By Ramsey Hachem, M.D.
Washington University School of Medicine Barnes-Jewish Hospital
Division of Pulmonary and Critical Care
December, 2005
Unfortunately, rejection is one of the most common complications after lung transplantation. Rejection represents the recipient’s immune response to the transplanted lung. From a teleological perspective, the immune system’s purpose is to identify and attack invading organisms such as viruses and bacteria. For example, when someone comes down with the flu, an infection caused by the influenza virus, the immune system recognizes the invading virus and responds in a number of ways to kill infected cells and control the infection. To do so, the immune system must first recognize that the invading organism is foreign, or that it is distinct from self. This occurs very early in life when immune cells that are self-directed are deleted and only those that are non-self-directed remain, ready to expand and multiply in response to an infection. These non-self- directed immune cells make up our defense mechanism against infections. On the other hand when self-directed immune cells propagate, an autoimmune disease, such as lupus, may develop.
In the setting of organ transplantation, immune cells recognize the transplanted organ as foreign and attack it as they would an infecting virus or bacteria. Among all solid organ transplants, the lung is most susceptible to rejection for reasons that are not clear. Two types of rejection exist after lung transplantation; acute rejection typically occurs within the first year after transplantation, while chronic rejection is often a later complication. Acute rejection is most common in the first three to six months, and as many as 50% to 60% of recipients develop at least one episode of acute rejection in the first year. This type of rejection usually does not cause any symptoms and blood tests, chest x-rays, and even pulmonary function tests are often unchanged from the previous baseline results. The diagnosis is best made with bronchoscopy and lung biopsy. Most lung transplant programs have adopted surveillance protocols for bronchoscopy in the first year to exclude occult acute rejection.
The severity of acute rejection, based on lung biopsy findings, is graded on a scale of 0 to 4; no rejection is graded as A0, minimal rejection is graded as A1, mild rejection is graded A2, moderate rejection is graded A3, and severe rejection is graded A4. While the significance of an isolated episode of minimal rejection (A1) is unclear, most programs consider any rejection grade higher than A1 to be significant and institute some form of treatment. The cornerstone of therapy is augmenting the immunosuppressive regimen; most commonly, patients receive a bolus of intravenous steroids for three days followed by an adjustment in the immunosuppressive medicines. Subsequently, a follow-up bronchoscopy is typically preformed to exclude persistent rejection three to eight weeks later.
Fortunately, acute rejection usually responds well to treatment with high dose intravenous steroids. However, some episodes are steroid-resistant and require more intensive immunosuppression with anti-lymphocyte antibody preparations. These agents are developed by immunizing horses or rabbits with human lymphocytes, the immune cells that cause rejection. The horse or rabbit then mounts an immune response to the human cells by producing lymphocyte directed antibodies, or immune proteins. These are harvested, purified, and when administered to patients deplete the rejection causing lymphocytes.
Nonetheless, despite effective treatment, acute rejection remains the main risk factor for chronic rejection, and chronic rejection remains the leading obstacle to better long-term outcomes after lung transplantation. As commonly reported, the five-year survival after lung transplantation is approximately 50% and the primary cause of death beyond the first year is chronic rejection. Chronic rejection manifests as inflammation and scarring of the small airways that can cause progressive loss of lung function over time. Early in the course of chronic rejection, few symptoms, if any, are apparent and the only evident sign may be a decline in pulmonary function tests. Early detection with frequent pulmonary function testing (every four to eight weeks) offers the best hope of successful treatment because the loss in lung function is often irreversible. As for acute rejection, the cornerstone of therapy is augmenting the immunosuppressive regimen. This is most commonly done with bolus intravenous steroids or anti-lymphocyte antibody preparations. However, the results of treatment for chronic rejection are sometimes disappointing. Augmenting immunosuppression may arrest the airway inflammation that is often a part of chronic rejection, but scarring of the small airways is typically irreversible. Thus, arresting the progressive loss of lung function is often the goal of treatment.
A focus of future research projects will be to attempt to detect rejection and graft-directed immune activation early, so that treatment may avert irreversible graft injury and loss of lung function.