Lung Transplantation

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Practice Essentials

Lung transplantation is an accepted modality of treatment for advanced stage lung disease. Since 1988, nearly 40,000 lung transplants and over 1200 heart/lung transplantations have been performed in the Unites States, representing approximately 5% of all organ transplants.[1]  

The Agency for Healthcare Research and Quality (AHRQ) in the United States concluded that "lung transplantation has evolved as a clinical procedure achieving a favorable risk-benefit ratio and acceptable 1- and 2-year survival rates."[2] The International Society for Heart and Lung Transplantation continues to monitor lung transplantation and has an ongoing registry, which is reported annually.[3]

Highly sophisticated and extraordinary therapies, such as lung transplantation, are performed at a great cost to society. Presently, active research is being conducted on enhancing the patient's quality of life following lung transplantation. Several studies have reported a significant improvement in different quality-of-life domains, tested pretransplant and posttransplant. Other studies comparing candidates and lung transplant recipients have demonstrated significant improvements in energy levels, physical functioning, mobility, and symptoms such as dyspnea and anxiety. The recipients have expressed greater satisfaction with their lives and their health following lung transplantation.

Attempts to compute the costs of lung transplantation to general society and to determine the cost effectiveness of this therapy have been made. Cost evaluations should take into account both the actual cost and the improved quality of life provided by this therapy compared to standard care. The cost is expressed in units of QALY (quality-adjusted life-year), which reflects the real or anticipated survival time and health-related quality of life.

In 1995, the University of Washington Medical Center estimated that lung transplantation costs $176,817 per QALY compared with traditional therapy.[4]  A study of 3000 Medicare patients who received lung transplantations between 2005-2011 found that the average cost of lung transplantation was $135,622. However, high-volume transplant centers (35 or more lung transplantations annually) had a mean transplantation cost of $131,352. In addition, median length of stay in the intensive care unit fell significantly with increasing lung transplantation volume, from 14 days in low-volume centers to 11 days in intermediate centers and 10 days in high-volume centers.[5]

Additionally, after adjusting for recipient health risk, low-volume centers had an 11.66% greater transplant admission cost (P = 0.040), a 41% greater risk for in-hospital mortality (P = 0.015), and a 14% greater risk for early hospital readmission (P = 0.033) compared with high-volume centers. There was no significant difference in transplant cost, in-hospital mortality, or early hospital readmission between intermediate- and high-volume centers.[5]

Living donor transplantation

Transplantation of lobes from living donors involves bilateral implantation of the lower lobes from two blood group–compatible living donors. Donation of a lobe decreases the donor's lung volume by an average of approximately 15% and, consequently, is not associated with long-term functional limitation.

Living-donor lobar lung transplantation (LDLLT) has been used as an option for patients who are considered too ill to await cadaveric transplantation.[6] The procedure was initially performed in patients with cystic fibrosis, although the indications were subsequently broadened. The functional and survival outcomes with LDLLT are similar to those achieved with conventional transplantation of cadaveric lungs. 

There have been a total of 253 LDLLT in the United States since 1990; however, no LDLLT has been performed in the US since 2013.[1]  

Despite fairly extensive experience, no donor mortality has been reported. In a study of 369 live lung donors serious complications occurred in 18% of donors; 2.2% underwent reoperation and 6.5% had an early rehospitalization. No deaths occurred and no donors underwent lung transplantation during 4000+ person-years of follow-up (death: minimum 4, maximum 17 years; transplant: minimum 5, maximum 19). Live lung donation remains a potential option for recipients when using deceased donor lungs lacks feasibility. However, in the United States the use of two live donors for each recipient and the risk of morbidity associated with live lung donation do not justify this approach when deceased lung donors remain available.[7]

In recent years, most of the reports on LDLLT have been from Japan, where the average waiting time for a cadaveric lung is exceeding 800 days. LDLLT has been performed both for adult and pediatric patients suffering from various end-stage lung diseases including restrictive, obstructive, vascular, and infectious conditions.[8]

Compared with bilateral cadaveric lung transplants, long-term studies have shown that the relatively smaller-sized lobes can provide similar pulmonary function and exercise capacity. Living lobar lung transplantation should be considered in a patient with a clinically deteriorating condition. Although no deaths have been reported in the donor cohort, a risk of death between 0.5% and 1% should be quoted, pending further data. A case series of 128 living lobar lung transplantations performed in 123 patients between 1993 and 2003 was published.[9]  The actuarial survival among the living lobar recipients was 70%, 54%, and 45%, at 1, 3, and 5 years, respectively.[9]

For patient education information, see Lung Disease and Respiratory Health Center, as well as Heart and Lung Transplant and Bronchoscopy.

Background

Animal experimentation by various pioneers, including Demikhov and Metras, in 1940s and 1950s demonstrated that the procedure is feasible technically.[10]  Hardy performed the first human lung transplantation in 1963. The donation was essentially after cardiac death, and the recipient of the left lung transplant survived only 18 days.[11]  From 1963-1978, multiple attempts at lung transplantation failed because of rejection and problems with anastomotic bronchial and tracheal healing.

In the 1980s, the introduction of cyclosporine, a powerful immunosuppressant, generated renewed interest in the area of organ transplantation, including lung transplantation. Alternative techniques for improving bronchial healing were devised. These techniques included refining the bronchial–pulmonary collateral circulation by limiting the length of the donor bronchus and revascularizing the bronchial circulation extrinsically by wrapping the anastomosis with omentum or a pericardial patch in early years.

The first successful single lung transplant was reported by Dr. Joel Cooper at the University of Toronto in 1986.[12]  In 1988, Dr. Alexander Patterson described the technique of en bloc double-lung transplantation.[13]  This particular en bloc technique was associated with tracheal anastomotic complications as a result of poor vascularity; as a result, bilateral sequential single-lung transplantation has become the standard of care for patients requiring bilateral lung replacement.

Dr. Denton Cooley and associates were the first to attempt heart-lung transplantation in 1968, when they performed a transplant in a 2-year-old girl with an atrioventricular canal defect and pulmonary hypertension; the patient died 14 hours postoperatively.[14]  Canine studies were ongoing during the subsequent years, but it was not until the late 1970s that Reitz and colleagues at Stanford, using cyclosporine, achieved clinically acceptable results in primates.[15]  In 1981, the first successful heart-lung transplant was performed at Stanford in a 45-year-old woman who went on to do well for more than 5 years after the procedure.[15]

Indications

Causes of respiratory failure in patients with advanced-stage pulmonary disease are as follows:

Patients should be considered for lung transplantation when they meet the following criteria:

In 2014, the International Society for Heart and Lung Transplantation (ISHLT) released an updated consensus opinion regarding the appropriate timing of referral and listing of candidates for lung transplantation. The statement concluded that lung transplantation should be considered for adults with chronic, end-stage lung disease who meet all the following general criteria[16] :

Preoperative evaluation of specific diseases

The appropriate timing for referral to a transplant program and placement on the transplantation waiting list is based on the patient's functional status and life expectancy. Criteria for referral and listing vary with the specific underlying pulmonary diseases.

The chance of surviving the waiting period depends on the underlying disease and the system for allocation of donor organs. Waiting times are variable and based on many factors, such as height and blood group.

Chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is the most common indication for which lung transplantation is performed. The BODE index can be used to assess the need for transplantation in patients with COPD. It consists of the following[17] :

The ISHLT criteria for timing of referral for lung transplantation in patients with COPD are as follows[16] :

The ISHLT recommends listing COPD patients for transplantation when they meet one or more of the following criteria:

Interstitial lung diseases

The natural history of various interstitial diseases is quite variable. Idiopathic pulmonary fibrosis, of the usual interstitial variant, which is the second most frequent disease for which lung transplantation is performed, has a median survival of approximately 2.5 to 3.5 years from the time of diagnosis. Dismal survival rates of these patients on waiting lists indicate that these patients should have early referrals for transplantation evaluation.

ISHLT criteria for timing of referral in patients with interstitial lung disease are as follows[16] :

ISHLT criteria for timing of listing for transplantation in patients with interstitial lung disease are as follows[16] :

Cystic fibrosis and bronchiectasis

Cystic fibrosis is the third most common indication for which lung transplantation is performed. These patients develop a high risk of mortality when their FEV1 decreases to 30% or less. At this level of FEV1, the mortality rate increases to 45% at 2 years. Other indicators of poor prognosis are weight loss, recurrent pneumothoraces, frequent hospitalization, and hemoptysis.

Liou and colleagues have validated a 5-year survivorship model for cystic fibrosis. This model identified the following eight characteristics, in addition to FEV1 as a percentage of predicted normal values, to accurately predict survival in patients with cystic fibrosis[18] :

The authors also have developed two worksheets, which help calculate weight-for-age z- score and 5-year predicted survival. This survivorship model has potential for use in investigating the effect of novel therapies and assignment of patients on lung transplantation waiting lists.

ISHLT criteria for timing of referral in patients with cystic fibrosis are as follows[16] :

Clinical decline may be characterized by increasing frequency of exacerbations associated with any of the following:

ISHLT criteria for timing of listing for transplantation in patients with cystic fibrosis are as follows[16] :

Pulmonary arterial hypertension

The median survival for patients with primary pulmonary hypertension is 2.8 years. The indicators of poor survival are NYHA functional class III or IV, elevated mean right atrial pressure, elevated mean pulmonary arterial pressure and decreased cardiac index, and reduced diffusion. Mean pulmonary arterial pressure greater than 85 mm Hg is associated with a median survival of less than 12 months. A response to vasodilator therapy is associated with improved survival.

Present treatment of choice for NYHA class III and IV patients with pulmonary hypertension is long-term prostacyclin therapy, especially if they fail to demonstrate vasoreactivity during formal vasodilator trial. Prostacyclin has demonstrated improved survival, improved exercise capacity, and better quality of life.[19, 20] Transplantation is indicated only if the patient cannot tolerate or fails prostacyclin therapy. In patients who have developed severe right heart failure, the right heart pressures and functions return to near normal values following lung transplantation alone.

ISHLT criteria for referral for transplantation in patients with pulmonary hypertension are as follows[16] :

ISHLT criteria for listing for transplantation in patients with pulmonary hypertension are as follows[16] :

Contraindications

Lung transplantation for advanced-stage lung disease is a complex therapy with significant risk of perioperative morbility and mortality. Therefore, each patient needs to be evaluated individually, considering absolute and relative contraindications.

Absolute contraindications

According to the International Society for Heart and Lung Transplantation, the absolute contraindications are as follows[16] :

Extrapulmonary organ dysfunction

Patients with a significant heart, liver, or kidney disease are not transplant candidates. The immunosuppressive drugs are nephrotoxic, and a creatinine clearance of less than 50 mL/min is a risk factor for subsequent development of renal failure. Significant coronary artery disease predisposes a patient to myocardial infarction in the perioperative period.

A patient with severe left ventricular systolic or diastolic dysfunction is not a candidate for lung transplantation. The presence of significant liver disease, as indicated by a total bilirubin level of greater than 2 mg/dL, is associated with an unfavorable outcome following transplant.

Relative contraindications

Adults older than 75 years are unlikely to be candidates for lung transplantation in most cases. Although age by itself should not be considered a contraindication to transplant, increasing age generally is associated with comorbid conditions that are either absolute or relative contraindications.

Relative contraindications include the following[16] :

Age

Adults older than 75 years are unlikely to be candidates for lung transplantation in most cases. Although age by itself should not be considered a contraindication to transplant, increasing age generally is associated with comorbid conditions that are either absolute or relative contraindications.[16]

Pooled data have shown no statistical difference between patients younger than 65 years and patients older than 65 years, although a trend toward lower survival for recipients older than 65 years was present. Most centers have an age cut-off of 50 years for heart-lung transplantation, 60 years for bilateral sequential lung transplantation, and 65 years for single-lung transplantation (SLT).[10]

Atherosclerosis

Lung transplantation is relatively contraindicated in patients with atherosclerotic disease who are at risk for end-organ disease after transplantation. However, some patients with coronary artery disease will be candidates for percutaneous coronary intervention or coronary artery bypass grafting (CABG) prior to transplantation or, in some instances, combined lung transplant and CABG.

Infection

Lung transplantation can be considered in patients infected with hepatitis B and/or C who are stable on appropriate therapy without significant clinical, radiologic, or biochemical signs of cirrhosis or portal hypertension. Lung transplantation in candidates with hepatitis B and/or C should be performed in centers with experienced hepatology units.

Lung transplantation can be considered in HIV-infected patients with undetectable HIV RNA who are compliant on combined antiretroviral therapy. The most suitable candidates should have no current acquired immunodeficiency syndrome (AIDS)–defining illness. Lung transplantation in HIV-positive candidates should be performed in centers with expertise in the care of HIV-positive patients.

Lung transplantation can be considered in patients infected with Burkholderia cenocepacia, Burkholderia gladioli, and multi-drug–resistant Mycobacterium abscessus if the infection is sufficiently treated preoperatively and there is a reasonable expectation for adequate control postoperatively. To be considered suitable transplant candidates, these patients should be evaluated by centers with significant experience managing these infections in the transplant setting, and patients should be made aware of the increased risk of transplant because of these infections.

Ventilator dependence

The limited data suggest that patients who are dependent on a ventilator prior to the transplant have higher mortality rates but may be candidates for lung transplantation.[21, 22] Singer et al found that ventilator dependence was associated with decreased overall survival; risk of death was highest in the first 6 months posttransplant.[23] A prolonged wait while the patient is on a mechanical ventilator may lead to various complications such as infections, cardiovascular deconditioning, and muscle atrophy, all of which further compromise the outcome of the transplant.

Psychosocial issues

Individuals who currently smoke, abuse drugs, or drink alcohol heavily are not candidates for transplantation. Patients with other psychosocial issues, such as poor compliance and psychiatric disorders that may complicate posttransplant therapy, are not considered good candidates.

Corticosteroid therapy

In the past, corticosteroid treatment was considered a contraindication to transplantation because of concerns about anastomotic dehiscence.[24] Low-dose steroid therapy (ie, < 20 mg/d) is acceptable in a transplant candidate.

Infection

In patients with cystic fibrosis, infection with B cepacia is associated with significant mortality rates because this organism is resistant to all antibiotics. Some centers do not offer transplants to patients infected with B cepacia. Also, patients who have active tuberculosis infection are not candidates for transplantation. Nontuberculous mycobacterial colonization is not a contraindication. Aspergillus fumigatus colonization of a patient with cystic fibrosis is only a relative contraindication. These patients are treated with itraconazole prior to transplant in an attempt to eradicate colonization with this fungus.

Body weight

Patients who have cachexia (BMI < 16 kg/m2) likely have poor nutritional status and would have a poor outcome following transplantation. Obesity (BMI > 30) is a concern because of postoperative atelectasis and pneumonia.

Other comorbid conditions

Other medical conditions that have not resulted in end-stage organ damage should be optimally treated before transplantation. Examples include the following:

Although the practices of individual transplant centers may vary, patients with systemic connective tissue diseases do not necessarily have unfavorable outcomes if their disease is quiescent. These patients may be considered as transplant candidates on an individual basis.

Prognosis

The International Society for Heart and Lung Transplantation Registry reports a 1-year survival rate of 78% and 5-year survival rate of 51% following lung transplantation.[3]  Mortality is highest in the first year, and attrition was consistent across the subsequent time periods. In the first 30 days, graft failure, non-cytomegalovirus (CMV) infections, cardiovascular complications, and technical problems account for most of the mortality. After the first year, bronchiolitis obliterans syndrome (BOS) and non-CMV infections were the predominant causes of death. By 5 years, malignancies and cardiovascular causes account for almost 17% of reported causes of death.

Overall survival according to pre-transplant diagnosis shows that after 1 year, patients with chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) had the worst long-term survival.[3]  In general, bilateral procedures have better survival in each diagnosis category, especially in patients with COPD. Survival according to pretransplant CMV serologic status was most influenced by the CMV status of the donor. Survival during the first 5 years after transplantation was significantly better among recipients of a transplant from a donor who was CMV-seronegative.

Early diffuse alveolar damage may be associated with bronchiolitis obliterans syndrome and early mortality. Late diffuse alveolar damage may increase the risk of restrictive allograft syndrome.[25]

One study compared survival in patients with and without the supranormal expiratory and normal inspiratory flow rates (SUPRA pattern). The study found improved survival in patients with the SUPRA pattern and suggests potential therapeutic approaches to improve outcomes in patients who have undergone bilateral lung and heart-lung transplant.[26]

Whether lung transplantation truly increases survival over the natural history of the underlying disease remains difficult to ascertain in the absence of randomized trials. A survival advantage has been reported for patients with cystic fibrosis and pulmonary fibrosis who have received transplants, but this advantage has not been demonstrated for patients with emphysema.

Patients are referred for transplantation at a point in the course of their disease at which death is considered likely within 2-3 years. Therefore, transplantation would be expected to confer a survival advantage. Severe dyspnea and poor quality of life can be additional considerations for lung transplantation.

Laboratory Studies

Pretransplant laboratory values must be determined to evaluate the appropriateness of the candidate for transplantation. The following are the laboratory tests:

Imaging Studies

The pretransplant workup includes the following studies:

Surgical Therapy

Certain features of the transplant center are associated with enhanced success. Experience has shown that transplant success correlates with the number of procedures performed at the center. Features that generally are accepted as desirable of a good program include the following:

Donor-related issues

The donor selection criteria may vary from center to center, and the general guidelines that are used are listed below. Most transplant centers will use lungs from a donor who is positive for cytomegalovirus (CMV) for transplant into a donor who is not positive for CMV, but postoperative CMV prophylaxis is required in that situation. Other acceptable donor criteria are as follows:

Waiting list for lung transplantation

The United Network for Organ Sharing has an ongoing assessment of waiting times for all potential transplant recipients. In 2005, the lung allocation system changed to one in which priority for transplantation is determined by medical urgency and expected outcome. The lung allocation score is based on survival models that estimate waitlist and posttransplant survival, and it reflects the net transplant benefit.

Early evaluations of the new system indicated that waiting time had decreased, the total number of transplants had increased, waitlist mortality might be decreasing, and survival after transplantation remained unchanged. Over time, refinements in the lung allocation score will likely reduce waitlist mortality further and maintain or perhaps improve survival after transplantation.[27]

Preoperative Details

Lung transplantation is a rapidly evolving field; therefore, a dogmatic approach cannot be recommended. Various issues that must be considered when choosing the procedure include the shortage of organ donors, the etiology of the original disease, and the center's experience with graft and patient survival. The following general guidelines for the selection of the procedure are based on the nature of the original disease and have been adapted from Egan et al.[28]

Heart-lung transplantation is used for the following:

Double-lung transplantation is used for the following:

Single-lung transplantation is used for the following:

Other factors that must be taken into account on an individual basis are ventilator dependence,[32, 21] previous cardiovascular thoracic surgery, and preexisting medical conditions (eg, hypertension, diabetes mellitus, osteoporosis). The posttransplantation medical regimen can worsen these illnesses.

A previous thoracic procedure alone rarely precludes lung transplantation; however, if cardiopulmonary bypass (CPB) is required for the transplant procedure, a potential for complications exists.[33] With current surgical techniques, pretransplantation corticosteroid therapy has not been associated with airway complications, and a maintenance regimen of prednisone (10-20 mg/d) is not a contraindication for transplantation.

Despite the chronic infections that occur in patients with cystic fibrosis, the infectious complications after transplantation have been comparable between patients with cystic fibrosis and patients without cystic fibrosis. Posttransplant infection with Burkholderia cepacia can be associated with high mortality rates.

Many transplant candidates also have the risk factors for coronary artery disease; therefore, a cardiac workup (including coronary angiography) is performed commonly. Severe coronary artery disease is a contraindication to lung transplantation; however, coronary artery bypass grafting at the same time as lung transplantation has been performed with a reasonably good outcome in some centers. Less invasive preoperative interventions, such as percutaneous transluminal coronary angioplasty and stenting, are preferred.

Donor selection and harvesting

Criteria for lung donation identify donors with evidence of good gas exchange and an absence of infection of the airway or parenchyma. The donor lung should appear healthy on chest radiographs. Donor lungs should be within 25-30% of the predicted size of the recipient's lungs. Ideally, patients who have COPD should be matched with donors who are between 3 and 5 cm of the recipient height. For patients who have restrictive disease, the donor lungs should be slightly undersized, ie, the donor's height should be within 2 cm of the recipient's height.

All potential donors need to undergo bedside bronchoscopy. A gram stain and culture are taken of the bronchoalveolar fluid and sent for immediate analysis. Upon bronchoscopy, the finding of diffuse bronchial mucosal inflammation is a contraindication for harvesting. However, lungs with purulent secretions that cannot be cleared with bronchoscopy and without mucosal inflammation, in the presence of a clear chest radiograph and preserved gas exchange, are suitable for donation.

In particular, the blood gas on 100% oxygen, which is referred to the challenge gas, should remain greater than 300 mm Hg. The donor should ideally have no more than a 20 pack-year history of smoking. In the United Kingdom, transplantation using lungs from donors with positive smoking histories improves the overall survival of patients. Even though lungs from these donors are associated with worse outcomes, the probability of survival is greater if they are accepted than if the patient waits for a lung from a donor with a negative smoking history.[34]

If found to be suitable, the donor still needs to undergo intraoperative evaluation of the organs. Intraoperative inspection of the pleural space and lung is performed to assess unsuspected trauma, bullous disease, or mass lesions. Recruitment maneuvers may be performed intraoperatively to assure atelectasis is minimized. Pulmonary vein gases may also be collected intraoperatively to ensure good oxygenation of the patient, which, again, should be greater than 300 mm Hg on 100% oxygen.

Donor lung management

Donor lungs are very fragile; therefore, predonation management is essential. To reduce injury, the positive end-expiratory pressure (PEEP) should be less than 5 cm H20 and the tidal volumes are normally 10 mL/kg. The following details key elements of the donor management:

Criteria for brain death in a donor

An irreversible cessation of all brain and brainstem function is defined as brain death in a potential donor. In 1981, the President's Commission formulated guidelines for determining death.[35] Brain death is determined by clinical criteria when two separate examinations are performed 24 hours apart or by ancillary studies to assess brain activities. An absence of drugs, hypothermia, or metabolic derangements must be confirmed.

Clinical criteria for brain death are as follows:

Ancillary criteria for brain death in a donor are as follows:

Donation after cardiac death

The early- and medium-term outcome in donation-after-cardiac-death lung recipients can be compared with that of donation-after-brain-death lung recipients. In a retrospective study comparing these two groups of recipients, there were no differences between groups with regard to patient characteristics, with the exception of a higher number of donation-after-cardiac death patients having obliterative bronchiolitis. The donor pool can safely be expanded by using lungs from donors after cardiac death.[36]

Lung preservation

With current techniques, satisfactory graft function can be obtained after an ischemic interval of as long as 6-8 hours. Ischemic injury to the pulmonary vascular endothelium increases permeability and results in pulmonary edema.

Hypothermic flush perfusion is the method used most commonly for pulmonary preservation in clinical practice. After systemic heparinization of the donor, the pulmonary vasculature is flushed with a cold solution. Commonly used solutions are modified Euro-Collins solution, University of Wisconsin solution, and Perfadex. These are delivered via a large pulmonary artery cannula at a volume of 50-60 mL/kg over 4-5 minutes. Most flush solutions are administered at a temperature of 4°C, while topical cooling is carried out by filling the pleural cavity with iced crystalloid solution. The harvested lungs are immersed in crystalloid solution, packed in ice, and transported at a temperature of 1-4°C. The infusion and transport is performed during active ventilation and static inflation with O2 respectively.

Ex vivo lung reconditioning

Ex vivo lung reconditioning can increase lung donor availability by permitting the use of marginal donor lungs that were initially deemed unsuitable for transplantation because of inadequate arterial oxygen pressure.[37] For reconditioning, donor lungs are removed along with the heart and undergo ex vivo lung perfusion (EVLP) in an extracorporeal membrane oxygenation circuit. The lungs are gradually and gently rewarmed, reperfused, and ventilated, which reduces edema and atelectasis and allows full inspection and assessment.[37, 38]

Two protocols for EVLP have been developed: Lund and Toronto. The Lund model utilizes a priming/perfusion solution specifically designed for EVLP, such as the Steen solution, which was developed by Swedish surgeon Stig Steen.[37] It is a buffered extracellular solution that includes human albumin to provide an optimal colloid osmotic pressure.The EVLP procedure is performed with a mixture of Steen solution and washed erythrocytes in order to reach a hematocrit of 15%, and the left atrium is kept open, providing the possibility of a normal cardiac output (5-6 L/min) during EVLP. In the Toronto protocol, the EVLP procedure is carried out with an acellular Steen solution and a closed left atrium.[38]

In a 10-year follow-up study, researchers from Lund University reported no difference in long-term survival or pulmonary function between 15 patients who received conventional double-lung transplantations and six patients who received initially rejected donor lungs that had been reconditioned using EVLP. Rates of freedom from chronic lung allograft dysfunction (CLAD) were likewise comparable.[39]

In April 2019 the US Food & Drug Administration (FDA) approved the XVIVO Perfusion System (XPS™) with STEEN Solution™ Perfusate (XVIVO Perfusion, Inc, Englewood, CO) for use on previously unaccepted donor lungs that will be transplanted into a patient with end-stage lung disease.  Donor lungs can remain in the machine for up to 5 hours, for reconditioning and assessment.[40]

 

Intraoperative Details

Anesthetic management

An understanding of the physiology of the various lung transplant recipients with different disease states leads to greater insight into perioperative ventilator management. All lung transplantation procedures should be performed with CPB available on standby.

Continuous hemodynamic monitoring, oximetry, and ventricular function assessment by transesophageal echocardiography is performed intraoperatively.

Single-lung transplantation

For single-lung transplantation (SLT), the native lung with the poorest pulmonary function according to the preoperative quantitative perfusion scan is excised. If both the lungs have similar function, the right side is preferred because surgical exposure and instituting cardiopulmonary bypass (CPB), if required, is easier.

The lung is exposed via a posterolateral thoracotomy through the fifth intercostal space. The ipsilateral groin is included in the surgical field in the event that cannulation of the heart via the chest is not possible and femoral vessels are required for partial CPB. Following excision of the native lung, the donor lung is wrapped in sponges soaked with cold crystalloid solution and placed into the hemithorax.

The bronchial anastomosis is performed first. See the image below.



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Bronchial anastomosis. Posterior wall closure is performed with a continuous suture.

Although several techniques have been described, the length of both the donor and recipient bronchi is minimized in order to preserve collateral blood supply and to achieve some degree of anastomotic overlap. The smaller bronchus is telescoped into the larger bronchus with either a technique of interrupted sutures or a combination of running sutures on the membranous layer and interrupted sutures externally. The anastomosis is covered by local peribronchial tissue, pedicle flaps of thymic tissue, or pericardial fat. The pulmonary artery anastomosis of the donor and recipient vessels requires careful approximation to avoid kinking. For the left atrial anastomosis, the confluence of the recipient pulmonary veins is incised to create a left atrial cuff. See the images below.



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Right atrial anastomosis. Continuous anastomosis with the common pulmonary vein joined to the atrium.



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Completed atrial anastomosis.



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Donor lung showing hilar surface.



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The clamps are exposing the donor vein.



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Donor bronchus, artery to the right and vein to the left.



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Right donor bronchus.



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A close-up shot of the donor vein.

After completion of these anastomoses, the lung is reinflated gently; the perfusion is reestablished after evacuating air via the left atrial suture line. Following resumption of ventilation to the donor lung, the suture lines are secured. Hemostasis is obtained, 2 chest tubes are placed, and the chest is closed in a standard fashion. Following reintubation with a single lumen tube, flexible bronchoscopy is performed to inspect the bronchial anastomosis and clear the airway of blood or residual secretions.

Pulmonary vein augmentation for single-lung transplantation

Donor harvesting procedure requires careful surgical technique to preserve an adequate donor left atrial cuff around the confluence of the superior and inferior pulmonary veins. The surgeon divides the donor left atrium halfway between the left venous confluence and the coronary sinus. In some situations, especially when the heart and lungs are harvested separately, the donor lungs are left with little or no atrial tissue around the venous confluence. Construction of a neoatrial cuff from the divided edges of each of the 2 pulmonary veins ensures utilization of graft for transplantation. The newly formed cuff then is used for atrial anastomosis. This technique can be applied to the left or right lung and also can be applied to create an additional length of pulmonary artery. These simple but effective surgical techniques expand the donor availability for lung transplantation.

Double-lung transplantation

The most frequently performed double-lung transplantation (DLT) procedure actually is bilateral sequential SLT. This procedure is associated with a significantly lower incidence of bronchial complications than the en-bloc DLT procedure and is technically less difficult to perform than en-bloc DLT.

The exposure for bilateral sequential lung transplantation is via bilateral anterolateral thoracotomies through the fourth or fifth intercostal space. These can be connected by a transverse sternotomy, ie, the "clam-shell" incision. For patients with emphysema who undergo DLT, the contralateral hemithorax may be left closed until after the first lung graft is completed. Mobilization and pneumonectomy of the native lung and the implantation of the lung graft are conducted in the same manner as described for SLT. Thymic and anterior mediastinal tissue may be mobilized to cover the bronchial anastomosis.

Heart-lung transplantation

Either a standard median sternotomy or a clam-shell incision may be used for heart-lung transplantation. Following the institution of CPB, the lungs are removed by an extrapericardial approach, ie, incising and stapling of the bronchovascular structures at the pulmonary hila. The donor right atrium is incised from the inferior vena cava to the right atrial appendage. The right atrium is examined to exclude an atrial septal defect and for adequate closure of the superior vena cava. If a tracheal anastomosis is used, the posterior pericardium is incised between the ascending aorta and the superior vena cava to expose the distal trachea.

Some centers prefer bilateral bronchial anastomosis using a telescoping technique as described for SLT. This approach avoids dissection in the posterior mediastinum and may be associated with fewer anastomotic complications. After the right atrial anastomosis is completed, the aortic anastomosis is performed. The aortic cross clamp is removed, and, after reinflation of the lungs, the heart is de-aired via the pulmonary artery and the left ventricle. The heart is defibrillated to begin circulation, and the patient is weaned from CPB.

Postoperative Details

The postoperative period is the crucial time when unexpected complications may develop. Most centers follow the standard treatment protocols and monitor patients who have undergone transplantation at regular multidisciplinary rounds.

Respiratory management

Patients should be maintained on a nontoxic fraction of inspired oxygen, and barotrauma should be minimized. Volume control ventilation with a tidal volume of 8-10 mL/kg and a peak end-expiratory pressure (PEEP) of 5 cm H2 O generally is instituted. The transplanted lung is susceptible to capillary leak in the postoperative period. Therefore, the pulmonary capillary wedge pressure should be kept lower to minimize the formation of low-pressure pulmonary edema. Aggressive diuresis while maintaining adequate cardiac output and tissue perfusion is recommended.

Attention to bronchial hygiene is important. Frequent suctioning and bronchoscopy may be necessary for postoperative atelectasis in patients who have undergone lung transplant. Hyperinflation of the native lung may occur in patients with emphysema. This may lead to barotrauma and the development of air leaks that require chest tube placement. Phrenic nerve injury is known to occur in a significant number of patients. Unilateral phrenic nerve paralysis may compromise respiratory status to some extent, and bilateral phrenic nerve injury certainly would result in prolonged mechanical ventilation. In most patients, phrenic nerve palsy is transient and generally improves over the following weeks to months.

Adequate postoperative analgesia is helpful in weaning these patients from the ventilator. An epidural is normally placed in most patients. Extubation is performed when the patient's mental status is normal and when the patient has achieved reasonable spontaneous ventilation and gas exchange, generally 24-48 hours following the procedure. In patients with significant pulmonary hypertension who undergo transplantation, a risk exists for the development of pulmonary edema in the donor lung.

Hemodynamics

Postoperative hypotension may be related to hypovolemia, sepsis, or vascular anastomotic complications. Left or right ventricular failure secondary to myocardial ischemia or infarction should be considered in the differential.

Postoperative supraventricular dysrhythmias are common in the initial few weeks. The dysrhythmias may occur because of electrolyte abnormalities, hypervolemia, or inotropic drugs, and secondary to intraoperative manipulation of the heart. The arrhythmias respond to routine management with calcium channel blockers or amiodarone, and, sometimes, electrical cardioversion is performed if hemodynamic collapse is present.

Postoperative gastrointestinal complications

A paralytic ileus or gastroparesis may develop postoperatively. These may be related to electrolyte abnormalities, narcotics, or the effect of drugs. They improve following routine management.

Postoperative renal complications

Immunosuppressive agents, such as cyclosporin A and tacrolimus, are nephrotoxic. Their blood levels should be monitored routinely and frequently in the postoperative phase.

Fluid management

The goal of fluid management after lung transplantation is to minimize edema formation in the transplanted lung while maintaining adequate cardiac function. The effects of ischemia and reperfusion injury and the absence of lymphatics all may contribute to the development of pulmonary edema. Pulmonary capillary wedge pressure should be kept as low as possible after surgery, without compromising ventricular preload and cardiac output.

Antimicrobial therapy

Bacterial prophylaxis against gram-positive organisms and a broad-spectrum antibiotic for the organisms identified preoperatively should be administered. Patients with cystic fibrosis require coverage for pseudomonal species, usually with antipseudomonal cephalosporin. These antibiotics can be tailored depending on the donor and recipient cultures collected at the time of transplantation.

Routine prophylaxis for fungal organisms is useful when the recipient's sputum cultures show the presence of Aspergillus. Herpes simplex infections have been eliminated by routine acyclovir prophylaxis after lung transplantation. Cytomegalovirus (CMV) infection remains a significant problem following lung transplantation. The incidence of CMV infection after lung transplantation is related to the preoperative CMV status of both the donor and the recipient. The use of ganciclovir prophylaxis has reduced the incidence of primary disease significantly and has improved outcome. Pneumocystis jiroveci infection has been eliminated by the routine use of trimethoprim-sulfamethoxazole, which is administered three times per week following surgery.

Nutrition

Maintaining optimal nutrition in the postoperative period is beneficial for improving surgical outcome. When prolonged ventilatory support is required, the use of enteral alimentation is mandatory.

Surgical complications

Major technical complications following lung transplantation are rare. Pulmonary artery obstruction can occur as a result of anastomotic stenosis, kinking, or extrinsic compression. Left atrial anastomotic obstruction also can occur because of faulty anastomotic technique or extrinsic compression by a clot, pericardium, or an omental flap.

Acute graft dysfunction without evidence of vascular anastomotic complications has been described.[41] The cause is not known, but unsuspected contusion or aspiration could be possible causes. Management includes evaluation of the vascular anastomosis and maintenance of oxygenation.[42]

Pleural space complications are not uncommon, but their occurrence is considered rare. Pneumothorax may occur on either side of the lung graft or on the side of the native lung. Pleural effusions are common after lung transplantation, particularly when a significant size disparity exists. Management of these effusions usually is conservative in nature, using diuretic therapy. Thoracentesis and tube drainage are indicated only if an effusion is complicated by pneumothorax or respiratory compromise.

Airway complications have been significantly less common in the recent reports of lung transplantation. Because revascularization of the bronchial arterial circulation is not present, the donor bronchus must rely on collateral perfusion from the pulmonary circulation in the initial postimplementation period. Airway ischemia manifests as mucosal ulcerations followed by abnormalities that can range from anastomotic dehiscence to an anastomotic stenosis. However, present surgical techniques have limited the scope of these complications.

Follow-up

Monitoring and surveillance of the patient after the lung transplant procedure is divided into immediate, early, and late periods.

Immediate postoperative period

In the immediate postoperative period, the patient is monitored invasively with arterial, central venous, and Swan Ganz catheters. Chest radiographs are performed on a daily basis. Reperfusion injury is suggested by hypoxemia and diffuse infiltrates. A perfusion scan within the first week may provide additional assessment of the function of the allograft. Reperfusion injury is measured by calculating the PaO 2 -to-FiO 2 ratio. Usually, the greater the injury, the longer the time to extubation.

Routine immediate prophylaxis with antibiotics is performed. Patients with bronchiectasis or cystic fibrosis require antipseudomonal prophylaxis. Adequate pain control is important for aggressive chest physiotherapy and early rehabilitation of these individuals.

Early postoperative period

The first 3 months following transplantation is the early postoperative period.

Daily chest radiographs are required in the first postoperative week. These are reduced in frequency according to the patient's clinical status. Spirometry is performed as soon as is practical after surgery, at predischarge, and periodically thereafter. Some centers have the patients perform daily home spirometry and report any drop in forced expiratory volume in 1 second (FEV1) of 5-10%. The FEV1, forced vital capacity (FVC), and diffusing capacity steadily rise in the lung transplant recipient during the first 3 months.

Fiberoptic bronchoscopy and bronchoalveolar lavage are performed if the patient demonstrates new infiltrates on chest radiographs, a decrease in lung function on spirometry, or the presence of new symptoms. Transbronchial biopsies completed at the time of bronchoscopy are used to assess the presence of acute rejection.

The role of routine transbronchial lung biopsy in an asymptomatic patient with stable lung function is controversial.[43] However, most centers perform surveillance bronchoscopies and transbronchial biopsies in order to detect asymptomatic acute rejection. Acute rejections that are greater than A2 category are treated with enhanced immunosuppression. The overall utility of this practice has not been established in clinical trials.

Late postoperative period

Late monitoring is beyond 3 months following transplantation. Chronic rejection is referred to as bronchiolitis obliterans syndrome (BOS). The diagnosis of BOS is based on physiologic and pathologic criteria. A sustained decrease of greater than 20% in FEV1 or the pathologic presence of obliterans bronchiolitis are the 2 most common variables present for the diagnosis of BOS.

Immunosuppression

Inducing a state of immune suppression is the key to successful lung transplantation. The immunosuppressive regimens used for lung transplantation are based on the successful protocols that have evolved for kidney and heart transplantation. Most centers use a combination of tacrolimus, mycophenolate mofetil (MMF), and glucocorticoids as the 3-drug regimen for immunosuppression.

Tacrolimus

Tacrolimus is a macrolide compound that binds to the immunophilin protein called the FK-binding protein, which then inhibits calcineurin within the cell. Tacrolimus has been used for immunosuppression as part of a 3-drug regimen taking the place of cyclosporine in many centers. Tacrolimus has been found to be superior to cyclosporine in lung transplantation in terms of decreased incidences of acute rejection and chronic rejection.[44] Toxicity of tacrolimus is similar to that of cyclosporine and includes renal dysfunction, hypertension, neurotoxicity, and glucose intolerance.

Mycophenolate mofetil

Mycophenolate mofetil (MMF) is an immunosuppressive agent that has replaced azathioprine in heart and lung transplantation.[45] The mechanism of action of MMF is via selective inhibition of T- and B-cell proliferation. MMF blocks de novo purine biosynthesis, a step that is required for the lymphocyte cell division. This is the source of MMF's increased selectivity and decreased toxicity: T and B lymphocytes use only the de novo pathway in purine biosynthesis, whereas other cell lines that use both de novo and salvage pathways are not inhibited.

Several prospective randomized trials have demonstrated a significant reduction in episodes of acute rejection with MMF compared with azathioprine in kidney transplant recipients. Use of MMF also has shown comparable efficacy to azathioprine in reducing acute rejection in heart transplant patients.[45] Studies have reported that lung transplant recipients treated with MMF experienced fewer acute rejection episodes over a 12-month period.[46, 47]

A multicenter, prospective, randomized trial of MMF versus azathioprine demonstrated a comparable efficacy of these two agents in reducing episodes of acute rejection at 6 months of follow-up. Patients treated with MMF developed less frequent cytomegalovirus (CMV) infections, although other adverse events leading to discontinuation of medication were more frequent. Additional clinical trials are required to evaluate efficacy of MMF in reducing obliterative bronchiolitis and improvement in long-term survival.

The usual dosing schedule for MMF is 1 g PO bid; the dose is titrated to maintain the white blood cell count (WBC) at more than 4000 cells/mm3. Levels of 12-15 ng/dL are usually maintained for the first 6 months.

Cyclosporine

Cyclosporine was the mainstay of immunosuppression before the introduction of tacrolimus. Serum levels of 300-400 mg/mL usually are maintained for the first month; thereafter, levels of 150-200 mg/mL are considered therapeutic. Nephrotoxicity, the major adverse effect of cyclosporine, results from vasoconstriction of the afferent glomerular arterioles.

Azathioprine

Azathioprine is a purine analog that is converted to several active metabolites, including 6-mercaptopurine. These metabolites have inhibitory effects on the hematologic proliferation of T cells and B cells. Azathioprine is begun at a dosage of 2-2.5 mg/kg/d, and the dose is adjusted to maintain a WBC of no less than 4000 cells/mm3.

Rapamycin

Rapamycin is the newest immunosuppressive agent to be introduced. Its mode of action is less well understood but has antilymphoproliferative activity.[48] Due to its antihealing properties, it is not usually used immediately posttransplant but rather when chronic rejection or bronchiolitis obliterans syndrome becomes evident. It is also associated with renal toxicity and pneumonitis.

Corticosteroids

Corticosteroids have various effects on the immune system, primarily mediated by their interaction with a high-affinity cytoplasmic steroid receptor. Prednisone, prednisolone, and methylprednisolone all are used for transplant patients. Intraoperatively, methylprednisolone is administered prior to the reperfusion of the grafted lung. Postoperatively, moderate doses of corticosteroids in combination with tacrolimus and MMF are used for the induction of immunosuppression. An oral dose of prednisone at 0.5 mg/kg/d usually is begun 5-7 days postoperatively.

Antilymphocyte antibody preparations

Antilymphocyte antibody preparations, the so-called cytolytic therapies, have been used in patients undergoing clinical lung transplantation. These preparations include antilymphocyte globulin, antithymocyte globulin, a murine monoclonal antibody to the CD3 complex of human lymphocyte (OKT3) and an anti-IL-2R antagonist antibody preparation. The use of these agents generally is for induction therapy.[3]

Current approach to immunosuppressive therapy

Induction therapy after lung transplantation, which is practiced at approximately 50% of transplant centers worldwide, may reduce and delay acute rejection episodes and may also reduce the incidence of chronic rejection. Unfortunately, no large, prospective, randomized, placebo-controlled trials exist to confirm the benefits of induction therapy compared with conventional immunosuppression and to compare different agents. Current evidence suggests that the induction therapy may be associated with better outcomes, although controversy exists.[49]

Maintenance therapy with a triple-drug regimen is still the conventional practice for lung transplantation. The first-line treatment of an episode of acute rejection is high-dose intravenous steroid pulses. For ongoing or recurrent acute rejection, the strategy is to add rapamycin. The second choice for refractory acute rejection is treatment with antithrombocyte globulin (ATG) or OKT3. In refractory cases, high-dose intravenous immune globulin can be used.

For treatment of chronic rejection, which is referred to as bronchiolitis obliterans syndrome, the most difficult issue following lung transplantation remains unsettled. Patients whose regimen includes cyclosporine should be switched to tacrolimus from cyclosporine. For patients unresponsive to the change to tacrolimus from cyclosporine, high-dose steroid pulses and ATG are still frequently used. Rapamycin may also be introduced as a fourth agent. Other possible therapies are total lymphoid irradiation and photopheresis, which are really last resorts.

Complications

Reimplantation response

The reimplantation response (ie, reperfusion injury) is felt to be a form of noncardiogenic pulmonary edema related to surgical trauma, organ ischemia, denervation, and lymphatic interruption. The condition occurs in more than 97% of transplanted lungs. Reimplantation response is a diagnosis of exclusion; left ventricular failure, transplant rejection, fluid overload, and infection all must be excluded.

The response almost always begins by the first day after the transplant and always is present by day 3. It frequently progresses over the first few days but peaks by day 4 or 5. Another etiology, such as infection or rejection, should be considered for any new process beginning after this time. Most patients have normal findings or only minimal residual abnormality by 10 days after the transplant.



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This chest radiograph performed 24 hours following right unilateral lung transplantation is within normal limits.



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Seventy-two hours following lung transplantation, this patient developed dyspnea and hypoxemia. The bronchoscopy and bronchoalveolar lavage revealed n....

Graft dysfunction

Early graft dysfunction occurs within the first 24 hours after the transplant. It occurs in fewer than 10% of cases and is characterized histologically by diffuse alveolar damage. The dysfunction usually is the result of severe donor lung ischemia, donor lung injury, or vascular anastomotic stenosis.[42, 41]

Primary graft dysfunction

Primary graft dysfunction may result from ischemia-reperfusion injury. In patients with idiopathic pulmonary fibrosis, elevated pentraxin-3 levels seem to be associated with the development of primary graft dysfunction after lung transplantation.[50] Variants in the gene encoding pentraxin-3 are risk factors for primary graft dysfunction in lung transplant patients and are associated with increased plasma levels of pentraxin-3.[51]

Rejection

In 2016, the International Society for Heart and Lung Transplantation (ISHLT) published a consensus opinion of the definition and diagnostic criteria for pulmonary antibody-mediated rejection (AMR). AMR as categorized as either clinical or subclinical with the following definitions[52]

Clinical AMR is further categorized by ISHLT as definite, probable and possible based on the degree of certainty of the presence or absence of a number of pathologic, serologic, clinical, and immunologic criteria that include the following[52] :

Exclusion of other causes of allograft dysfunction increases confidence in the diagnosis but is not essential. 

Hyperacute rejection

Hyperacute rejection occurs in cases of an immunoglobulin G donor-specific human leukocyte antigen (HLA) antibody-positive crossmatch and results in acute diffuse alveolar damage.

Acute rejection

Most patients develop at least one episode of rejection within the first 3 weeks following transplantation, typically in the first 5-10 days. Patients with rejection can develop dyspnea, fever, leukocytosis, and a widened alveolar-arterial oxygen gradient; however, patients with mild rejection can be asymptomatic. Pulmonary function testing may show a decrease in forced expiratory volume in 1 second (FEV1) and vital capacity (VC). Transbronchial biopsy usually is performed to establish the diagnosis and exclude infection. Often, a dramatic response to treatment with corticosteroids and increased immunosuppression is observed within 24 hours.

Pathologically, acute rejection initially manifests as a perivascular lymphocytic infiltrate. With progression, this infiltrate becomes more widespread and extends into the alveolar septa and, subsequently, into the alveoli. Recently, the pathologic classification of lung rejection has undergone revisions as our understanding of the process has evolved.[53]

In approximately half the cases of rejection, the findings on chest radiograph are normal. If observed, the findings often are nonspecific, such as new, worsening, or persistent perihilar and basal reticular interstitial disease (ie, septal lines) and/or consolidations 5-10 days after the transplant. Findings observed on CT scans include ground-glass opacities, septal thickening, nodules, and consolidations. If findings are present, rejection can be confirmed by their rapid clearing, typically within 48 hours of steroid therapy.

The infiltrates observed during the first week after the lung transplantation usually are caused by the reimplantation response (ie, reperfusion edema). Persistent infiltrates beyond the first week suggest infection or acute rejection. Infection during the first month after the transplant usually is bacterial in nature, and opportunistic infections become more common after that time. The presence of nodules on the chest radiograph results from infection, a posttransplantation lymphoproliferative disorder (PTLD), or a recent transbronchial biopsy.

Pulmonary rejection

Solid organ rejection has been classified into three categories based on well-defined clinical and histologic features: hyperacute rejection, acute rejection, and chronic rejection.[53]

Hyperacute rejection

Hyperacute rejection arises within minutes after the newly transplanted organ begins to be perfused. Hyperacute rejection is mediated through preexisting antibodies against ABO blood groups, HLAs, or other antigens that interact with vascular endothelium. These cause activation of complement and the other cytokines and also lead to cell-mediated injury. The grafted organ demonstrates intravascular thrombosis, necrosis of vessel walls, and preoperative infiltration with mononuclear and polymorphonuclear cells. ABO blood group matching and preoperative screening for antibodies against common antigens largely has eliminated this problem. This is usually a fatal complication.

Acute rejection

Acute rejection is the host's response as the host recognizes the graft as foreign. The elements of the major histocompatability complex (MHC) are the factors responsible for recognizing the grafted organ and initiating cell-mediated inflammation. Two major classes of HLA antigens exist, and these are divided into class I and class II. Class I are HLA-A, HLA-B, and HLA-C; these are expressed on nearly all cells. They interact with CD8+ and T cells. Class II antigens (HLA-DP, HLA-DQ, HLA-DR) are expressed on specific cells, such as B lymphocytes, mononuclear phagocytes, and dendritic cells.

Acute rejection is diagnosed by clinical and histological criteria. The clinical criteria commonly are adopted for diagnosis in the early postoperative period. The features of acute rejection are dyspnea, fatigue, dry cough, low-grade fever, a decrease in oxygenation of greater than 10 mm Hg, the development of new or changing radiographic opacities, and a decrease in FEV1 of more than 10% below baseline value. Infections are the other most common differential diagnoses and cause significant morbidity in the early postoperative period; therefore, they must be excluded. Because the clinical criteria present later, when the acute rejection is more severe, they may be nonspecific in the early stages and many centers confirm the presence of rejection histologically.

Acute rejection is classified into five grades based on the severity and extent of the perivascular lymphocytic infiltration. The range is from no significant abnormality (grade A0) to severe abnormality (grade A4), in which extensive involvement of the interstitium and air space is present over and above, pneumocyte damage is present, and vasculitis (and even parenchymal infarction) are present.[53]

The clinical course of acute rejection can be variable. Most individuals develop at least one episode of acute rejection within the first 3 months. A significant number of patients are asymptomatic and are diagnosed by surveillance transbronchial biopsy. Chest radiographs may be helpful because ill-defined perihilar and lower lobe opacities, along with septal lines and pleural effusions, may suggest acute rejection.

Episodes of acute rejection are prevented by induction and maintenance of satisfactory immunosuppression. Most centers routinely use a triple immunosuppressive regimen, consisting of corticosteroids, mycophenolate mofetil (MMF) and tacrolimus.

The mainstay of therapy for acute rejection is pulse intravenous methylprednisolone, followed by higher oral prednisone doses. Tacrolimus and MMF are maximized. Methylprednisolone is used in a dose of 500-1000 mg/d intravenously, and oral prednisone is increased to 0.5-1 mg/kg/d with subsequent tapering. Steroid-resistant acute rejections may be treated with antilymphocyte therapy, which usually results in successful resolution of most cases of acute rejection.



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Severe acute rejection within 10 days of lung transplantation (lower magnification). The typical histological findings are perivascular lymphocytic in....



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Severe acute rejection within 10 days of lung transplantation (high power). Courtesy of Zhaolin Xu, MD.



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The transbronchial biopsy shows perivascular aggregates of lymphocytes in the low-power field, which is indicating acute rejection in this patient 60 ....



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The transbronchial biopsy shows perivascular aggregates of lymphocytes in the high-power field, which indicates acute rejection in this patient 60 day....

Bronchiolitis obliterans syndrome (chronic rejection)

The incidence of bronchiolitis obliterans syndrome (BOS) is highest after the first year following lung transplantation. However, the risk of BOS increases to 60-80% 5-10 years after the lung transplantation procedure. It is the most important complication that adversely affects the long-term survival of graft recipients.

Symptoms occur secondary to the airflow obstruction that progresses over time. These patients develop exertional dyspnea, a nonproductive cough, wheezing, and/or low-grade fever. Although the symptoms resemble bronchial asthma, the limited response to bronchodilator and corticosteroid therapy makes these ineffective.

BOS has a variable course. The disease may be progressive, it may plateau, or it may progress gradually in a stepwise fashion. Therefore, early detection of this complication is paramount. Obliterative bronchiolitis is staged according to the level of airflow obstruction as measured by FEV1. Four stages are described, based on severity, from grade 0 to grade III, as follows:

Pathologically, bronchiolar inflammation and narrowing of the lumen are present, and bronchiectasis is present in larger airways. The active lesions demonstrate lymphocytic inflammation and the formation of granulation tissue. Fibrotic tissue compromises the airway lumen in a constrictive fashion. In advanced stages, collagen is deposited and fibrosis of the bronchiolar wall can cause occlusion of the lumen.

The pathogenesis of BOS may be initiated by alloimmune and infectious inflammation of bronchiolar structures, followed by a fibroproliferative response. Diagnosis is confirmed by high-resolution computed tomography (HRCT) scans and a complete battery of pulmonary function tests. HRCT scans demonstrate bronchiectasis, thickening of septal lines, hyperlucency, peribronchial and perivascular infiltrates, and mosaic attenuation of lung parenchyma. Because of the air trapped in different regions of the lung, the mosaic pattern is most prominent during expiratory images.

Pulmonary function tests reveal expiratory airflow obstruction. A decrement of at least 20% in the FEV1 and FEV1 -to-FVC ratio occurs. The diffusing capacity of lung volumes generally is maintained or may decrease slightly.

Prevention and treatment of bronchiolitis obliterans

Acute rejection is a major risk factor for BOS. Therefore, prevention of acute rejection likely leads to a decreased incidence of obliterative bronchiolitis. Some centers perform surveillance transbronchial biopsies during the first 2 years following transplantation. When the biopsies demonstrate acute rejection of grade A2 or higher, patients are treated with intensified immunosuppression. CMV infection also may be a risk factor for the development of obliterative bronchiolitis. Therefore, preventing CMV infection by transfusing CMV-negative blood products and using prophylactic ganciclovir may reduce the incidence of this devastating disease.

Early detection of BOS in a preclinical stage is ideal so that aggressive attempts can be made to prevent a fully developed syndrome. However, to date, no particular marker to indicate obliterative bronchiolitis, either from the peripheral blood or bronchoalveolar lavage fluid, has predicted a risk for this disease.

The treatment for established BOS has not proven to be effective.[54] The International Society for Heart and Lung Transplantation, American Thoracic Society, and European Respiratory Society have published a clinical practice guideline on the diagnosis and management of BOS. All the treatment recommendations in the guideline are conditional, as the supporting evidence is of very low quality. The recommendations are as follows[55] :

The guidelines suggest not using sustained high-dose systemic corticosteroids (≥ 30 mg/day of prednisone or the equivalent) for the treatment of BOS, given the lack of proven benefit and the potential for serious adverse effects.

The guidelines note that beneficial effects have been reported for approximately 35–40% of lung transplant recipients treated with azithromycin, especially patients with BAL neutrophilia. Azithromycin is given orally at 250 mg per day for 5 days and then 250 mg three times per week, for a minimum of 3 months. It is unclear whether azithromycin should be continued long-term in patients who show a beneficial response.

Airway complications

A systemic arterial supply is not established at the time of lung transplantation surgery. Viability of the anastomosis depends on collateral flow from the pulmonary circulation. For end-to-end anastomoses, the use of an omental, pericardial, or intercostal muscle anastomotic wrap in the early postoperative period has reduced the incidence of ischemia-induced airway necrosis and dehiscence.

More recently, many institutions have switched to a procedure that does not require a wrap procedure, one that uses a telescoping anastomosis. Nonetheless, procedures that employ wrapping with pericardium or some other tissue still are performed occasionally. In the telescoping anastomosis, the membranous (ie, outer) portion of the donor bronchus is sutured end-to-end to the recipient bronchus, but the cartilaginous inner portion is inserted into the recipient bronchus for 1 or 2 cartilaginous rings. The internal margin of the anastomosis is not sutured and may result in an endoluminal flap.

Diaphragmatic dysfunction resulting from phrenic nerve paralysis is uncommon (fewer than 4% of cases).

Bronchial dehiscence

Bronchial dehiscence is the most common anastomotic airway complication in the early postoperative period. It occurs in 2-3% of cases. Ischemia at the anastomotic site is the major factor in the development of this complication. Dehiscence probably is best assessed by bronchoscopy; however, CT scans typically demonstrate the presence of extraluminal gas, which is 100% sensitive and 72% specific for dehiscence. Patients with telescoping anastomoses also may develop small anastomotic diverticula, which appear as smooth rounded air collections at the inferior-medial aspect of the anastomosis.

Stricture

Anastomotic stricture occurs in approximately 10% of cases, and the risk for stenosis may be increased with a telescoping anastomosis. Stenoses often manifest with progressive airflow obstruction that can be difficult to differentiate from other causes, such as acute rejection or bronchiolitis obliterans syndrome. Stricture probably is best evaluated by bronchoscopy; however, CT scans often demonstrate the area of narrowing. Treatment is stenting, typically with an expandable metallic stent. More recently, balloon dilatation has obviated the need for stents in some centers.

Vascular complications

Stenoses at vascular anastomoses are uncommon (fewer than 4% of cases) but are more common at the arterial anastomosis than at the venous anastomosis. The risk of pulmonary infarction is greatest in the immediate postoperative period because the newly transplanted lung does not have an alternate pathway for bronchial circulation.

Renal complications

Acute kidney injury is a common complication after lung transplantation. In a retrospective analysis of 657 patients who underwent lung transplantation between 1997 and 2009, a total of 424 patients (65%) had at least one acute kidney injury event in the first 2 weeks posttransplant. The same study showed an increased risk of chronic kidney disease at 1-year posttransplant. Patient survival rates decreased as the Acute Kidney Injury Network (AKIN) score increased. One-year patient survival rates were 91%, 82%, 66% in the no AKI, AKIN 1, and AKIN 2–3 groups, respectively.[56]

Infections

Infection is the leading cause of death in lung transplant recipients. Factors that increase a patient's susceptibility to infection after transplant include immunosuppression, reduced mucociliary clearance, decreased cough reflex resulting from denervation, and interruption of lymphatic drainage. For more information, see Infections After Solid Organ Transplantation.

Bacterial/viral pneumonia

Bacterial pneumonias are the most common infection following lung transplantation[57] and occur in more than 35% of patients during the first year after the transplant (highest incidence is during the first month posttransplant). Bacterial pneumonias remain a major infectious complication throughout the patient's life. The donor lung is affected more commonly. Gram-negative organisms are most common, especially Enterobacter and Pseudomonas. Bronchitis secondary to Pseudomonas species or Staphylococcus aureus infection also is observed. Bacterial pneumonia typically manifests radiographically as a lobar or multilobar consolidation.

Viral pneumonias develop in approximately 11% of patients who have undergone lung transplants, and they occur at any time following transplantation.

Opportunistic infections

Opportunistic infections also are common after lung transplant surgery (34-59% of patients), but the infections do not seem to affect overall patient mortality rates.

CMV infection

CMV is the second most common cause of pneumonia in patients who have received lung transplants, and it is the most common opportunistic infection (35-60% of opportunistic infections).[57] CMV is the most significant viral infection, and it usually occurs 1-4 months after the transplant. Primary infection is the most serious and is observed in 50-100% of patients who are seronegative who receive grafts from a donor who is seropositive. In patients who are seropositive, secondary CMV infection develops from reactivation of latent disease following the institution of immunosuppressive therapy or from infection with a different strain of CMV.

Infected patients may be asymptomatic or may develop a fulminant pneumonia, possibly with extrathoracic findings such as retinitis, hepatitis, and gastritis. Presenting symptoms include dyspnea, fever, and cough. The diagnosis of CMV pneumonia can be made by bronchoscopy with lavage and biopsy. Prophylactic therapy with acyclovir and immune globulin has not reduced the incidence of CMV infection in patients who have undergone transplant procedures.

The most common finding on chest radiographs in patients with CMV infection is diffuse parenchymal haziness. CT scan findings in patients with CMV infection include areas of ground-glass attenuation; reticulation; multiple, small, ill-defined 1- to 3-mm nodules; and, even less commonly, areas of dense consolidation.

A retrospective study found that CMV replication in the lung allograft is common following lung transplantation and increases the risk of bronchiolitis obliterans syndrome.[58] Longer antiviral prophylaxis strategies may suppress CMV, leading to improved long-term outcome.

Herpes simplex virus infection

A less common cause of viral infections includes the herpes simplex virus (HSV). Patients with HSV infection present with fever, cough, and dyspnea, but they demonstrate symptomatic improvement after therapy with intravenous acyclovir. Radiographic findings may be absent or may demonstrate diffuse ground-glass opacities.

Fungal infections

Opportunistic fungal infections are less common than viral infections, but they are associated with higher mortality. Fungal pneumonias usually occur 10-60 days following transplant and more commonly involve the transplanted lung. The most common findings of fungal infection on CT scans are a combination of nodules (multiple, variable sizes, irregular margins), consolidation, and ground-glass opacification. Pleural effusion also is common (63% of cases).

Aspergillus infection

Locally invasive or disseminated Aspergillus infection accounts for 2-33% of posttransplant infections and 4-7% of deaths in patients who undergo lung transplants. Aspergillus infection most commonly is characterized by local invasion of a necrotic bronchial anastomosis (ie, ulcerative tracheobronchitis), which typically occurs within 4 months of transplantation. Inhaled amphotericin B is often used in the immediate posttransplant period to help eliminate this complication.[57] Patients are also discharged on voriconazole as daily prophylaxis for the first year. Long-term use of voriconazole may be associated with an increased incidence of cutaneous squamous cell carcinoma in lung transplant patients.[59]

Pneumocystis jiroveci pneumonia

Patients who have undergone lung transplant procedures have an increased susceptibility to P jiroveci infection, but prophylaxis with trimethoprim-sulfamethoxazole is effective in preventing the infection (incidence is nearly 0%).[57] Without prophylaxis, the incidence of P jiroveci infection approaches 90%.

Posttransplantation lymphoproliferative disorders

Patients who have undergone organ transplantation are at increased risk for developing posttransplantation lymphoproliferative disorders (PTLDs) ranging from benign polyclonal hyperplasia to aggressive high-grade lymphoma (most are B-cell type). The disorders tend to occur within 1 year after transplantation (peak is 3-4 mo posttransplant). PTLDs develop in 4-10% of patients who have undergone lung transplants, as opposed to an approximate 2% incidence in other solid organ transplant recipients.

Patients with PTLDs may be asymptomatic, or they may have nonspecific complaints such as fever, weight loss, dyspnea, and lethargy. Following lung transplant, PTLDs most commonly are isolated to the lung. Solitary or multiple pulmonary nodules ranging in size from 1-2 mm to 5 cm are the most common pulmonary manifestations in patients with PTLDs. Mediastinal and hilar adenopathy also can be observed in 22-50% of cases. Patients who present with a solitary pulmonary nodule have a better overall prognosis. T-cell PTLDs tend to occur later and tend not to be associated with Epstein-Barr virus (EBV) infection. T-cell PTLDs are associated with a worse prognosis.

Differential considerations for multiple lung nodules include infection (ie, bacterial or fungal), especially with Aspergillus or Nocardia. These infections tend to cavitate and have an upper-lobe predominance. Furthermore, repeated transbronchial biopsies are known to produce parenchymal nodular densities of no special significance.

Most PTLDs are associated with concomitant EBV infections, and this may be the etiologic agent. EBV stimulates B-lymphocyte proliferation, which is unopposed because of a cyclosporin-induced inhibition of T lymphocytes. Treatment consists of decreasing or ceasing immunosuppressive therapy (ie, cyclosporin) and administering antiviral agents (ie, acyclovir). After immunomodulation, regression occurs in 23-61% of patients.

Cancer

Patients who have undergone solid organ transplantation are at increased risk for infection-related and unrelated cancers due to immunosuppression and oncogenic viral infections.

In a large cohort study that used data from the US Scientific Registry of Transplant Recipients and 13 state and regional cancer registries, overall cancer risk was elevated with an incidence of 1375 per 100,000 person-years.[60] Lung cancer risk was most elevated in lung recipients. Non-Hodgkin lymphoma and cancers of the lung, liver, and kidney were also reported as common malignancies in organ transplant patients.

Activity

Exercise training after lung transplantation is recommended. According to one study, daily walking improves health and self-reported physical functioning in post-transplant patients. Exercise also significantly lowers ambulatory blood pressures.[61]

Guidelines Summary

Selection of Lung Transplantation Candidates

In 2014, the International Society for Heart and Lung Transplantation (ISHLT) released an updated consensus opinion regarding the appropriate timing of referral and listing of candidates for lung transplantation. The statement concluded that lung transplantation should be considered for adults with chronic, end-stage lung disease who meet all the following general criteria[16] :

Absolute contraindication include[16] :

Relative contraindications include:

Disease-specific Candidate Selection

The International Society for Heart and Lung Transplantation consensus opinion includes recommendations for the timing of referral and of listing for lung transplantation by specific diseases as summarized below.[16]

COPD

Timing of referral:

Timing of listing (presence of one criterion is sufficient):

Interstitial lung disease

Timing of referral:

Timing of listing:

Cystic fibrosis

Timing of referral:

Timing of listing:

Pulmonary vascular diseases

Timing of referral:

Timing of transplant listing:

 

Antibody-mediated Rejection of the Lung

In 2016, the International Society for Heart and Lung Transplantation (ISHLT) published a consensus opinion of the definition and diagnostic criteria for pulmonary antibody-mediated rejection (AMR). AMR as categorized as either clinical or subclinical with the following definitions[52] :

Clinical AMR: 

"The presence of allograft dysfunction (defined as alterations in pulmonary physiology, gas exchange properties, radiologic features or deteriorating functional performance) associated with AMR. Clinical AMR may be asymptomatic, such as a small but significant change in pulmonary physiology."

Sub-clinical AMR: 

"Histologic criteria of AMR detected on surveillance transbronchial biopsies (with or without C4d and with or without the presence of DSA) in the absence of allograft dysfunction."

Clinical AMR is further categorized by ISHLT as definite, probable and possible based on the degree of certainty of the presence or absence of a number of pathologic, serologic, clinical and immunologic criteria that include[52] :

Exclusion of other causes of allograft dysfunction increases confidence in the diagnosis but is not essential. 

How common are lung transplantations?What is the cost effectiveness of lung transplantation?What is living donor lung transplantation?What is the evolution of lung transplantation procedures?What are the indications for lung transplantation?What are the ISHLT guidelines on the timing of referral and listing of candidates for lung transplantation?Which factors determine the appropriate timing for referral to a lung transplant program?What is the BODE index to assess the need for lung transplantation in patients with COPD?What are the ISHLT criteria for referral and listing for lung transplantation in patients with COPD?What are the ISHLT criteria for referral and listing for lung transplantation in patients with interstitial lung diseases?What are the ISHLT criteria for referral and listing for lung transplantation in patients with cystic fibrosis and bronchiectasis?What are the ISHLT criteria for referral and listing for lung transplantation in patients with pulmonary arterial hypertension?What are the ISHLT absolute contraindications for lung transplantation?Which extrapulmonary organ dysfunctions are absolute contraindications for lung transplantation?What are the relative contraindications for lung transplantation?Why is age a relative contraindication for lung transplantation?Is atherosclerotic disease a contraindication for lung transplantation?Which infections are relative contraindications for lung transplantation?Why is ventilator dependence a relative contraindication for lung transplantation?Which psychosocial issues are relative contraindications for lung transplantation?Why are corticosteroids a relative contraindication for lung transplantation?What are the contraindications for lung transplantation in patients with cystic fibrosis?When is body weight a relative contraindication for lung transplantation?Which comorbidities are relative contraindications for lung transplantation?What are the reported outcomes following lung transplantation?What is the role of lab tests in the pretransplant workup for lung transplantation?What is included in the pretransplant workup for lung transplantation?Which transplant center features are associated with better lung transplantation outcomes?What are the donor selection criteria for lung transplantation?What is the waiting time for lung transplantation recipients?When is heart-lung transplantation indicated?When is double-lung transplantation indicated?When is single-lung transplantation indicated?Which factors affect the selection of lung transplantation procedure?What is included in the preoperative evaluation of lung transplantation donors?How are donor lungs managed prior to transplantation?What are the criteria for brain death in a lung donor?What is the difference in outcome between donation-after-cardiac death lung recipients and donation-after-brain-death lung recipients?How are donor lungs preserved prior to transplantation?How are patients monitored during lung transplantation?How are single-lung transplantations performed?How are donor lungs harvested for transplantation?How are double-lung transplantations performed?How are heart-lung transplantations performed?Why is the postoperative period crucial in determining lung transplantation success?What is included in postoperative respiratory management following lung transplantation?What are the postoperative hemodynamics following lung transplantation?What are the possible postoperative GI complications following lung transplantation?What causes postoperative renal complications following lung transplantation?What is included in postoperative fluid management following lung transplantation?What is the role of antimicrobial therapy following lung transplantation?How is nutrition maintained following lung transplantation?What are the possible surgical complications from lung transplantation?How are patients monitored in the immediate postoperative period following lung transplantation?How are patients monitored in the early postoperative period following lung transplantation?How are patients monitored in the late postoperative period following lung transplantation?What is the role of immunosuppression in lung transplantation protocols?What is the role of tacrolimus in lung transplantation?What is the role of mycophenolate mofetil (MMF) in lung transplantation?What is the role of cyclosporine in lung transplantation?What is the role of azathioprine in lung transplantation?What is the role of rapamycin in lung transplantation?What is the role of corticosteroids in lung transplantation?What is the role of antilymphocyte antibody preparations in lung transplantation?What is the role of induction therapy in lung transplantation?What is included in immunotherapy maintenance following lung transplantation?What is reimplantation response following lung transplantation?What is graft dysfunction following lung transplantation?What are the ISHLT definition and diagnostic criteria for pulmonary antibody-mediated rejection (AMR)?What is hyperacute AMR rejection following lung transplantation?What causes hyperacute rejection of a lung transplant?What is acute AMR rejection following lung transplantation?How is rejection categorized following lung transplantation?What causes acute rejection of a lung transplant and how is it managed?What causes bronchiolitis obliterans syndrome (chronic rejection) following lung transplantation?How is bronchiolitis obliterans syndrome (chronic rejection) following lung transplantation prevented and treated?What are the possible airway complications of lung transplantation?What are the possible vascular complications of lung transplantation?What are the possible renal complications of lung transplantation?Which infections may complicate a lung transplantation?How are posttransplantation lymphoproliferative disorders (PTLDs) diagnosed and treated following lung transplantation?What is the increased risk for cancer following lung transplantation?Which organization has released guidelines on the timing of referral and listing for lung transplantation?What are the ISHLT guidelines on selection of lung transplantation candidates with COPD?What are the ISHLT guidelines on selection of lung transplantation candidates with interstitial lung disease?What are the ISHLT guidelines on selection of lung transplantation candidates with cystic fibrosis?What are the ISHLT guidelines on selection of lung transplantation candidates with pulmonary vascular diseases?What are the ISHLT guidelines on selection of lung transplantation candidates with COPD?What are the ISHLT guidelines on antibody-mediated rejection (AMR) of lung transplantation?

Author

Bryan A Whitson, MD, PhD, Assistant Professor of Cardiac Surgery, Division of Cardiac Surgery, Department of Surgery, Lead Surgeon, Lung Transplant Program, Co‐Director, Collaboration for Organ Perfusion, Protection, Engineering and Regeneration (COPPER) Laboratory, Comprehensive Transplant Center, The Ohio State University Wexner Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Shreekanth V Karwande, MBBS, Chair, Professor, Department of Surgery, Division of Cardiothoracic Surgery, University of Utah School of Medicine and Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Mary C Mancini, MD, PhD, MMM, Surgeon-in-Chief and Director of Cardiothoracic Surgery, Christus Highland

Disclosure: Nothing to disclose.

Additional Contributors

Jeffrey C Milliken, MD, Chief, Division of Cardiothoracic Surgery, University of California at Irvine Medical Center; Clinical Professor, Department of Surgery, University of California, Irvine, School of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

Susan D Moffatt-Bruce, MD, PhD, FRCS(C), FACS Chief Quality and Patient Safety Officer, Deputy Director, Comprehensive Transplant Center, Ohio State University Wexner Medical Center; Associate Dean of Clinical Affairs, Quality and Patient Safety, Associate Professor of Surgery, Department of Surgery, Ohio State University College of Medicine

Susan D Moffatt-Bruce, MD, PhD, FRCS(C), FACS is a member of the following medical societies: Alpha Omega Alpha, American College of Surgeons, American Society of Transplant Surgeons, American Society of Transplantation, American Thoracic Society, Central Surgical Association, International Society for Heart and Lung Transplantation, Ohio State Medical Association, Royal College of Physicians and Surgeons of Canada, SocietyofThoracic Surgeons, Transplantation Society, and Western Thoracic Surgical Association

Disclosure: Nothing to disclose.

Sat Sharma, MD, FRCPC Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St Boniface General Hospital

Sat Sharma, MD, FRCPC is a member of the following medical societies: American Academy of Sleep Medicine, American College of Chest Physicians, American College of Physicians-American Society of Internal Medicine, American Thoracic Society, Canadian Medical Association, Royal College of Physicians and Surgeons of Canada, Royal Society of Medicine, Society of Critical Care Medicine, and World Medical Association

Disclosure: Nothing to disclose.

Helmut Unruh, MD Director, Manitoba Lung Transplant Program; Head, Section of Thoracic Surgery, Director of Research, Department of Surgery, University of Manitoba Faculty of Medicine, Canada

Disclosure: Nothing to disclose.

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Bronchial anastomosis. Posterior wall closure is performed with a continuous suture.

Right atrial anastomosis. Continuous anastomosis with the common pulmonary vein joined to the atrium.

Completed atrial anastomosis.

Donor lung showing hilar surface.

The clamps are exposing the donor vein.

Donor bronchus, artery to the right and vein to the left.

Right donor bronchus.

A close-up shot of the donor vein.

This chest radiograph performed 24 hours following right unilateral lung transplantation is within normal limits.

Seventy-two hours following lung transplantation, this patient developed dyspnea and hypoxemia. The bronchoscopy and bronchoalveolar lavage revealed no evidence of bacterial infection. The likely cause of this deterioration is reperfusion/reimplantation response.

Severe acute rejection within 10 days of lung transplantation (lower magnification). The typical histological findings are perivascular lymphocytic infiltrates. Courtesy of Zhaolin Xu, MD.

Severe acute rejection within 10 days of lung transplantation (high power). Courtesy of Zhaolin Xu, MD.

The transbronchial biopsy shows perivascular aggregates of lymphocytes in the low-power field, which is indicating acute rejection in this patient 60 days after the lung transplant. This is grade II rejection. Courtesy of Zhaolin Xu, MD.

The transbronchial biopsy shows perivascular aggregates of lymphocytes in the high-power field, which indicates acute rejection in this patient 60 days after the lung transplant. This is grade II rejection. Courtesy of Zhaolin Xu, MD.

This chest radiograph performed 24 hours following right unilateral lung transplantation is within normal limits.

Seventy-two hours following lung transplantation, this patient developed dyspnea and hypoxemia. The bronchoscopy and bronchoalveolar lavage revealed no evidence of bacterial infection. The likely cause of this deterioration is reperfusion/reimplantation response.

A 19-year-old woman had living donor transplantation. She developed pulmonary artery stenosis several months later. This was treated with a pulmonary artery stent. Courtesy of A. Szabo, RN.

This patient developed anterior mediastinal abscess 1 year following bilateral sequential lung transplantation. Courtesy of A. Szabo, RN.

Lateral chest radiograph on a patient who developed anterior mediastinal abscess 1 year following bilateral sequential lung transplantation. Courtesy of A. Szabo, RN.

The CT scan of the chest of a patient with confirmed anterior mediastinal abscess 1 year following bilateral sequential lung transplantation. Courtesy of A. Szabo, RN.

A 34-year-old man developed branchio-otorenal (BOR) syndrome 3 years following sequential bilateral lung transplant (BLT). The chest radiograph shows characteristic findings of hyperinflation and hyperlucent lung fields. Courtesy of A. Szabo, RN.

Lateral radiograph of a 34-year-old man who developed branchio-otorenal (BOR) syndrome 3 years following sequential bilateral lung transplant (BLT). The chest radiograph shows characteristic findings of hyperinflation and hyperlucent lung fields. Courtesy of A. Szabo, RN.

The high-resolution CT scan showing findings of branchio-otorenal (BOR) syndrome following bilateral lung transplantation (BLT).

Bronchopleural fistula following right pneumonectomy and left single-lung transplantation (SLT).

Severe acute rejection within 10 days of lung transplantation (lower magnification). The typical histological findings are perivascular lymphocytic infiltrates. Courtesy of Zhaolin Xu, MD.

Severe acute rejection within 10 days of lung transplantation (high power). Courtesy of Zhaolin Xu, MD.

The transbronchial biopsy shows perivascular aggregates of lymphocytes in the low-power field, which is indicating acute rejection in this patient 60 days after the lung transplant. This is grade II rejection. Courtesy of Zhaolin Xu, MD.

The transbronchial biopsy shows perivascular aggregates of lymphocytes in the high-power field, which indicates acute rejection in this patient 60 days after the lung transplant. This is grade II rejection. Courtesy of Zhaolin Xu, MD.

Bronchial anastomosis. Posterior wall closure is performed with a continuous suture.

Right atrial anastomosis. Continuous anastomosis with the common pulmonary vein joined to the atrium.

Completed atrial anastomosis.

Donor lung showing hilar surface.

The clamps are exposing the donor vein.

Donor bronchus, artery to the right and vein to the left.

Right donor bronchus.

A close-up shot of the donor vein.

Bilateral lung transplantation to treat cystic fibrosis in a 23-year-old woman. Anteroposterior (AP) chest radiograph shows mild edema in the right perihilar region soon after surgery; this finding is consistent with an implantation response.

Anteroposterior (AP) chest radiograph obtained the following day shows increased edema.

Bilateral lung transplants in 23-year-old woman who developed infection at the bronchial anastomoses. CT scan shows right bronchial stenosis (arrow).

CT image shows left bronchial stenosis (arrow).

Posteroanterior (PA) chest radiograph in a 23-year-old woman who underwent bilateral lung transplantation because of cystic fibrosis. Image shows left upper-lobe collapse. Bilateral bronchial stents are in place.

Lateral radiograph shows left upper-lobe collapse. Arrow points to a bronchial stent. Bronchoscopy showed that scar tissue obliterated the orifice to the left upper-lobe bronchus.

CT image in a 61-year-old-woman with a single-lung transplant for emphysema with Aspergillus infection. Image shows an ill-defined nodule in the right upper lobe with a surrounding halo of ground-glass opacity (arrow), a finding virtually diagnostic of Aspergillus infection in the correct clinical setting.

Aspergillus infection 61-year-old man with a left lung transplant because of idiopathic pulmonary fibrosis. Frontal chest radiograph shows a normal left (transplant) lung and lower-lobe consolidation in the right (native) lung.

CT of patient shows patchy areas of consolidation in the right lower lobe and a clear left lung. Biopsy showed Aspergillus infection.

Cytomegaloviral (CMV) infection in a 52-year-old man with a right lung transplant because of emphysema. Frontal chest radiograph shows right lower-lobe and left mid-lung consolidation and a small right pleural effusion. Note that the less-compliant transplant lung pulls the mediastinum to the right.

CT of patient with cytomegaloviral (CMV) pneumonia shows patchy consolidation, greater on the right (transplant lung) than on the left, and a right pleural effusion.

Chest radiograph in bilateral lung transplant recipient showing bilateral pneumothoraces (arrows).

CT shows pneumothorax in common pleural space (arrow).

Lung carcinoma in lung transplant recipient. PA chest radiograph shows a spiculated nodule in the lower lobe of the native right lung.

Primary lung carcinoma in lung transplant recipient. CT scan of patient with previous radiograph shows spiculated nodule in the lower lobe of the emphysematous native right lung (arrow).

Post-transplant lymphoproliferative disorder in double lung transplant recipient. Contrast-enhanced CT scan shows low attenuation mass (arrow) in the anterior mediastinum.