Lung Transplantation Treatment & Management

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

Tacrolimus

Tacrolimus (FK-506) 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 cyclosporin A in many centers. Recently, tacrolimus has been found to be superior to cyclosporin A in lung transplantation in terms of decreased incidences of acute rejection and chronic rejection.^[18] Toxicity of tacrolimus is similar to that of cyclosporin A 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.^[19] 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. Increased selectivity and decreased toxicity of MMF is because T and B lymphocytes use only 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 renal transplant recipients. Use of MMF also has shown comparable efficacy to azathioprine in reducing acute rejection in heart transplant patients.^[19] Studies have reported that patients treated with MMF experienced fewer acute rejection episodes in lung transplant recipients over a 12-month period.^{[20, 21]}

A recent multicenter, prospective, randomized trial of MMF versus azathioprine, demonstrated a comparable efficacy of these 2 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 is 1 g PO bid; the dose is titrated to maintain the white blood cell count at more than 4000 cells/mm³. Levels of 12-15 ng/dL are usually maintained for the first 6 months.

Cyclosporin A

Cyclosporin A 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 cyclosporin, 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 white blood cell (WBC) count 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.^[22] 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, with approximately 50% of the centers worldwide practicing induction therapy.^[1]

Current approach to immunosuppressive therapy

Induction therapy after lung transplantation 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.^[23]

Maintenance therapy with triple-drug therapy 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, a newer antiproliferative drug. 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 taking a cyclosporin A regimen should be switched to tacrolimus from cyclosporine. For patients unresponsive to the change to tacrolimus from cyclosporin A, 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.

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:

• Well-qualified medical and surgical personnel
• Local and readily available support in areas of immunology, pulmonary medicine, infectious diseases, cardiology, and rehabilitation
• Qualified house staff that is available on a 24-h basis
• Number of lung transplants performed that is adequate to develop and maintain proficiency
• Presence of active programs in basic and clinical research related to transplantation (desirable)

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 CMV for transplant into a donor who is not positive for cytomegalovirus (CMV), but postoperative CMV prophylaxis is required if this happens. Other acceptable donor criteria are as follows:

• Younger than 65 years for lung transplantation and younger than 45 years for heart-lung transplantation
• Absence of severe chest trauma or infection
• Absence of prolonged cardiac arrest (heart-lung only)
• Minimal pulmonary secretions
• Negative screens for HIV, hepatitis C, and hepatitis B
• Blood type (ABO) compatibility
• Close match of lung size between donor and recipient
• PaO2 > 300 mm Hg on 100% fraction of inspired oxygen (FiO ₂ )
• Clear chest radiograph
• No history of malignant neoplasms

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; under the new system, 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 indicate that waiting time has decreased, the total number of transplants has increased, waitlist mortality may be decreasing, and survival after transplantation remains unchanged. Over time, refinements in the lung allocation score will likely reduce waitlist mortality further and maintain or perhaps improve survival after transplantation.^[24]

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. 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, as follows:^[25]

• Heart-lung transplantation

  • Eisenmenger syndrome with irreparable cardiac defect
  • Pulmonary hypertension with cor pulmonale
  • End-stage lung disease with concurrent severe cardiac disease^{[26, 27]}
• Double-lung transplantation

  • Cystic fibrosis^[28]
  • Generalized bronchiectasis
  • Young patients with chronic obstructive pulmonary disease (COPD)
  • Pulmonary artery hypertension
• Single-lung transplantation

  • Restrictive fibrotic lung disease
  • Eisenmenger syndrome with reparable cardiac anomaly
  • Older patients with COPD

Other factors that must be taken into account on an individual basis are ventilator dependence,^{[29, 15]} 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.^[30] With current surgical techniques, pretransplantation corticosteroid therapy has not been associated with airway complications, and a maintenance dose 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 B 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.

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:

• Minimal oxygen < 50%; PaO2 90-100 mm Hg
• Tidal volume 10 mL/kg
• Net fluid balance: negative
• Central venous pressure (CVP) < 10 cm H2O
• PEEP 5 cm H2O
• Recruitment maneuvers q3-4 h
• Antibiotics
• Vasopressors in lieu of fluid: vasopressin

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.^[31] Brain death is determined by clinical criteria when 2 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. Brain death criteria are as follows:

• Clinical

  • Known cause of condition
  • Temperature higher than 95°F
  • No drug intoxication or neuromuscular blocking agent
  • No significant metabolic derangement
  • No gag, cough, or corneal reflexes
  • Absence of dull-eye reflex
  • Pupils fixed and dilated
  • No spontaneous respirations or movements
  • Negative results on apnea test
• Ancillary

  • Isoelectric electroencephalogram
  • CT evidence of herniation
  • Negative results on cerebral blood flow study (ie, brain scan or intracranial angiography)

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 2 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.^[32]

Lung preservation

With the 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.

Transplantation of lobes from living donors is a recently developed technique involving bilateral implantation of the lower lobes from 2 blood group–compatible living donors. The procedure has been performed in patients with cystic fibrosis, although the indications recently have been broadened. The functional and survival outcomes are similar to those achieved with conventional transplantation of cadaveric lungs. 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.

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.

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.

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.

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 (carinii) jiroveci infection has been eliminated by the routine use of trimethoprim-sulfamethoxazole, which is administered 3 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. 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.

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.

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.^[33] 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.

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, ie, 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.

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.

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.^[34]

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.^[35]

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 3 categories based on well-defined clinical and histologic features: hyperacute rejection, acute rejection, and chronic rejection.^[35]

Hyperactive 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 5 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.^[35]

The clinical course of acute rejection can be variable. Most individuals develop at least 1 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.

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:

• Stage 0 – FEV₁ greater than 80% of baseline
• Stage I – FEV₁ 66-80% of baseline
• Stage II – FEV₁ 51-65% of baseline
• Stage III – FEV₁ 50% or less of baseline

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 CT (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

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.^[36] Treatment consists of administering additional immunosuppressive agents. High-dose intravenous methylprednisolone and antilymphocyte antibody preparations, including all OKT3 and antithrombocyte globulin (ATG), may stabilize the declining function of the lung. The newer regimens including rapamycin, azithromycin, and HMG-CoA reductase inhibitors are currently used without tremendous success.

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.

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.

Miscellaneous complications

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

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.

Bacterial/viral pneumonia

Bacterial pneumonias are the most common infection following lung transplantation^[37] 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 S 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).^[37] 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.^[38] 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.^[37] Patients are also discharged on voriconazole as daily prophylaxis for the first year.

Pneumocystis (carinii) 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%).^[37] 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.^[39] 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.

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.^[1] Mortality is highest in the first year, and attrition was consistent across the subsequent time periods. In the first 30 days, graft failure, noncytomegalovirus (CMV) infections, cardiovascular complications, and technical problems account for most of the mortality. After the first year, bronchiolitis obliterans syndrome (BOS) and nonCMV 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.^[1] 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.

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.^[40]

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.

Cost of lung transplantation

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 QUALY (quality-adjusted life-year), which reflects the real or anticipated survival time and health-related quality of life. The University of Washington Medical Center estimated that lung transplantation costs $176,817 per QUALY compared to traditional therapy. Canadian centers have reported a lower cost effectiveness of lung transplantation ($62,860 per life-year gained, Canadian dollars, 1993).

Living donor transplantation

For patients who are considered too ill to await cadaveric transplantation, living lobar lung transplantation may be an option.^[41] Despite fairly extensive experience, no donor mortality has been reported, and morbidity has been relatively low. Compared to 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.^[42] The actuarial survival among the living lobar recipients was 70%, 54%, and 45%, at 1, 3, and 5 years, respectively.^[42]