Management of Chronic Rejection
after Lung Transplantation


By Ramsey Hachem, M.D.

Washington University School of Medicine Barnes-Jewish Hospital
Division of Pulmonary and Critical Care

June, 2007

Chronic rejection, or bronchiolitis obliterans syndrome, has clearly emerged as the leading obstacle to better long-term outcomes after lung transplantation. Unfortunately over the past ten or fifteen years, long-term outcomes after lung transplantation have remained disappointing. Furthermore, outcomes after lung transplantation have remained significantly worse than after other solid organ transplantation such as kidney, liver, and heart primarily because chronic rejection is much more prevalent after lung transplantation. Our understanding of the immune and biological processes that result in chronic rejection have been limited and this has hampered therapeutic efforts. Histologically, chronic rejection manifests as scarring of the small airways in the lungs (the bronchioles), and the airway lumen narrows as the scar builds up in the airway wall. Eventually, the lumen of these small airways is completely obliterated and the term bronchiolitis obliterans or obliterative bronchiolitis is descriptive. Physiologically, this manifests as a decline in the forced expiratory volume in 1 second (FEV1) and the forced expiratory flow rate between 25% and 75% of the vital capacity (FEF25-75%). Symptoms may be absent early in the process, but as the scarring progresses patients begin to notice breathlessness with activities and sometimes a cough. This highlights the importance of close monitoring of lung function as treatment may slow or even halt the progression of chronic rejection.

Our understanding of obliterative bronchiolitis focuses mainly on the immune system and therapeutic interventions are directed at more intensive immunosuppression. However, recent work has suggested that other non-immune insults including gastroesophageal reflux with silent aspiration of stomach contents, respiratory viral infections, and ischemia-reperfusion lung injury early after the transplant can result in obliterative bronchiolitis. Nonetheless, it is not clear that these injuries cause obliterative bronchiolitis directly rather than acting as stimulants for immune system activation. Regardless, treatment for chronic rejection is usually individualized although specific strategies vary among centers. Substituting tacrolimus for cyclosporine is perhaps the most agreed upon intervention primarily because the two drugs have similar side-effect profiles but tacrolimus may be more efficacious. Additional augmentation of the maintenance immunosuppressive regimen includes substituting mycophenolate mofetil or sirolimus for azathioprine. A relatively new adjunctive treatment is the addition of azithromycin as an immuno-modulating agent. Azithromycin is an antibiotic that is often prescribed for respiratory tract infections. However, it has been used after lung transplantation to stabilize lung function. The results are variable, but since the drug is generally well tolerated and has minimal side-effects there are few downsides to trying it. Nonetheless, when more aggressive intervention is warranted because lung function is declining rapidly or substantially, cytolytic therapy is often instituted. This consists of horse or rabbit derived antibodies directed against human lymphocytes, the immune cells that are thought to be paramount in orchestrating rejection. Cytolytic therapy is given in the hospital as a daily infusion over five to seven days. There are some infusion related side-effects including fever, nausea, diarrhea, and joint pain and the treatment results in profound immunosuppression for several months increasing the risk of infectious complications. Nonetheless, this often stabilizes declining lung function, and in general the benefits outweigh the potential adverse effects. In addition, combination approaches including cytolytic therapy and changes in the maintenance immunosuppressive regimen can be done simultaneously if necessary.

Additional treatments beyond cytolytic therapy and augmenting the maintenance immunosuppressive regimen include photopheresis and total lymphoid irradiation. These are typically considered second line treatments. Photopheresis entails collecting peripheral blood (often drawn through a large-bore in-dwelling catheter), separating the immune cells, exposing them to a sensitizing agent, and irradiating them with ultraviolet light. The exact mechanism of action remains unknown, but this either kills activated immune cells or promotes their suppression by other regulatory cells. Photopheresis is typically performed twice weekly for the first month, then tapered to monthly over the next five months. The results have been promising, but the onset of action is slow. Alternatively, total lymphoid irradiation is the most aggressive immunosuppressive therapy and consists of radiation treatments to the main thoracic and abdominal lymph nodes. This results in more profound immunosuppression and is associated with a significant risk of infectious complications. It is therefore reserved as a last treatment option for chronic rejection.

Recently, a mouse model of lung transplantation has been developed. It is expected that this will be very important in our understanding of the mechanisms of rejection after lung transplantation. Clearly, this will be necessary for better future therapeutic interventions in humans.