Lung transplant rejection occurs when the body’s immune system recognizes the new lung as foreign tissue and attempts to attack it, much like it would fight off a virus or infection. This natural response is one of the most significant challenges faced by people who receive lung transplants, though medical advances have made many forms of rejection treatable with careful monitoring and specialized care.

Understanding How Common Rejection Really Is

Lung transplant rejection is far more common than many people realize, and understanding its frequency helps patients and families prepare for what lies ahead. Transplant rejection happens because the body’s defense system, which normally protects against illness, sees the donated lung as something that doesn’t belong. The immune system creates special proteins called antibodies, which are designed to recognize and attack anything the body perceives as an invader.

The numbers surrounding lung transplant rejection are striking and important to understand. According to medical research, acute rejection of transplanted lungs occurs in up to 90 percent of patients at some point after their surgery.^[3] This remarkably high rate doesn’t mean the transplant has failed or that patients are in immediate danger. Rather, it reflects how vigilant the immune system remains and why regular monitoring is so essential. Within the first year after transplantation, somewhere between 28 and 50 percent of recipients experience at least one episode of rejection that requires treatment.^[2][5]

Chronic rejection presents a different challenge. This longer-term complication affects approximately 45 percent of patients within five years after transplant, and more than half of those who survive beyond five years will experience some form of chronic rejection.^[2][4] These statistics might seem daunting, but they’re balanced by the fact that many episodes of acute rejection can be treated effectively, often without hospitalization.

Types of Rejection and When They Occur

Medical professionals categorize lung transplant rejection into three main types, based on when they occur and what causes them. Each type has distinct characteristics and requires different approaches to treatment.

Hyperacute rejection is the most immediate and severe form, occurring within the first 24 hours after transplant surgery. This type happens when the recipient already has antibodies in their blood that react against specific proteins on the donor lung’s cells, called human leukocyte antigens or HLA. These are essentially identification markers that help the body distinguish its own tissues from foreign ones. Because this form of rejection is so dangerous, transplant centers carefully screen for these antibodies before surgery to prevent this complication.^[2]

Acute rejection typically occurs anywhere from the first week up to the first year following transplantation. This type can be triggered by two different mechanisms. The first involves certain white blood cells called T-lymphocytes, which are part of the body’s cellular immune response. These cells recognize the donor lung as foreign and launch an attack against the organ’s tissues. The second mechanism involves antibodies targeting the major compatibility antigens in the donor lung, similar to hyperacute rejection but developing more gradually.^[2]

Chronic lung allograft dysfunction, or CLAD, represents the most challenging form of rejection. Unlike acute rejection, chronic rejection doesn’t have one clear, identifiable cause. Instead, experts believe it results from multiple factors working together over time. These contributing factors include repeated episodes of acute rejection that may have been too mild to detect or treat, various infections affecting the transplanted lung, and complications such as stomach acid backing up into the airways from gastroesophageal reflux disease.^[2]

What Increases the Risk of Rejection

Understanding risk factors helps transplant teams and patients work together to minimize the chances of rejection. Some factors carry more weight than others, and medical experts have organized them into categories based on how strongly they’re linked to rejection.

The strongest risk factors, considered “probable” by transplant specialists, include previous episodes of acute rejection, which can set the stage for future problems. A condition called lymphocytic bronchitis, where white blood cells infiltrate the airways, also increases risk substantially. Infection with cytomegalovirus or CMV, particularly when it causes inflammation in the lungs, raises the likelihood of rejection. Perhaps most critically, patients who don’t consistently take their prescribed medications face dramatically higher rejection rates.^[2]

Other risk factors have been identified as “potential” contributors, meaning the evidence linking them to rejection is somewhat less definitive but still concerning. CMV infection without lung inflammation falls into this category, as do other types of infections and various immune-related conditions that can develop after transplant.^[2]

Recent groundbreaking research has uncovered new information about why chronic rejection develops. Scientists discovered that abnormal cells emerge in the transplanted lung, and these cells engage in harmful “conversations” with the recipient’s immune cells. These interactions perpetuate lung damage and drive the rejection process forward. This discovery, which examined nearly 1.6 million cells, has opened doors to potential new treatments that could interrupt these damaging cellular interactions.^[7]

Recognizing the Signs of Rejection

Knowing what symptoms to watch for empowers patients and caregivers to seek help promptly when rejection might be occurring. The challenge lies in the fact that rejection symptoms often resemble those of common infections, making professional evaluation essential whenever new symptoms appear.

The most noticeable symptom of rejection is typically shortness of breath, especially during physical activity. As rejection progresses and lung function declines, patients may find themselves becoming winded with tasks that previously felt manageable. This happens because rejection damages the lung tissue, reducing its ability to transfer oxygen into the bloodstream efficiently.^[4]

Many patients experiencing rejection develop a cough, sometimes accompanied by increased mucus production. The cough may be persistent and bothersome, though it’s not always present. Fatigue often accompanies rejection, as the body struggles with reduced oxygen levels and the ongoing immune response. Some patients feel generally unwell, with flu-like aches throughout their body. Fever and chills can occur, particularly with more severe rejection episodes.^[4][8]

One of the most important tools for detecting rejection early is home monitoring of lung function. Transplant centers typically send patients home with a spirometry machine, a handheld device that measures how much air a person can exhale in one second. Patients use this device twice daily, recording their results. If the volume drops by more than 10 percent from baseline readings, this signals a potential problem that requires immediate evaluation by the transplant team.^[3]

How Rejection is Diagnosed and Graded

Confirming rejection requires more than recognizing symptoms. When a patient shows signs that might indicate rejection, doctors perform a biopsy of the transplanted lung. During this procedure, doctors insert a flexible tube through the airways and take small tissue samples from the lung. Laboratory specialists then examine these samples under a microscope, looking for specific patterns that indicate rejection.

In acute cellular rejection, the telltale sign is the presence of lymphocytes infiltrating the lung tissue. These white blood cells shouldn’t normally be present in such numbers, and their presence indicates the immune system is actively attacking the transplanted organ. Doctors grade the severity of rejection on a scale from zero to four, with zero meaning no rejection and four representing the most severe cases. This grading system helps doctors decide what level of treatment is needed.^[3]

Diagnosing antibody-mediated rejection is more complex and requires a team approach. Doctors look at multiple pieces of evidence together, including biopsy results, blood tests showing specific antibodies, and the patient’s clinical condition. This type of rejection has become better understood in recent years, though it remains challenging to diagnose and treat.^[5]

For chronic rejection, doctors rely heavily on monitoring lung function over time. The most common form of chronic rejection, called bronchiolitis obliterans syndrome or BOS, is identified by a persistent decline in how much air patients can exhale forcefully. When lung function measurements show consistent decline that doesn’t recover, this suggests chronic rejection is developing. A less common but more serious form called restrictive allograft syndrome or RAS causes the lungs to become progressively smaller and stiffer, making it difficult for patients to breathe in adequate air.^[3][5]

Treatment Options for Different Types of Rejection

The good news is that acute rejection is highly treatable in most cases. When doctors diagnose rejection with a severity score of three or four, they typically start treatment immediately. The standard first-line therapy involves high doses of steroids, powerful medications that suppress the immune system and halt the attack on the transplanted lung. Many patients can take these medications at home, continuing with their normal activities while the treatment works to reverse the rejection. The steroids essentially trick the immune system into backing down from its assault on the new organ.^[3]

If steroid treatment doesn’t successfully reverse the rejection, doctors turn to other immunosuppressive medications. These might include what doctors call lympholytic medications, which specifically target and reduce the white blood cells attacking the lung. The goal of all these treatments is to calm the immune response while preserving enough immune function to protect against infections.^[3]

To prevent antibody-mediated rejection, transplant centers monitor patients closely for antibody formation. During the first year, blood tests check for antibodies monthly. In the second year, testing occurs every three months, then annually thereafter. If antibodies begin forming, doctors can intervene quickly with plasma exchange therapy. This treatment involves removing blood from the patient, running it through a specialized machine that filters out the harmful antibodies, and returning the cleaned blood to the body. Think of it as a highly selective cleaning process for the bloodstream.^[3]

Chronic rejection presents the greatest treatment challenge. Unlike acute rejection, chronic rejection typically cannot be reversed once it develops. This is why prevention is so crucial. The leading treatment that has shown benefit is a common antibiotic called azithromycin, which belongs to a class of drugs called macrolides. While originally developed to fight bacterial infections, azithromycin appears to have anti-inflammatory properties that can stabilize or even slightly improve lung function in some patients with chronic rejection.^[12]

Other treatments that have shown promise in some studies include switching from one immunosuppressive drug to another, surgical procedures to address acid reflux, and various experimental therapies. Some transplant centers have tried treatments like extracorporeal photopheresis, where white blood cells are exposed to ultraviolet light outside the body before being returned, or radiation therapy targeting lymphoid tissue. A medication called pirfenidone, which fights scarring in the lungs, has also been studied. However, none of these treatments work consistently for all patients, and research continues to find better options.^[12]

A recent study from Scandinavia has already changed how transplant centers approach prevention of both acute and chronic rejection. After ten years of research comparing two commonly used medications, tacrolimus and cyclosporine, scientists found clear evidence that one works better than the other. This discovery has led to changes in treatment protocols throughout Scandinavia and at many transplant centers worldwide, potentially improving outcomes for future transplant recipients.^[13]

How Rejection Affects the Body’s Normal Processes

Understanding what happens inside the body during rejection helps explain why symptoms occur and why treatment is necessary. When rejection begins, the immune system launches a coordinated attack similar to what happens when fighting an infection. White blood cells travel to the transplanted lung and infiltrate its tissues, particularly targeting the blood vessels that supply oxygen and nutrients to the organ.

In acute cellular rejection, lymphocytes accumulate in and around the small blood vessels in the lung. These immune cells release chemicals that cause inflammation and damage to the vessel walls. As this damage progresses, the lung tissue itself becomes inflamed and swollen. This inflammation interferes with the lung’s primary job of transferring oxygen from inhaled air into the bloodstream. Patients feel short of breath because their damaged lung cannot efficiently oxygenate their blood.^[3]

In chronic rejection, particularly bronchiolitis obliterans syndrome, the damage occurs in the small airways called bronchioles. Scar tissue gradually forms in these tiny passages, causing them to narrow and eventually become completely blocked. This scarring creates a one-way valve effect where air can enter the lungs but has difficulty getting back out, similar to what happens in asthma but progressive and irreversible. The scarring process involves specialized cells called fibroblasts that deposit collagen and other structural proteins, essentially building walls that close off the airways.^[3]

In restrictive allograft syndrome, the damage pattern differs. Instead of the airways becoming blocked, the lung tissue itself becomes stiff and scarred. The lungs lose their normal elasticity, shrinking in size and becoming increasingly rigid. Patients struggle to breathe in because their lungs can no longer expand properly to fill with air. This form of chronic rejection tends to progress more rapidly and carries a worse prognosis than bronchiolitis obliterans syndrome.^[3]

Recent research has revealed that abnormal cells appear in the transplanted lung during chronic rejection. These cells include types marked by proteins called KRT17 and KRT5, which normally aren’t present in healthy lung tissue. These rogue cells communicate with the recipient’s immune cells through chemical signals, creating a vicious cycle of inflammation and scarring that drives chronic rejection forward. This discovery helps explain why chronic rejection has been so difficult to treat and points toward new potential treatments that could interrupt these harmful cellular conversations.^[7]

Long-term Outlook and Survival Rates

Lung transplantation has improved dramatically over the years, but it still faces greater challenges than transplants of other solid organs. The five-year survival rate for lung transplant recipients is reported at approximately 58 percent, meaning that just over half of patients who receive lung transplants are still alive five years later.^[2] This survival rate is lower than that seen with kidney, liver, or heart transplants, reflecting the unique challenges lungs face as organs exposed constantly to the environment.

During the first year after transplant, graft failure accounts for nearly 23 percent of deaths. After surviving the first year, chronic lung allograft dysfunction becomes the leading cause of death among lung transplant recipients. This underscores why preventing and treating rejection remains so crucial to long-term survival.^[5]

Despite these sobering statistics, many patients do very well after lung transplantation. Success depends on multiple factors including careful patient selection, excellence of the transplant center, consistent medication adherence, prompt recognition and treatment of rejection episodes, and avoiding infections. Centers that perform higher volumes of lung transplants generally achieve better outcomes, as their teams develop greater expertise in managing the complex care these patients require.^[3]