What is Lung Transplant Rejection?
There’s been a rise in the number of lung transplants performed every year in the United States and globally. This increase is due to better organizing of nationwide data, improvements in surgical methods, and the development of new drugs that prevent the body from rejecting the transplanted organ. However, people who receive lung transplants still have high chances of the transplants failing in the short and long term compared to other organ transplants. About 58% of lung transplant recipients are reported to be alive five years after the transplant.
While complications after surgery, blood vessel problems, and infections significantly contribute to early and late failures of lung transplants, the body rejecting the transplanted lung is also a common issue. Recent reports suggest that within one year of the transplant, about half of the patients experience ‘acute’ rejection, where the body starts to attack the new lung soon after the transplant. And within five years of the transplant, about 45% of patients experience ‘chronic’ rejection, where the body slowly starts to reject the new lung over a long period of time.
Based on when they occur after the transplant, lung transplant rejection can be divided into three categories:
1. ‘Hyperacute’ transplant rejection: Happens within the first 24 hours after the transplant.
2. ‘Acute’ transplant rejection: Occurs anywhere from the first week to the first year after the transplant.
3. ‘Chronic lung allograft dysfunction’ (CLAD): This is another type of chronic rejection that can occur within the first year after the transplant.
What Causes Lung Transplant Rejection?
Hyperacute lung transplant rejection mainly happens because of pre-existing antibodies in the recipient that react against the human leukocyte antigen (HLA) of the donor. Human leukocyte antigen, in simple terms, is a protein found on the surface of white blood cells that plays an important role in the body’s immune response to foreign substances.
Acute cellular rejection, which usually takes place during the first year after a lung transplant, can occur due to the activity of a type of white blood cell known as T-lymphocytes and their reaction against what are known as major histocompatibility complex antigens (these are proteins on the donor’s lung cells that help the immune system recognize foreign substances).
Chronic lung transplant rejection, on the other hand, usually doesn’t have a clear cause. It seems to be linked to a combination of factors. These might include repeated instances of mild acute rejection that might not have clear symptoms, infections after the transplant, and gastroesophageal reflux disease causing aspiration (this is when stomach acids back up into the esophagus and are then inhaled into the lungs).
An international group of experts in heart and lung transplantation, along with subsequent research, have classified various risk factors into three categories – probable, potential, and hypothetical.
Probable risk factors are things that are fairly certain to increase the risk of lung transplant rejection. They include severe rejection reactions, inflammation of the bronchi with lymphocytes (a type of white blood cell), a type of lung inflammation caused by cytomegalovirus (a type of virus), and failure to consistently take prescribed medication.
Potential risk factors are things that might increase the risk of rejection, like a cytomegalovirus infection that doesn’t cause lung inflammation, a type of lung inflammation called organizing pneumonia, infections caused by bacteria, fungi, or viruses other than cytomegalovirus, lung donors who are older, prolonged graft ischemic time (the period when the lung is kept without blood supply before transplant), and specific reactions to the antigens in the donor tissue.
Hypothetical risk factors are things that are suspected to increase the risk, but clear proof is still lacking. These include the disease that led to the need for a lung transplant in the first place, mismatching of the human leukocyte antigen between the donor and the recipient, the recipient’s genetic makeup, and gastroesophageal reflux causing aspiration.
Risk Factors and Frequency for Lung Transplant Rejection
The process of antibody-mediated lung transplant rejection is relatively uncommon. This is primarily due to pre-transplant screenings that identify if the recipient has any harmful antibodies (known as HLA antibodies), allowing doctors to avoid unsuitable donors. This screening process is referred to as a “virtual crossmatch”.
According to the International Society for Heart and Lung Transplantation, roughly 29% of the 12,980 lung transplant recipients from 2004 to 2014 experienced at least one rejection within their first year after leaving the hospital. Furthermore, between 1994 and 2014, it was predicted that 50% faced chronic rejection within five years of their transplant, and 67% within ten years.
Signs and Symptoms of Lung Transplant Rejection
Hyperacute lung rejection is a serious condition that can occur within 24 hours of a lung transplant procedure. Symptoms include rapid breathing problems and severe low oxygen levels due to sudden lung swelling and widespread lung damage. These symptoms are similar to Acute Respiratory Distress Syndrome (ARDS), a life-threatening lung condition. A lung imaging test will show widespread clouds of gray or white in the transplanted lung.
Acute cellular lung rejection can happen up to 2 years after the lung transplant but it’s most common in the first 6 months. This condition can show no symptoms or it can display symptoms such as low-grade fever, cough, shortness of breath, or serious breathing problems. A physical examination might appear normal or show generalized signs like decreased breath sounds or a crackling sound when inhaling.
Bronchiolitis obliterans is a lung condition that can show up as a decrease in the volume of air that can be forcefully blown out in one second, without any other symptoms. However, if symptoms do present, they are usually general in nature and can vary from symptoms of a respiratory infection including dry cough, difficulty in breathing on exertion and low-grade fever. In severe cases, it can lead to quick decline in lung function and respiratory failure.
Testing for Lung Transplant Rejection
To determine if someone who has undergone a lung transplant is experiencing a very rapid rejection of the transplanted lung, doctors begin by testing for certain proteins in the blood that are related to the immune system (HLA antibodies) and reviewing previous test results. Complete blood count, heart enzymes, and brain natriuretic peptide are some of the additional diagnoses that are evaluated.
Tests such as electrocardiogram, echocardiogram, and swan Ganz catheterization help assess whether there is any dysfunction in the left ventricle of the heart. A CT scan serves to rule out lung clots, surgical complications, and diseases of the pleura (the thin tissue that covers the lungs).
Bronchoscopy, a procedure where a doctor looks into your lungs through a thin viewing instrument, with bronchoalveolar lavage (a procedure to wash and collect cells from the inside of the lungs), gives the doctor the ability to inspect the airway connection and get samples for testing. Patients without symptoms can be diagnosed during a routine surveillance bronchoscopy, while CT findings in symptomatic patients help guide taking tissue samples from focused areas of the lung.
A diagnosis of acute cellular rejection requires ruling out certain infections and identifying changes characteristic of rejection in the tissue biopsied. Lab tests and imaging are not sensitive or specific enough to diagnose this condition.
A definitive diagnosis of antibody-mediated rejection (another type of organ rejection) requires evidence of a specific circulating antigen, histopathological findings, and positive immunostaining for a molecule known as complement 4d. It is less common among organ rejections and is more difficult to establish.
Detection of Chronic Lung Allograft Dysfunction (CLAD) is indicated by a 20% or greater decline in lung function measures (FEV1/FVC) from the best postoperative value, signalling the need for urgent action to try to reverse it. In recent times, doctors generally start investigations immediately if there is a greater than 10% sustained drop in lung function, to rule out causes other than rejection.
Trouble diagnosing bronchiolitis obliterans (a form of lung disease that can happen after lung transplantation) can occur, since lab findings, imaging, and bronchoalveolar lavage results might not be very informative, but these should be obtained to dismiss other potential reasons for decline in lung function. This problem raises an alarm if there is a decrease in the speed of forced outflow of air (FEV1) for over 3 weeks and a greater than 20% decline from baseline.
Despite challenges in diagnosis with taking samples of tissue (biopsy), bronchoscopy is still important to exclude conditions like infection, aspiration, and damage from stomach acids going back into the esophagus (reflux).
To tell it apart from bronchiolitis obliterans, RAS is indicated if there is a greater than 10% decrease in your total lung capacity (TLC). The CT shows changes in the lungs which look like frosted glass on images, trailed by upper lobe predominant traction bronchiectasis (a lung condition that happens when the airways of the lungs become damaged and widen), fibrosis (lung tissue becoming stiff and scarred), and hilar retraction (change in the central part of the lungs). About 30% of CLAD patients develop RAS over a period of 5 years.
Before diagnosing bronchiolitis obliterans (BOS), it’s essential to rule out two conditions that can look identical: gastroesophageal reflux-related bronchiolitis obliterans (related to heartburn), and neutrophilic reversible allograft dysfunction (which can be treated with a drug called azithromycin). These conditions are different from BOS in that they may be reversible if treated appropriately.
All “suspected CLAD” patients are given a three-month trial of azithromycin. The chest CT scan in patients responding to treatment usually begins with peribronchiolar tree in bud infiltrates (a type of abnormality visible on the CT scan).
Treatment Options for Lung Transplant Rejection
To prevent the body from rejecting a solid organ transplant, a type of treatment called induction regimen is used, this treatment specifically uses another two medicines as agents: antilymphocyte and antithymocyte globulin. In simpler terms, these drugs work by reducing the chances of an organ being rejected by the body. Today, the use of these agents has declined with the introduction of newer drugs known as interleukin 2 (IL-2) receptor antagonists. An explanation of their work is, they target certain receptors on cells of our immune system involved in inflammation and inhibit these cells’ growth and function. Now, almost in 71% of lung transplants, IL-2 receptor antagonists are used as part of the induction regimen.
Most often, in the treatment of organ rejection, a regimen involving corticosteroids and two other agents is used. Corticosteroids are medicines that reduce inflammation. Commonly, medicines that function by inhibiting an enzyme called calcineurin are used, this enzyme plays a role in the activation of cells involved in inflammation. Two commonly used drugs are cyclosporin and tacrolimus. Also, another drug called mycophenolate mofetil is commonly used due to its safety profile.
The treatment of organ rejection after transplantation depends on many factors, including the type and severity of the rejection. However, no specific drugs are approved for treating antibody-mediated lung transplant rejection. In such cases, the interventions aim at reducing the antibodies that are causing the rejection. The type of intervention chosen depends on the severity of the disease, the patient’s clinical course, and their response to therapy.
In cases of acute cellular rejection, the treatment mostly depends upon the severity of the rejection and the patient’s clinical condition. In severe cases, the treatment often recommended is with a type of medicine called glucocorticoids. Depending on the patient’s response to treatment, the treatment method may be adjusted. After treating lung rejection, it’s found that improvement in clinical symptoms doesn’t always mean an improvement in lung tissue health as seen under the microscope.
For a specific rejection condition called bronchiolitis obliterans syndrome (BOS), there is no recommended treatment protocol. However, the International Society of Heart and Lung Transplant/American Thoracic Society/European Respiratory Society suggests trying a drug known as Azithromycin for new-onset bronchiolitis obliterans. This drug might stop or reverse the worsening of lung function.
When there’s continuous worsening of lung function even after previous interventions, a range of other treatments may be considered on a case-by-case basis. Treatments and preventive measures for a condition known as gastroesophageal reflux disease (GERD), a risk factor for BOS, can also be considered. However, corticosteroids, which are commonly used for treating acute lung transplant rejection, are not recommended for the management of bronchiolitis obliterans syndrome. When BOS progresses to a very severe stage where all other therapies have failed, the doctors might consider going for a retransplant with the same process used for the first-time lung transplantation.
Another rejection scenario known as restrictive allograft syndrome (RAS) requires similar treatment strategies to those for BOS. However, it’s important to note that retransplant outcomes in cases of RAS are usually worse. Hence, the decision for lung allocation while considering a diagnosis of RAS involves more strict assessment.
What else can Lung Transplant Rejection be?
If a patient’s lung transplant is suspected to be failing, doctors have several potential causes they’ll try to rule out. These can broadly be categorized into three groups:
Antibody-Mediated Rejection:
- Primary graft dysfunction
- Pulmonary edema caused by heart issues or fluid overload
- Pneumonia despite taking preventive antibiotics
- Complications from the blood vessel connections (vascular anastomoses)
- Pleural complication (effusion or hemothorax)
- Pulmonary embolism
- Occlusion of the venous anastomosis
- Transfusion-related acute lung injury (TRALI)
- Aspiration pneumonia
Acute Cellular Rejection:
- Humoral rejection
- Bronchiolitis obliterans syndrome
- Recurrent original lung disease
- Infection
- Airway anatomical complications
Chronic Rejection:
- Late-onset acute cellular rejection
- Azithromycin-responsive allograft dysfunction
- Esophageal reflux-related bronchiolitis obliterans
- Infection
- Airway complications from the lung transplant
- Recurrence of the original lung disease
- Post-transplant lymphoproliferative disorder
- Native lung hyperinflation
What to expect with Lung Transplant Rejection
In a study of 21 patients who suffered from acute antibody-mediated rejection (AMR), a condition where the body’s immune system attacks transplanted organs, 15 of them improved and survived, while 6 unfortunately passed away. After being diagnosed with this rejection, patients usually stayed alive for a median of 593 days. Generally, patients could live from 3 to 5 years after this condition develops, unless they received another transplant. Certain conditions like early-onset BOS and severe BOS can make the survival rate worse.
In one research, it was found that a chronic rejection condition after a lung transplant called bronchiolitis obliterans syndrome (BOS) grades 2 and 3, could triple the risk of death at each stage. In another research involving 109 lung transplant patients with BOS, survival rate was 51% at 3 years after the onset of BOS. The onset of BOS increased the risk of death nearly six times. Another study reported a mortality rate of 28% in patients with BOS.
Even though it’s less common, a condition called restrictive allograft syndrome which makes it hard for the lungs to fully expand, usually results in more severe outcomes, with survival usually ranging from 6 to 18 months from the time of diagnosis. Sometimes, BOS can progress into this restrictive syndrome and this transformation usually signifies a bad prognosis. Patients with a lung condition called AFOP also had poor outcomes, with an average survival time of only 0.3 years. Conditions like BAL eosinophilia (higher than normal white blood cells), sarcoidosis (inflammation that produces tiny lumps of cells in various organs), or interstitial lung disease (a disease affecting the tissue and space around the air sacs of the lungs) as an indication for transplant, mismatch between donor and recipient in terms of a virus called CMV, younger age, and being female were identified as risk factors.
Possible Complications When Diagnosed with Lung Transplant Rejection
Getting a lung transplant and then experiencing a rejection shortly after might make further rejections more likely. It can also lead to the development of a lung condition known as bronchiolitis obliterans syndrome. This condition can cause inflammation and damage to the airways in your lungs.
Preventing Lung Transplant Rejection
The two main issues people may face after a lung transplant are infections and their body not accepting the new lung (a condition known as rejection). Both these issues can have similar indicators, making it challenging to tell them apart just based on how a person is feeling. Sometimes, these issues may even be present without showing any signs. It’s crucial to remember that rejection is quite common, especially in the first six months following the transplant, but it can happen at any time.
For these reasons, it’s important for patients to understand that routine check-ups, testing, and taking medications to help their body accept the new lung are all crucial parts of life after a lung transplant. These steps are critical in closely monitoring for any complications that might arise after the procedure.
