By Ramsey Hachem, M.D.
Washington University School of Medicine Barnes-Jewish Hospital
Division of Pulmonary and Critical Care
February, 2006
Lung transplantation has become an established treatment option for a variety of end-stage lung diseases, but the long-term outcomes remain some- what disappointing. The 5 year survival after lung transplantation worldwide is approximately 50%, and unfortunately, this has not improved substantially over the past 15 years. In the first 12 months after transplantation, graft failure and infectious complications are the leading causes of death, but beyond the first year, chronic rejection is the primary cause of mortality, accounting for approximately 40% of deaths. Furthermore, chronic rejection after lung transplantation is considerably more common than after most other solid organ transplants. The reasons for this are uncertain, but it is hypothesized that since the lungs are in continuous contact with the environment, they are constantly exposed to inhaled particles and infectious agents that continuously stimulate the immune system. Nonetheless, it is clear that this higher incidence of chronic rejection is the chief reason for the lower survival rates after lung transplantation than after most solid organ transplants.
Chronic rejection manifests as inflammation and scarring of the small airways in the lungs. Its onset is often insidious and asymptomatic, but some cases begin with symptoms similar to a respiratory tract infection such as cough, congestion, or chest tightness. Physical examination and chest x-rays are often unrevealing, but the hallmark finding is a decrement in lung function, highlighting the importance of regular and frequent spirometry measurements. The evaluation of this decrement typically includes bronchoscopy if the drop in lung function is sufficient. However, the purpose of bronchoscopy in these situations is usually to exclude other potential explanations because the lung biopsies obtained with bronchoscopy often miss the scarred and inflamed small airways characteristic of chronic rejection. In fact, the sensitivity of transbronchial biopsy for the diagnosis of chronic rejection is approximately 30%.
The mainstay of therapy is augmenting the immunosuppressive regimen. There are multiple options and the choice depends to a large extent on the rate of decline of lung function. Small decrements that occur over months are often addressed with changes in the maintenance immunosuppressive regimen; the alternatives include substituting tacrolimus for cyclosporine, or mycophenolate mofetil or sirolimus for azathioprine. Additionally, small but acute drops in lung function may be treated with a boost and taper of the prednisone dose. However, when the FEV1 declines 10-20% from baseline, more aggressive immunosuppression is necessary. This is most often done with cytolytic therapy, which is designed to deplete T-lymphocytes and interfere with their normal functions. T-lymphocytes comprise a subtype of white blood cells that combat viral infections and in the setting of an organ transplant, mediate rejection. Currently in the US, two cytolytic agents are commercially available, a rabbit derived and a horse derived preparation. These are manufactured by immunizing a rabbit or a horse with human thymocytes or lymphocytes; the animal then develops an immune response to the human immune cells in the form of antibodies (immune proteins), which are then harvested and purified. Because it carries some risk of potentially serious side effects, cytolytic therapy is generally administered in the hospital over a period of 5 to 7 days. Common side effects include fever, joint and muscle aches, nausea, abdominal pain, and diarrhea. To minimize these side effects, pre-medications are usually given including methylprednisolone, acetaminophen, and anti-histamines. Obviously, because the purpose of this treatment is to augment immunosuppression, people who receive cytolytic therapy are at increased risk of infectious complications in the weeks to months after completing the treatment.
The results of cytolytic therapy are variable; for most patients, this stabilizes lung function for months to years and for a few it improves lung function to some extent. However, some patients demonstrate no response to cytolytic therapy and continue to have a progressive decline in lung function. There are two potential options in such cases, photopheresis and total lymphoid irradiation (TLI), both intensive immunosuppressive therapies. Photopheresis consists of separating the patient’s immune cells from blood, sensitizing them, and exposing them to ultraviolet light. This kills activated immune cells targeting the transplanted organ. In addition, it appears that when other immune cells engulf these dead cells they can mediate immunity against immune cells targeting the transplanted organ. Overall, photopheresis is well tolerated and the majority of complications are related to the need for an indwelling intravenous catheter. A course of photopheresis is generally given over six months with two treatments, each lasting approximately 4 hours, weekly in the first month tapering to monthly treatments by the end of the course. Experience with photopheresis for chronic rejection after lung transplantation is growing and it appears to be an effective albeit slow treatment. TLI is the most aggressive therapy for rejection and consists of radiation directed at the major lymphoid tissues in the body, which results in intensive depletion of immune cells. However, the treatments, 10 total performed weekly or twice weekly, carry the potential for some serious side effects including anemia, thrombocytopenia (low platelets), and a profound immunosuppression. Thus, TLI is generally reserved as a last treatment option for chronic rejection.
Lastly, in recent years, azithromycin, a common antibiotic usually prescribed for upper respiratory tract infections, has become an additional adjunctive treatment for chronic rejection. It is given orally three times weekly, after a daily 5 day loading course, indefinitely. The exact mechanism of action remains uncertain, but it appears to exert some immunomodulatory effects beyond its antibacterial properties. It is generally very well tolerated, and the results have sometimes been dramatic.
In summary, chronic rejection is a common complication after lung transplantation and remains the major obstacle to better long-term outcomes. However, the therapeutic armamentarium is growing and hopefully future studies will develop novel regimens with fewer side effects and better results.