Stuart C. Sweet

Development of the New Lung Allocation System in the United States

This article reviews the development of the new U.S. lung allocation system that took effect in spring 2005. In 1998, the Health Resources and Services Administration of the U.S. Department of Health and Human Services published the Organ Procurement and Transplantation Network (OPTN) Final Rule. Under the rule, which became effective in 2000, the OPTN had to demonstrate that existing allocation policies met certain conditions or change the policies to meet a range of criteria, including broader geographic sharing of organs, reducing the use of waiting time as an allocation criterion and creating equitable organ allocation systems using objective medical criteria and medical urgency to allocate donor organs for transplant. This mandate resulted in reviews of all organ allocation policies, and led to the creation of the Lung Allocation Subcommittee of the OPTN Thoracic Organ Transplantation Committee. This paper reviews the deliberations of the Subcommittee in identifying priorities for a new lung allocation system, the analyses undertaken by the OPTN and the Scientific Registry for Transplant Recipients and the evolution of a new lung allocation system that ranks candidates for lungs based on a Lung Allocation Score, incorporating waiting list and posttransplant survival probabilities.

Pediatric Transplantation in the United States, 1995–2004

Solid organ transplantation is accepted as a standard lifesaving therapy for end‐stage organ failure in children. This article reviews trends in pediatric transplantation from 1996 to 2005 using OPTN data analyzed by the Scientific Registry of Transplant Recipients. Over this period, children have contributed significantly to the donor pool, and although the number of pediatric donors has fallen from 1062 to 900, this still accounts for 12% of all deceased donors. In 2005, 2% of 89 884 candidates listed for transplantation were less than 18 years old; in 2005, 1955 children, or 7% of 28 105 recipients, received a transplant. Improvement in waiting list mortality is documented for most organs, but pretransplant mortality, especially among the youngest children, remains a concern. Posttransplant survival for both patients and allografts similarly has shown improvement throughout the period; in most cases, survival is as good as or better than that seen in adults. Examination of immunosuppressive practices shows an increasing tendency across organs toward tacrolimus‐based regimens. In addition, use of induction immunotherapy in the form of anti‐lymphocyte antibody preparations, especially the interleukin‐2 receptor antagonists, has increased steadily. Despite documented advances in care and outcomes for children undergoing transplantation, several considerations remain that require attention as we attempt to optimize transplant management.

Pediatric Lung Allocation: The Rest of the Story

In their article ‘‘The Equitable Allocation of Deceased Donor Lungs for Transplant in Children in the United States,’’ Snyder et al (1) provide an objective analysis of the waiting list mortality and transplant rate for children under 12 years of age before and after the implementation of the US lung allocation system. The primary conclusion from their article is that there is no significant difference between either metric for pediatric lung transplant candidates in the 6to 11-year-old age group compared to older children and adults. Although the authors acknowledge the fact that children under 12 continue to receive organs based on waiting time creates significantly different listing practices in comparison to older candidates (likely underestimating waiting list mortality for children under 12), the tacit implication is that the widely publicized case advanced by the parents of SarahMurnaghan, the child in Philadelphia, is without merit.

An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome

Bronchiolitis obliterans syndrome (BOS) is a major complication of lung transplantation that is associated with poor survival. The International Society for Heart and Lung Transplantation, American Thoracic Society, and European Respiratory Society convened a committee of international experts to describe and/or provide recommendations for 1) the definition of BOS, 2) the risk factors for developing BOS, 3) the diagnosis of BOS, and 4) the management and prevention of BOS. A pragmatic evidence synthesis was performed to identify all unique citations related to BOS published from 1980 through to March, 2013. The expert committee discussed the available research evidence upon which the updated definition of BOS, identified risk factors and recommendations are based. The committee followed the GRADE (Grading of Recommendation, Assessment, Development and Evaluation) approach to develop specific clinical recommendations. The term BOS should be used to describe a delayed allograft dysfunction with persistent decline in forced expiratory volume in 1 s that is not caused by other known and potentially reversible causes of post-transplant loss of lung function. The committee formulated specific recommendations about the use of systemic corticosteroids, cyclosporine, tacrolimus, azithromycin and about re-transplantation in patients with suspected and confirmed BOS. The diagnosis of BOS requires the careful exclusion of other post-transplant complications that can cause delayed lung allograft dysfunction, and several risk factors have been identified that have a significant association with the onset of BOS. Currently available therapies have not been proven to result in significant benefit in the prevention or treatment of BOS. Adequately designed and executed randomised controlled trials that properly measure and report all patient-important outcomes are needed to identify optimal therapies for established BOS and effective strategies for its prevention. Diagnosis of BOS requires careful exclusion of other complications that can cause delayed lung allograft dysfunction http://ow.ly/AZmbr

Lung transplantation for pulmonary vascular disease

BACKGROUND Pulmonary hypertension (PHT) is a lethal condition resulting in markedly diminished life expectancy. Continuous prostaglandin I2 infusion has made an important contribution to symptom management, but it is not a panacea. Lung or heart-lung transplantation remains an important treatment option for end-stage PHT patients unresponsive to prostaglandin I2. This study reviews the outcomes after transplantation for PHT in our program. METHODS A retrospective chart review was performed for 100 consecutive patients with either primary PHT (48%) or secondary PHT (52%) transplants since 1989. Living recipients were contacted to confirm health and functional status. RESULTS Fifty-five adult and 45 pediatric patients underwent 51 bilateral lung transplants, 39 single lung transplants, and 10 heart-lung transplants. Mean age was 23.7 years (range, 1.2 months to 54.8 years) and mean pre-transplant New York Heart Association class was 3.2. Pre-transplant hemodynamics revealed a mean right atrial pressure of 9.6+/-5.4 mm Hg and mean pulmonary artery pressure of 64+/-14.4 mm Hg. Hospital mortality was 17% with early death predominantly because of graft failure and infection. With an average follow-up of 5.0 years, 1- and 5-year actuarial survival was 75% and 57%, respectively. Mean pulmonary artery pressure on follow-up catheterization was 22+/-6.0 mm Hg, and mean follow-up New York Heart Association class was 1.3 (p < 0.001 for both compared with pre-transplant). Diagnosis and type of transplant did not confer a significant difference in survival between groups. CONCLUSIONS Whereas lung or heart-lung transplant for PHT is associated with higher early mortality than other pulmonary disease entities, it provides similar long-term outcomes with dramatic improvement in both quality of life and physiologic aspects.

Lung transplantation in the United States, 1998-2007.

This article highlights trends and changes in lung and heart‐lung transplantation in the United States from 1998 to 2007. The most significant change over the last decade was implementation of the Lung Allocation Score (LAS) allocation system in May 2005. Subsequently, the number of active wait‐listed lung candidates declined 54% from pre‐LAS (2004) levels to the end of 2007; there was also a reduction in median waiting time, from 792 days in 2004 to 141 days in 2007. The number of lung transplants performed yearly increased through the decade to a peak of 1 465 in 2007; the greatest single year increase occurred in 2005. Despite candidates with increasingly higher LAS scores being transplanted in the LAS era, recipient death rates have remained relatively stable since 2003 and better than in previous years. Idiopathic pulmonary fibrosis became the most common diagnosis group to receive a lung transplant in 2007 while emphysema was the most common diagnosis in previous years. The number of retransplants and transplants in those aged ≥65 performed yearly have increased significantly since 1998, up 295% and 643%, respectively. A decreasing percentage of lung transplant recipients are children (3.5% in 2007, n = 51). With LAS refinement ongoing, monitoring of future impact is warranted.

Pediatric transplantation, 1994–2003

This article uses OPTN/SRTR data to review trends in pediatric transplantation over the last decade. In 2003, children younger than 18 made up 3% of the 82,885 candidates for organ transplantation and 7% of the 25,469 organ transplant recipients. Children accounted for 14% of the 6,455 deceased organ donors. Pediatric organ transplant recipients differ from their adult counterparts in several important aspects, including the underlying etiology of organ failure, the complexity of the surgical procedures, the pharmacokinetic properties of common immunosuppressants, the immune response following transplantation, the number and degree of comorbid conditions, and the susceptibility to post‐transplant complications, especially infectious diseases. Specialized pediatric organ transplant programs have been developed to address these special problems, The transplant community has responded to the particular needs of children and has provided them special consideration in the allocation of deceased donor organs. As a result of these programs and protocols, children are now frequently the most successful recipients of organ transplantation; their outcomes following kidney, liver, and heart transplantation rank among the best. This article demonstrates that substantial improvement is needed in several areas: adolescent outcomes, outcomes following intestine transplants, and waiting list mortality among pediatric heart and lung candidates,

Rejection is reduced in thoracic organ recipients when transplanted in the first year of life

BACKGROUND Infant heart transplant recipients have been reported to have decreased rates of rejection when clinical criteria are used for diagnosis. This study compares the rates of acute episodes of rejection in heart and lung transplant recipients transplanted in the first year of life to those of older recipients utilizing pathologic criteria. METHODS Records of 100 consecutive lung transplant recipients (cystic fibrosis patients excluded) and 107 consecutive heart transplant recipients were reviewed with respect to: time to first rejection; total number; single versus multiple; and early (<90 days) versus late (>180 days) biopsy-proven rejection episodes. Rejection was defined as ISHLT biopsy Grade 3A or A2 for heart and lung transplant recipients, respectively. Biopsy and immunosuppression protocols were similar between groups. RESULTS Kaplan-Meier analysis for freedom from rejection showed infant heart recipients were more often rejection-free (p = 0.004) as were infant lung recipients (p = 0.0001). Multivariate analysis revealed age at transplant as the most significant factor in predicting time to first rejection (age <1 year: risk ratio 0.19 [0.068-0.54] for lung transplant recipients and risk ratio 0.46 [0.27-0.78] for heart transplant recipients). Early rejection episodes occurred with less frequency in both the infant heart (19 of 63 [30%] versus 24 of 44 [50%]; p = 0.016) and lung (3 of 26 [12%] versus 63 of 74 [85%]; p = 0.001) groups. Late episodes of rejection were also less frequent in infant heart (4 of 53 [8%] versus 10 of 36 [28%], p = 0.016) and lung (0 of 23 [0%] versus 29 of 65 [45%]; p = 0.001) recipients. Multiple (> or =2) rejection episodes occurred less in infant heart (4 of 63 [6%] versus 9 of 41 [22%]; p = 0.037) and lung recipients (0 of 26 [0%] versus 17 of 74 [23%]; p = 0.003). CONCLUSIONS These results demonstrate that age of <1 at time of thoracic transplantation confers significant protection from early, late and multiple episodes of acute rejection, as well as significantly greater freedom from rejection and time to first rejection.

Posttransplant Lymphoproliferative Disease in Children: Correlation of Histology to Clinical Behavior

Purpose To determine whether the morphologic features of posttransplant lymphoproliferative disease (PTLD) correlated to a response to therapy. Patients and Methods We reviewed our experience with PTLD in the pediatric population. We identified 32 patients with a total of 36 episodes of PTLD. The diagnosis was confirmed by tissue examination and classified according to the degree of monomorphic features of the lesion. Thirty-four of 36 episodes were managed with immunosuppression reduction, and the patients were assessed for their response to this strategy. Chemotherapy was used to treat 10 of 15 patients who had progressive disease, and their subsequent course was also analyzed. Results Sixteen of 17 (94%) patients with polymorphic morphology responded to immunosuppression reduction compared with only 5 of 17 (29%) patients with monomorphic features (P < 0.001). All of the patients with progressive disease who did not receive additional therapy died. Standard chemotherapy regimens for lymphoma were administered to 10 patients with progressive disease, with a high response rate (90%), durable remissions, and acceptable toxicity. Conclusions We conclude that the morphologic characteristics of PTLD provide information to potentially help guide treatment strategies in the management of this disease. Standard chemotherapy regimens for malignant lymphoma appear to be a viable treatment option for patients with progressive disease, although further investigation is needed.

Antibody-mediated rejection of the lung: A consensus report of the International Society for Heart and Lung Transplantation

Antibody-mediated rejection (AMR) is a recognized cause of allograft dysfunction in lung transplant recipients. Unlike AMR in other solid-organ transplant recipients, there are no standardized diagnostic criteria or an agreed-upon definition. Hence, a working group was created by the International Society for Heart and Lung Transplantation with the aim of determining criteria for pulmonary AMR and establishing a definition. Diagnostic criteria and a working consensus definition were established. Key diagnostic criteria include the presence of antibodies directed toward donor human leukocyte antigens and characteristic lung histology with or without evidence of complement 4d within the graft. Exclusion of other causes of allograft dysfunction increases confidence in the diagnosis but is not essential. Pulmonary AMR may be clinical (allograft dysfunction which can be asymptomatic) or sub-clinical (normal allograft function). This consensus definition will have clinical, therapeutic and research implications.