Association of Transplant Center With Survival Benefit Among Adults Undergoing Heart Transplant in the United States.

Importance: In the United States, the number of deceased donor hearts available for transplant is limited. As a proxy for medical urgency, the US heart allocation system ranks heart transplant candidates largely according to the supportive therapy prescribed by transplant centers. Objective: To determine if there is a significant association between transplant center and survival benefit in the US heart allocation system. Design, Setting, and Participants: Observational study of 29 199 adult candidates for heart transplant listed on the national transplant registry from January 2006 through December 2015 with follow-up complete through August 2018. Exposures: Transplant center. Main Outcomes and Measures: The survival benefit associated with heart transplant as defined by the difference between survival after heart transplant and waiting list survival without transplant at 5 years. Each transplant center's mean survival benefit was estimated using a mixed-effects proportional hazards model with transplant as a time-dependent covariate, adjusted for year of transplant, donor quality, ischemic time, and candidate status. Results: Of 29 199 candidates (mean age, 52 years; 26% women) on the transplant waiting list at 113 centers, 19 815 (68%) underwent heart transplant. Among heart transplant recipients, 5389 (27%) died or underwent another transplant operation during the study period. Of the 9384 candidates who did not undergo heart transplant, 5669 (60%) died (2644 while on the waiting list and 3025 after being delisted). Estimated 5-year survival was 77% (interquartile range [IQR], 74% to 80%) among transplant recipients and 33% (IQR, 17% to 51%) among those who did not undergo heart transplant, which is a survival benefit of 44% (IQR, 27% to 59%). Survival benefit ranged from 30% to 55% across centers and 31 centers (27%) had significantly higher survival benefit than the mean and 30 centers (27%) had significantly lower survival benefit than the mean. Compared with low survival benefit centers, high survival benefit centers performed heart transplant for patients with lower estimated expected waiting list survival without transplant (29% at high survival benefit centers vs 39% at low survival benefit centers; survival difference, -10% [95% CI, -12% to -8.1%]), although the adjusted 5-year survival after transplant was not significantly different between high and low survival benefit centers (77.6% vs 77.1%, respectively; survival difference, 0.5% [95% CI, -1.3% to 2.3%]). Overall, for every 10% decrease in estimated transplant candidate waiting list survival at a given center, there was an increase of 6.2% (95% CI, 5.2% to 7.3%) in the 5-year survival benefit associated with heart transplant. Conclusions and Relevance: In this registry-based study of US heart transplant candidates, transplant center was associated with the survival benefit of transplant. Although the adjusted 5-year survival after transplant was not significantly different between high and low survival benefit centers, compared with centers with survival benefit significantly below the mean, centers with survival benefit significantly above the mean performed heart transplant for recipients who had significantly lower estimated expected 5-year waiting list survival without transplant.

Transplant recipients are vulnerable to coverage denial under Medicare Part D.

Transplant immunosuppressants are often used off-label because of insufficient randomized prospective trial data to achieve organ-specific US Food and Drug Administration (FDA) approval. Transplant recipients who rely on Medicare Part D for immunosuppressant drug coverage are vulnerable to coverage denial for off-label prescriptions, unless use is supported by Centers for Medicare & Medicaid Services (CMS)-approved compendia. An integrated dataset including national transplant registry data and 3 years of dispensed pharmacy records was used to identify the prevalence of immunosuppression use that is both off-label and not supported by CMS-approved compendia. Numbers of potentially vulnerable transplant recipients were identified. Off-label and off-compendia immunosuppression regimens are frequently prescribed (3-year mean: lung 66.5%, intestine 34.2%, pancreas 33.4%, heart 21.8%, liver 16.5%, kidney 0%). The annual retail cost of these at-risk medications exceeds $30 million. This population-based study of transplant immunosuppressants vulnerable to claim denials under Medicare Part D coverage demonstrates a substantial gap between clinical practice, current FDA approval processes, and policy mandates for pharmaceutical coverage. This coverage barrier reduces access to life-saving medications for patients without alternative resources and may increase the risk of graft loss and death from medication nonadherence.

Impact of the lung allocation score.

The number of donors falls short of the number of patients on the wait list for lung transplantation making it necessary to ration the available donor organs. The ideal allocation system is guided by ethical principles and scientifically accurate at identifying patients who will gain the greatest degree of benefit from receiving the organ, in terms of both pre- and posttransplantation survival. The lung allocation score (LAS) was developed in 2005 to reduce mortality on the wait list, prioritize candidates based on urgency, minimize the role of geography, and maximize transplant benefit. The LAS has not made much of an impact on the geographic disparity of listing patients for lung transplantation, but it did achieve the goal of reducing wait-list mortality and prioritizing patients based on urgency. In prioritizing patients with the most urgent status, a new controversy has come into the forefront: whether or not the increased number of critically ill recipients maximizes transplant benefit. Despite the controversy, the LAS system is an improvement compared with the traditional first-come, first-served system, and it has even been adopted by Eurotransplant. In the future, as modifications are made to improve the LAS, the issue of critically ill patients and maximizing posttransplant benefit will be the focus.

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).

Assessing the accuracy of the lung allocation score.

BACKGROUND: The United States (US) Lung Allocation Score (LAS) relies on the performance of 2 survival models that estimate waitlist and post-transplant survival. These models were developed using data from 2005 to 2008, and it is unknown if they remain accurate. METHODS: We performed an observational cohort study of US lung transplantation candidates and recipients greater than 12 years of age between February 19, 2015 and February 19, 2019. We evaluated the LAS waitlist and post-transplant models with the concordance probability estimate and by comparing predicted vs observed 1-year restricted mean survival times by risk decile. We then compared a nonparametric estimate of the observed LAS with the predicted LAS for each percentile of recipients. RESULTS: The waitlist model ranked candidates (N = 11,539) in the correct risk order 72% of the time (95% CI 71%-73%), and underestimated candidate one-year survival by 136 days for the highest risk decile (p < 0.001). The post-transplant model ranked recipients (N = 9,377) in the correct risk order 57% of the time (95% CI 55-58%), and underestimated recipient one-year survival by 70 days for the highest risk decile (p < 0.001). Overall, the LAS at transplant explained only 56% of the variation in observed outcomes, and was increasingly inaccurate at higher predicted values. CONCLUSIONS: The waitlist and the post-transplant models that constitute the LAS are inaccurate, limiting the ability of the system to rank candidates on the waitlist in the correct order. The LAS should therefore be updated and the underlying models should be modernized.

Differentiated transplant derived airway epithelial cell cytokine secretion is not regulated by cyclosporine.

BACKGROUND: While lung transplantation is an increasingly utilized therapy for advanced lung diseases, chronic rejection in the form of bronchiolitis obliterans syndrome (BOS) continues to result in significant allograft dysfunction and patient mortality. Despite correlation of clinical events with eventual development of BOS, the causative pathophysiology remains unknown. Airway epithelial cells within the region of inflammation and fibrosis associated with BOS may have a participatory role. METHODS: Transplant derived airway epithelial cells differentiated in air liquid interface culture were treated with IL-1ß and/or cyclosporine, after which secretion of cytokines and growth factor and gene expression for markers of epithelial to mesenchymal transition were analyzed. RESULTS: Secretion of IL-6, IL-8, and TNF-α, but not TGF-ß1, was increased by IL-1ß stimulation. In contrast to previous studies using epithelial cells grown in submersion culture, treatment of differentiated cells in ALI culture with cyclosporine did not elicit cytokine or growth factor secretion, and did not alter IL-6, IL-8, or TNF-α production in response to IL-1ß treatment. Neither IL-1ß nor cyclosporine elicited expression of markers of the epithelial to mesenchymal transition E-cadherin, EDN-fibronectin, and α-smooth muscle actin. CONCLUSION: Transplant derived differentiated airway epithelial cell IL-6, IL-8, and TNF-α secretion is not regulated by cyclosporine in vitro; these cells thus may participate in local inflammatory responses in the setting of immunosuppression. Further, treatment with IL-1ß did not elicit gene expression of markers of epithelial to mesenchymal transition. These data present a model of differentiated airway epithelial cells that may be useful in understanding epithelial participation in airway inflammation and allograft rejection in lung transplantation.

Extended valganciclovir prophylaxis to prevent cytomegalovirus after lung transplantation: a randomized, controlled trial.

BACKGROUND: Cytomegalovirus (CMV) is the most prevalent opportunistic infection after lung transplantation. Current strategies do not prevent CMV in most at-risk patients. OBJECTIVE: To determine whether extending prophylaxis with oral valganciclovir from the standard 3 months to 12 months after lung transplantation is efficacious. DESIGN: Randomized, clinical trial. Patients were randomly assigned by a central automated system to treatment or placebo. Patients and investigators were blinded to treatment status. (ClinicalTrials.gov registration number: NCT00227370) SETTING: Multicenter trial involving 11 U.S. lung transplant centers. PATIENTS: 136 lung transplant recipients who completed 3 months of valganciclovir prophylaxis. INTERVENTION: 9 additional months of oral valganciclovir (n = 70) or placebo (n = 66). MEASUREMENTS: The primary end point was freedom from CMV disease (syndrome or tissue-invasive) on an intention-to-treat basis 300 days after randomization. Secondary end points were CMV disease severity, CMV infection, acute rejection, opportunistic infections, ganciclovir resistance, and safety. RESULTS: CMV disease occurred in 32% of the short-course group versus 4% of the extended-course group (P < 0.001). Significant reductions were observed with CMV infection (64% vs. 10%; P < 0.001) and disease severity (110 000 vs. 3200 copies/mL, P = 0.009) with extended treatment. Rates of acute rejection, opportunistic infections, adverse events, CMV UL97 ganciclovir-resistance mutations, and laboratory abnormalities were similar between groups. During the 6 months after study completion, a low incidence of CMV disease was observed in both groups. LIMITATION: Longer-term effects of extended prophylaxis were not assessed. CONCLUSION: In adult lung transplant recipients who have received 3 months of valganciclovir, extending prophylaxis by an additional 9 months significantly reduces CMV infection, disease, and disease severity without increased ganciclovir resistance or toxicity. A beneficial effect with regard to prevention of CMV disease seems to extend at least through 18 months after transplantation.

The impact of the lung allocation score.

The lung allocation score (LAS) was developed in an effort to facilitate lung transplantation to more urgent and ill patients, to decrease wait time, and to change the allocation process to a more merit-based system. Four years after the implementation of the LAS, we now evaluate the impact and outcomes of this system. We have found that registrations on the wait list as well as wait time have decreased. Mortality on the wait list has decreased. There has been significant change in the distribution of diagnoses receiving transplantation with no significant difference in survival in most areas. Patients with higher LAS scores have increased short-term mortality. The LAS has affected the allocation process as well as significant outcomes in the transplant patient population.

Early readmission is a predictor of overall survival following isolated lung transplantation.

Causes of early readmissions following lung transplantation are not well understood, and the impact is poorly reported. We reviewed 221 consecutive lung transplantations and identified patients readmitted within 90 days. A case control analysis was performed to determine the characteristics that predict readmission and the impact of readmission on survival. Ninety (44%) of the 205 operative survivors required a total of 125 readmissions during the 90 days after transplantation. Twenty-eight patients (13.7%) required multiple readmissions. Causes for readmissions were pulmonary complication (59%), gastrointestinal (18%), cardiac (5%), metabolic (2.5%), neurological (2.5%), hematological (2%), and miscellaneous (11%). The sex, native disease, or type of transplant did not predict readmission. Requirement of cardiopulmonary bypass for transplantation showed a trend toward significance (P = 0.08). The 90-day conditional survival at 1, 3, and 5 years for those patients readmitted within 90 days were 76%, 59%, and 52%, respectively, compared to 93%, 80%, and 76% for patients not readmitted (P = 0.01). Requirement for readmission within 90 days following transplantation is associated with increased mortality. Sex, native disease, and type of transplant are not predictors of readmission or survival.

Geographic Variation in the Treatment of U.S. Adult Heart Transplant Candidates.

BACKGROUND: The current U.S. priority ranking for heart candidates is based on treatment intensity, not objective markers of severity of illness. This system may encourage centers to overtreat candidates. OBJECTIVES: This study sought to describe national variation in the intensity of treatment of adult heart transplantation candidates and identify center-level predictors of potential overtreatment. METHODS: The registrations of all U.S. adult heart transplantation candidates from 2010 to 2015 were collected from the SRTR (Scientific Registry of Transplant Recipients). "Potential overtreatment" was defined as treatment of a candidate who did not meet American Heart Association cardiogenic shock criteria with either high-dose inotropes or an intra-aortic balloon pump. Multilevel logistic regression and propensity score models were used to adjust for candidate variability at each center. Center-level variables associated with potential overtreatment were identified. RESULTS: From 2010 to 2015, 108 centers listed 12,762 adult candidates who were not in cardiogenic shock for heart transplantation. Of these, 1,471 (11.6%) were potentially overtreated with high-dose inotropes or intra-aortic balloon pumps. In the bottom quartile of centers, only 2.1% of candidates were potentially overtreated compared with 27.6% at top quartile centers, an interquartile difference of 25.5% (95% confidence interval: 21% to 30%). Adjusting for candidate differences did not significantly alter the interquartile difference. Local competition with 2 or more centers increased the odds of potential overtreatment by 50% (adjusted odds ratio: 1.50; 95% confidence interval: 1.07 to 2.11). CONCLUSIONS: There is wide variation in the treatment practices of adult heart transplantation centers. Competition for transplantable donor hearts is associated with the potential overtreatment of hemodynamically stable candidates. Overtreatment may compromise the fair and efficient allocation of scarce deceased donor hearts.

Organ allocation in lung transplant.

Since the first successful single-lung transplant in 1983 and double-lung transplant in 1986, thousands of patients have benefited from the procedures. Until 1995, allocation of donor lungs was based purely on time on the waiting list. In 1995, a 90-day credit was given to patients with idiopathic pulmonary fibrosis, while still maintaining allocation based on waiting list time. In 2005, the lung allocation score (LAS) was implemented, dramatically changing the way lungs are allocated. This article will explore the reasons for the creation of the LAS, the design of the score, early experience with transplant results under the new system, and further changes that may be made to the system of lung allocation. As surgical techniques and medical management evolve, so to will the management of potential donors and the allocation of their organs, with the aim of benefiting patients needing lung transplantation in the United States.

Elevation of interleukin-15 protein expression in bronchoalveolar fluid in acute lung allograft rejection.

BACKGROUND: Acute rejection remains a major source of morbidity in lung transplantation. Although interleukin (IL)-2 has been the principal T-cell growth factor implicated in acute rejection, IL-2 blockade does not prevent acute rejection completely. Recently, IL-15, a stromal cell-derived cytokine, has been found to share a similar biological function with IL-2. We hypothesized that IL-15 levels may be elevated in acute lung rejection in the presence of IL-2 blockade. METHODS: Acute allograft rejection developed in 21 of 42 lung transplant recipients. BAL fluid (BALF) was analyzed for IL-2 and IL-15 protein expression by standard enzyme-linked immunosorbent assay. RESULTS: The average (+/- SD) BALF IL-15 level was higher in lung transplant recipients with acute rejection compared to those without rejection (25 +/- 25 pg/mL vs 4.5 +/- 1.5 pg/mL, respectively; p < 0.0001). In addition, there appeared to be a bimodal distribution of BALF IL-15 levels in lung transplant recipients with acute rejection. BALF IL-2 levels were not associated with acute rejection. BALF IL-15 levels were not associated with bacterial, fungal, or cytomegalovirus infection. CONCLUSION: These data show that BALF IL-15 levels are elevated in acute lung allograft rejection in the presence of IL-2 receptor blockade and may be an important mediator for acute rejection in lung transplantation.

Clinical pathway after lung transplantation shortens hospital length of stay without affecting outcome.

Transplant programs are under pressure to resolve multiple challenges related to quality, cost, and access in a resource-driven customer-focused health care environment. We reviewed outcomes of patients undergoing isolated lung transplantation using a single postoperative clinical pathway, developed between the specialties of Thoracic Surgery, Pulmonary and Critical Care Medicine, and Nursing. The data were retrospectively reviewed for mortality, length to extubation (LE), hospital length of stay (LOS), and readmissions of 183 consecutive patients. One hundred ten women and 73 men with a mean age of 48 +/- 12 years underwent 90 bilateral, 88 single, and 6 repeat lung transplantations. Median LE was 17 hours, and the LOS was 7 days. The operative mortality was 6.5%. One- and 3-year survivals were 82% and 73%, respectively. We conclude that a single multidisciplinary clinical pathway can facilitate early discharge from the hospital. Early hospital discharge after lung transplantation does not compromise early or late outcome.

Trends in the Use of Inotropes to List Adult Heart Transplant Candidates at Status 1A.

BACKGROUND: The number of adult heart transplant candidates waiting at the most urgent status 1A has increased over time despite the expansion of geographic sharing of hearts in 2006. We aimed to determine whether candidates listed with inotropes contribute to the excess status 1A candidates. METHODS AND RESULTS: The initial registrations of all adult heart-only candidates listed from 2000 to 2015 were analyzed using the Scientific Registry of Transplant Recipients data set. Trends in listing status, justifications, and candidate factors were measured. Adjusted trends in listing status pre- and post-geographic sharing were estimated using multilevel logistic regression. Competing risks models provided trends in transplant-free waitlist survival. There were 46 853 adult heart-alone listings during 2000 to 2015. Pre-sharing, status 1A listing was unchanged over time (adjusted odds ratio, 0.98; 95% confidence interval, 0.78-1.23). Post-sharing, the adjusted odds of status 1A listing increased 117% over 9 years (adjusted odds ratio 2.17, 95% confidence interval, 1.82-2.58). The number of candidates listed as status 1A with inotropes increased by 193 a year, whereas the dobutamine, dopamine, and milrinone doses used decreased 49%, 55%, and 29% (P<0.001). The risk of waitlist death or deterioration of status 1A inotrope candidates relative to status 2 candidates decreased 62% for 2006 to 2010 and 70% for 2011 to 2015 compared with that for 2003 to 2006. CONCLUSIONS: After the wider geographic sharing of hearts in 2006, transplant programs used multiple inotropes to list candidates at status 1A more frequently with progressively lower doses. Concurrently, the status 1A inotrope candidate waitlist outcomes improved substantially. These trends suggest that overtreatment with multiple inotropes contributes to the current critical excess of status 1A candidates.

Comprehensive Care of the Lung Transplant Patient.

Lung transplantation has evolved into a life-saving treatment with improved quality of life for patients with end-stage respiratory failure unresponsive to other medical or surgical interventions. With improving survival rates, the number of lung transplant recipients with preexisting and posttransplant comorbidities that require attention continues to increase. A partnership between transplant and nontransplant care providers is necessary to deliver comprehensive and optimal care for transplant candidates and recipients. The goals of this partnership include timely referral and assistance with transplant evaluation, optimization of comorbidities and preparation for transplantation, management of common posttransplant medical comorbidities, immunization, screening for malignancy, and counseling for a healthy lifestyle to maximize the likelihood of a good outcome. We aim to provide an outline of the main aspects of the care of candidates for and recipients of lung transplants for nontransplant physicians and other care providers.

Patient factors associated with lung transplant referral and waitlist for patients with cystic fibrosis and pulmonary fibrosis.

BACKGROUND: Since 2005, the Lung Allocation Score (LAS) has prioritized patient benefit and post-transplant survival, reducing waitlist to transplant time to <200 days and decreasing mortality on the waitlist. A current challenge is the wait for the waitlist-the time between the patient's transplant-eligible diagnosis and waitlist registration. METHODS: We investigated whether sociodemographic (age, sex, race, insurance, marital status, median household income) and clinical (forced expiratory volume in 1 second [FEV1] percent of predicted, body mass index, depression/anxiety, alcohol/substance misuse, absolute/relative contraindications) factors influenced referral and waitlist registration. We conducted a retrospective cohort study through chart review of hospitalized patients on the University of Chicago general medicine service from 2006 to 2014 who met transplant-eligible criteria and ICD-9 billing codes for cystic fibrosis (CF) and pulmonary fibrosis (PF). We analyzed the times from transplant eligibility to referral, work-up and waitlisting using Kaplan-Meier curves and log-rank tests. RESULTS: Overall, the referral rate for transplant-eligible patients was 64%. Of those referred, approximately 36% reach the lung transplant waitlist. Referred CF patients were significantly more likely to reach the transplant waitlist than PF patients (CF 60% vs PF 22%, p < 0.05). In addition, CF patients had a shorter wait from transplant eligibility to waitlist than PF patients (329 vs 2,369 days, respectively [25th percentile], p < 0.05). Patients with PF and CF both faced delays from eligibility to referral and waitlist. CONCLUSIONS: Quality improvement efforts are needed to better identify and refer appropriate patients for lung transplant evaluation. Targeted interventions may facilitate more efficient evaluation completion and waitlist appearance.

Sequential gene expression profiling in lung transplant recipients with chronic rejection.

STUDY OBJECTIVES: Chronic allograft rejection is the leading cause of morbidity and mortality for long-term survivors of lung transplantation. Previous studies have implicated only isolated genes in the development of chronic rejection and have not examined multiple pathways in an individual concurrently. Using microarray technology, we identified and compared gene expression profiling in lung transplant recipients with and without chronic rejection, and follow sequential expression of genes differentially expressed between the two groups. DESIGN: Prospective, cohort study. SETTING: Single lung transplant center. PATIENTS OR PARTICIPANTS: Eleven transplant recipients with chronic rejection were matched with 9 control transplant recipients. INTERVENTIONS: All recipients underwent surveillance bronchoscopies at predetermined times to rule out infection and/or acute rejection. Gene expression profiling was obtained from hybridizing BAL fluid cell RNA to a 96-gene microarray. MEASUREMENTS AND RESULTS: Fifteen genes were found to be significantly differentially expressed between the two patient groups, and they are involved in inflammatory, fibrotic, and apoptotic pathways. Temporal expression of the significant genes demonstrated a change in their levels at the onset of chronic rejection, with normalization to prerejection levels as rejection continued. CONCLUSIONS: We conclude that microarray technology is valuable in studying the mechanism of chronic lung rejection, and the expression of genes in multiple pathways is elevated in patients with chronic lung rejection.

Analysis of the human cytomegalovirus genomic region from UL146 through UL147A reveals sequence hypervariability, genotypic stability, and overlapping transcripts.

BACKGROUND: Although the sequence of the human cytomegalovirus (HCMV) genome is generally conserved among unrelated clinical strains, some open reading frames (ORFs) are highly variable. UL146 and UL147, which encode CXC chemokine homologues are among these variable ORFs. RESULTS: The region of the HCMV genome from UL146 through UL147A was analyzed in clinical strains for sequence variability, genotypic stability, and transcriptional expression. The UL146 sequences in clinical strains from two geographically distant sites were assigned to 12 sequence groups that differ by over 60% at the amino acid level. The same groups were generated by sequences from the UL146-UL147 intergenic region and the UL147 ORF. In contrast to the high level of sequence variability among unrelated clinical strains, the sequences of UL146 through UL147A from isolates of the same strain were highly stable after repeated passage both in vitro and in vivo. Riboprobes homologous to these ORFs detected multiple overlapping transcripts differing in temporal expression. UL146 sequences are present only on the largest transcript, which also contains all of the downstream ORFs including UL148 and UL132. The sizes and hybridization patterns of the transcripts are consistent with a common 3'-terminus downstream of the UL132 ORF. Early-late expression of the transcripts associated with UL146 and UL147 is compatible with the potential role of CXC chemokines in pathogenesis associated with viral replication. CONCLUSION: Clinical isolates from two different geographic sites cluster in the same groups based on the hypervariability of the UL146, UL147, or the intergenic sequences, which provides strong evidence for linkage and no evidence for interstrain recombination within this region. The sequence of individual strains was absolutely stable in vitro and in vivo, which indicates that sequence drift is not a mechanism for the observed sequence hypervariability. There is also no evidence of transcriptional splicing, although multiple overlapping transcripts extending into the adjacent UL148 and UL132 open reading frames were detected using gene-specific probes.

Intraabdominal complications after lung transplantation.

BACKGROUND: Because more lung transplant recipients survive the perioperative period, nonpulmonary complications become a major source of morbidity and mortality. Of these, intraabdominal complications are of particular concern because of the potential need for surgical intervention. So appropriate management of these complications becomes paramount. STUDY DESIGN: We retrospectively reviewed 229 lung transplant recipients in a university medical center, between January 1997 and December 2004 developed in forty-seven patients. Abdominal complications. Detailed reviews of these patients' hospital charts were performed. Complications were categorized as early or late depending on if they occurred within 30 days of transplantation or later. The primary outcomes variable studied was mortality. RESULTS: Fifty-three surgical consultations for abdominal symptoms were requested in these 47 patients. Twenty-two of the 47 patients (47%) with intraabdominal complications required 24 operative interventions. Overall 5-year survival was substantially worse in patients with intraabdominal complications (34%) than in those without (62%, p=0.01). There was no marked difference in the 30-day mortality for patients experiencing early (27%, 4 of 15) versus late (24%, 9 of 38) complications. Mortality in patients with intraabdominal complications was lower among those treated operatively (n=2, 9%) compared with those treated nonoperatively (n=11, 44%, p=0.02). CONCLUSIONS: Mortality for patients with intraabdominal complications is high after lung transplantation. Operative intervention is well tolerated and associated with lower mortality. A high index of suspicion and timely operative intervention are necessary for the treatment of intraabdominal complications in lung transplant recipients.