONCLUSIONS: Lung transplant recipients develop low levels of pneumocyte repopulation by bone marrow-derived stem cells or their progeny. These cells contribute minimally to the type II pneumocyte proliferation that is often present in these patients as a sequela to alveolar injury.

Does lung transplantation improve health-related quality of life? The University of Florida experience.

BACKGROUND: Health-related quality of life (HRQoL) is an important clinical end-point in evaluating the overall success of lung transplantation. The primary purpose of this study, therefore, was to document the degree of change in HRQoL in a sample of patients evaluated before and after lung transplantation. METHODS: Sixty-six adults who underwent single or bilateral lung transplantation at the University of Florida between March 1994 and May 2001 completed assessments of HRQoL (SF-36 Health Survey, Transplant Symptom Frequency Questionnaire), both before and after transplant. Pre- and post-transplant assessments of forced expiratory volume in 1 second (FEV1) percent predicted and 6-minute walk test performance were also obtained. RESULTS: HRQoL before transplant was significantly lower than in normative samples of chronic obstructive pulmonary disease (COPD) patients and adults in the general population. However, repeated measures analyses of co-variance showed significant improvements on 7 of 8 SF-36 sub-scales, as well as the physical component summary and the mental component summary. Improvements in FEV1 percent predicted and 6-minute walk test performance were also found. Patients with longer time since transplantation reported more frequent and problematic symptoms commonly associated with immunosuppression, including depression, headaches and changes in physical appearance, among others. CONCLUSIONS: Lung transplantation appears to yield significant HRQoL benefits for patients. Many patients do, however, experience frequent symptoms associated with immunosuppression that may limit the full benefit of transplantation, and some of these symptoms appear to worsen over time. Future research efforts should focus on the development, implementation and evaluation of clinical interventions designed to optimize HRQoL both before and after lung transplantation.

Reliability of diagnostic criteria for bronchiolitis obliterans syndrome after lung transplantation: a survey.

BACKGROUND: Long-term outcomes after lung transplantation are limited due to chronic lung allograft dysfunction (CLAD). Bronchiolitis obliterans syndrome (BOS) is the most common form of obstructive CLAD and its definition derives from spirometric measurements. Given the importance of this diagnosis, both the accuracy and reliability of the definition of CLAD are crucial in understanding the pathophysiology of this disease to develop therapeutic options and influence outcome after lung transplantation. METHODS: A web-based survey was designed and distributed to members of the Pulmonary Council of the International Society for Heart and Lung Transplantation (ISHLT) to better understand the accuracy and reliability of pulmonary function criteria in diagnosing BOS. Spirometric data from five patient scenarios that were discordant among reviewers regarding BOS determination from the Assessment of Immunosuppressive Regimen in Suppressing Acute and Chronic Rejection (AIRSAC) trial were randomly selected and summarized in this survey. Survey questions included the respondent's general understanding of the BOS definition, the determination of BOS, and difficulties with the current BOS definition. RESULTS: Eighty-seven respondents from the Pulmonary Council of the ISHLT responded to this survey. There was an overall 70% interobserver agreement regarding the presence or absence of BOS. Among those who agreed upon the presence of BOS, there was a 41% interobserver agreement regarding its time of onset. Despite this variability, the majority of respondents were not only familiar and agreed with the BOS criteria, they also felt confident in applying these criteria. CONCLUSIONS: Our survey identified potential limitations with the current criteria for diagnosing BOS. With recognition of the various CLAD phenotypes, further refinements of these diagnostic criteria will allow for an improved ability to identify and characterize patients who develop or are at risk for BOS, prognosticate outcomes, and, most importantly, marshal in future strategies directed at treating and preventing chronic lung dysfunction after lung transplantation.

Evaluation of Alemtuzumab Versus Basiliximab Induction: A Retrospective Cohort Study in Lung Transplant Recipients.

BACKGROUND: Acute cellular rejection (ACR) is a major early complication after lung transplantation (LT) and is a risk factor for chronic rejection. Induction immunosuppression has been used as a strategy to reduce early ACR. Recently, our LT program changed our primary induction protocol from basiliximab with standard maintenance immunosuppression to alemtuzumab induction with reduced dose maintenance immunosuppression. The objective of this study was to compare incidence of ACR after this change in the first 6 months after transplantation. METHODS: A retrospective, cohort review of patients 18 years or older, which received their first LT between January 2010 and September 2012. RESULTS: The primary outcome was comparison of average lung biopsy scores at 6 months. Secondary outcomes included development of grade A2 or higher rejection, infectious outcomes, overall graft and patient survival. At 6 months, the average biopsy score was significantly lower in the alemtuzumab group than the basiliximab group (0.12 ± 0.29 vs 0.74 ± 0.67; P < 0.0001) (Table 2). Grade 2 or higher rejection was significantly higher in the basiliximab group (P < 0.0001). CONCLUSIONS: Alemtuzumab provided superior outcomes in regard to average biopsy score and lower incidence of grade 2 or higher rejection at 6 months. There were no differences in infectious complications or overall graft or patient survival between the 2 groups.

Resistance training prevents vertebral osteoporosis in lung transplant recipients.

BACKGROUND: Osteoporosis and vertebral fractures are a consequence of glucocorticoid immunosuppression therapy in lung transplant recipients (LTR). The purpose of this study was to determine the therapeutic efficacy of a 6-month program of specific resistance exercise designed to reverse glucocorticoid-induced vertebral osteoporosis. METHODS: Sixteen lung transplant candidates were randomly and prospectively assigned to a group (n=8) that performed 6 months of exercise on a lumbar extensor machine or to a control group (n=8). Resistance exercise was initiated at 2 months after transplantation. Bone mineral density (BMD) of the lumbar vertebra (L2-3) was assessed using a dual-energy X-ray absorptiometer (DXA). DXA scans were performed before and 2 months after transplantation and after 6 months of lumbar extensor training or control period. RESULTS: Lumbar BMD did not differ (P>0.05) between the two groups at study entry. Both the trained (0.63 to 0.54 g/cm2 of hydroxyapatite) and control groups (0.62 to 0.53 g/cm2 of hydroxyapatite) lost significant and comparable amounts (-14.5%) of BMD between study entry and 2 months posttransplantation. The control group lost further (P

Impact of body weight on long-term survival after lung transplantation.

STUDY OBJECTIVES: The purpose of this study was to determine the impact of a pretransplantation determination of body mass index (BMI) on survival after lung transplantation. DESIGN AND PATIENTS: Univariate and multivariate survival analyses of a single institution database consisting of 85 patients who had undergone lung transplantations between March 1994 and October 1998. SETTING: University of Florida Health Science Center. RESULTS: Kaplan-Meier survival curves showed that patients who were obese (ie, BMI, > or = 30) at a pretransplantation assessment had a marked decrease in posttransplantation survival time (log rank, p < 0.05; Wilcoxon, p < 0.05). The final Cox regression model revealed that the most powerful predictors of mortality after lung transplantation were higher pretransplantation BMI and the development of obliterative bronchiolitis. CONCLUSIONS: Our results suggest that the posttransplantation risk for mortality is possibly three times greater for obese patients than for nonobese patients. Additional study is needed to identify the mechanisms for such higher risk in obese patients. Our data also suggest that transplantation centers should not routinely reject underweight patients (ie, BMI, < 18.5) or overweight patients (ie, BMI, 25 to 29.9) for lung transplantation listing solely on the basis of weight, as their outcomes may not be significantly different than patients with normal BMIs.

Interobserver variability in grading transbronchial lung biopsy specimens after lung transplantation.

BACKGROUND: Acute rejection remains a major source of morbidity after lung transplantation. Given the importance of this diagnosis, an international grading system was developed to standardize the diagnosis of acute lung-allograft rejection. The reliability of this grading system has not been adequately assessed by previous studies. METHODS: We examined the level of agreement in grading transbronchial biopsy specimens obtained from a large multicenter study (AIRSAC [Comparison of a Tacrolimus/Sirolimus/Prednisone Regimen vs Tacrolimus/Azathioprine/Prednisone Immunosuppressive Regimen in Lung Transplantation] trial). Biopsy specimens were initially graded for acute rejection and lymphocytic bronchiolitis by the site pathologist and subsequently graded by a central pathologist. Reliability of interobserver grading was evaluated using Cohen κ coefficients. RESULTS: A total of 481 transbronchial biopsy specimens were graded by both the site and central pathologists. The overall concordance rates were 74% and 89% for grade A and grade B biopsy specimens, respectively. When samples from biopsies performed at different time points after transplantation were assessed, there was a higher level of agreement early (≤ 6 weeks) after transplant compared with later time points for acute rejection. However, there was still only moderate agreement for both grade A (κ score 0.479; 95% CI, 0.29-0.67) and grade B (κ score 0.465; 95% CI, 0.08-0.85) rejection. CONCLUSIONS: These results expand upon previous reports of interobserver variability in grading transbronchial biopsy specimens after lung transplantation. Given the variability in grading these specimens, we advocate further education of the histopathologic findings in lung transplant biopsy specimens, as well as revisiting the current criteria for grading transbronchial biopsy specimens to improve concordance among lung transplant pathologists. TRIAL REGISTRY: ClinicalTrials.gov; No. NCT00321906; URL: www.clinicaltrials.gov.

Decreased incidence of cytomegalovirus infection with sirolimus in a post hoc randomized, multicenter study in lung transplantation.

BACKGROUND: Cytomegalovirus (CMV) is the most common opportunistic infection in lung transplantation. A recent multicenter, randomized trial (the AIRSAC study) comparing sirolimus to azathioprine in lung transplant recipients showed a decreased incidence of CMV events in the sirolimus cohort. To better characterize this relationship of decreased incidence of CMV events with sirolimus, we examined known risk factors and characteristics of CMV events from the AIRSAC database. METHODS: The AIRSAC database included 181 lung transplant patients from 8 U.S.-based lung transplant centers that were randomized to sirolimus or azathioprine at 3 months post-transplantation. CMV incidence, prophylaxis, diagnosis and treatment data were all prospectively collected. Prophylaxis and treatment of CMV were at the discretion of each institution. RESULTS: The overall incidence of any CMV event was decreased in the sirolimus arm when compared with the azathioprine arm at 1 year after lung transplantation (relative risk [RR] = 0.67, confidence interval [CI] 0.55 to 0.82, p < 0.01). This decreased incidence of CMV events with sirolimus remained significant after adjusting for confounding factors of CMV serostatus and CMV prophylaxis. CONCLUSIONS: These data support results from other solid-organ transplantation studies and suggest further investigation of this agent in the treatment of lung transplant recipients at high risk for CMV events.