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ATC 2012:
PULMONARY TRANSPLANTATION HIGHLIGHTS

Cynthia J Gries, MD, MSc
University of Pittsburgh Medical Center


cynthia griesAlthough it was sad to face the fact that not all transplant meetings are held in cities where beer is cheaper than soda or where I can use my Google Translate app to learn how to say "Chci nějaký salám", historic Boston was a perfect venue for the American Transplant Congress (ATC) this past June. As the current chair of the Thoracic and Critical Care Community Practice in the American Society of Transplantation (AST) and member of the ISHLT, I have been asked to share some of ATC highlights for ISHLT members interested in lung transplantation.

In one of the sunrise symposiums, an overview on emerging infectious disease issues in lung transplant patients was presented. One of the studies described included a phase 2 trial designed to evaluate the safety, tolerability, and ability of CMX001 to prevent or control Cytomegalovirus (CMV) disease in CMV seropositive allogeneic stem cell transplant recipients. CMX001 is a viral DNA polymerase inhibitor that is 400-fold more potent against CMV than Cidofovir. It is orally bioavailable and unlike Cidofovir there is no evidence of nephrotoxicity. Subjects who received 100 mg of CMX001 twice a week met the primary endpoint: a statistically significant reduction in CMV viremia (CMV > 200 copies/mL) or disease at the end of treatment (p<0.001).1

Dr. Mark Nicolls, Chief of Pulmonary and Critical Care Medicine at Stanford University presented his results that were published in the Journal of Clinical Investigation regarding the attenuation of obliterative bronchiolitis in mice using an adenovirus-mediated HIF-1α gene transfer. Nicholls' team evaluated HIF-1α, a proangiogenic growth factor, in the repair of the damaged microvasculature of orthotopic tracheal transplants in mice. His team found that HIF-1α is required for microvascular repair in transplant rejection and that accentuating HIF-1α promotes airway microvasculature health during rejection and limits acute rejection. He also showed that CD4 T-cells and antibody-dependent complement activation independently mediate ischemia and that CD8 T-cells are required for post-rejection neovascularization. These conclusions suggest that targeted complement inhibitors may help prevent ischemia and limit the development of chronic rejection.2

The group from the University of Pittsburgh brought us one step closer to personalized medicine in transplantation with their presentation regarding the association of different recipient genetic polymorphisms and CMV reactivation and disease. In particular, this study evaluated genetic polymorphisms of proinflammatory cytokines (TNF-α, IFN-γ, IL-6, IL12b), regulatory cytokines (IL-10, CTLA4), growth factors (TGF- ), chemokine/chemokine receptors (CCR5, CCL2). They found that different genetic polymorphisms were associated with an increased risk of CMV reactivation and disease in both CMV recipient positive (R+) and CMV negative recipients who received a lung from a CMV positive donor (R-/D+). They found that R+ patients with TNF-α High, CTLA4-23 AA, and CCR-180 CT/TT had a significantly higher rate of viremic episodes. In R-/D+ patients, a significantly higher rate of virema was associated with people who had IL-6 High while patients with CCL2 TT and IL12b AA had a significantly lower rate of viremia (p<0.01). The authors from this presentation suggest that utilization of these genetic markers may facilitate an individual prophylaxis management of developing CMV in lung transplant patients.3

august linksIn a "Hot off the Presses: Late Breaking Science" abstract presentation, the group from Madison Wisconsin showed that skewing of regulatory T-cells towards CD39- subtype promoted Collagen type V (Col V) specific Th17 response in lung transplant patients. Cd39 is an ectonucleotide that hydrolyzes ATP and suppresses pathogenic Th17 immune response by regulatory T cells (Tregs) in lupus and multiple sclerosis. Their results showed that the Col V responsive patients had reduced CD39+ Treg in circulation compared to healthy donors. In addition, they showed that inhibition of CD39 during antigenic stimulation increased the Col V-specific Th17 response and induced a Col V-specific Th17 response in Col V unresponsive patients. They also demonstrated an inhibition of Col V response by blockage of ATP signaling using a trans vivo DTH analysis, while addition of adenosine receptor A2a agonist also suppressed the Col V specific Th17 responses.4

In addition to the abundance of immunobiology talks at ATC, ATC is rich with information regarding donor management and allocation. At the ATC, results from the Scientific Registry of Transplant Recipient analysis on the effects of the most recent proposed revisions to the US Lung Allocation Score on Access to Lung Transplantation were released. The LAS is being revised to better reflect the risk of waitlist urgency and post-transplant survival in the post-LAS era. A full description of the proposed revision can be found at http://optn.transplant.hrsa.gov/PublicComment/pubcommentPropSub_305.pdf.

In this study, the SRTR showed that the revised model changed the LAS < 5 points for 85% of the candidates. The projected LAS in 72.5% of the candidates in group B (pulmonary hypertension group) increased more than 5 points (maxium increase of 26 points). They also showed that on average, candidates in group B decreased ranking on the list (increased priority) by almost 360 counts, while that of all other diagnosis groups increased rank (decreased priority) by less than 15 counts. Despite these changes, there was little change in ranking for the highest priority patients.5

SRTR data was used to assess the risk of pre-transplant use of Plavix in kidney transplant recipients. In this study, 3.7% of 46,586 kidney transplant patients had a pharmacy claim that Plavix was used within 90 days of transplantation. Results of this study showed that pre-transplant use of Plavix significantly increased adjusted risk for post-transplant death and graft failure. The use of Plavix within 90 days prior to transplantation was associated with a 47% increased risk of post-transplant death compared to those that did not use Plavix.6

Cases of transmission of human immune deficiency syndrome (HIV) and hepatitis C virus (HCV) by organ transplantation have been reported. Serology has been estimated to miss up to 1/11,000 HIV and 1/1000 HCV infections in organ donors. With this concern, an increasing number of OPOs have added nucleic acid testing (NAT) to their screening of deceased organ donors as NAT has a shorter window period and may detect infections earlier than serology. A study of 3 OPO affiliated labs evaluated the discordant serology and nucleic acid testing results for HIV, HBV and HCV in 2010. They found that NAT detected 0.3%, 0.2% and 0.1% additional HIV, HBV and HCV infections in serology referrals. However, many of the HIV NAT+ results were found to be non-reproducible on repeat testing.7

Finally, in order to improve donor yield or the number of the number of organs transplanted per donor the Organ Procurement Transplant Network (OPTN) Board of Directors has recently approved monitoring the performance of organ procurement organizations (OPOs) in the US. In order, to predict how many centers will potentially be reviewed, the SRTR performed a retrospective study on patients who were transplanted between July 1, 2007 and June 30, 2011. They calculated observed versus expected organ yield per donor in 2-year cohorts. The authors found that as high as 14% of the 58 OPOs evaluated warranted further review into their performance of donor yield. This suggests that a significant number of programs may be subjected to performance reviews as OPTN initiates monitoring.8

Disclosure Statement: The author has no conflicts of interest to disclose.

References:

  1. Marty, F., in American Transplant Conference. 2012: Boston, Massachusetts.
  2. Jiang, X., et al., Adenovirus-mediated HIF-1alpha gene transfer promotes repair of mouse airway allograft microvasculature and attenuates chronic rejection. J Clin Invest, 2011. 121(6): p. 2336-49.
  3. Zeevi et al. Impact of Cytokine and Chemokine Gene Polymorphisms on CMV Infection in a Large Cohort of Lung Transplant Recipients. Abstract 72. Am J Transplant 2012;12(S3):48
  4. Hegde et al. Skewing of Regulatory T Cells towards CD39- Subtype Promotes Collagen Type V Specific Th17 Response in Lung Transplant Patients. Abstract LB03. Am J Transplant 2012;12(S3):188.
  5. Valapour et al. Effect of Proposed Revisions to the US Lung Allocation Score on Access to Lung Transplantation. Abstract 506. Am J Transplant 2012;12(S3):180.
  6. Tuttle-Newhall et al. Potential Use of Pre-Transplant Medications as SRTR Risk Adjusters: The Example of Plavix. Abstract 1696. Am J Transplant 2012;12(S3):525.
  7. Theodoropoulous et al. Discordant Serology and Nucleic Acid Testing (NAT) Results for HIV, HBV and HCV in 2010. Abstract 4. Am J Transplant 2012;12(S3):28.
  8. Yaun et al. Monitoring Performance of Organ Procurement Organizations in the United States: Observed and Expected Donor Yield. Abstract 509. Am J Transplant 2012;12(S3):181.