Broader Geographic Sharing of Pediatric Donor Lungs Improves Pediatric Access to Transplant.

US pediatric transplant candidates have limited access to lung transplant due to the small number of donors within current geographic boundaries, leading to assertions that the current lung allocation system does not adequately serve pediatric patients. We hypothesized that broader geographic sharing of pediatric (adolescent, 12-17 years; child, <12 years) donor lungs would increase pediatric candidate access to transplant. We used the thoracic simulated allocation model to simulate broader geographic sharing. Simulation 1 used current allocation rules. Simulation 2 offered adolescent donor lungs across a wider geographic area to adolescents. Simulation 3 offered child donor lungs across a wider geographic area to adolescents. Simulation 4 combined simulations 2 and 3. Simulation 5 prioritized adolescent donor lungs to children across a wider geographic area. Simulation 4 resulted in 461 adolescent transplants per 100 patient-years on the waiting list (range 417-542), compared with 206 (range 180-228) under current rules. Simulation 5 resulted in 388 adolescent transplants per 100 patient-years on the waiting list (range 348-418) and likely increased transplant rates for children. Adult transplant rates, waitlist mortality, and 1-year posttransplant mortality were not adversely affected. Broader geographic sharing of pediatric donor lungs may increase pediatric candidate access to lung transplant.

OPTN/SRTR 2013 Annual Data Report: lung.

Lungs are allocated to adult and adolescent transplant candidates (aged ⩾ 12 years) on the basis of age, geography, blood type compatibility, and the lung allocation score (LAS), which reflects risk of waitlist mortality and probability of posttransplant survival. In 2013, the most adult candidates, 2394, of any year were added to the list. Overall median waiting time for candidates listed in 2013 was 4.0 months. The preferred procedure remained bilateral lung transplant, representing approximately 70% of lung transplants in 2013. Measures of short-term and longterm survival have plateaued since the implementation of the LAS in 2005. The number of new child candidates (aged 0-11 years) added to the lung transplant waiting list increased to 39 in 2013. A total of 28 lung transplants were performed in child recipients, 3 for ages younger than 1 year, 9 for ages 1 to 5 years, and 16 for ages 6 to 11 years. The diagnosis of pulmonary hypertension was associated with higher survival rates than cystic fibrosis or other diagnosis (pulmonary fibrosis, bronchiolitis obliterans, bronchopulmonary dysplasia). For child candidates, infection was the leading cause of death in year 1 posttransplant and graft failure in years 2 to 5.

The equitable allocation of deceased donor lungs for transplant in children in the United States.

On June 5, 2013, a US Federal Court ordered a temporary restraining order to allow two children within the court's jurisdiction to be registered on the adolescent lung transplant waiting list. On June 10, 2013, the Organ Procurement and Transplantation Network's Executive Committee altered lung allocation policy to offer candidates aged younger than 12 years greater access to adult lungs at the discretion of the national Lung Review Board. The Scientific Registry of Transplant Recipients reviewed trends over time in deceased donor lung transplant waitlist mortality and transplant rates, comparing children and adults. Mortality rates of candidates active on the waiting list have been higher for children aged 0-5 years, but have not differed for children aged 6-11 years compared with adolescents aged 12-17 years or adults aged 18 years or older. Transplant rates among active waitlist candidates have been comparable across all age groups. Thus, there is little evidence that the allocation system led to differences in waitlist mortality or transplant rates for children compared with adults. However, these comparisons are difficult to interpret given that current policies likely led to unaccounted differences in the severity of illness at the time of listing.

OPTN/SRTR 2012 Annual Data Report: lung.

Lung transplants are increasingly used as treatment for end-stage lung diseases not amenable to other medical and surgical therapies. Lungs are allocated to adult and adolescent transplant candidates on the basis of age, geography, blood type compatibility, and the Lung Allocation Score, which reflects risk of wait-list mortality and probability of posttransplant survival. The overall median waiting time in 2012 was 4 months, and 65.3% of candidates underwent transplant within 1 year of listing; however, this proportion varied greatly by donation service area. Unadjusted median survival of lung transplant recipients was 5.3 years in 2012, and median survival conditional on living for 1 year posttransplant was 6.7 years. Among pediatric lung candidates in 2012, 32.1% were wait-listed for less than 1 year, 17.9% for 1 to less than 2 years, 16.7% for 2 to less than 4 years, and 33.3% for 4 or more years. Both graft and patient survival have continued to improve; survival rates for recipients aged 6-11 years are better than for younger recipients. Compared with recipients of other solid organ transplants, lung transplant recipients experienced the highest rates of rehospitalization for transplant complications: 43.7 per 100 patients in year 1 and 36.0 in year 2.

OPTN/SRTR 2011 Annual Data Report: lung.

Lungs are allocated in part based on the Lung Allocation Score (LAS), which considers risk of death without transplant and posttransplant. Wait-list additions have been increasing steadily after an initial decline following LAS implementation. In 2011, the largest number of adult candidates were added to the waiting list in a single year since 1998; donation and transplant rates have been unable to keep pace with wait-list additions. Candidates aged 65 years or older have been added faster than candidates in other age groups. After an initial decline following LAS implementation, wait-list mortality increased to 15.7 per 100 wait-list years in 2011. Short- and long-term graft survival improved in 2011; 10-year graft failure fell to an all-time low. Since 1998, the number of new pediatric (aged 0-11 years) candidates added yearly to the waiting list has declined. In 2011, 19 pediatric lung transplants were performed, a transplant rate of 34.7 per 100 wait-list years. The percentage of patients hospitalized before transplant has not changed. Both graft and patient survival have continued to improve over the past decade. Posttransplant complications for pediatric lung transplant recipients, similar to complications for adult recipients, include hypertension, renal dysfunction, diabetes, bronchiolitis obliterans syndrome, and malignancy.

Validation of the proposed International Society for Heart and Lung Transplantation grading system for primary graft dysfunction after lung transplantation.

BACKGROUND: A scoring system was recently proposed to grade the severity of primary graft dysfunction (PGD), a frequent early complication of lung transplantation. The purposes of this study are to: (1) validate the PGD grading system with respect to patient outcomes; and (2) compare the performance of criteria employing the arterial oxygenation to fraction of inspired oxygen (P/F) ratio to an alternative grading system employing the oxygenation index (OI). METHODS: We retrospectively reviewed the medical records of 402 patients having undergone lung transplantation at our institution from 1992 through 2004. The ISHLT PGD grading system was modified and grades were assigned up to 48 hours post-transplantation as follows: Grade 1 PGD, P/F > 300; Grade 2, P/F 200 to 300; and Grade 3, P/F < 200. A worst score T(0-48) was also assigned, which reflects the highest grade recorded between T0 and T48. RESULTS: The prevalence of severe PGD (P/F Grade 3) declined after transplant, from 25% at T0 to 15% at T48. Grouping patients by P/F grade at T48 demonstrated the clearest differentiation of 90-day death rates (Grade 1, 7%; Grade 2, 12%; Grade 3, 33%) (p = 0.0001). T48 OI grade also differentiates 90-day death rates. There was no difference in longer-term survival between patients with PGD Grades 1 and 2. OI grade at T0 qualitatively improved differential mortality between Grades 1 and 2; however, the differences did not reach statistical significance. Patients with a worst score T(0-48) of Grade 3 PGD did have significantly decreased long-term survival, as well as longer ICU and hospital stay, when compared with Grades 1 and 2 PGD. Significant risk factors for short- and long-term mortality in our multivariate model were P/F Grade 3 [worst score T(0-48) as well as T0 grade], single-lung transplant, use of cardiopulmonary bypass and high pre-operative mean pulmonary artery pressure. CONCLUSIONS: There is an increased risk of short- and long-term mortality and length of hospital stay associated with severe (Grade 3) PGD. The proposed ISHLT grading system can rapidly identify patients with poor outcomes who may benefit from early, aggressive treatment. Refinement of the scoring system may further improve patient risk stratification.

Effect of preoperative pulmonary artery pressure on early survival after lung transplantation for idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the second largest indication for lung transplantation worldwide. Average 90-day mortality rates for this procedure are 22%. It is unclear what factors predispose patients with IPF to this increased early posttransplant mortality. Pulmonary hypertension may increase the risk of development of early posttransplant complications through several mechanisms. We examined the effect of secondary pulmonary hypertension on 90-day mortality after lung transplantation for IPF. METHODS: An International Society for Heart and Lung Transplant Registry cohort study of 830 patients with IPF transplanted from January 1995 to June 2002 was undertaken. Risk factors were assessed individually and adjusted for confounding by a multivariable logistic regression model. RESULTS: In the univariate analysis, pulmonary hypertension and bilateral-lung transplantation were significant risk factors for increased 90-day mortality. Multivariate analysis confirmed that mean pulmonary artery pressure and bilateral procedure remain independent risk factors after adjustment for potential confounders. Recipient age, ischemia time, cytomegalovirus status mismatch, and donor age were not independent risk factors for early mortality. CONCLUSIONS: Bilateral-lung transplantation carries a greater risk of early mortality than single-lung transplantation for IPF. Increasing pulmonary artery pressure is a risk factor for death after single-lung transplantation in IPF. Mean pulmonary artery pressure should be included in the overall risk assessment of patients with IPF evaluated for lung transplantation.

Medium-term results of extracorporeal membrane oxygenation for severe acute lung injury after lung transplantation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has been used successfully for early, severe reperfusion injury after lung transplantation. The purposes of this study are to: (1) document the medium-term survival of patients treated with ECMO; and (2) assess the extent of recovery of their pulmonary function. METHODS: We retrospectively reviewed charts of 172 patients having lung transplants at our institution from 1997 through 2002. The group included 16 patients (9% of total; 10 bilateral, 5 single, 1 living lobar) treated with ECMO for primary allograft failure after single or bilateral single-lung transplantation. Survival and bronchiolitis obliterans syndrome (BOS)-free survival rates were calculated. Pulmonary function was assessed at 2 months, 1 year and 2 years post-transplant. RESULTS: Median hospital stay was 48 days for the ECMO group and 16 days for the overall group (p < 0.05). The 90-day survival was 60% in the ECMO group, and 90% in the overall group. The 2-year survival was 46% in the ECMO group, and 69% in the overall group. Mean forced expiratory volume in 1 second (FEV(1)) in the ECMO group at 1 year was 59 +/- 13% of predicted, and at 2 years 60 +/- 15% of predicted; it was not significantly different for the overall group. CONCLUSIONS: Patients treated with ECMO for primary allograft failure after lung transplantation showed acceptable medium-term survival and pulmonary function.

Community respiratory virus infections following lung transplantation.

Respiratory infections remain a significant cause of morbidity and mortality after lung transplantation. In addition to cytomegalovirus, the community respiratory viruses such as respiratory syncytial virus (RSV), parainfluenza virus (PIV), influenza virus, and adenovirus, are important causes of infection in transplant recipients, often involve the lower respiratory tract, and may be associated with significant morbidity and mortality. In this review, we summarize the current state of knowledge regarding the epidemiology, clinical manifestations, diagnosis, treatment and outcomes associated with RSV, PIV, influenza virus, and adenovirus infections in lung transplant recipients.

Use of complementary therapies, adherence, and quality of life in lung transplant recipients.

PURPOSES: The purpose of this study was to describe complementary and alternative medicine (CAM) use by lung transplant patients and to determine whether CAM users differ from nonusers with respect to health status, quality of life, or medical adherence. METHODS: A mailed survey seeking CAM, quality of life, and adherence information was sent to 145 lung transplant recipients, and 99 responded. RESULTS: The majority (88%) used at least 1 form of CAM (median, 2; range, 0-17). Prayer (68%), support groups (43%), and relaxation techniques (31%) were the most common. Only 44% of users reported discussing CAM with their providers. CAM users were adherent to their transplant regimen. Few differences were found between CAM users and nonusers. Education, high symptom burden, female sex, and depression symptoms were associated with various types of CAM use. CONCLUSION: Most lung transplant recipients are using CAM. Providers must explore potential for interaction or enhancement between CAM and standard therapy to optimize care.

Pre-transplant corticosteroid use and outcome in lung transplantation.

BACKGROUND: The early experience of lung transplantation was plagued with airway anastomotic complications. The use of corticosteroids in the pre-transplant period has been implicated as a major contributing factor in bronchial dehiscence, and many patients have been denied transplantation on the basis of corticosteroid use. We conducted the current study to assess the risks associated with pre-transplant corticosteroid use. METHODS: We analyzed records of 73 single- and bilateral-single lung transplant recipients who had chronic obstructive pulmonary disease or alpha(1)-antitrypsin deficiency as their underlying disease from 1986 to 1996. Twenty-six patients (steroid group) received daily corticosteroid therapy (prednisone, 1.5 to 40 mg/day) up to the time of transplantation, whereas 47 patients did not receive chronic corticosteroids and had no corticosteroid therapy within 3 months of transplantation (non-steroid group). RESULTS: The demographic profiles of the 2 groups were comparable. We noted no statistical significances in length of hospital stay, duration of intensive care, and post-operative pulmonary function. The rates of cytomegalovirus infection, acute rejection, bronchiolitis obliterans syndrome, and survival were also similar. The non-steroid group seemed to have a higher rate of bronchial stenosis at 3 years (29% vs 6%, p = 0.03). Bronchial dehiscence did not occur in either study group. CONCLUSIONS: Pre-transplant use of corticosteroids does not adversely affect outcome following lung transplantation.

RAD in stable lung and heart/lung transplant recipients: safety, tolerability, pharmacokinetics, and impact of cystic fibrosis.

BACKGROUND: RAD is a novel macrolide with potent immunosuppressive and antiproliferative activities. This study characterizes the safety, tolerability, and pharmacokinetics of two different single oral doses of RAD in stable lung and heart/lung transplant recipients with and without cystic fibrosis (CF). METHODS: This was a Phase I, multicenter, randomized, double-blind, two-period, two-sequence, crossover study. Single doses of RAD capsules at doses of 0.035 mg/kg (2.5 mg maximum) or 0.10 mg/kg (7.5 mg maximum) were administered with cyclosporine (Neoral [cyclosporine, USP] modified), steroids, and azathioprine on Day 1. The alternate dose was administered on Day 16. Laboratory assessments, vital signs, and adverse events were recorded throughout the study. RAD pharmacokinetic profiles were assessed over a 7-day period following each dose. Steady-state cyclosporine (CsA) profiles were assessed at baseline and with each RAD dose; RAD and CsA trough concentrations were obtained throughout the study period. RESULTS: Of the 20 patients randomized, 8 had CF and 12 did not. Single doses of RAD were safe and well tolerated. Headache was the most common side effect. RAD produced a mild, dose-dependent, reversible decrease in platelet and leukocyte counts. Cholesterol and triglycerides were minimally affected. At both doses, CF patients had significantly lower peak concentrations of RAD than did non-CF patients (p = 0.03); however, overall exposure (area under the curve/dose) was not different between the groups (p = 0.63). At the higher dose, there was a clinically minor under-proportionality in AUC, averaging -11%. Steady-state pharmacokinetics of CsA were not affected by RAD co-administration.RAD was safe and well tolerated by stable lung and heart/lung transplant recipients with and without CF. The presence of CF did not influence the extent of RAD exposure. Single doses of RAD did not affect the pharmacokinetics of CsA. Ongoing studies are assessing the long-term safety and efficacy of RAD in lung and heart/lung transplantation.

Worldwide thoracic organ transplantation: a report from the UNOS/ISHLT international registry for thoracic organ transplantation.

Based on data reported to the UNOS/ISHLT Thoracic and International Registry for Thoracic Organ Transplantation: 1. The number of heart transplant operations performed in the United States decreased between 1998-1999 and 17 (1%) more procedures were performed in 1999 (2,181) than in 2000 (2,198). Sixty-nine more lung transplants (an 8% increase) were reported in 2000 than in 1999. 2. Coronary artery disease and cardiomyopathy were the most frequently cited indications for heart transplantation in the US and have been reported at similar rates during the past 10 years. Combined, these diagnoses account for approximately 85% of all heart transplants. In 2000, half of all lung transplants were performed for emphysema/COPD or alpha-1 antitrypsin deficiency. The most frequently reported diagnoses for thoracic transplantation outside the US were: cardiomyopathy (49%) for heart, cystic fibrosis (30%) for double lung, emphysema/COPD (34%) for single lung and primary pulmonary hypertension (21%) for heart-lung transplants. 3. US heart transplant recipients were predominately male (76%), aged 50-64 (51%) and white (81%). US lung transplant recipients were also predominately between ages 50-64 (47%) and white (90%), but unlike heart recipients were more likely to be female (51%). No meaningful variance from the US recipient demographic profile was noted for the non-US recipients during the same time period. 4. Pediatric recipients (< 18 years of age) received 11% of the reported heart transplants and 6% of the reported lung transplants in the US. 5. Among US thoracic transplant recipients during 1999, the one-year survival rates were 84% for heart, 59% for heart-lung and 77% for lung. The 5-year survival rates for transplants performed during 1995 were: 71% for heart, 56% for heart-lung and 44% for lung transplants. 6. The long-term patient survival rates were: 23% at 19 years for heart, 16% at 11 years for lung and 23% at 14 years for heart-lung recipients. 7. During the first year after transplantation, 66% of heart recipients and 44% of lung recipients did not require rehospitalization. Among those recipients who were rehospitalized, the major cause was infection.

Temporary ECMO support following lung and heart-lung transplantation.

7 days) failure. Seven (78%) patients in the early group were weaned off ECMO and 5 (56%) survived to hospital discharge. In the late group, none of the patients could be weaned off ECMO, yielding 100% mortality. ECMO support instituted for pulmonary graft failure that occurred within 24 hours of transplantation may improve patient survival.

Staging of bronchiolitis obliterans syndrome using home spirometry.

OBJECTIVES: To compare the detection of bronchiolitis obliterans syndrome (BOS) in lung transplant recipients by clinic pulmonary function laboratory measurement and home spirometry. DESIGN: The subjects served as their own control group. SETTING: A university-based thoracic transplant center. SUBJECTS: Forty-five lung transplant recipients (26 women and 19 men; average +/- SD age, 47.7+/-11.4 years old at the time of transplantation). Lung function declined to at least BOS stage 1 in 17 of the 45 subjects. MEASUREMENTS: All subjects were participants in a home monitoring program utilizing home spirometry measurements. Clinic spirometry and home spirometry measurements were collected concurrently. The determinations of BOS staging were based on home and clinic FEV1 values using retrospective analysis and development of the home-based BOS staging algorithm. RESULTS: BOS stage 1 was detected an average of 341 to 276 days earlier with home spirometry than with clinic pulmonary function testing in the 17 subjects who had a pulmonary decline to BOS stage 1, depending on the persistence of the decline (1 day or 3 days, respectively). The difference in BOS detection time was statistically significant for both persistence requirements (p < 0.001). CONCLUSIONS: Home spirometry detects pulmonary decline earlier than clinic spirometry; home spirometry can be a reliable and safe alternative to frequent pulmonary function testing in lung recipients.

Adjuvant treatment of refractory lung transplant rejection with extracorporeal photopheresis.

BACKGROUND: Extracorporeal photopheresis is an immunomodulatory technique in which a patient's leukocytes are exposed to ultraviolet-A light after pretreatment with 8-methoxypsoralen (methoxsalen). There have been few reports describing the use of extracorporeal photopheresis in lung transplant recipients. METHODS: We reviewed our experience using extracorporeal photopheresis in 8 lung transplant recipients since 1992. All 8 patients had progressively decreasing graft function and 7 were in bronchiolitis obliterans syndrome grade 3 before the initiation of photopheresis. One patient had undergone a second transplant operation for obliterative bronchiolitis. Two patients had a pretransplantation diagnosis of chronic obstructive pulmonary disease, 1 alpha1-antitrypsin deficiency, 1 cystic fibrosis, 1 bronchiectasis, 1 idiopathic pulmonary fibrosis, and 2 primary pulmonary hypertension. Before refractory rejection developed, all patients had been treated with 3-drug immunosuppression and anti-T-cell therapy. The median time from transplantation to the start of extracorporeal photopheresis was 16.5 months and the median number of treatments was 6. RESULTS: The condition of 5 of 8 patients subjectively improved after extracorporeal photopheresis therapy. In these 5 patients photopheresis was associated with stabilization of the forced expiratory volume in 1 second. In 2 patients there was histologic reversal of rejection after photopheresis. With a median follow-up of 36 months, 7 patients are alive and well. Three patients required retransplantation at a median of 21 months after completion of the treatments. Four patients have remained in stable condition after photopheresis. There were no complications related to extracorporeal photopheresis. CONCLUSION: We believe that this treatment is a safe option for patients with refractory lung allograft rejection when increased immunosuppression is contraindicated or ineffective.