David Weill

A consensus document for the selection of lung transplant candidates: 2014--an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation.

The appropriate selection of lung transplant recipients is an important determinant of outcomes. This consensus document is an update of the recipient selection guidelines published in 2006. The Pulmonary Council of the International Society for Heart and Lung Transplantation (ISHLT) organized a Writing Committee of international experts to provide consensus opinion regarding the appropriate timing of referral and listing of candidates for lung transplantation. A comprehensive search of the medical literature was conducted with the assistance of a medical librarian. Writing Committee members were assigned specific topics to research and discuss. The Chairs of the Writing Committee were responsible for evaluating the completeness of the literature search, providing editorial support for the manuscript, and organizing group discussions regarding its content. The consensus document makes specific recommendations regarding the timing of referral and of listing for lung transplantation. These recommendations include discussions not present in previous ISHLT guidelines, including lung allocation scores, bridging to transplant with mechanical circulatory and ventilator support, and expanded indications for lung transplantation. In the absence of high-grade evidence to support decision making, these consensus guidelines remain part of a continuum of expert opinion based on available studies and personal experience. Some positions are immutable. Although transplant is rightly a treatment of last resort for end-stage lung disease, early referral allows proper evaluation and thorough patient education. Subsequent waiting list activation implies a tacit agreement that transplant offers a significant individual survival advantage. It is both the challenge and the responsibility of the transplant community globally to ensure organ allocation maximizes the potential benefits of a scarce resource, thereby achieving that advantage.

Following Universal Prophylaxis with Intravenous Ganciclovir and Cytomegalovirus Immune Globulin, Valganciclovir is Safe and Effective for Prevention of CMV Infection Following Lung Transplantation

We prospectively determined the safety and efficacy of valganciclovir for prevention of cytomegalovirus (CMV) in at‐risk (donor positive/recipient negative [D+/R−] or R+) lung transplant recipients. We also determined the length of prophylaxis required to significantly decrease both CMV infection and disease. Consecutive lung transplant recipients surviving >30 days (n = 90) received combination prophylaxis with intravenous (i.v.) ganciclovir (GCV) 5 mg/kg/day and cytomegalovirus immune globulin (CMV‐IVIG) followed by valganciclovir (450 mg twice‐daily) to complete 180, 270 or 365 days of prophylaxis. This group was compared to a historical group (n = 140) who received high‐dose oral acyclovir following i.v. GCV and CMV‐IVIG. CMV disease was significantly lower in patients receiving valganciclovir compared to acyclovir (2.2% vs. 20%; p < 0.0001). Freedom from CMV infection and disease was significantly greater (p < 0.02) in patients receiving 180, 270 or 365 days of prophylaxis (90%, 95% and 90%, respectively) compared to those receiving 100–179 days (64%) or <100 days (59%). No patient receiving valganciclovir died during the study. Following prophylaxis with i.v. GCV and CMV‐IVIG, valganciclovir is safe and effective for prevention of CMV infection and disease in at‐risk lung transplant recipients. The required length of prophylaxis was at least 180 days.

Heart and Lung Transplantation in the United States, 1997-2006

This article highlights trends in heart and lung transplantation between 1997 and 2006, drawing on data from the OPTN and SRTR. The total number of candidates actively awaiting heart transplantation declined by 45% over the last decade, dropping from 2414 patients in 1997 to 1327 patients in 2006. The overall death rates among patients awaiting heart transplantation declined over the same period. The distribution of recipients among the different status groups at the time of heart transplantation changed little between the inception of the new classification system in 1999 and 2005. Deaths in the first year after heart transplantation have steadily decreased. At the end of 2006, 2885 candidates were awaiting a lung transplant, up 10% from the 1997 count. The median time‐to‐transplant for listed patients decreased by 87% over the decade, dropping from 1053 days in 1997 to 132 days in 2006. Selection for listing and transplantation has shifted toward more urgent patients since the May 2005 implementation of a new lung allocation system based on survival benefit and urgency rather than waiting time. Only 31 heart‐lung transplants were performed in 2006, down from a high of 62 in 1997.

Effect of Etiology and Timing of Respiratory Tract Infections on Development of Bronchiolitis Obliterans Syndrome

BACKGROUND Among the many potential risk factors influencing the development of bronchiolitis obliterans syndrome (BOS), acute cellular rejection is the most frequently identified. Despite the unique susceptibility of the lung allograft to pathogens, the association with respiratory tract infections remains unclear. In this study we analyze the role respiratory tract infections have on the development of BOS after lung transplantation. METHODS Data from a single center were analyzed from 161 lung recipients transplanted from November 1990 to November 2005, and who survived >180 days. Univariate and multivariate Cox regression analyses were performed using BOS development and the time-scale was reported with hazard ratios (HRs) and confidence intervals (CIs). RESULTS Significant findings by univariate analysis per 100 patient-days prior to BOS onset included acute rejection, cytomegalovirus (CMV) pneumonitis, Gram-negative respiratory tract infections, Gram-positive respiratory tract infections and fungal pneumonias. Multivariate analysis indicated acute rejection, Gram-negative, Gram-positive and fungal pneumonias with HRs (CI) of 84 (23 to 309), 6.6 (1.2 to 37), 6,371 (84 to 485,000) and 314 (53 to 1,856) to be associated with BOS, respectively. Acute rejection, CMV pneumonitis, Gram-positive pneumonia and fungal pneumonitis in the first 100 days had HRs (CI) of 1.8 (1.1 to 3.2), 3.1 (1.3 to 6.9), 3.8 (1.5 to 9.4) and 2.1 (1.1 to 4.0), respectively, and acute rejection and fungal pneumonitis in the late post-operative period with HRs (CI) of 2.3 (1.2 to 4.4) and 1.5 (1.1 to 1.9), respectively. CONCLUSIONS In addition to acute rejection, pneumonias with GP, GN and fungal pathogens occurring prior to BOS are independent determinants of chronic allograft dysfunction. Early recognition and treatment of these pathogens in lung transplant recipients may improve long-term outcomes after transplantation.

Noninvasive monitoring of infection and rejection after lung transplantation.

Significance Over 3,500 patients receive life-saving lung transplants every year. Nonetheless, complications due to infection and rejection occur frequently and undermine the long-term benefits of lung transplantation. Although clinicians strive to carefully monitor patients, diagnostic options are often limited. Rejection monitoring currently relies on invasive tissue biopsies, and tests of infection are predominately limited to testing one pathogen at a time. This manuscript describes a noninvasive assay based on sequencing of circulating cell-free DNA that simultaneously enables diagnosis of rejection and broad screening of infections. The survival rate following lung transplantation is among the lowest of all solid-organ transplants, and current diagnostic tests often fail to distinguish between infection and rejection, the two primary posttransplant clinical complications. We describe a diagnostic assay that simultaneously monitors for rejection and infection in lung transplant recipients by sequencing of cell-free DNA (cfDNA) in plasma. We determined that the levels of donor-derived cfDNA directly correlate with the results of invasive tests of rejection (area under the curve 0.9). We also analyzed the nonhuman cfDNA as a hypothesis-free approach to test for infections. Cytomegalovirus is most frequently assayed clinically, and the levels of CMV-derived sequences in cfDNA are consistent with clinical results. We furthermore show that hypothesis-free monitoring for pathogens using cfDNA reveals undiagnosed cases of infection, and that certain infectious pathogens such as human herpesvirus (HHV) 6, HHV-7, and adenovirus, which are not often tested clinically, occur with high frequency in this cohort.

Increasing Lung Allocation Scores Predict Worsened Survival Among Lung Transplant Recipients

Implemented in 2005, the lung allocation score (LAS) aims to distribute donor organs based on overall survival benefits for all potential recipients, rather than on waiting list time accrued. While prior work has shown that patients with scores greater than 46 are at increased risk of death, it is not known whether that risk is equivalent among such patients when stratified by LAS score and diagnosis. We retrospectively evaluated 5331 adult lung transplant recipients from May 2005 to February 2009 to determine the association of LAS (groups based on scores of ≤46, 47–59, 60–79 and ≥80) and posttransplant survival. When compared with patients with LAS ≤ 46, only those with LAS ≥ 60 had an increased risk of death (LAS 60–79: hazard ratio [HR], 1.52; 95% confidence interval [CI], 1.21–1.90; LAS ≥ 80: HR, 2.03; CI, 1.61–2.55; p < 0.001) despite shorter median waiting list times. This risk persisted after adjusting for age, diagnosis, transplant center volume and donor characteristics. By specific diagnosis, an increased hazard was observed in patients with COPD with LAS ≥ 80, as well as those with IPF with LAS ≥ 60.

Ganciclovir for cytomegalovirus: a call for indefinite prophylaxis in lung transplantation.

BACKGROUND Universal ganciclovir (GCV) prophylaxis is a strategy aimed at reducing cytomegalovirus (CMV) infection and delaying the development of bronchiolitis obliterans syndrome (BOS). However, the optimal duration of GCV prophylaxis remains unclear. We report our experience with GCV prophylaxis administered indefinitely and its effect on CMV pneumonitis, BOS and survival after lung transplantation (LT). METHODS One hundred fifty-one patients surviving >100 days after LT were analyzed. GCV was given to 130 CMV donor- or recipient-seropositive patients. Data from 90 patients who received indefinite GCV prophylaxis (IND) and 40 patients who discontinued their GCV prophylaxis (STOP) were compared. RESULTS CMV pneumonitis occurred in 16%, 8%, 17% and 19% of patients in the D+R+, D-R+, D+R- and D-R- groups, respectively. In the STOP cohort, 15 of 40 patients developed CMV pneumonitis (median time 79 days) after GCV was stopped. Ten of these 15 patients developed BOS (median time 116 days) after discontinuing GCV. The risk of CMV pneumonitis in the STOP cohort was significantly higher when GCV prophylaxis was discontinued within the first year. Cumulative incidence of CMV pneumonitis in the IND and STOP groups at 5 years was 2% and 57%, respectively (p < 0.001). BOS-free survival and survival were similar across both groups. CONCLUSIONS Indefinite GCV prophylaxis prevents CMV pneumonitis in 98% of LT recipients. Thirty-eight percent of patients discontinuing prophylaxis developed CMV pneumonitis, 50% of whom progressed to BOS within 1 year. Continuing ganciclovir prophylaxis indefinitely after lung transplantation should be considered.

Effects of sinus surgery on lung transplantation outcomes in cystic fibrosis.

Background In cystic fibrosis (CF) patients who are candidates for lung transplant, pretransplant sinus surgery has been advocated to avoid bacterial seeding of the transplanted lungs. This study reviews the 17-year experience of pretransplant sinus surgery among CF patients at a major transplant center. Methods Retrospective chart review was performed in all CF patients who underwent heart-lung or lung transplantation at Stanford Medical Center between 1988 and 2005. Postoperative culture data from bronchoalveolar lavage (BAL) and sinus aspirates were evaluated, in addition to survival data. Results Eighty-seven CF transplant recipients underwent pretransplant sinus surgery; 87% (n = 59/68) of patients showed recolonization of the lung grafts with Pseudomonas on BAL cultures. The median postoperative time to recolonization was 19 days. Bacterial floras cultured from sinuses were similar in type and prevalence as the floras cultured from BAL. When compared with published series of comparable cohorts in which pretransplant sinus surgery was not performed, there was no statistically significant difference in the prevalence of Pseudomonas recolonization. Times to recolonization also were similar. Survival rates in our cohort were similar to national survival rates for CF lung transplant recipients. Conclusion Despite pretransplant sinus surgery, recolonization of lung grafts occurs commonly and rapidly with a spectrum of flora that mimics the sinus flora. Survival rates of CF patients who undergo prophylactic sinus surgery are similar to those from centers where prophylactic sinus surgery is not performed routinely. Pretransplant sinus surgery does not appear to prevent lung graft recolonization and is not associated with overall survival benefit.

A multi‐drug regimen for respiratory syncytial virus and parainfluenza virus infections in adult lung and heart–lung transplant recipients

V. Liu, G.S. Dhillon, D. Weill. A multi‐drug regimen for respiratory syncytial virus and parainfluenza virus infections in adult lung and heart–lung transplant recipients.
Transpl Infect Dis 2010: 12: 38–44. All rights reserved

Combination Prophylaxis with Ganciclovir and Cytomegalovirus (CMV) Immune Globulin After Lung Transplantation: Effective CMV Prevention Following Daclizumab Induction

Despite the serious direct and indirect deleterious effects caused by cytomegalovirus (CMV), the optimal prophylactic strategy remains unknown. We sought to determine whether combination prophylaxis using intravenous ganciclovir (GCV) and CMV‐IVIG reduced the incidence of CMV compared to GCV alone. Donor CMV positive/recipient negative (D+/R–) patients received GCV (6 weeks i.v. + 6 weeks oral) and CMV‐IVIG (every 2 weeks for 7 doses), while R+ patients received GCV (2 weeks i.v. + 4 weeks oral) and CMV‐IVIG (every 2 weeks for 3 doses). The group receiving combination prophylaxis (GpA) was compared to a historical, case‐controlled group receiving GCV alone (GpB). Groups were matched by CMV donor/recipient serology, pretransplant diagnosis, age, and sex in reverse chronological order. Cyclosporine, azathioprine, and prednisone were used in both groups. Additionally, GpA received daclizumab induction therapy. Groups were compared as to the incidence of CMV disease, CMV infection, and acute rejection (AR). In GpA, 38 patients were evaluable and matched to 48 patients in GpB. Three GpA patients (8%) (2 D+/R–) developed CMV disease vs. 16 patients (33%) in GpB, p = 0.0077, Fishers exact. There was also a trend toward a delay in CMV onset (148 days in GpA vs. 92 days in GpB, p = 0.07, Mann–Whitney). CMV infection did not occur in GpA, and one case occurred in GpB. There was no difference in the incidence of AR (66% in GpA vs. 79% in GpB, p = 0.22, Fishers exact) or the need for cytolytic therapy between groups. Despite the use of daclizumab induction therapy, combination prophylaxis with GCV and CMV‐IVIG reduced the incidence and probably delayed the onset of CMV infection compared to GCV alone. Longer follow‐up will be needed to evaluate the impact of combination therapy on the incidence of bronchiolitis obliterans syndrome (BOS).