Lung transplantation outcomes after crossing low-level donor specific antibodies without planned augmented immunosuppression.

It is unknown whether some donor specific antibodies (DSA) can be crossed at the time of lung transplant without desensitization or augmented induction immunosuppression. This study assessed whether crossing low-level pre-transplant DSA (defined as mean fluorescence intensity [MFI] 1000-6000) without augmented immunosuppression is associated with worse retransplant-free or chronic lung allograft dysfunction (CLAD)-free survival. Of the 458 included recipients, low-level pre-transplant DSA was crossed in 39 (8.6%) patients. The median follow-up time was 2.2 years. There were 15 (38.5%) patients with Class I DSA and 24 (61.5%) with Class II DSA. There was no difference in adjusted overall retransplant-free survival between recipients where pre-transplant DSA was and was not crossed (HR: .98 [95% CI = .49-1.99], P = .96). There was also no difference in CLAD-free survival (HR: .71 [95% CI = .38-1.33], P = .28). There was no difference in Grade 3 PGD at 72 h (OR: 1.13 [95% CI = .52-2.48], P = .75) or definite or probable AMR (HR: 2.22 [95% CI = .64-7.61], P = .21). Lung transplantation in the presence of low-level DSA without planned augmented immunosuppression is not associated with worse overall or CLAD-free survival among recipients with intermediate-term follow-up.

Human leukocyte antigens antibodies after lung transplantation: Primary results of the HALT study.

Donor-specific antibodies (DSA) to mismatched human leukocyte antigens (HLA) are associated with worse outcomes after lung transplantation. To determine the incidence and characteristics of DSA early after lung transplantation, we conducted a prospective multicenter observational study that used standardized treatment and testing protocols. Among 119 transplant recipients, 43 (36%) developed DSA: 6 (14%) developed DSA only to class I HLA, 23 (53%) developed DSA only to class II HLA, and 14 (33%) developed DSA to both class I and class II HLA. The median DSA mean fluorescence intensity (MFI) was 3197. We identified a significant association between the Lung Allocation Score and the development of DSA (HR = 1.02, 95% CI: 1.001-1.03, P = .047) and a significant association between DSA with an MFI ≥ 3000 and acute cellular rejection (ACR) grade ≥ A2 (HR = 2.11, 95% CI: 1.04-4.27, P = .039). However, we did not detect an association between DSA and survival. We conclude that DSA occur frequently early after lung transplantation, and most target class II HLA. DSA with an MFI ≥ 3000 have a significant association with ACR. Extended follow-up is necessary to determine the impact of DSA on other important outcomes.

Management of the Potential Organ Donor in the ICU: Society of Critical Care Medicine/American College of Chest Physicians/Association of Organ Procurement Organizations Consensus Statement.

This document was developed through the collaborative efforts of the Society of Critical Care Medicine, the American College of Chest Physicians, and the Association of Organ Procurement Organizations. Under the auspices of these societies, a multidisciplinary, multi-institutional task force was convened, incorporating expertise in critical care medicine, organ donor management, and transplantation. Members of the task force were divided into 13 subcommittees, each focused on one of the following general or organ-specific areas: death determination using neurologic criteria, donation after circulatory death determination, authorization process, general contraindications to donation, hemodynamic management, endocrine dysfunction and hormone replacement therapy, pediatric donor management, cardiac donation, lung donation, liver donation, kidney donation, small bowel donation, and pancreas donation. Subcommittees were charged with generating a series of management-related questions related to their topic. For each question, subcommittees provided a summary of relevant literature and specific recommendations. The specific recommendations were approved by all members of the task force and then assembled into a complete document. Because the available literature was overwhelmingly comprised of observational studies and case series, representing low-quality evidence, a decision was made that the document would assume the form of a consensus statement rather than a formally graded guideline. The goal of this document is to provide critical care practitioners with essential information and practical recommendations related to management of the potential organ donor, based on the available literature and expert consensus.

Plasmacytic post-transplant lymphoproliferative disorder: a case series of nine patients.

Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of organ transplantation. Although PTLD typically has a B-cell histology, an uncommon variant, plasmacytic PTLD can present as a monoclonal plasma cell proliferation similar to plasmacytomas seen in multiple myeloma. A retrospective analysis was performed on nine patients at our center with plasmacytic PTLD as characterized by plasmacytic histology with the presence of CD138 and lack of CD20. Of the 210 adult solid organ transplant PTLD patients diagnosed between 1988 and 2012, 9 (4%) had a histological appearance consistent with plasmacytic PTLD. The median time from transplant to diagnosis was 3.7 years (range 8 months-24 years). All patients presented with extranodal and often subcutaneous solid tumors. Laboratory features included elevated LDH and beta-2 microglobulin levels, monoclonal gammopathy, and EBV positivity of the tumor. Unlike conventional multiple myeloma, patients had normal calcium levels and only mild anemia. Six patients who have completed treatment achieved complete responses with radiation therapy and/or reduction in immunosuppression with two patients now greater than 5 years in continuous complete response. Plasmacytic PTLD, despite its plasmacytic histology, is responsive to conventional therapies used for B-cell PTLD including reduction in immunosuppression and radiation therapy.

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).

Donor transmission of malignant melanoma in a lung transplant recipient 32 years after curative resection.

In the current era of organ shortages and long wait times for life-saving transplants, marginal or extended donors are increasingly being considered; one such category of marginal organs is from donors with a previous history of malignancy. Melanoma in particular has been associated with increased risk of developing late recurrence. In this report, we describe a case of fatal donor melanoma transmission to a 64-year-old lung transplant recipient 32 years after surgical excision of the melanoma. Based on this report and review of the available literature, we conclude that a history of donor melanoma, regardless of the stage and time interval from 'curative' surgical resection, should remain a strong relative contraindication to transplantation.

Plasma levels of receptor for advanced glycation end products, blood transfusion, and risk of primary graft dysfunction.

RATIONALE: The receptor for advanced glycation end products (RAGE) is an important marker of lung epithelial injury and may be associated with impaired alveolar fluid clearance. We hypothesized that patients with primary graft dysfunction (PGD) after lung transplantation would have higher RAGE levels in plasma than patients without PGD. OBJECTIVES: To test the association of soluble RAGE (sRAGE) levels with PGD in a prospective, multicenter cohort study. METHODS: We measured plasma levels of sRAGE at 6 and 24 hours after allograft reperfusion in 317 lung transplant recipients at seven centers. The primary outcome was grade 3 PGD (Pa(O(2))/Fi(O(2)) < 200 with alveolar infiltrates) within the first 72 hours after transplantation. MEASUREMENTS AND MAIN RESULTS: Patients who developed PGD had higher levels of sRAGE than patients without PGD at both 6 hours (median 9.3 ng/ml vs. 7.5 ng/ml, respectively; P = 0.028) and at 24 hours post-transplantation (median 4.3 ng/ml vs. 1.9 ng/ml, respectively; P < 0.001). Multivariable logistic regression analyses indicated that the relationship between levels of sRAGE and PGD was attenuated by elevated right heart pressures and by the use of cardiopulmonary bypass. Median sRAGE levels were higher in subjects with cardiopulmonary bypass at both 6 hours (P = 0.003) and 24 hours (P < 0.001). sRAGE levels at 6 hours were significantly associated with intraoperative red cell transfusion (Spearman's rho = 0.39, P = 0.002 in those with PGD), and in multivariable linear regression analyses this association was independent of confounding variables (P = 0.02). CONCLUSIONS: Elevated plasma levels of sRAGE are associated with PGD after lung transplantation. Furthermore, plasma sRAGE levels are associated with blood product transfusion and use of cardiopulmonary bypass.

Malignancy after lung transplantation.

Lung transplantation is an established therapeutic option for selected patients with advanced lung diseases. As early outcomes after lung transplantation have improved, chronic medical illnesses have emerged as significant obstacles to long-term survival. Among them is post-transplant malignancy, currently representing the 2nd most common cause of death 5-10 years after transplantation. Chronic immunosuppressive therapy and resulting impairment of anti-tumor immune surveillance is thought to have a central role in cancer development after solid organ transplantation (SOT). Lung transplant recipients receive more immunosuppression than other SOT populations, likely contributing to even higher risk of cancer among this group. The most common cancers in lung transplant recipients are non-melanoma skin cancers, followed by lung cancer and post-transplant lymphoproliferative disorder (PTLD). The purpose of this review is to outline the common malignancies following lung transplant, their risk factors, prognosis and current means for both prevention and treatment.

Risk factors for early primary graft dysfunction after lung transplantation: a registry study.

BACKGROUND: Primary graft dysfunction (PGD) is a leading cause of early morbidity and mortality in lung transplantation. We sought to identify risk factors for PGD using the United Network for Organ Sharing/International Society for Heart and Lung Transplant (UNOS/ISHLT) Registry. METHODS: A total of 6984 lung transplants between 1994 and 2002 were available for analysis. Potential risk factors were tested for association with PGD and multivariable logistic regression was applied to adjust for confounding. RESULTS: The overall incidence of PGD was 10.7% (95% CI 9.9-11.4). In multivariable analyses, factors independently associated with PGD were donor age >45 yr (p < 0.001); donor head trauma (p = 0.03); recipient body mass index >25 kg/m(2) (p = 0.005); recipient female gender (p = 0.001); use of Eurocollins preservation solution (p = 0.001); single lung transplant (p = 0.005); increased ischemic time (p < 0.001); and elevated recipient pulmonary artery systolic pressure at transplant (p < 0.001). Recipient transplant diagnosis was strongly associated with PGD, with primary or secondary pulmonary hypertension (p < 0.001 for both), and idiopathic (p < 0.001) or secondary pulmonary fibrosis (p = 0.011) as significant and independent risk factors for PGD. CONCLUSIONS: Risk factors for PGD in the UNOS/ISHLT registry are consistent with prior smaller studies. Recipient, donor, and therapy variables are independently associated with PGD, as defined in a large registry.

Lung Transplantation.

Lung transplantation is an appropriate therapeutic option for select patients with end-stage lung diseases and offers the possibility of improved quality of life and longer survival. Unfortunately, the transplant recipient is at risk for numerous immunologic, infectious, and medical complications that threaten both of these goals. Median survival after lung transplantation is approximately 6 years. Optimizing outcomes requires close partnership between the patient, transplant center, and primary medical team. Early referral to a transplant center should be considered for patients with idiopathic pulmonary fibrosis and related interstitial lung diseases due to risk of acute exacerbation and accelerated development of respiratory failure.

Causes, Preventability, and Cost of Unplanned Rehospitalizations Within 30 Days of Discharge After Lung Transplantation.

BACKGROUND: Unplanned rehospitalizations (UR) within 30 days of discharge are common after lung transplantation. It is unknown whether UR represents preventable gaps in care or necessary interventions for complex patients. The objective of this study was to assess the incidence, causes, risk factors, and preventability of UR after initial discharge after lung transplantation. METHODS: This was a single-center prospective cohort study. Subjects completed a modified short physical performance battery to assess frailty at listing and at initial hospital discharge after transplantation and the State-Trait Anxiety Inventory at discharge. For each UR, a study staff member and the patient's admitting or attending clinician used an ordinal scale (0, not; 1, possibly; 2, definitely preventable) to rate readmission preventability. A total sum score of 2 or higher defined a preventable UR. RESULTS: Of the 90 enrolled patients, 30 (33.3%) had an UR. The single most common reasons were infection (7 [23.3%]) and atrial tachyarrhythmia (5 [16.7%]). Among the 30 URs, 9 (30.0%) were deemed preventable. Unplanned rehospitalization that happened before day 30 were more likely to be considered preventable than those between days 30 and 90 (30.0% versus 6.2%, P = 0.04). Discharge frailty, defined as short physical performance battery less than 6, was the only variable associated with UR on multivariable analysis (odds ratio, 3.4; 95% confidence interval, 1.1-11.8; P = 0.04). CONCLUSIONS: Although clinicians do not rate the majority of UR after lung transplant as preventable, discharge frailty is associated with UR. Further research should identify whether modification of discharge frailty can reduce UR.

Surgical therapies for pulmonary arterial hypertension.

Surgical therapies for the treatment of pulmonary arterial hypertension typically are reserved for patients who are deemed to be refractory to medical therapy and have evidence of progressive right-sided heart failure. Atrial septostomy, a primarily palliative procedure, may stave off hemodynamic collapse from right-sided heart failure long enough to permit a more definitive surgical treatment such as lung or combined heart-lung transplantation. This article discusses indications for and results of atrial septostomy and lung and heart-lung transplantation in patients who have pulmonary arterial hypertension.

Noninfectious Acute Lung Injury Syndromes Early After Hematopoietic Stem Cell Transplantation.

Noninfectious acute lung injury syndromes are major causes of respiratory failure and early mortality after hematopoietic stem cell transplantation (HSCT). Pulmonary edema and transfusion-related acute lung injuries are important respiratory complications seen after HSCT and in the nontransplant setting. Early transplant-specific causes of lung injury, such as idiopathic pneumonia syndrome, are reviewed. Several complications, such as drug-induced pneumonitis and cryptogenic organizing pneumonia, that occur in both the early and later time periods after HSCT are also briefly discussed. The important role of pretransplant pulmonary function testing measurements in predicting posttransplant respiratory failure is highlighted.

Impact of primary graft failure on outcomes following lung transplantation.

STUDY OBJECTIVES: Primary graft failure (PGF) is a severe acute lung injury syndrome that occurs following lung transplantation. We compared the clinical outcomes of patients who developed PGF with those who did not. METHODS: We conducted a retrospective cohort study including 255 consecutive lung transplant procedures. PGF was defined as (1) diffuse alveolar opacities developing within 72 h of transplantation, (2) an arterial partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) ratio of < 200 beyond 48 h postoperatively, and (3) no other secondary cause of graft dysfunction. PGF was tested for acceptance with 30-day and all-cause hospital mortality rates, overall survival, hospital length of stay (HLOS), duration of mechanical ventilation, and best 6-min walk test (6MWT) distance achieved within 12 months. SETTING: Academic medical center. RESULTS: The overall incidence of PGF was 11.8% (95% confidence interval [CI], 7.9 to 15.9%). The all-cause mortality rate at 30 days was 63.3% in patients with PGF and 8.8% in patients without PGF (relative risk [RR], 7.15; 95% CI, 4.34 to 11.80%; p < 0.001). A total of 73.3% of patients with PGF died during hospitalization vs 14.2% of patients without PGF (RR, 5.18%; 95% CI, 3.51 to 7.63; p < 0.001). The median HLOS in 30-day survivors was 47 days in patients with PGF vs 15 days in those without PGF (p < 0.001), and the mean duration of mechanical ventilation was 15 days in patients with PGF vs 1 day in those without PGF (p < 0.001). By 12 months, a total of 28.5% of survivors with PGF achieved a normal age-appropriate 6MWT distance vs 71.4% of survivors without PGF at 12 months (p = 0.014). The median best 6MWT distance achieved within the first 12 months was 1,196 feet in patients with PGF vs 1,546 feet in those without PGF (p = 0.009). CONCLUSIONS: PGF has a significant impact on mortality, HLOS, and duration of mechanical ventilation following lung transplantation. Survivors of PGF have a protracted recovery with impaired physical function up to 1 year following transplantation.

Renal and vestibular toxicity due to inhaled tobramycin in a lung transplant recipient.

Chronic rejection is the major hurdle to long-term survival after lung transplantation. Endobronchial infection with Pseudomonas aeruginosa is common in patients with chronic rejection and this may further contribute to deterioration of the allograft. Inhaled tobramycin is commonly used to treat P aeruginosa airways infection in patients with cystic fibrosis. The safety of inhaled tobramycin in transplant recipients, however, has not been established. We describe the first report of a lung transplant recipient who developed renal failure and vestibular injury after receiving inhaled tobramycin. We review the literature regarding the safety of inhaled tobramycin and discuss potential mechanisms that may promote systemic toxicity in transplant recipients.

Noninfectious pulmonary complications after lung transplantation.

This article reviews several important noninfectious pulmonary complications that threaten survival, pulmonary function, and quality of life after lung transplantation. Topics reviewed include primary graft dysfunction (PGD), native lung hyperinflation, anastomotic complications, phrenic nerve injury, pleural complications, lung cancer, pulmonary toxicity associated with immunosuppressive medications, and exercise limitation.

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.