M. Crespo

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.

Aspergillus galactomannan antigen in the bronchoalveolar lavage fluid for the diagnosis of invasive aspergillosis in lung transplant recipients

Background. The clinical utility of Platelia Aspergillus enzyme immunoassay (EIA) for galactomannan (GM) antigen detection in bronchoalveolar lavage (BAL) for the diagnosis of invasive aspergillosis (IA) in lung transplant recipients is not known. Methods. BAL fluid samples from consecutive lung transplant recipients who underwent bronchoscopy were prospectively analyzed for GM. Results. A total of 333 BAL samples from 116 patients were tested. Invasive aspergillosis was documented in 5.2% (6/116) of the patients. Samples analyzed included 9 BALs from two patients with proven IA, 19 BALs from four patients with probable IA, and 305 BALs from 110 patients without IA. At the index cutoff value of ≥0.5, the sensitivity was 60%; specificity was 95%, with positive and negative likelihood ratios of 14 and 0.41, respectively. Increasing the index cutoff value to ≥1.0 yielded a sensitivity of 60%, a specificity of 98%, and the positive and negative likelihood ratios of 28 and 0.40, respectively. Two of six patients with IA receiving antifungal prophylaxis had false-negative results. Conclusions. A Platelia EIA index cut-off ≥1.0 in the BAL fluid in a lung transplant recipient with a compatible clinical illness may be considered as suggestive of IA.

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.

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.

Comparison of an Aspergillus Real-time Polymerase Chain Reaction Assay With Galactomannan Testing of Bronchoalvelolar Lavage Fluid for the Diagnosis of Invasive Pulmonary Aspergillosis in Lung Transplant Recipients

BACKGROUND Early diagnosis and treatment of invasive pulmonary aspergillosis (IPA) improves outcome. METHODS We compared the performance of publicly available pan-Aspergillus, Aspergillus fumigatus-, and Aspergillus terreus-specific real-time polymerase chain reaction (PCR) assays with the Platelia galactomannan (GM) assay in 150 bronchoalveolar lavage (BAL) samples from lung transplant recipients (16 proven/probable IPA, 26 Aspergillus colonization, 11 non-Aspergillus mold colonization, and 97 negative controls). RESULTS The sensitivity and specificity of pan-Aspergillus PCR (optimal quantification cycle [Cq], ≤35.0 by receiver operating characteristic analysis) and GM (≥.5) for diagnosing IPA were 100% (95% confidence interval, 79%-100%) and 88% (79%-92%), and 93% (68%-100%) and 89% (82%-93%), respectively. The sensitivity and specificity of A. fumigatus-specific PCR were 85% (55%-89%) and 96% (91%-98%), respectively. A. terreus-specific PCR was positive for the 1 patient with IPA due to this species; specificity was 99% (148 of 149 samples). Aspergillus PCR identified 1 patient with IPA not diagnosed by GM. For BAL samples associated with Aspergillus colonization, the specificity of GM (92%) was higher than that of pan-Aspergillus PCR (50%; P = .003). Among negative control samples, the specificity of pan-Aspergillus PCR (97%) was higher than that of BAL GM (88%; P = .03). Positive results for both BAL PCR and GM testing improved the specificity to 97% with minimal detriment to sensitivity (93%). CONCLUSIONS A recently developed pan-Aspergillus PCR assay and GM testing of BAL fluid may facilitate the diagnosis of IPA after lung transplantation. A. fumigatus- and A. terreus-specific real-time PCR assays may be useful in rapidly identifying the most common cause of IPA and a species that is intrinsically resistant to amphotericin B, respectively.

Voriconazole exposure and geographic location are independent risk factors for squamous cell carcinoma of the skin among lung transplant recipients

BACKGROUND Skin cancer, in particular squamous cell carcinoma (SCC), is the most common malignancy after solid-organ transplantation. SCC has been reported in immunosuppressed patients receiving voriconazole, but the agent has not been shown to be a risk factor. Universal voriconazole prophylaxis and alemtuzumab induction are standard in our lung transplant program. METHODS We performed a retrospective, case-control study (matched 1:3) among lung transplant recipients at our center from 2003 to 2008. RESULTS SCC was diagnosed in 3.1% (17 of 543) of patients at a median follow-up of 36 months. Median time to development of SCC was 19 months post-transplant. Risk factors for SCC by univariate analysis included older age (p = 0.02), residence in locations with high levels of sun exposure (p = 0.0001), single-lung transplant (p = 0.02) and duration (p = 0.03) and cumulative dose (p = 0.03) of voriconazole. Duration of voriconazole (hazard ratio [HR] = 2.1; p = 0.04) and residence in locations with high sun exposure (HR = 3.8; p = 0.0004) were independent risk factors by multivariate analysis. SCC lesions were located on the head and neck in 94% of cases, and 53% had multiple lesions. All patients were treated with surgery. At least one independent lesion developed subsequently in 47% of patients. Local spread and distant metastases each occurred in 7% of cases. There were no deaths among the cases. CONCLUSIONS Voriconazole exposure is a risk factor for SCC after lung transplantation, particularly among older patients living in areas with high sun exposure. Voriconazole should be used cautiously in these patients.

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.

Antireflux Surgery Preserves Lung Function in Patients With Gastroesophageal Reflux Disease and End-stage Lung Disease Before and After Lung Transplantation

BACKGROUND Gastroesophageal reflux disease (GERD) is common in patients with end-stage lung disease (ESLD). GERD may cause obliterative bronchiolitis after lung transplantation (LTx), represented by a decline in forced expiratory volume in 1 second (FEV(1)). OBJECTIVES To identify the patterns of reflux in patients with ESLD and to determine whether antireflux surgery (ARS) positively impacts lung function. DESIGN Retrospective review of prospectively collected data. SETTING Tertiary care university hospital. PATIENTS Forty-three patients with ESLD and documented GERD (pre-LTx, 19; post-LTx, 24). INTERVENTIONS Antireflux surgery. MAIN OUTCOME MEASURES Reflux patterns including laryngopharyngeal reflux as measured by esophageal impedance, and FEV(1), and episodes of pneumonia and acute rejection before and after ARS. RESULTS Before ARS, 19 of 43 patients (44%) were minimally symptomatic or asymptomatic. Laryngopharyngeal reflux events, which occurred primarily in the upright position, were common in post-LTx (56%) and pre-LTx (31%) patients. At 1 year after ARS, FEV(1) significantly improved in 91% of the post-LTx patients (P < .01) and 85% of the pre-LTx patients (P = .02). Of patients with pre-ARS declining FEV(1), 92% of post-LTx and 88% of pre-LTx patients had a reversal of this trend. Episodes of pneumonia and acute rejection were significantly reduced in post-LTx patients (P = .03) or stablilized in pre-LTx patients (P = .09). CONCLUSIONS There should be a low threshold for performing objective esophageal testing including esophageal impedance because GERD may be occult and ARS may improve or prolong allograft and native lung function.

Successful Outcome of Human Metapneumovirus (hMPV) Pneumonia in a Lung Transplant Recipient Treated With Intravenous Ribavirin

Human metapneumovirus (hMPV) has recently been shown to be a prominent cause of respiratory infections in immunocompromised hosts, and is associated with high morbidity and mortality. We report a case of hMPV pneumonia in a lung transplant recipient presenting with respiratory failure and sepsis syndrome. hMPV was diagnosed by polymerase chain reaction, and treated with intravenous ribavirin with a successful outcome.

Obesity and Primary Graft Dysfunction after Lung Transplantation: The Lung Transplant Outcomes Group Obesity Study

RATIONALE Obesity has been linked to acute lung injury and is a risk factor for early mortality after lung transplantation. OBJECTIVES To examine the associations of obesity and plasma adipokines with the risk of primary graft dysfunction after lung transplantation. METHODS We performed a prospective cohort study of 512 adult lung transplant recipients with chronic obstructive pulmonary disease or interstitial lung disease enrolled in the Lung Transplant Outcomes Group Study. In a nested case-control study, we measured plasma leptin, adiponectin, and resistin before lung transplantation and 6 and 24 hours after lung transplantation in 40 cases of primary graft dysfunction and 80 control subjects. Generalized linear mixed models and logistic regression were used to estimate risk ratios and odds ratios. MEASUREMENTS AND MAIN RESULTS Grade 3 primary graft dysfunction developed within 72 hours of transplantation in 29% participants. Obesity was associated with a twofold increased risk of primary graft dysfunction (adjusted risk ratio 2.1; 95% confidence interval, 1.7-2.6). The risk of primary graft dysfunction increased by 40% (confidence interval, 30–50%) for each 5 kg/m(2) increase in body mass index after accounting for center, diagnosis, cardiopulmonary bypass, and transplant procedure. Higher plasma leptin levels were associated with a greater risk of primary graft dysfunction (sex-adjusted P = 0.02). The associations of both obesity and leptin with primary graft dysfunction tended to be stronger among those who did not undergo cardiopulmonary bypass. CONCLUSIONS Obesity is an independent risk factor for primary graft dysfunction after lung transplantation.