Lung Transplant Rejection

Lung transplant rejection is a common complication that occurs when the body’s immune system attacks the newly transplanted lung, treating it as a foreign invader. While rejection affects most lung transplant recipients, many forms are treatable, and understanding the signs and treatments can help patients maintain their health after transplant.

Table of contents

• What is lung transplant rejection
• How common is rejection
• Types of lung transplant rejection
• What causes rejection
• Signs and symptoms
• How rejection is diagnosed
• Treatment options
• Monitoring after transplant

What is lung transplant rejection

Rejection is a normal reaction of the body to a foreign object. When a new lung is placed in a patient’s body, the body sees the transplanted organ as a threat and tries to attack it^[8]. The immune system (the body’s defense system against infections and diseases) makes proteins called antibodies to try to destroy the new organ, not realizing that the transplanted lung is beneficial^[8].

Rejection occurs when the body’s immune system creates antibodies that recognize and attack the new lung as if it were a foreign invader, similar to how the body would attack a virus^[3]. To allow the organ to successfully live in a new body, medications must be given to trick the immune system into accepting the transplant as its own^[8]. These medications must be continued indefinitely as long as the transplanted organ remains^[8].

How common is rejection

Lung transplant rejection is more common than patients and families might think. Acute cellular rejection of lung transplants occurs in up to 90 percent of patients^[3]. The registry of the International Society of Heart and Lung Transplantation reports 28% of lung transplant recipients experience at least one episode of treated acute rejection in the first year following transplantation^[5].

Recently reported incidence rates vary between 50% acute rejection rate within one year and 45% chronic rejection incidence within five years after transplant^[2]. Chronic rejection is a major complication after lung transplant, affecting more than half of patients that survive beyond five years after transplant^[4].

Despite these high rates, lung transplantation recipients continue to have a five-year survival rate reported at 58%^[2]. The important message is that while chronic rejections typically can’t be reversed, acute rejections are very treatable, and many patients can even be treated at home with the care of a transplantation expert^[3].

Types of lung transplant rejection

Based on the timeline of occurrence and diagnosis after transplant, lung transplant rejection can be categorized into three main subtypes^[2]:

Hyperacute transplant rejection

Hyperacute transplant rejection occurs within the first 24 hours after surgery^[2]. This type of rejection is mostly caused by preformed antibodies in the recipient against the human leukocyte antigen (HLA) (proteins on cells that help the immune system distinguish between the body’s own cells and foreign cells) of the donor^[2].

Acute transplant rejection

Acute transplant rejection occurs within the first week to the first year after transplant^[2]. Acute cellular rejection can be caused by T-lymphocyte (a type of white blood cell) mediated reactions and antibody-mediated reactions directed against major compatibility proteins in the donor’s lung^[2]. Acute rejection occurs with quick symptoms, while chronic rejection is more serious and affects about 10 percent of patients^[3].

The types of acute rejection include acute cellular rejection, lymphocytic bronchiolitis (inflammation of small airways), and antibody-mediated rejection^[5]. All of these are risk factors for the subsequent development of chronic lung problems^[5].

Chronic lung allograft dysfunction (CLAD)

Chronic lung allograft dysfunction can occur within less than one year, but more commonly develops later after transplant^[2]. Chronic lung allograft dysfunction (CLAD) is a term developed to encompass the different manifestations of chronic rejection that can occur in lung transplant recipients^[4]. CLAD is the major barrier to long-term survival following lung transplantation and is the leading cause of death beyond the first year after transplant^[5].

The most common form of chronic lung transplant rejection is bronchiolitis obliterans syndrome (BOS)^[4]. BOS is characterized by destruction of the small airways and narrowing and scarring of the airways within the donor lung, leading to progressive decline in the function of the transplanted lung^[4]. The condition affects the bronchioles through thickening in the airway of the lungs, causing air to come in but not out, similar to asthma^[3].

Restrictive allograft syndrome (RAS) is a second type of chronic rejection. In this condition, the lungs become smaller and smaller, causing difficulty with breathing because the patient cannot expand the lungs to breathe in air^[3]. RAS is associated with a worse prognosis than BOS^[5].

What causes rejection

Chronic lung transplant rejection usually has no clear single identifiable cause, and experts relate it to multiple processes contributing to each other^[2]. Contributing conditions could be recurrent subclinical acute rejection episodes, transplant infection, and aspiration with gastroesophageal reflux disease (a condition where stomach acid flows back into the food pipe)^[2].

A panel of experts organized by the International Society for Heart and Lung Transplantation has categorized various risk factors as probable, potential, or hypothetical^[2]. Probable risk factors include acute rejection, lymphocytic bronchiolitis, cytomegalovirus (CMV) pneumonitis (lung infection caused by a virus), and medication noncompliance^[2]. Potential risk factors include CMV infection without pneumonitis^[2].

It is not clear why some patients who receive a lung transplant develop chronic rejection or develop it sooner than others^[4]. Multiple factors likely contribute to high rates of rejection following lung transplantation, including increased susceptibility of the lung to injury and infection as well as constant environmental exposure^[5].

Signs and symptoms

The first thing doctors see in patients having lung transplant rejection is decreased functionality of the lungs^[3]. The most common signs and symptoms of rejection include^[8]:

• Fever
• Chills
• Flu-like aches
• Shortness of breath

In the case of bronchiolitis obliterans syndrome, initially a person may not experience any symptoms, but as time goes on common symptoms that may develop are shortness of breath (especially with activity), fatigue, and cough, sometimes with increased mucus production^[4]. These symptoms are also similar to those that develop during an infection. This is why it is important to report any new symptoms or problems to your lung transplant team so that a proper diagnosis can be made, as the treatment is quite different^[4].

If you experience any of these symptoms, you should call the transplant team immediately^[8].

How rejection is diagnosed

Every lung transplant recipient is sent home with a spirometry machine (a device that measures lung function), which is used twice a day to measure the amount of air they can exhale in one second^[3]. If the volume drops by more than 10 percent, patients are asked to call their doctor so they can be evaluated^[3].

During an evaluation, a doctor can confirm whether patients are experiencing lung rejection by performing a biopsy (removing a small piece of tissue to examine under a microscope) and looking for lymphocytes, a type of white blood cell that circulates in the blood and, in the case of rejection, attacks the blood vessels of the lungs^[3]. Doctors rank the severity of the rejection on a scale of zero to four, with four being the most severe^[3].

Acute cellular rejection and lymphocytic bronchiolitis have well defined criteria for diagnosis based on examining tissue samples and grading^[5]. Diagnosis of antibody-mediated rejection requires input from multiple healthcare specialists^[5].

BOS is defined by a persistent obstructive decline in lung function^[5]. BOS typically occurs as a late complication of lung transplant, but in rare cases can occur as early as three months following transplant^[4].

Treatment options

Treatment for acute rejection

Patients who have a rejection score of three or four typically require treatment in the form of anti-rejection medication to trick the immune system into accepting the new lung^[3]. Treatment usually begins with high doses of steroids (medications that reduce inflammation) that patients can take at home until the rejection reverses^[3]. If steroids aren’t effective, doctors turn to other treatment options, such as lympholitic medications^[3].

To ensure patients don’t develop antibodies after lung transplantation, they are screened for them each month during the first year, every three months the second year, and annually after that^[3]. If antibodies are forming, patients are quickly treated with plasma exchange. In this therapy, the patient’s blood is drawn, put it through a dialysis machine to remove the antibodies, and the “clean” blood is returned to the patient’s body^[3].

Many patients can be treated at home with the care of a transplantation expert, which is a relief for patients who’ve already had to go through a difficult lung transplant^[3].

Treatment for chronic rejection

When treatment for an acute lung rejection doesn’t work, the patient can develop chronic rejection of the new lung^[3]. Chronic rejections can’t usually be reversed^[3]. There currently are no effective treatments for chronic lung allograft dysfunction once it develops, leaving patients with only one option: re-transplantation^[7].

The best supported treatment to date for chronic rejection is the antibiotic azithromycin which has been associated with a small improvement in lung function in a minority of patients^[12]. Other therapies that have more limited evidence include switching immunosuppression from one medication to another, surgery for gastroesophageal reflux, montelukast (a medication for asthma), extracorporeal photopheresis (a treatment that exposes blood cells to light), aerosolized cyclosporine, anti-lymphocyte therapies, total lymphoid irradiation, and the antifibrotic agent pirfenidone^[12].

Medications after transplant

Because antibodies play such a pivotal role in fighting off infections throughout the body, some patients wonder whether their immune system will change when antibodies are removed^[3]. The answer usually is no. By activating some lymphocytes called T-cells, the immune system is still able to respond to infections^[3].

Monitoring after transplant

Patients must do many tests during transplant evaluation and while they wait for transplant surgery^[19]. Pulmonary function test (PFT) measures how well the lungs work. A six-minute walk test (6MWT) measures how far a patient can walk in six minutes. A pulse oximeter measures how much oxygen is in the blood^[19].

These tests show changes in how well the lungs work, show if a patient needs to be on oxygen to support breathing, and may change the patient’s position on the waitlist^[19]. Most patients need supplemental oxygen, and it is important to work with the transplant nurse coordinator and social worker to help the patient be prepared for an emergency^[19].

After returning home, patients want to resume normal living. If they want to go to a movie or a social occasion and feel up to it, they should do it^[20]. The key is moderation and understanding limits. Initially, patients will probably have less energy than they did before surgery, as it takes time for the body to heal and adjust to new medications^[20].

Exercise becomes an important part of life after transplant, enabling a faster return to routine activities and helping maintain overall improved health^[20]. When patients return home, it is recommended that they exercise daily, walking 15-20 minutes daily, and gradually increasing time as tolerated^[20].