Lung transplant rejection is one of the most common complications following this life-saving surgery, affecting the majority of recipients at some point during their recovery journey. Understanding how rejection works, recognizing its signs early, and knowing the available treatment options can make a significant difference in preserving the function of transplanted lungs and improving long-term survival.

Why Rejection Happens and What Patients Should Know

When someone receives a new lung through transplantation, their body naturally sees this organ as something foreign and unfamiliar. The immune system, which is the body’s defense network designed to protect against infections and diseases, creates special proteins called antibodies that recognize the transplanted lung as an intruder, similar to how it would respond to a virus or harmful bacteria. This protective response, while normally helpful, becomes problematic after transplantation because the body begins to attack the new lung tissue.^[1]

Rejection is surprisingly common among lung transplant recipients. Research shows that acute rejection occurs in up to 90 percent of patients who undergo lung transplantation, making it far more frequent than many people expect. According to registry data, approximately 28 percent of lung transplant recipients experience at least one episode of treated acute rejection during their first year following the procedure.^[2][3]

The goal of managing lung transplant rejection is not necessarily to eliminate it completely—since some degree of immune response is nearly inevitable—but rather to control it quickly and effectively. Treatment focuses on preventing the rejection from progressing, preserving lung function, maintaining quality of life, and reducing the risk of chronic complications that can develop over time. The approach to managing rejection depends on several factors including the timing after transplant, the severity of the rejection episode, and the individual patient’s overall health status.^[4]

Standard Treatment Approaches for Lung Transplant Rejection

The cornerstone of preventing and treating lung transplant rejection involves medications called immunosuppressants, which work by reducing the activity of the immune system. These drugs essentially “trick” the body into accepting the transplanted lung rather than attacking it. All lung transplant recipients must take immunosuppressive medications indefinitely to protect their new organ.^[1][3]

The standard immunosuppressive regimen typically involves a combination of several medications working together. Most transplant centers traditionally use drugs from different classes to achieve optimal immune suppression while minimizing side effects. The two main maintenance medications historically used are tacrolimus and cyclosporine, both of which belong to a class called calcineurin inhibitors. Recent research has shown that tacrolimus is more effective than cyclosporine in preventing both acute and chronic rejection, leading to changes in treatment protocols throughout Scandinavia and many transplant centers worldwide.^[13]

When acute rejection is detected, the first-line treatment typically involves high doses of corticosteroids (commonly called steroids). These powerful anti-inflammatory medications can often reverse the rejection episode when started promptly. Many patients can take these medications at home, which provides relief for individuals who have already undergone the significant stress of transplant surgery and hospitalization. The treatment continues until the rejection reverses, which is confirmed through follow-up testing and monitoring of lung function.^[3][9]

During an evaluation for possible rejection, doctors perform a biopsy of the lung tissue to look for specific white blood cells called lymphocytes. These cells, when present in the blood vessels of the lungs, indicate that the immune system is attacking the transplanted organ. The severity of rejection is ranked on a scale from zero to four, with four representing the most severe form. Patients with rejection scores of three or four typically require more aggressive treatment to prevent permanent lung damage.^[3][9]

If steroid treatment proves ineffective, transplant teams turn to additional therapeutic options. One such option involves lympholytic medications, which are specialized drugs that target and reduce lymphocytes more specifically. Another important intervention is plasma exchange, a procedure where the patient’s blood is drawn, passed through a dialysis-like machine to remove harmful antibodies, and then returned to the body. This treatment is particularly useful when antibodies are forming against the donor lung. Transplant centers typically screen for these antibodies monthly during the first year, every three months during the second year, and annually thereafter.^[3][9]

For patients experiencing antibody-mediated rejection (AMR), which occurs when the immune system produces specific antibodies against the donor’s tissue, diagnosis requires a multidisciplinary approach involving pathologists, immunologists, and transplant specialists working together. Treatment for AMR often combines multiple strategies including adjustment of immunosuppressive medications, plasma exchange, and sometimes specialized therapies targeting antibody production.^[5]

A particularly promising medication that has emerged as an effective treatment is the antibiotic azithromycin. Originally developed to treat bacterial infections, this drug has shown unexpected benefits in managing certain types of lung transplant rejection. Studies have found that azithromycin can lead to small but meaningful improvements in lung function for a minority of patients, especially those with specific patterns of chronic rejection.^[12]

The side effects of immunosuppressive medications can be significant and require careful monitoring. Common side effects include increased susceptibility to infections (since the immune system is suppressed), tremors, weakness, blurred vision, elevated blood sugar levels, high blood pressure, kidney problems, and skin changes including acne. Some medications cause cosmetic changes such as increased facial hair growth or gum swelling. Because of these potential complications, patients require regular blood tests to monitor drug levels and assess organ function throughout their lives.^[5]

Chronic Rejection and Long-term Complications

When acute rejection episodes are not successfully treated, or when multiple subtle rejection episodes occur over time, patients can develop chronic lung allograft dysfunction (CLAD). This condition represents the greatest barrier to long-term survival following lung transplantation and is the leading cause of death after the first year. More than half of lung transplant recipients who survive beyond five years will experience some form of chronic rejection.^[4][5]

CLAD manifests in different forms, with the most common being bronchiolitis obliterans syndrome (BOS). This condition involves destruction and scarring of the small airways within the transplanted lung, leading to progressive narrowing and obstruction. Patients with BOS experience a persistent decline in lung function, making it increasingly difficult to breathe, especially during physical activity. The condition typically develops as a late complication but can occasionally appear as early as three months following transplant.^[4][9]

A second, less common but more serious phenotype of CLAD is restrictive allograft syndrome (RAS). In this condition, the lungs become progressively smaller and stiffer, making it difficult for patients to expand their lungs adequately to breathe in air. RAS is associated with a worse prognosis compared to BOS, and treatment options are even more limited.^[5][9]

The causes of chronic rejection are complex and not fully understood. Experts believe that multiple factors contribute to its development, including recurrent episodes of acute rejection that may not always cause obvious symptoms, infections (particularly with cytomegalovirus or CMV), and aspiration related to gastroesophageal reflux disease (GERD), where stomach contents back up into the esophagus and can be inhaled into the lungs. The International Society for Heart and Lung Transplantation has categorized risk factors as probable, potential, or hypothetical based on the strength of scientific evidence supporting their role.^[2][10]

Unfortunately, chronic rejection typically cannot be reversed once it has developed to an advanced stage. Treatment focuses on slowing progression and managing symptoms. Beyond azithromycin, other therapies with limited supporting evidence include switching from cyclosporine to tacrolimus, performing surgical correction of gastroesophageal reflux through fundoplication, using the medication montelukast (typically prescribed for asthma), extracorporeal photopheresis (a procedure that treats blood cells with ultraviolet light), inhaled cyclosporine delivered directly to the lungs, anti-lymphocyte therapies, radiation therapy directed at lymphoid tissue, and the anti-scarring medication pirfenidone. Most of these treatments are supported primarily by case reports and small observational studies rather than large randomized controlled trials.^[12]

For patients with severe chronic rejection that continues to progress despite all medical interventions, the only remaining option may be re-transplantation—receiving a second lung transplant. This decision involves careful consideration of many factors including the patient’s overall health, availability of donor organs, and likelihood of success.^[12]

Monitoring and Early Detection

Early detection of rejection is critical for successful treatment and preservation of lung function. For this reason, every lung transplant recipient is sent home with a spirometry machine, a device that measures how much air a person can forcefully exhale in one second. Patients use this device twice daily to monitor their lung function at home. If the measured volume drops by more than 10 percent from baseline, patients are instructed to contact their transplant team immediately for evaluation.^[3][9]

The symptoms of rejection can be subtle initially but become more pronounced as the condition progresses. Common warning signs include increasing shortness of breath (particularly with activities that were previously manageable), persistent fatigue, new or worsening cough (sometimes with increased mucus production), fever, chills, flu-like body aches, and declining oxygen levels measured by a pulse oximeter (a small device that clips onto a finger to measure oxygen in the blood). Because these symptoms can also indicate infections, which are common in transplant recipients taking immunosuppressive drugs, proper medical evaluation is essential to determine the correct diagnosis and treatment.^[4][8]

Regular follow-up appointments with the transplant team are a critical part of long-term care. During these visits, doctors perform various tests to assess lung function, check for signs of rejection or infection, monitor medication levels in the blood, and screen for other complications. The frequency of these appointments is typically highest in the first year after transplant and gradually decreases over time, though lifelong monitoring remains necessary.^[5]

Treatment in Clinical Trials and Emerging Research

Understanding the biological mechanisms behind lung transplant rejection has been challenging for researchers, but recent scientific advances are providing new insights that could lead to innovative treatments. A groundbreaking study published in 2025 examined nearly 1.6 million cells from transplanted lungs to create a comprehensive cellular and molecular map of chronic rejection. This research identified specific abnormal cell types that drive lung scarring and discovered harmful communication patterns between cells from the donor lung and the recipient’s immune system.^[7][21]

Scientists discovered that certain rogue cells (specifically KRT17 and KRT5 cells) appear to play a central role in driving lung scarring not only in transplant rejection but also across multiple other lung diseases including idiopathic pulmonary fibrosis, interstitial lung disease, COPD, and COVID-19 lung damage. This finding is particularly exciting because it suggests that treatments developed to target these cells could potentially benefit patients with various lung scarring conditions, not just those who have received transplants. The research team described chronic lung transplant rejection as having been a “black box” for years—doctors knew it happened but didn’t fully understand why. These new discoveries are now spurring immediate exploration of potential drug targets.^[7][21]

The discovery of specific cellular communication pathways involved in rejection opens doors for developing targeted therapies. By understanding which molecules and signals pass between harmful cells, researchers can design drugs that interrupt these damaging conversations. This precision medicine approach holds promise for more effective treatments with potentially fewer side effects compared to broadly acting immunosuppressive drugs.^[7]

Clinical trials continue to investigate various innovative approaches to preventing and treating lung transplant rejection. These studies test new immunosuppressive medications, novel combinations of existing drugs, and entirely different therapeutic strategies such as targeting specific immune pathways or modifying how the donor lung is preserved before transplantation. Participating in clinical trials not only gives patients access to cutting-edge treatments before they become widely available but also contributes valuable information that helps improve care for future transplant recipients.^[5]

While most clinical research focuses on preventing rejection after it begins, some studies are investigating ways to induce tolerance—a state where the recipient’s immune system permanently accepts the donor lung without needing ongoing immunosuppression. Achieving tolerance would be transformative, eliminating the need for lifelong immunosuppressive medications and their associated side effects and complications. However, this remains a long-term goal, with much research still needed before tolerance-inducing therapies could become a clinical reality.^[5]

Most common treatment methods

• Immunosuppressive medications
  • Tacrolimus and cyclosporine (calcineurin inhibitors) form the backbone of maintenance therapy to prevent rejection
  • Recent studies show tacrolimus is more effective than cyclosporine in preventing both acute and chronic rejection
  • These medications must be taken indefinitely to protect the transplanted lung
  • Regular blood tests monitor drug levels and adjust dosing to balance effectiveness against side effects
• Steroid therapy
  • High-dose corticosteroids are the first-line treatment for acute rejection episodes
  • Many patients can take steroids at home until rejection reverses
  • Treatment is guided by lung function monitoring and follow-up biopsies
  • Effective for rejection scores of three or four on the severity scale
• Plasma exchange therapy
  • Blood is drawn and passed through a dialysis machine to remove harmful antibodies
  • Cleaned blood is returned to the patient’s body
  • Used when antibodies are forming against the donor lung tissue
  • Particularly important for antibody-mediated rejection
• Azithromycin therapy
  • Macrolide antibiotic that has shown unexpected benefits in managing chronic rejection
  • Best supported treatment for chronic lung allograft dysfunction
  • Associated with small improvements in lung function in a minority of patients
  • Particularly helpful for certain patterns of bronchiolitis obliterans syndrome
• Lympholytic medications
  • Specialized drugs that target and reduce lymphocytes specifically
  • Used when steroid therapy proves ineffective
  • Part of more aggressive treatment strategies for severe rejection
• Additional therapeutic approaches
  • Extracorporeal photopheresis treats blood cells with ultraviolet light
  • Inhaled cyclosporine delivers immunosuppression directly to the lungs
  • Montelukast may help in selected cases
  • Pirfenidone (anti-scarring medication) is being studied for chronic rejection
  • Fundoplication surgery corrects gastroesophageal reflux to reduce aspiration risk