Lung Transplant Rejection

Etiology

Hyperacute lung transplant rejection is mostly caused by preformed antibodies in the recipient against the human leukocyte antigen (HLA) of the donor.[3][4] Acute cellular rejection can be caused by T-lymphocyte mediated (acute cellular rejection) and antibody-mediated reaction directed against major histocompatibility complex antigens in the donor's lung and usually occurs within the first year of transplant.[5]

Chronic lung transplant rejection usually has no clear single identifiable etiology, and experts relate it to multiple processes contributing to each other. Contributing conditions could be recurrent subclinical acute rejection episodes, transplant infection, and aspiration with gastroesophageal reflux disease.[6] A panel of experts organized by the International Society for Heart and Lung Transplantation (ISHLT) and subsequent studies has categorized various risk factors as probable, potential, or hypothetical.

Probable Risk Factors

Probable risk factors include:

• Acute rejection
• Lymphocytic bronchitis
• Cytomegalovirus (CMV) pneumonitis
• Medication noncompliance

Potential Risk Factors

Potential risk factors include:

• CMV infection without pneumonitis
• Organizing pneumonia
• Bacterial, fungal, or non-CMV viral infection
• Older donor age
• Large graft ischemic time
• Donor antigen-specific reactivity

Hypothetical Risk Factors

Hypothetical risk factors include:

• Underlying disease
• Human leukocyte antigen (HLA)-mismatching
• Genotype of recipient
• Gastroesophageal reflux with aspiration

Epidemiology

Antibody-mediated lung transplant is currently a rare type of rejection.[7][8] This is mainly a result of the pretransplant screening for HLA antibodies in the recipient and avoiding incompatible donors. The process is called "virtual crossmatch."[9] 

The Registry of the International Society for Heart and Lung Transplantation reported that at least 29% of 12980 lung transplant recipients between 2004 and 2014 had at least one rejection episode in the first year after discharge.[10] Estimated chronic rejection between 1994 and 2014 was 50% and 67% within 5 and 10 years after transplantation, respectively.[11]

Pathophysiology

Acute Allograft Rejection

Acute allograft rejection is classified into 2 pathophysiological subtypes:

1. Acute cellular rejection: A more common form of acute rejection, mediated by a T-cell immune response against major histocompatibility complex antigens in the donor's lung; usually occurs within the first year of transplant.
2. Acute antibody-mediated rejection: A few weeks to months after the transplant, a separate antibody-mediated pathological process against donor HLA antigens or autoantigens can cause acute respiratory impairment.

CLAD

CLAD is a term coined for any evidence of a decline in lung function beyond a year after transplant and persisting for more than 3 weeks. Based on the physiology of pulmonary function impairment and the microscopic pathology, it has 2 distinct phenotypes:

1. Bronchiolitis obliterans syndrome (BOS): Predominantly obstructive disease
2. Restrictive allograft syndrome (RAS): Predominantly restrictive disease

Histopathology

Acute Cellular Reaction

Pathology shows lymphohistiocytic infiltrates on small arterioles, venules, and bronchioles. Thus, acute cellular rejection is graded by the severity of inflammation separately in the vascular compartment (A0 to A4) and airway (B0 to B2R).

Acute Antibody-mediated Rejection

The distinguishing feature from acute cellular rejection is a form of acute lung injury with diffuse alveolar damage without capillaritis.

BOS

Histopathology demonstrates a fibrotic process obliterating the lumen of small bronchioles, resulting in an irreversible, progressive obstructive disease.

Restrictive Allograft Syndrome (RAS)

The pathological process involves pleuroparenchymal fibroelastosis involving the upper lobes. Acute fibrinoid-organizing pneumonia (AFOP) has also been reported in transbronchial biopsies. Bronchioles are patent, unlike BOS with peribronchial and alveolar fibrin deposits.

History and Physical

Hyperacute lung rejection usually happens within 24 hours after the procedure, with a rapid onset of respiratory distress and severe hypoxia resulting from acute pulmonary edema and diffuse alveolar damage. The clinical presentation is thus similar to acute respiratory distress syndrome (ARDS), carrying a high fatality rate. Imaging is significant for diffuse opacities in the transplanted lung.[5][12][13]      

Acute cellular lung rejection can present for up to 2 years but is most prevalent in the first 6 months.[14] The presentation can range from no symptoms to low-grade fever, cough, dyspnea, or severe respiratory distress. The physical examination might be normal or reveal nonspecific findings such as decreased breath sounds or crackles.[15] 

Bronchiolitis obliterans can present with an asymptomatic decline in forced expiratory volume 1s (FEV₁). Symptoms, if present, are nonspecific and can range from upper respiratory tract infection symptoms, such as dry cough, dyspnea on exertion, and occasionally a low-grade fever, to a rapid decline in pulmonary function and respiratory failure.[16][17]

Evaluation

Evaluation for hyperacute rejection in a lung transplant rejection starts with immunologic testing for HLA antibodies and reviewing pretransplant virtual crossmatch results. Evaluation for other diagnoses includes complete blood count, cardiac enzymes, brain natriuretic peptide, electrocardiogram, echocardiogram, or swan Ganz catheterization to evaluate for left ventricular dysfunction. Computed tomography (CT) imaging to evaluate for pulmonary embolism, surgical complications, and pleural disease is also routinely performed. Bronchoscopy with bronchoalveolar lavage (BAL) is done to evaluate the airway anastomosis site and obtain samples for microbial studies and pathology. Asymptomatic patients can be diagnosed based on transbronchial biopsy from routine surveillance bronchoscopy, whereas CT findings in symptomatic patients lead to targeted bronchoscopic biopsy. Transbronchial biopsies are obtained from the lower lobes if the lungs have diffuse changes. Otherwise, CT helps localize the area of maximal disease and diagnostic yield by biopsy.

The diagnosis of acute cellular rejection is based on excluding infections (especially cytomegalovirus) and transbronchial lung biopsy findings of characteristic histopathologic changes in the specimen. Laboratory studies and imaging findings are neither sensitive nor specific.[18][19]

A definitive diagnosis of acute antibody-mediated rejection requires a demonstration of donor-specific circulating antigen, histopathological findings as above, and immunostaining positive for complement 4d. It is less common among acute allograft rejections and is more challenging to establish.

Regarding CLAD, quantitative criteria involve a 20% or greater decline in FEV₁ or forced vital capacity (FVC) from the best postoperative value. Detection of CLAD necessitates an urgency in establishing etiology and attempting a reversal of function. As the response is time-sensitive, there has been an increasing consensus to label a greater than 10% sustained drop in FEV₁ as "suspected CLAD." Therefore, investigations to rule out alternative etiologies other than rejection can start immediately. Studies include sputum culture, bronchoscopy with bronchoalveolar lavage, endobronchial and transbronchial biopsy, and chest CT with both inspiratory and expiratory imaging.

Laboratory, imaging, and bronchioalveolar lavage findings are not very helpful in diagnosing bronchiolitis obliterans but should be obtained to exclude other potential causes of the decline in pulmonary function. The hallmark for raising the alarm is an obstructive defect in pulmonary function test (PFT) with a sustained decrease in FEV₁ for more than 3 weeks and a greater than 20% decline from baseline. CT imaging in the expiratory phase demonstrates a mosaic appearance consistent with air trapping. In a micro CT study, greater than 60% of the airways beyond the 6-generation bronchiole demonstrated obstruction and constrictive bronchiolitis.[20] Establishing a diagnosis by transbronchial biopsy is challenging due to sampling errors and low sensitivity and specificity. However, bronchoscopy is still of value to rule out infection, aspiration, and reflux-induced damage.

To differentiate it from BOS, the distinctive PFT feature of RAS is a restrictive pattern of a defect greater than a 10% drop in total lung capacity (TLC). Since the patient's self-monitored spirometers do not capture TLC, an alternative PFT-based approach is to detect a sustained drop in FEV₁ but a progressive rise in the FEV₁/FVC ratio. CT shows central or peripheral ground glass changes followed by upper lobe predominant traction bronchiectasis, fibrosis, and hilar retraction. RAS seems to occur in 30% of CLAD patients over 5 years.

Before establishing a diagnosis of BOS, it is crucial to be aware of and exclude the possibility of 2 clinical entities that can have an identical clinical presentation, PFT findings, and CT features: (1) gastroesophageal reflux-related bronchiolitis obliterans, and (2) neutrophilic reversible allograft dysfunction, also known as azithromycin-responsive allograft dysfunction.

Both conditions prognostically differ from classic BOS because of their reversibility if appropriate treatment is pursued (fundoplication in the former and azithromycin 3 times a week prolonged course in the latter). Response to azithromycin in a subgroup of BOS patients with near normalization of FEV₁ has traditionally been correlated with BAL neutrophilia (>15%). However, the correlation with neutrophilic predominance does not always correlate with azithromycin response.[21][22] One approach, therefore, has been to initiate a 3-month trial of azithromycin in all patients with "suspected CLAD." The chest CT in responsive patients usually starts with the peribronchiolar tree in bud infiltrates.

Treatment / Management

Prevention of Rejection

Like other solid organ transplants, an initial induction regimen with antilymphocyte/antithymocyte globulin (ALG/ATG) has a well-demonstrated role in reducing the incidence of acute rejection. However, their use in clinical practice has fallen since introducing the interleukin 2 (IL-2) receptor antagonists basiliximab and daclizumab (the latter is no longer available commercially in the US).[23] They selectively target IL-2 receptors on activated T-cells and inhibit their proliferation and differentiation. According to the ISHLT registry, the IL-2 antagonist-mediated induction regimen was used in 71% of lung transplants in 2018. Basiliximab is administered intraoperatively and again on the fourth posttransplant day. Muromonab-CD3, another induction therapy agent, is no longer preferred because of its severe toxicity profile.

ISHLT recommends a variety of maintenance immunosuppression regimens involving corticosteroids and 2 other agents. The most commonly adopted regimen is a calcineurin inhibitor: cyclosporin or tacrolimus with mycophenolate mofetil and prednisone.[24] Cyclosporin inhibits calcineurin, which is involved in T-cell activation and IL-2 production. Similarly, tacrolimus inhibits IL-2 production by binding to an immunophilin. Cyclosporin is poorly absorbed in cystic fibrosis patients, requiring escalation of dose. Tacrolimus is used more often than cyclosporin. Head-to-head studies show no significant survival difference in 1 and 2 years, but there is a significant reduction in BOS and acute rejection. Similarly, mycophenolate mofetil is currently preferred over azathioprine due to its safety profile and increased selectivity.

Treatment of Rejection

Antibody-mediated

There are no approved medications for the treatment of antibody-mediated lung transplant rejection. The therapeutic principle of interventions involves reducing circulating antibodies through intravenous immunoglobulins, exchange plasmapheresis, anti-CD20 monoclonal antibodies (rituximab), or proteasome inhibitors such as bortezomib. Treatment choice is based on the severity of illness, clinical course, and response to therapy. Antimicrobial therapy can be started in hyperacute rejection until infection is ruled out.[7][25][26](B2)

Acute cellular

Treatment decisions depend on 2 factors: the clinical features and the degree of rejection of the biopsy. Treatment is usually recommended for grade 3A and 4A. With lower rejection grades, the decision may differ between transplant centers based on clinical presentation and clinician and patient preference.[27][28] Empiric antimicrobial therapy is usually started for patients where infection is possible or cannot be ruled out.[29] The main treatment is pulse dose glucocorticoids. The preferred agent is intravenous methylprednisolone 15 mg/kg/day for 3 days.[27][28] The dose is tapered down to a baseline steroid dose. Early rejections seemed to have a better response to steroids.[30] The role and interval of follow-up bronchoscopy are not clear. In one follow-up bronchoscopy study after lung rejection treatment, a correlation between histologic and clinical improvement was found in only half of the cases.[31] For refractory rejection after pulse dose steroids, options are repeated steroid course or switching to maintenance immunosuppression cyclosporine to tacrolimus.[32][33] More refractory cases may need treatment with antibody therapy.[34][35](B2)

BOS

There is no recommended protocol or guidelines for treatment. International Society of Heart and Lung Transplant /American Thoracic Society/European Respiratory Society (ISHLT/ATS/ERS) suggested a trial of oral azithromycin for new-onset bronchiolitis obliterans, which may stop or reverse lung function deterioration. The dose is 250 mg/day for 5 days and then at 250 mg 3 times weekly for a minimum of 3 months. There is no clear evidence of whether azithromycin should be continued long-term with a therapeutic response or discontinued without response.[36] It is also important to re-evaluate and optimize the current immunosuppressive regimen. Cyclosporine can be switched to tacrolimus, and azathioprine can be switched to mycophenolate.[37][38] (A1)

Suppose there is still a decline in the functional tests (FEV₁/FVC) despite previous interventions. In that case, plasmapheresis, extracorporeal photopheresis, inhaled cyclosporine, and mTOR inhibitors are other potential treatments and might be used based on case-by-case selection. As gastroesophageal reflux disease (GERD) has been presented as a risk factor for BOS, testing for GERD is done for patients with new-onset BOS, and those patients who have confirmed reflux disease might benefit from evaluation for potential fundoplication. Although corticosteroids are the mainstay of treatment for acute lung transplant rejection, they are not recommended for the management of bronchiolitis obliterans syndrome.[36] When BOS progresses to end-stage disease refractory to all other therapies, retransplant evaluation is recommended with the same selection process as used for first-time lung transplantation.[36] Only retransplantation provides a meaningful possibility of long-term survival.[36](A1)

RAS treatment strategies are similar to those for BOS, with high failure rates. There are anecdotal reports of some improvement with pirfenidone and a CD52 antagonist, alemtuzumab. More importantly, unlike BOS, retransplant outcomes in RAS are worse; therefore, lung allocation on a diagnosis of RAS involves stricter criteria.

Differential Diagnosis

The differential diagnoses for lung transplant rejection include the following:

Antibody-mediated Rejection

Antibody-mediated rejection includes:

• Primary graft dysfunction
• Pulmonary edema caused by left ventricle dysfunction (myocardial infarction) or fluid overload
• Pneumonia despite prophylactic antibiotics
• Vascular anastomosis complications
• Pulmonary embolism
• Occlusion of the venous anastomosis
• Pleural complication (effusion or hemothorax)
• Transfusion-related acute lung injury (TRALI)
• Aspiration pneumonitis

Acute Cellular Rejection

Acute cellular rejection includes:

• Humoral rejection
• Bronchiolitis obliterans syndrome
• Recurrence of primary pulmonary disease
• Infection
• Airway anatomical complications

Chronic Rejection

Chronic rejection includes:

• Late-onset acute cellular rejection
• Azithromycin-responsive allograft dysfunction
• Esophageal reflux-related bronchiolitis obliterans
• Infection
• Airway complications of lung transplantation
• Recurrence of the underlying lung disease
• Post-transplant lymphoproliferative disorder
• Native lung hyperinflation

Prognosis

In a case series of 21 recipients with a confirmed acute antibody-mediated rejection (AMR), fifteen recipients improved clinically and survived hospital discharge, but 6 died of refractory antibody-mediated rejection. The median survival after the diagnosis of antibody-mediated rejection was 593 days.[7] Survival estimates range from 3 to 5 years unless retransplanted. Early-onset BOS and grade 2 or 3 BOS are predictive of worse survival.

In one study, the development and progression of chronic allograft rejection after lung transplantation (bronchiolitis obliterans syndrome grades 2 and 3) is associated with a 3-fold increase in the risk of death at each stage.[39] In another study of 109 lung transplant patients with the development of bronchiolitis obliterans syndrome, post-BOS onset survival was 51% at 3 years. BOS onset conferred an increased risk of death with a hazard ratio (HR) of 5.96.[40] Mortality was 28% in another study (22 of 77 patients) with BOS.[41]

Although less common, restrictive allograft syndrome has worse outcomes, with survival estimates between 6 and 18 months from diagnosis. Bronchiolitis obliterans syndrome can occasionally progress into restrictive allograft syndrome. Patients with such transformation portend the worst prognosis. Patients with AFOP also have a worse prognosis, with a median survival of only 0.3 years. Risk factors include BAL eosinophilia, sarcoidosis, or interstitial lung disease (ILD) as an indication for transplant, CMV donor/receptor mismatch, younger age, and female sex.

Complications

Acute lung transplant rejection may increase the risk of a recurrence of acute rejections and the development of bronchiolitis obliterans syndrome.