By Ramsey Hachem, M.D.
Washington University School of Medicine Barnes-Jewish Hospital
Division of Pulmonary and Critical Care
June, 2009
In the immediate period after solid organ transplantation, the transplanted organ may not function properly. This syndrome of poor graft function varies considerably in severity from case to case. After lung transplantation, this is termed primary graft dysfunction (PGD) and the severity varies from an abnormal chest x-ray without overt respiratory symptoms to severe respiratory failure requiring mechanical ventilation and intensive care support. There are multiple causes for primary graft dysfunction, and it is likely that the combination of these insults contribute to the lung injury. First, the majority of transplanted lungs are retrieved from brain-dead donors; a small number of living donor lung transplants are performed in the US, but these make up a minority of all lung transplant procedures. Lungs from a brain-dead donor may be injured as a result of aspiration of small amounts of stomach contents, pneumonia, or as a result of brain death itself. Obviously, if the lung injury is readily apparent when the donor lungs are examined (by x-ray, bronchoscopy, blood gas analysis, etc…), they are usually not retrieved and not used for transplantation. In fact, lungs are retrieved for transplantation from only 15-20% of organ donors because lungs are more susceptible to injury at the time of brain death than other organs. In contrast, kidneys are retrieved for transplantation from approximately 70-80% of organ donors. Nonetheless, while the gross examination of the lungs may be satisfactory, a microscopic injury may still exist.
At the time of retrieving the lungs, they are removed from the donor, flushed with a special preservation fluid, and cooled on ice. From that point until the transplant takes place, the lungs are not perfused with blood. This period of ischemia damages the lungs further, and there is usually a 7-hour period of permissible ischemia before the lungs are too severely damaged. When the lungs are then transplanted and begin to receive the recipients’ blood, the lung injury is further propagated. Ischemia followed by reperfusion is the primary cause of poor graft function in the early period after transplantation, and the severity of this early graft injury can be very variable. Reasons for this variability in the severity of the injury are not entirely clear, but some clinical risk factors have been identified. Patients with pulmonary fibrosis and those with pulmonary hypertension have a higher risk of this complication, but patients with other diagnoses are not immune. Work is ongoing to identify molecular and genetic variables in both donors and recipients that may predispose to severe forms of this injury.
In 2006, the International Society for Heart and Lung Transplantation (ISHLT) developed a clinical definition to standardize the nomenclature among transplant centers and grade the severity of graft injury. Primary graft dysfunction (PGD) can seriously jeopardize the outcome after transplantation and may be life-threatening in its most severe form. Approximately 10-15% of recipients develop severe PGD immediately after the transplant, but a significant proportion of these improve over the ensuing 48-72 hours. Nonetheless, there is a high risk of superimposed pneumonia because invasive mechanical ventilation and intensive immunosuppression are necessary. Clearly, pneumonia can further damage the lungs and jeopardize the outcome. Unfortunately, no specific treatments have been developed for PGD after lung transplantation to date, and the mainstay of therapy is supportive care. In addition, multiple prophylactic interventions have been investigated, but none have been beneficial.
Finally, PGD has recently been linked to the development of bronchiolitis obliterans syndrome (BOS), or chronic rejection. In fact, there is a direct relationship between the severity of PGD and the risk of BOS. For example, patients who develop severe PGD are almost 3 times more likely to develop BOS than those who did not have PGD, while those who developed mild PGD are almost twice as likely to develop BOS than those who did not have PGD. How PGD predisposes to BOS months or years later is unclear. However, it is likely that the lung injury that characterizes PGD exposes certain proteins in the lungs and makes the organs more immunogenic thereby increasing the risk of chronic rejection. Unfortunately, treatments that might uncouple the association between PGD and BOS have not been identified. Nonetheless, work is ongoing to better understand this immunologic link between PGD and BOS, and clearly this will be necessary to mitigate the high risk of BOS.