Past studies include the following:
Cytomegalovirus Pneumonitis is a Risk for Bronchiolitis Obliterans Syndrome (BOS) in Lung Transplantation
Risk factors for BOS are varied, but post-transplant infections, cytomegalovirus (CMV) pneumonitis infection in particular, have been shown to play a significant role. Current treatment regimens have limited the acute risk of infectious episodes but controversy over the long-term impact of CMV pneumonitis infection remains.
Cytomegalovirus pneumonitis infection rates and long-term outcomes over a six year period were retrospectively collected for 231 Duke lung transplant recipients.
CMV pneumonitis was diagnosed in 21 percent of study participants, with two-thirds of those infections having occurred within the first six months post-transplant.
Despite the availability of effective treatment, CMV pneumonitis, occurring at any time post transplant, was associated with an increased risk for BOS.
These findings suggested a need for more effective CMV prophylaxis regimens.
Snyder LD, Finlen-Copeland CA et al. Cytomegalovirus pneumonitis is a risk for bronchiolitis obliterans syndrome in lung transplantation. Am J Respir Crit Care Med 2010; 181(12):1391-6.
Extended Valganciclovir Prophylaxis to Prevent Cytomegalovirus After Lung Transplantation
In light of the association between CMV-P and BOS, identifying the most effective and safest duration of CMV prophylaxis (medication aimed at prevention) is critical.
Multiple previous observational studies have yielded inconsistent results; therefore, Scott Palmer, MD, MHS, designed a placebo-controlled, randomized multicenter, clinical trial to definitively determine the best CMV prophylaxis regimen.
A double-blind, placebo controlled, randomized CMV prevention trial monitored the CMV infection rates of 136 patients from eleven US transplant centers for eighteen months post-transplant.
The patients were split into two groups, one in which patients (n=66) were given three months of Valganciclovir (the standard duration at that time) followed by placebo for an additional nine months, and the other in which patients (n=70) were given twelve months of Valganciclovir.
CMV occurred in 32 percent of patients receiving three months of Valganciclovir compared to 4 percent of patients receiving the twelve month regimen. Importantly, no significant adverse effects resulting from the prolonged drug administration in the twelve month group were found.
Extending CMV Valganciclovir prophylaxis to twelve months was shown to safely and effectively reduce the incidence of CMV infection. Duke has changed its clinical protocol to reflect the study findings, and most Duke lung recipients now receive at least one year of Valganciclovir prophylaxis. This approach might lead to improved long-term survival.
Palmer Scott M, Limaye, Ajit P et al. Extended Valganciclovir Prophylaxis to prevent cytomegalovirus after lung transplantation. Ann Intern Med 2004; 152:761-769.
Early Fundoplication Prevents Chronic Allograft Dysfunction in Patients with Gastroesophageal Reflux Disease
Data suggests that gastric reflux may be a risk factor for the development of BOS. Nissen fundoplication, a surgical procedure used to treat gastroesophageal reflux disease may reduce the adverse impact that gastric reflux poses on BOS.
A retrospective analysis placed 457 Duke lung transplant recipients into four groups based upon history of pre-or post-transplant reflux and Nissen fundoplication status. These groups included patients with the following:
- No history of reflux n=180)
- History of reflux and no fundoplication (n=125)
- History of reflux with early (<90 days) fundoplication (n=14)
- History of reflux with late (>=90 days) fundoplication (n=62)
In the 14 patients with early fundoplication, none developed BOS at one and three years post-transplant compared to patients with no fundoplication and history of reflux (BOS incidence: 4 percent at one year and 40 percent at three years).
Furthermore, all early fundoplication patients remained alive at one and three years compared to patients with reflux and no fundoplication, 8 percent of whom had died by year one and 24 percent by year three.
Our clinical approach is to carefully evaluate all lung transplant candidates before transplant and again after transplant. If patients have pre or post-transplant reflux, then they undergo early post-transplant anti-reflux surgery as a lung protective strategy. Although more prospective randomized studies are needed, we believe that early fundoplication is a way to potentially decrease a patients risk for BOS.
Cantu, Edward et al. Early Fundoplication Prevents Chronic Allograft Dysfunction in Patients with Gastroesophogeal Reflux Disease.Ann Thorac Surg 2010; 78:1142-51.
Survival after Bronchiolitis Obliterans Syndrome among Bilateral Lung Transplant Recipients
Patients’ lung function after the onset of BOS is variable, with some patients suffering significant early declines and others with compromised but stable lung function. We sought to identify factors occurring prior to BOS onset that might provide insight into survival patterns after BOS.
Clinical and demographic factors for a five year period were retrospectively collected and analyzed to determine their impact on survival after BOS in a cohort of 95 Duke bilateral lung transplant recipients with BOS.
Early BOS onset (BOS occurring within two years post-transplant) had worse survival rates then late onset BOS patients, (one, three- and five-year survival rates after the onset of BOS = 59 percent, 37 percent, and 19 percent, respectively. Recipients with high grade BOS onset (grades 2 or 3 when BOS was first diagnosed) had worse survival than their BOS 1 onset grade counterparts (one-, three- and five-year survival rates after the onset of BOS = 48 percent, 22 percent, and 11 percent. Surprisingly, no other clinical or demographic factors affected survival patterns after the onset of BOS.
We have defined BOS subgroups with worse survival. Patients with high grade onset or early onset BOS, those at greatest risk for death after BOS, therefore should be offered augmented treatment early in their BOS course.
Finlen-Copeland C. Ashley, Snyder Laurie D et al. Survival after Bronchiolitis Obliterans Syndrome among Bilateral Lung Transplant Recipients. Am J Respir Crit Care Med 2010;182:784-789.
Genetic Regulation of Rejection and survival Following Human Lung Transplantation by the Innate Immune Receptor CD14
We hypothesized that an important arm of the pulmonary immune system called innate immunity could promote development of acute lung rejection and BOS. In order to test this idea, we considered the effect of polymorphic variants in an innate immune gene known as CD14 upon the onset and severity of transplant rejection. Patients with certain CD14 variants have increased innate immune activation and therefore might be expected to have worse transplant outcomes.
We retrospectively analyized 226 patients who were transplanted at Duke between October 1998-August 2003. Genotyping assays were completed on all patients to assess the effects of CD14 variants on rejection and development of BOS.
Patients with the CD14 TT genotype had significantly worse graft survival compared to CT or CC patients. The incidences of acute rejection at two years was significantly higher in the TT genotype (77 percent) vs. CT (69 percent) and CC (50 percent), and had the highest incidence of recurrent acute rejection (34 percent) over the first two years compared with CT (20 percent) and CC (8 percent).
Patients with the TT genotype developed BOS earlier than CT or CC genotypes. Additionally, high grade onsets of BOS (grades 2 or 3) were found to be significantly greater in TT genotypic subgroups (52 percent) vs CT or CC subgroups (31 percent).
Genetic variation may contribute to the risk for BOS; however, further validation is required in a larger sample of patients before genotyping could be applied to the clinical setting. These and other studies by our groups were the first to establish a role for innate immunity in human transplant rejection, thus suggesting novel strategies for prevention or treatment of lung rejection.
Palmer SM et al. Genetic Regulation of Rejection and survival Following Human Lung Transplantation by the Innate Immune Receptor CD14. American Journal of Transplantation 2007;7: 693-699.