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Lung Transplantation: Introduction Lung transplantation is a therapeutic consideration for many patients with nonmalignant end-stage lung disease, and it prolongs survival and improves quality of life in appropriately selected recipients. Since 1985 more than 25,000 procedures have been recorded worldwide, and ~2200 transplants have been reported annually in recent years. Indications The indications span the gamut of lung diseases. The most common indications in the last few years have been chronic obstructive pulmonary disease (COPD), ~30%; idiopathic pulmonary fibrosis (IPF), ~30%; cystic fibrosis (CF), ~15%; α1-antitrypsin deficiency emphysema, ~3%; and idiopathic pulmonary arterial hypertension (IPAH), ~2%. Other diseases have accounted for the balance of primary indications, and retransplantation has accounted for ~4% of procedures. Recipient Selection Transplantation should be considered when other therapeutic options have been exhausted and when the patient’s prognosis is expected to improve as a result of the procedure. Survival rates after transplantation can be compared with predictive indices for the patient’s disease, but each patient’s clinical course must be integrated into the assessment, too. Moreover, quality of life is a primary motive for transplantation for many patients, and the prospect of improved quality-adjusted survival is often attractive even if the survival advantage itself may be marginal. Disease-specific consensus guidelines for referring patients for evaluation and for proceeding with transplantation are summarized in Table P-1 and are linked to clinical, physiologic, radiographic, and pathologic features that influence the prognosis of the respective diseases. Candidates for lung transplantation are also thoroughly screened for comorbidities that might affect the outcome adversely. Conditions such as systemic hypertension, diabetes mellitus, gastroesophageal reflux, and osteoporosis are not unusual, but if uncomplicated and adequately managed, they do not disqualify patients from transplantation. The upper age limit is ~65–70 years at most centers. Table P-1 Disease-Specific Guidelines for Referral and Transplantation Chronic Obstructive Pulmonary Disease Referral BODE index >5 Transplantation BODE index 7–10 or any of the following criteria: Hospitalization for exacerbation, with PaCO2 >50 mmHg Pulmonary hypertension or cor pulmonale despite oxygen therapy FEV1<20% with either DLCO <20% or diffuse emphysema Cystic Fibrosis/Bronchiectasis Referral FEV1<30% or rapidly declining FEV1 Hospitalization in ICU for exacerbation Increasing frequency of exacerbations Refractory or recurrent pneumothorax Recurrent hemoptysis not controlled by bronchial artery embolization Transplantation Oxygen-dependent respiratory failure Hypercapnia Pulmonary hypertension Idiopathic Pulmonary Fibrosis Referral Pathologic or radiographic evidence of UIP regardless of vital capacity Transplantation Pathologic or radiographic evidence of UIP and any of the following criteria DLCO <39% Decrement in FVC ≥10% during 6 months of follow-up Decrease in SpO2 below 88% during a 6-min walk test Honeycombing on HRCT (fibrosis score >2) Idiopathic Pulmonary Arterial Hypertension Referral NYHA functional class III or IV regardless of therapy Rapidly progressive disease Transplantation Failing therapy with intravenous epoprostenol (or equivalent drug) Persistent NYHA functional class III or IV on maximal medical therapy Low (<350 m) or declining 6-min walk test Cardiac index <2 Lminm2 Right atrial pressure>15 mmHg Abbreviations: BODE, body-mass index (B), airflow obstruction (O), dyspnea (D), exercise capacity (E); FVC, forced vital capacity; FEV1, forced expiratory volume in 1 s; DLCO, diffusing capacity for carbon monoxide; PaCO2, partial pressure of carbon dioxide in arterial blood; SpO2, arterial oxygen saturation by pulse oximetry; ICU, intensive care unit; UIP, usual interstitial pneumonitis; HRCT, high-resolution computed tomography; NYHA, New York Heart Association. Standard exclusions include HIV infection, chronic active hepatitis B or C infection, uncontrolled or untreatable pulmonary or extrapulmonary infection, uncured malignancy, active cigarette smoking, drug or alcohol dependency, irreversible physical deconditioning, chronic nonadherence with medical care, significant disease of another vital organ (e.g., heart, liver, or kidney), and psychiatric or psychosocial situations that could substantially interfere with posttransplantation management. Other problems that may compromise the outcome constitute relative contraindications. Some typical issues are ventilator-dependent respiratory failure, previous thoracic surgical procedures, obesity, and coronary artery disease. Chronic infection with antibiotic-resistant Pseudomonas species, Burkholderia species, Aspergillus species, or nontuberculous mycobacteria is a unique concern in some patients with CF. The potential impact of these and other factors has to be judged in clinical context to determine an individual candidate’s suitability for transplantation. Waiting List and Organ Allocation Organ allocation policies are influenced by medical, ethical, geographic, and political factors, with systems varying from country to country. Regardless of the system, potential recipients are placed on a waiting list and must be matched for blood group compatibility and, with some latitude, for lung size with an acceptable donor. Most lungs are procured from deceased donors after brain death, but only ~15–17% of brain-death organ donors yield either one or two lungs suitable for transplantation. Lungs from donors after cardiac death have been utilized to a limited extent. A priority algorithm for allocating donor lungs was implemented in the United States in 2005. A lung allocation score that is based on the patient’s risk of death on the waiting list and likelihood of survival after transplantation determines priority. The score can range from zero to 100, and precedence for transplantation is ranked from highest to lowest scores. Both the lung disease and its severity affect a patient’s score; parameters in the score must be updated biannually but can be submitted for calculation of a new score whenever the patient’s condition changes. The median score for all candidates on the waiting list is usually ~34–35, but the distribution of scores tends to be higher among patients with IPF and CF than among patients with COPD and IPAH. Under this priority system, the median waiting time for transplantation has fallen to <6 months, and the annual number of deaths on waiting list has dropped by ~50%. The main indication for transplantation also shifted from COPD to IPF. Overall survival rates in first two years after have not changed substantially under this system; however, recipients with lung allocation scores>60 have had lower survival rates in the first two years compared with recipients with lower scores. Transplant Procedure Bilateral transplantation is mandatory for CF and other forms of bronchiectasis because the risk of spillover infection from a remaining native lung precludes single-lung transplantation. Heart-lung transplantation is obligatory for Eisenmenger syndrome with complex anomalies that cannot be readily repaired in conjunction with lung transplantation and for concomitant end-stage lung and heart disease. However, cardiac replacement is not necessary for cor pulmonale because right ventricular function will recover when pulmonary vascular afterload is normalized by lung transplantation. Either bilateral or single-lung transplantation is an option for other diseases unless there is a special consideration, but bilateral transplantation has been utilized increasingly for most indications. Recently, ~65% of procedures in the United States have been bilateral, and in the international registry, ~55% of transplants for COPD, ~50% for IPF, and ~90% for IPAH have been bilateral. Living donor lobar transplantation has a limited role in adult lung transplantation. It has been performed predominantly in teenagers or young adults with CF, and it usually has been reserved for patients who were unlikely to survive the wait for a deceased organ donor. Posttransplantation Management Induction therapy with an antilymphocyte globulin or an interleukin 2 receptor antagonist is utilized by ~50% of centers, and a three-drug maintenance immunosuppressive regimen that includes a calcineurin inhibitor (cyclosporine or tacrolimus), a purine synthesis antagonist (azathioprine or a mycophenolic acid precursor), and prednisone is traditional. Subsequently, other drugs, such as sirolimus, may be substituted into the regimen for various reasons. Prophylaxis for Pneumocystis jiroveci pneumonia is standard, and prophylaxis against cytomegalovirus (CMV) infection and fungal infection is part of many protocols. The dose of cyclosporine, tacrolimus, and sirolimus is adjusted by blood-level monitoring. All these agents are metabolized by the hepatic cytochrome P450 system, and interactions with medications that affect this pathway can significantly alter the clearance and blood level of these drugs. Routine management focuses on monitoring the allograft, regulating immunosuppressive therapy, and detecting problems or complications expeditiously. Regular contact with a nurse coordinator, physician follow-up, chest radiographs, blood tests, and spirometry are customary, and periodic surveillance bronchoscopies are employed in some programs. If recovery is uncomplicated, lung function rapidly improves and then stabilizes by 3–6 months after transplantation. Subsequently, the variation in spirometric measurements is small, and a sustained decline of ≥10–15% signals a potentially significant problem. Outcomes Survival Major registries publish survival (P-2). In the international registry, survival half-life for the main indications is in the range of 4–6 years; however, age and transplant procedure have a significant impact on outcome. For recipients 18–59 years of age, the survival half-life is 5–6 years, but it decreases to 4 years for those 60–65 years old and to 3 years for those >65 years old. Survival over 10 years has been significantly better after bilateral transplantation than after unilateral transplantation for COPD, α1-antitrypsin deficiency emphysema, IPF, and IPAH. Table P-2 Recipient Survival, by Pretransplantation Diagnosis (1990–2006) ( survival rate % “ ) Diagnosis n 3 Months 1 Year 3 Years 5 Years 10 Years Chronic obstructive pulmonary disease Bilateral Single 2444 5316 93 90 85 81 69 63 57 47 31 19 α1-Antitrypsin deficiency emphysema Bilateral Single 956 969 88 87 79 77 67 61 58 51 36 28 Cystic fibrosis 3275 90 82 66 56 39 Idiopathic pulmonary fibrosis Bilateral Single 1290 2641 81 85 72 73 59 56 48 43 28 19 Idiopathic pulmonary arterial hypertension Bilateral Single 710 260 75 71 69 61 59 51 51 41 33 24 Sarcoidosis 506 83 70 56 51 31 The main sources of perioperative mortality include technical complications of the operation, primary graft dysfunction, and infections. Acute rejection and CMV infection are common problems in the first year, but neither is usually fatal. Beyond the first year, chronic rejection and non-CMV infections cause the majority of deaths. Function Regardless of the disease, successful transplantation impressively restores cardiopulmonary function. After bilateral transplantation, pulmonary function tests are typically normal; after unilateral transplantation, a mild abnormality characteristic of the remaining diseased lung is still apparent. Formal exercise testing usually demonstrates some impairment in maximum work rate and maximum oxygen uptake, but few recipients report any limitation to activities of daily living. Quality of Life Both overall and health-related quality of life are enhanced. With multidimensional profiles, improvements extend across most domains and are sustained longitudinally unless chronic rejection or another complication develops. Other problems that detract from quality of life include renal dysfunction and drug side effects. Cost The cost of transplantation depends on the health care system, other health care policies, and economic factors that vary from country to country. In the United States in 2008 the average billed charge per transplant for the period 30 days before transplantation through 180 days after the transplant admission was $450,400 for single-lung transplantation and $657,800 for bilateral lung transplantation. For bilateral transplantation, the total cost included the following charges: all care during 30 days before transplantation, $20,700; donor organ procurement, $96,500; hospital transplant admission, $344,700; physician fees during transplant admission, $59,300; all inpatient and outpatient care during 180 days after transplant admission, $113,800; and all outpatient drugs, including immunosuppressants, from discharge for the transplant to 180 days after transplant admission, $22,800. Complications Lung transplantation can be complicated by a variety of problems (Table P-3). Aside from predicaments that are unique to transplantation, side effects and toxicities of the immunosuppressive medications can cause new medical problems or aggravate preexisting conditions. Table P-3 Major Potential Complications of Lung Transplantation and Immunosuppression Category Complication Allograft Primary graft dysfunction; anastomotic dehiscence or stenosis; ischemic airway injury with bronchostenosis or bronchomalacia; rejection; infection; recurrence of primary disease (sarcoidosis, lymphangioleiomyomatosis, giant cell interstitial pneumonitis, diffuse panbronchiolitis, pulmonary alveolar proteinosis, Langerhans cell histiocytosis) Thoracic Phrenic nerve injury—diaphragmatic dysfunction; recurrent laryngeal nerve injury—vocal cord dysfunction; cervical ganglia injury—Horner’s syndrome; pneumothorax; pleural effusion; chylothorax; empyema Cardiovascular Intraoperative or perioperative air embolism; postoperative pericarditis; perioperative myocardial injury/infarction; venous thromboembolism; supraventricular dysrhythmias; systemic hypertension Gastrointestinal Esophagitis [especially Candida, herpes, or cytomegalovirus (CMV)]; gastroparesis; gastroesophageal reflux; diarrhea (Clostridium difficile; medications, especially mycophenolate mofetil and sirolimus); colitis (C. difficile; CMV?) Hepatobiliary Hepatitis (especially CMV or medications); acalculous cholecystitis Renal Calcineurin inhibitor nephropathy; hemolytic-uremic syndrome (thrombotic microangiopathy) Neurologic Tremors; seizures; reversible posterior leukoencephalopathy; headaches Musculoskeletal Steroid myopathy; rhabdomyolysis (cyclosporine + HMG-CoA reductase inhibitor treatment); osteoporosis; avascular necrosis Metabolic Obesity; diabetes mellitus; hyperlipidemia; idiopathic hyperammonemia Hematologic Anemia; leukopenia; thrombocytopenia; thrombotic microangiopathy Oncologic Lymphoproliferative disease and lymphoma; skin cancers; other malignancies Graft Dysfunction Primary graft dysfunction (PGD) is an acute lung injury that is a manifestation of multiple potential insults to the donor organ inherent in the transplantation process. The principal clinical features are diffuse pulmonary infiltrates and hypoxemia within 72 h of transplantation; however, the presentation can be mimicked by pulmonary venous obstruction, hyperacute rejection, pulmonary edema, and pneumonia. The severity is variable, and a standardized grading system has been established. Up to 50% of recipients may have some degree of PGD, and ~10–20% have severe PGD. The treatment follows the conventional, supportive paradigm for acute lung injury. Inhaled nitric oxide and extracorporeal membrane oxygenation have been used in severe cases; retransplantation also has been performed, but retransplantation in the first 30 days has a poor survival rate (~30% at 1 year). Most recipients with mild PGD recover, but the mortality rate for severe PGD has been ~40–60%. PGD also is associated with longer postoperative ventilator support, longer intensive care unit and hospital stays, higher costs, and excess morbidity rates and severe PGD is probably a risk factor for the later development of chronic rejection. Airway Complications The bronchial blood supply to the donor lung is disrupted during procurement. Bronchial revascularization during transplantation is technically feasible in some cases, but it is not widely practiced. Consequently, after implantation the donor bronchus is dependent on retrograde bronchial blood flow from the pulmonary circulation and is vulnerable to ischemia. The spectrum of airway problems includes anastomotic necrosis and dehiscence, occlusive granulation tissue, anastomotic or bronchial stenosis, and bronchomalacia. The incidence has been in the range of 7–18%, but the associated mortality rate has been low. These problems usually can be managed bronchoscopically with techniques such as simple endoscopic debridement, laser photoresection, balloon dilatation, and bronchial stenting. Rejection Rejection is the main limitation to better medium- and long-term survival. It is an immunologic response to alloantigen recognition, and both cell-mediated and antibody-mediated (humoral) cascades can play a role. Cellular rejection is effected by T lymphocyte interactions with donor alloantigens, mainly in the major histocompatibility complex (MHC), whereas humoral rejection is driven by antibodies to donor MHC alloantigens or possibly to non-MHC antigens on epithelial or endothelial cells. Rejection often is categorized as acute or chronic without mention of the mechanism. Acute rejection is cell-mediated, and its incidence is highest in the first 6–12 months after transplantation. In contrast, chronic rejection generally emerges later, and both alloimmune and nonalloimmune fibroproliferative reactions may contribute to its pathogenesis. Acute Cellular Rejection With current immunosuppressive regimens, ~25–40% of recipients have acute rejection in the first year. Acute cellular rejection (ACR) can be clinically silent, or it can be manifested by nonspecific symptoms or signs that may include cough, low-grade fever, dyspnea, hypoxemia, inspiratory crackles, interstitial infiltrates, and declining lung function; however, clinical impression is not reliable. The diagnosis is confirmed by transbronchial biopsies showing the characteristic lymphocytic infiltrates around arterioles or bronchioles, and a standardized pathologic scheme is used to grade the biopsies. Minimal ACR on a surveillance biopsy in a clinically stable recipient often is left untreated, but higher grades generally are treated regardless of the clinical situation. Treatment usually includes a short course of high-dose steroid therapy and adjustment of the maintenance immunosuppressive regimen. Most episodes respond to this approach; however, more intensive therapy is sometimes necessary for persistent or recurrent episodes. Chronic Rejection This complication is the main impediment to better long-term survival rates, and it is the source of substantial morbidity rates because of its impact on lung function and quality of life. Clinically, it is characterized physiologically by airflow limitation and pathologically by bronchiolitis obliterans; the process is denoted bronchiolitis obliterans syndrome (BOS). Transbronchial biopsies are relatively insensitive for detecting bronchiolitis obliterans, and pathologic confirmation is not required for diagnosis. Thus, after other causes of graft dysfunction have been excluded, the diagnosis of BOS is based primarily on a sustained decrement (≥20%) in forced expiratory volume in 1s (FEV1), although smaller declines in FEV1 (≥10%) or in forced expiratory flow FEF25–75% may presage BOS. Spirometric criteria for diagnosis and staging of BOS have been standardized. The prevalence of BOS approaches 50% by 5 years after transplantation. Antecedent ACR is the main risk factor, but PGD, CMV pneumonitis, other community-acquired respiratory viral infections, and gastroesophageal reflux have been implicated as well. BOS can present acutely and imitate infectious bronchitis, or it can manifest as an insidious decline in lung function. The chest radiograph is typically unchanged; computed tomography may reveal mosaic perfusion, air trapping, ground-glass opacities, or bronchiolectasis. Bronchoscopy is indicated to eliminate other processes, but transbronchial biopsies identify bronchiolitis obliterans in a minority of cases. BOS usually is treated with augmented immunosuppression, but there is no consensus about therapy. Strategies include changes in the maintenance drug regimen, including the addition of azithromycin, antilymphocyte globulin, photopheresis, and total lymphoid irradiation. Although therapy may stabilize lung function, the overall results of treatment have been disappointing; median survival after onset has been ~3–4 years. Retransplantation is a consideration if clinical circumstances and other comorbidities are not prohibitive, but survival has been inferior to that with primary transplantation. Humoral Rejection The role of antibody-mediated rejection is still evolving. Hyperacute rejection is caused by preformed human leukocyte (HLA) antibodies in the recipient, but it is minimized by pretransplantation antibody screening coupled with virtual or direct cross-matching with any potential donor. Donor-specific HLA antibodies develop after transplantation in up to 50% of recipients, and their presence has been associated with an increased risk of both ACR and BOS and with poorer overall survival. However, the mechanisms by which these antibodies could contribute to ACR or BOS or could otherwise be detrimental have not been unraveled. Formal criteria for antibody-mediated rejection have been defined for renal transplantation, but few cases in lung transplantation fulfill them. Nonetheless, episodes of acute lung allograft dysfunction occasionally have been attributed directly to antibody-mediated injury. If treatment is indicated, therapies that may deplete antibodies include plasmapheresis, intravenous immune globulin, and rituximab. Infection The lung allograft is especially susceptible to infection, which has been one of the leading causes of death. In addition to a blunted immune response from the immunosuppressive drugs, other normal defenses are compromised: the cough reflex is diminished, and mucociliary clearance is impaired in the transplanted lung. The spectrum of infections includes both opportunistic and nonopportunistic pathogens. Bacterial bronchitis or pneumonia can occur at any time, but it is very common in the perioperative period. Later, bronchitis occurs frequently in recipients with BOS, and Pseudomonas aeruginosa or methicillin-resistant Staphylococcus aureus is often the culprit. CMV is the most common viral infection. Although gastroenteritis, colitis, and hepatitis can occur, CMV viremia and CMV pneumonia are the main illnesses. Most episodes occur in the first 6 months, and treatment with ganciclovir is effective unless resistance develops. Other community-acquired viruses such as influenza, parainfluenza, and respiratory syncytial virus also contribute to respiratory complications. The most problematic fungal infections are caused by Aspergillus species. The spectrum encompasses simple pulmonary colonization, tracheobronchitis, invasive pulmonary aspergillosis, and disseminated aspergillosis, and the clinical scenario dictates treatment. Other Complications Other potential complications are listed in Table P-3. Many of them are related to side effects or toxicities of the immunosuppressive drugs. Management of these general medical problems is guided by standard practices, but the complex milieu of transplantation requires close collaboration and good communication among health care providers.
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