D. Zaldonis

Voriconazole Prophylaxis in Lung Transplant Recipients

Lung transplant recipients have one of the highest rates of invasive aspergillosis (IA) in solid organ transplantation. We used a single center, nonrandomized, retrospective, sequential study design to evaluate fungal infection rates in lung transplant recipients who were managed with either universal prophylaxis with voriconazole (n = 65) or targeted prophylaxis (n = 30) with itraconazole ± inhaled amphotericin in patients at high risk (pre‐ or posttransplant Aspergillus colonization [except Aspergillus niger]). The rate of IA at 1 year was better in lung transplant recipients receiving voriconazole prophylaxis as compared to the cohort managed with targeted prophylaxis (1.5% vs. 23%; p = 0.001). Twenty‐nine percent of cases in the targeted prophylaxis group were in patients colonized with A. niger who did not receive itraconazole. A threefold or higher increase in liver enzymes was noted in 37–60% of patients receiving voriconazole prophylaxis as compared to 15–41% of patients in the targeted prophylaxis cohort. Fourteen percent in the voriconazole group as compared to 8% in the targeted prophylaxis group had to discontinue antifungal medications due to side effects. Voriconazole prophylaxis can be used in preventing IA in lung transplant recipients. Regular monitoring of liver enzymes and serum concentrations of calcineurin inhibitors are required to avoid hepatotoxicity and nephrotoxicity.

Efficacy of extracorporeal membrane oxygenation as a bridge to lung transplantation

BACKGROUND Preoperative extracorporeal membrane oxygenation (ECMO) is a risk factor for poor outcome and currently considered a contraindication to lung transplantation. The lung allocation score system was introduced in May 2005 and prioritizes lung allocation to those with the greatest respiratory impairment. The purpose of this study is to determine whether ECMO as a bridge to lung transplantation is an acceptable option to support those in respiratory failure until donor lungs become available in the lung allocation score era. METHOD A retrospective review of 715 consecutive lung transplants performed between May 2005 and September 2011 was conducted using a prospectively collected institutional registry database. Twenty-four lung transplants (3.4%) were performed in the 31 patients with attempted pretransplant ECMO; 7 patients who received ECMO patients did not survive or were deemed unfit for transplantation. These patients were compared with a control group of 691 patients who did not receive pretransplant ECMO. RESULTS The duration of pretransplant ECMO was 171 ± 242 hours (median, 91 hours). Venovenous ECMO was used for respiratory failure in 15 patients, whereas venoarterial ECMO was used for circulatory collapse due to pulmonary hypertension in 9 patients. Patients in the retransplant ECMO group were younger (46 ± 15 years vs 57 ± 14 years, P < .01) compared with the control group, with no difference in recipient gender (male/female: 10/14 vs 380/311), donor age (33 ± 14 years vs 36 ± 15 years), or donor gender (male/female: 10/14 vs 352/339). Emphysema was less common (1, 4% vs 260, 38%, P < .01), and cystic fibrosis (5, 21% vs 72, 10%, P = .09), redo lung transplant (3, 13% vs 28, 4%, P = .08), and bronchiectasis (2, 8% vs 6, 1%, P = .03) were more common in the pretransplant ECMO group. Patients in the pretransplant ECMO group had a significantly higher lung allocation score (87 ± 9 vs 44 ± 15, P < .01). All patients in the pretransplant ECMO group underwent double lung transplants on pump (cardiopulmonary bypass/ECMO), and single lung transplants were performed in 171 patients (25%) and pump was used in 243 patients (35%) in the control group. The cardiopulmonary bypass time was longer in the pretransplant ECMO group (277 ± 69 minutes vs 225 ± 89 minutes, P = .02), with no difference in ischemic time (343 ± 93 minutes vs 330 ± 98 minutes, P = .54). Cadaveric lobar lung transplants were performed because of the urgency to overcome size mismatch with an oversized donor more frequently in 25% (n = 6, no mortality with the longest follow-up at 6 years) of patients in the pretransplant ECMO group versus 0.3% (n = 2) of patients in the control group (P < .01). Post-transplant ECMO was used for primary graft dysfunction in 13 patients (54%) in the pretransplant ECMO group and 41 patients (6%) in the control group (P < .01). The median hospital stay was 46 days in the pretransplant ECMO group versus 27 days in the control group (P = .16). The actuarial survivals after lung transplants at 1, 3, 6, 12, and 24 months were 96%, 88%, 83%, 74%, and 74%, respectively, in the pretransplant ECMO group, and 97%, 94%, 90%, 83%, and 74%, respectively, in the control group (P = .787). CONCLUSIONS Although the incidence of primary graft dysfunction requiring post-transplant ECMO is higher and the hospital stay is longer in patients receiving pretransplant ECMO, the graft survival is good (2-year survival, 74%). ECMO is efficacious as a bridge to lung transplantation with good post-lung transplant outcomes.

Tacrolimus Dosing in Adult Lung Transplant Patients Is Related to Cytochrome P4503A5 Gene Polymorphism

Tacrolimus is a potent immunosuppressive agent used in lung transplantation and is a substrate for both P‐glycoprotein (P‐gp, encoded by the gene MDR1) and cytochrome (CYP) P4503A. A previous study by the authors identified a correlation between the tacrolimus blood level per dose with CYP3A5 and MDR1 gene polymorphisms in pediatric heart transplant patients. The objective of this study was to confirm the influence of these polymorphisms on tacrolimus dosing in adult lung transplant patients. Adult lung transplant patients who had been followed for at least 1 year after lung transplantation were studied. Tacrolimus blood level (ng/mL) per dose (mg/day) at 1, 3, 6, 9, and 12 months after transplantation was calculated as [L/D]. DNA was extracted from blood. MDR1 3435 CC, CT, and TT; MDR1 2677 GG, GT, and TT; and CYP3A5*1 (expressor) and *3 (nonexpressor) genotypes were determined by PCR amplification, direct sequencing, and sequence evaluation. Eightythree patients were studied. At 1, 3, 6, 9, and 12 months after the transplant, a significant difference in [L/D] was found between the CYP3A5 expressor versus nonexpressor genotypes (mean ± SD of 1.49 ± 0.88 vs. 3.11 ± 4.27, p = 0.01; 1.23 ± 0.82 vs. 3.44 ± 8.97, p = 0.05; 1.32 ± 0.96 vs. 3.81 ± 6.66, p = 0.005; 0.95 ±1.19 vs. 3.74 ±5.98, p = 0.0015; and 0.45 ± 0.2 vs. 3.76 ± 6.75, p = 0.0001, respectively). MDR1 G2677T and C3435T genotypes had only minimal effects on [L/D] at 1 and 3 months after transplantation. This study confirms the relationship of CYP3A5 polymorphisms to tacrolimus dosing in organ transplant patients. CYP3A5 expressor genotypes required a larger tacrolimus dose to achieve the same blood levels than the CYP3A5 nonexpressors at all time points during the first posttransplant year. This was not uniformly true for MDR1. The authors therefore conclude that tacrolimus dosing in adult lung transplant patients is associated with CYP3A5 gene polymorphisms.

Extracorporeal Membrane Oxygenation as a Bridge to Lung Transplant: Midterm Outcomes

BACKGROUND Extracorporeal membrane oxygenation (ECMO) is used occasionally as a bridge to lung transplantation. The impact on mid-term survival is unknown. We analyzed outcomes after lung transplant over a 19-year period in patients who received ECMO support. METHODS From March 1991 to October 2010, 1,305 lung transplants were performed at our institution. Seventeen patients (1.3%) were supported with ECMO before lung transplant. Diagnoses included retransplantation (n = 6), pulmonary fibrosis (n = 6), cystic fibrosis (n = 4), and chronic obstructive pulmonary disease (n = 1). Fifteen patients underwent double lung transplant, one patient had single left lung transplant and one patient had a heart-lung transplant. Venovenous and venoarterial ECMO were implanted in eight and nine cases, respectively. Median duration of support was 3.2 days (range, 1 to 49 days). Mean patient follow-up was 2.3 years. RESULTS Thirty-day, 1-year, and 3-year survivals were 81%, 74%, and 65%, respectively, for the supported patients and 93%, 78%, and 62% in the control group (p = 0.56). Two-year survival was not affected by ECMO type, with survival of five out of nine patients supported by venoarterial ECMO vs seven out of eight patients supported by venovenous ECMO (p = 0.17). At 1- year follow-up, allograft function for the ECMO-supported patients did not differ from the control group (forced expiratory volume in one second, 2.35 L vs 2.09 L, p = 0.39) (forced vital capacity, 3.06 L vs 2.71 L, p = 0.34). CONCLUSIONS Extracorporeal membrane oxygenation as a bridge to lung transplantation is associated with higher perioperative mortality but acceptable mid-term survival in carefully selected patients. Late allograft function did not differ in patients who received ECMO support before lung transplant from those who did not receive ECMO.

Extracorporeal Membrane Oxygenation for Primary Graft Dysfunction After Lung Transplantation: Long-Term Survival

BACKGROUND Primary graft dysfunction (PGD) after lung transplantation is a major cause of morbidity and mortality. Venovenous or venoarterial extracorporeal membrane oxygenation (ECMO) allows lung recovery; however, the optimal approach and impact on long-term survival are unknown. We analyzed outcomes after ECMO use for PGD after lung transplantation at a single center over a 15-year period and assessed long-term survival. METHODS From March 1991 to March 2006, 763 lung or heart-lung transplants were performed at our center. Fifty-eight patients (7.6%) required early (0 to 7 days after transplant) ECMO support for PGD. Venovenous or venoarterial ECMO was implemented (32 and 26 cases) depending on the patients hemodynamic stability, surgeons preference, and the era of transplantation. Mean duration of support was 5.5 days (range, 1 to 20). Mean follow-up was 4.5 years. RESULTS Thirty-day and 1- and 5-year survivals were 56%, 40%, and 25%, respectively, for the entire group. Thirty-nine patients were weaned from ECMO, 21 venovenous and 18 venoarterial (53.8% and 46.2%), with 1- and 5-year survivals of 59% and 33%, inferior to recipients not requiring ECMO (p = 0.05). Survival at 30 days and at 1 and 5 years was similar for the patients supported with venoarterial or venovenous ECMO (58% versus 55%, p = 0.7; 42% versus 39%, p = 0.8; 29% versus 22%, p = 0.6). CONCLUSIONS Extracorporeal membrane oxygenation can provide acceptable support for PGD irrespective of the method used. Long-term survival of patients with primary graft dysfunction requiring ECMO (overall and weaned) was inferior to that of patients who did not require ECMO.

Variation in antifungal prophylaxis strategies in lung transplantation

Abstract: We conducted a survey of 50 lung transplant centers across the world to evaluate the variation in antifungal prophylaxis practices. These 50 centers performed 63% of the worlds lung transplants reported in 2001. Eighty‐six percent (43/50) of the centers responded to the survey. Sixty‐nine percent (30/43) of centers used universal antifungal prophylaxis. Aerosolized amphotericin B deoxycholate (AmBd) alone or in combination with itraconazole was used at 56% (24/43) of centers. The median duration of prophylaxis with aerosolized AmBd and itraconazole was 30 and 90 days, respectively. Seventy‐four percent of the centers surveyed agreed to participate in future research prophylaxis protocols, which they felt should include both diagnostic and therapeutic arms. Our survey is the first documentation of the international variation in antifungal prophylactic strategies in lung transplant recipients, and underscores the need for multicenter, randomized trials of antifungal prophylaxis in lung transplant recipients.

Experience With Immune Monitoring in Lung Transplant Recipients: Correlation of Low Immune Function With Infection

Background. Lung transplants, in particular, have the highest rate of infections among solid organ transplant recipients. However, there is no existing objective measure to predict the development of infections. We report the correlation between Cylex ImmuKnow (ng/mL ATP) values and various infectious syndromes in a large prospective cohort of lung transplant recipients. Methods. We followed up 175 lung transplants that developed 129 infectious episodes. Multiple logistic regression analysis was performed; generalized estimating equations were used to determine the odds ratio for infections. Results. The median ImmuKnow values in cytomegalovirus disease (49.3 ng/mL ATP), viral infection (70 ng/mL ATP), and bacterial pneumonia (92 ng/mL ATP) were significantly different from stable state (174.8 ng/mL ATP). The median ImmuKnow values of fungal disease (85 ng/mL ATP) and tracheobronchitis (123 ng/mL ATP) had a tendency to be lower than stable state (P=0.10), whereas patients with fungal colonization had comparable ImmunKnow values (167 vs. 174.8 ng/mL ATP). Of the patients colonized with fungus who subsequently developed fungal disease within 100 days, the median value of ImmuKnow was significantly lower than in those who did not develop fungal disease (22.5 vs. 183.5 ng/mL ATP; P<0.0001). Generalized estimating equation regression analysis showed ImmuKnow values less than or equal to 100 ng/mL ATP to be an independent predictor of infections (odds ratio 2.81). Conclusions. Cylex ImmuKnow assay monitoring has the potential to identify the patients at risk of developing infection and those colonized with fungus that are at risk of developing disease.

Extracorporeal Membrane Oxygenation for Advanced Refractory Shock in Acute and Chronic Cardiomyopathy

BACKGROUND Extracorporeal membrane oxygenation (ECMO) has been used to obtain rapid resuscitation and stabilization in advanced refractory cardiogenic shock (CS), but clear strategies to optimize outcomes and minimize futile support have not been established. METHODS We retrospectively reviewed our experience with ECMO in patients with advanced refractory CS, after an acute myocardial infarct (AMI) compared with patients receiving ECMO after an acute decompensating chronic cardiomyopathy (CCM). RESULTS Between January 2003 and February 2009, 33 patients required ECMO support for advanced refractory CS secondary to AMI (AMI-CS) and 9 patients were supported by ECMO in the presence of an acutely decompensated CCM (CCM-CS). Survival at 30 days, 1 and 2 years for patients with AMI-CS, was 64%, 48%, and 48% compared with 56%, 11%, and 11% at the same time points for those with CCM-CS (p = 0.05). In the AMI-CS group, 14 of 33 (42%) patients were weaned directly from ECMO after revascularization; 15 of 33 (45%) patients were bridged to ventricular assist device (VAD) support and subsequently either underwent heart transplantation (n = 6), were successfully weaned from VAD (n = 2) or died while on VAD support (n = 7). In the CCM-CS group, 7 patients were bridged to VAD support (77%), with 1 patient surviving after VAD weaning. CONCLUSIONS Extracorporeal membrane oxygenation in advanced refractory AMI-CS is associated with acceptable outcomes in a well-selected population. The ECMO in patients with an acute decompensation of a chronic CM should be carefully considered, to avoid futile support.

Recovery of Functional Memory T Cells in Lung Transplant Recipients Following Induction Therapy with Alemtuzumab

Profound T‐cell depletion with the monoclonal antibody alemtuzumab facilitates reduced maintenance immunosuppression in abdominal and lung transplantation. While the phenotype of the post‐depletional T cells has been characterized, little is known about their function. In the present study, global and CMV‐specific T‐cell function was assessed longitudinally in 23 lung transplant (LTx) recipients using T‐cell assays (ImmuKnow® and T Cell Memory™ , Cylex, Columbia, MD) during the first year posttransplant after induction therapy. Recovery of mitogen responses were seen at 2 weeks posttransplantation (65%PHA; 58% Con A), despite the low number of circulating T cells (<2%). These responses declined at 4–5 months (24%PHA; 54% Con A) and were partially reconstituted by 9 months (46% PHA; 73% Con A). CMV‐specific responses recovered in 80% of R+ patients as early as 2 weeks posttransplant (n = 5) and 72% of patients had a memory response by 3 months (n = 11). In contrast, only 2 of 5 patients who did not exhibit memory responses pre‐transplant (R–) developed transient CMV‐specific T‐cell responses. Our results show that profound depletion of T cells induced by alemtuzumab spares the functional subset of CMV‐specific memory T cells. Conversely, CMV R– patients predepletion may require a prolonged period of prophylaxis.

Five-year outcomes with alemtuzumab induction after lung transplantation

BACKGROUND Induction therapy with alemtuzumab, followed by lower than conventional intensity post-transplant immunosuppression (eg, tacrolimus monotherapy), has been associated with reduced morbidity and mortality in abdominal and heart transplantation. We examined 5-year outcomes in lung recipients receiving alemtuzumab in conjunction with reduced-intensity post-transplant immunosuppression (early lower-dose tacrolimus; lower-dose steroids, with or without mycophenolate mofetil), compared with lung recipients receiving other induction agents or no induction in association with post-transplant immunosuppression. METHODS A retrospective analysis was performed using prospectively collected data from a single-site clinical database of 336 lung recipients (aged ≥ 18) who received allografts between 1998 and 2005, classified by induction type: alemtuzumab, 127; Thymoglobulin, 43; daclizumab, 73; and none, 93. Survival analyses examined patient and graft survival, and freedom from acute cellular rejection (ACR), lymphocytic bronchiolitis, obliterative bronchiolitis (OB), bronchiolitis obliterans syndrome (BOS), and post-transplant lymphoproliferative disorder (PTLD). RESULTS Five-year patient and graft survival differed by group (p = 0.046, p = 0.038, respectively). Alemtuzumab patient/graft survival rates were 59%/59%. Survival rates were 60%/44% for Thymoglobulin, 47%/46% for no induction, and 44%/41% for daclizumab. Freedom from ACR, lymphocytic bronchiolitis, OB, and BOS differed by group (all values, p < 0.008); alemtuzumab recipients showed greater 5-year freedom from each outcome (30%/82%/86%/54%) than Thymoglobulin (20%/54%/62%/27%), daclizumab (19%/55%/70%/43%), and no-induction groups (18%/70%/69%/46%). The groups did not differ in PTLD rates (≥ 94% free of PTLD at 5 years; p = 0.864). Effects were unchanged after controlling for potential covariates. CONCLUSIONS Alemtuzumab induction may be associated with improved outcomes in lung transplantation. Randomized controlled trials are needed to establish any effects of this agent.