This chapter briefly touches on the background of lung transplantation, common terminology, and candidate selection. The primary focus, however, is on postoperative management of adult lung transplant patients, including a review of immunosuppressive agents as well as common complications and their management.
There are three general arms to the organ transplantation system in the United States:
United network for organ sharing (UNOS) operates the organ procurement and transplantation network (OPTN) and maintains a national registry for organ matching.
Organ procurement organizations (OPOs) are nongovernmental organizations that recover organs in their respective service areas and allocate them based on UNOS policies.
Transplant centers: as of November 2011, there were 246 transplant centers in the United States and 63 of these were performing lung transplantation.
The most common underlying lung diseases leading to transplantation are chronic obstructive pulmonary disease (COPD)/emphysema (including α1-antitrypsin deficiency), idiopathic pulmonary fibrosis (IPF), cystic fibrosis (CF), sarcoidosis, and idiopathic pulmonary arterial hypertension (IPAH).
Heart–lung transplantation is generally reserved for patients with Eisenmenger syndrome and an uncorrectable congenital heart defect.
The majority of lung transplant recipients are between 18 to 64 years of age, though the percentage of recipients >65 years has increased in recent years.1
Diagnosis and Candidate Evaluation
Donor organs remain in short supply.
Given the limitation in the organ pool, donor criteria have become increasingly liberalized. Standard criteria for acceptance are listed in Table 29-2.5
Efforts to broaden the donor pool include acceptance of marginal donors, donation after cardiac death (so-called DCD donor), and development of ex vivo organ reconditioning protocols.
Potential donors are screened for social and medical history, physical examination findings, cause of death, vital signs, documentation of arrest or hypotensive episodes, use of vasopressors and/or hydration, echocardiogram and ECG, and bronchoscopy.
Donors are also tested for HIV, hepatitis B and C, human T-cell leukemia virus type 1 (HTLV-1), syphilis, and cytomegalovirus (CMV, pretransfusion preferred). Organs that are positive for HIV or HTLV-1 are excluded from transplantation.
Malignancy usually prevents transplantation, except for localized skin cancers, cervical cancer, or neurologic tumors that rarely metastasize.
TABLE 29-1 CONTRAINDICATIONS TO LUNG TRANSPLANTATION
Recipient Selection and Organ Allocation
Each transplant center has its own specific evaluation requirements. Patients usually undergo a thorough battery of history, physical examination, pulmonary function and imaging tests. Cardiac, kidney, liver, and other vital organ functions are evaluated as needed based on the results of screening tests.
Following this evaluation, the suitability for transplantation and appropriate timing for listing are decided.
The donor and the recipient are matched for ABO blood groups, height, and the absence of circulating antidonor HLA antibodies (discussed further in the section on Rejection).
Prior to 2005, priority for lung organ allocation was determined primarily by waiting time. In 2005, the Lung Allocation System (LAS) was developed with the goal to allocate organs based primarily on medical urgency and expected outcome (i.e., success) after transplantation.6
TABLE 29-2 STANDARD LUNG TRANSPLANT DONOR CRITERIA
Age <55 yrs
PaO2 ≥300 mm Hg, ventilated with a fraction of inspired oxygen = 1, and positive end-expiratory pressure = 5 cm H2O
≤20 pack-year smoking history
Satisfactory bronchoscopic examination and gross inspection (before harvest)
Adapted from Snell GI, Westall GP. Selection and management of the lung donor. Clin Chest Med. 2011;32:223–32.
This new system generally favors high-urgency candidates and transplantation in sicker patients, although the overall outcomes after transplantation have not been affected substantially based on current data.
Single (SLT) and bilateral lung transplantation (BLT) are possible for COPD, α1-antitrypsin deficiency emphysema, IPF, IPAH, and in some cases of Eisenmenger syndrome.
BLT is mandatory for diffuse bronchiectasis associated with CF or other diseases.
Heart–lung transplantation is usually reserved for complex congenital heart diseases with pulmonary hypertension.
BLT is the most common procedure performed currently.
Induction: Some, but not all centers use induction immunosuppressive therapy immediately following transplantation. Treatment options have included interleukin (IL-2) receptor antagonists, antilymphocyte antibody preparations, or alemtuzumab (anti-CD52).7
Maintenance: Immunosuppression strategies vary among transplant centers but most use a triple-drug maintenance regimen consisting of a corticosteroid (methylprednisolone perioperatively, followed by prednisone), an antimetabolite (azathioprine or mycophenolate mofetil [MMF]), and a calcineurin inhibitor (cyclosporine [CsA] or tacrolimus).7
Steroids have anti-inflammatory effects in both the innate and adaptive arms of the immune system. Dosing is variable.
Metabolism and excretion: Hepatic metabolism, including cytochrome P450-3A4 isoform (CYP3A4), and urinary excretion.
Interactions: Barbiturates, phenytoin, rifampin, and St. John’s wort decrease corticosteroid effectiveness by inducing CYP3A4. Conversely, inhibitors of CYP3A4, such as azole antifungals and macrolides, may increase steroid levels. Steroids may also increase CsA levels and potentiate aspirin- or NSAID-induced gastritis.
Adverse drug reactions: Complications are common with chronic steroid use and include skin thinning, impaired wound healing, fat redistribution, hypertension, hypokalemia, hyperglycemia, adrenal insufficiency, osteoporosis, and mental status changes (ranging from restlessness and poor sleep to agitation and steroid psychosis). Corticosteroids may also increase or decrease the prothrombotic effect of warfarin.
Azathioprine is a purine analog that inhibits DNA and RNA synthesis, ultimately blocking proliferation of activated lymphocytes.
Initial dosing is 1–3 mg/kg PO/IV daily.
Bioavailability: Azathioprine is well absorbed after oral administration. Azathioprine and its metabolite 6-mercaptopurine are 30% bound to plasma proteins.
Metabolism and excretion: Hepatic metabolism and urinary excretion.
Interactions: Allopurinol may reduce metabolism and increase levels of azathioprine. Drugs with bone marrow suppression or toxicity should be avoided, as the effects can be additive. Warfarin levels may increase via unknown mechanisms.
Adverse drug reactions: Bone marrow toxicity can occur (thrombocytopenia, anemia, and leukopenia). Leukopenia is especially common in patients with mutations in
thiopurine S-methyltransferase, which can be screened with genetic testing if needed. Gastrointestinal (GI) side effects can include hepatitis, cholestatic jaundice, and pancreatitis.
MMF was initially developed as an antibiotic/antineoplastic/antipsoriatic agent. It is a selective, noncompetitive, and reversible inhibitor of inosine monophosphate dehydrogenase, blocking de novo purine synthesis. As B and T cells lack the salvage pathway of purine synthesis, they are selectively inhibited.
Initial dosing is 1–1.5 g PO/IV bid.
Bioavailability: MMF is given as an ester derivative owing to poor absorption. In this form it is rapidly absorbed orally. It is 97% albumin bound in plasma.
Metabolism and excretion: MMF is rapidly hydrolyzed to an active metabolite mycophenolic acid (MPA) in the liver. Also, it is later inactivated in the liver by glucuronidation. MPA is eliminated primarily in the urine as MPA glucuronide. In renal failure, accumulated MPA glucuronide may be converted to MPA, causing toxicity.
Interactions: Relatively few drug interactions occur. Antacids may reduce absorption. Cholestyramine and antibiotics that alter gut flora can decrease levels by reducing enterohepatic circulation. Drugs that interfere (e.g., probenecid) or compete for renal tubular secretion may increase MPA glucuronide levels. High doses of salicylates may increase free MPA levels.
Adverse drug reactions: MMF is generally well tolerated with GI side effects being most common (abdominal pain, nausea, vomiting, dyspepsia, diarrhea); these can be overcome by splitting doses or administering the drug with small amounts of food. Bone marrow toxicity is seen as well (anemia, leukopenia, and thrombocytopenia).
Monitoring: Therapeutic monitoring is not routinely performed. Concentrations may be monitored in renal failure or coadministration with CsA.
CsA is a fat-soluble fungal polypeptide that inhibits production of IL-2 from CD4+ cells. It binds cyclophilin in lymphocytes, and the complex then binds calcineurin, inhibiting cytokine gene transcription and lymphocyte proliferation.
Initial dosing is 5–10 mg/kg/d split into two doses.
Bioavailability: Oral bioavailability is variable and dependent on the drug formulation (sandimmune 10–90%, neoral 30–45%). It is also bile dependent and can be influenced by fat intake, diarrhea, and GI motility. CsA is mostly distributed outside of the blood volume and the fraction in plasma is 90% lipoprotein bound.
Metabolism and excretion: CsA is extensively metabolized in liver and intestine (CYP3A4). Elimination is primarily by excretion of metabolites in the bile. Only a small fraction is excreted unchanged via GI and genitourinary tracts.
Interactions: Drug interactions are very common as a result of CYP3A4 induction or inhibition. Drugs that decrease CsA levels include rifampin, phenytoin, carbamazepine, phenytoin, St. John’s wort, and hydroxymethylglutaryl (HMG) coenzyme A reductase inhibitors. Increased levels are seen with azole antifungals, macrolides, calcium channel blockers (verapamil and diltiazem; nifedipine has less effect), and grapefruit juice. Many nephrotoxic drugs have synergistic toxicity with CsA. Potassium-sparing diuretics should be avoided owing to the potential for hyperkalemia. Concomitant use of HMG coenzyme A reductase inhibitor therapy increases the risk of myopathy and rhabdomyolysis.
Adverse drug reactions: Renal side effects are common (hyperkalemia, hypomagnesemia, hypertension). Metabolic side effects include hyperlipidemia, gout, osteoporosis, hirsutism, and hyperglycemia. Neurologic effects include tremors, peripheral neuropathy, headaches, mental status changes, and, in rare instances, reversible posterior leukoencephalopathy. Gingival hypertrophy (especially in conjunction with nifedipine), a thrombotic thrombocytopenic purpura–like syndrome, and hepatotoxicity can be seen as well.
Monitoring: Therapeutic monitoring is performed due to intra- and interpatient variability of absorption, metabolism, and excretion, as well as the considerable side effect profile. Levels measured include trough, area under the curve, and C2 pseudopeak levels. Target levels vary with time interval after transplant, organ type, and rejection history.
Tacrolimus is a fungal-derived macrolide that inhibits IL-2 production. It binds to immunophilin FKBP12, and blocks calcineurin activity in a fashion similar to that of CsA.
Initial dosing range is ∼0.1 mg/kg/d PO divided into two doses.
Bioavailability: Oral bioavailability is poor (20–25%) but not bile acid dependent. It is fat soluble, and ∼80% of serum drug is RBC membrane bound.
Metabolism and excretion: Tacrolimus is metabolized in the liver and intestine (CYP3A4). Tacrolimus is excreted unchanged in bile, thus there is no need for adjustment in renal failure or hepatic disease.
Interactions: Similar to those with CsA.
Adverse drug reactions: Similar to those with CsA.
Monitoring: Trough levels are routinely used (and correlate with area under the curve measurements).
Sirolimus is a fungal-derived macrolide, also known as rapamycin. Unlike the calcineurin inhibitors tacrolimus and CsA, the sirolimus–immunophilin complex inhibits the mammalian target of rapamycin (mTOR) and blocks cytokine-mediated cell cycling and B- and T-cell function.
Initial dosing is 2 mg/d. It is diluted with water or juice (except grapefruit juice). A long half-life allows for once-daily dosing.
Bioavailability: Sirolimus is rapidly absorbed after oral administration but has poor bioavailability (∼14% with the oral solution but higher with tablets). It is 92% bound to plasma proteins.
Metabolism and excretion: It is metabolized in the liver and intestine (CYP3A4). More than 90% is eliminated via the gut.
Interactions: Similar to those with CsA. There is marked interaction with CsA itself, increasing the levels of CsA by >300%. CsA can be dosed 4 hours before sirolimus (but this complicates monitoring of blood levels).
Adverse drug reactions: Side effects include hypertension, hypercholesterolemia, and hypertriglyceridemia. Bone marrow toxicity (thrombocytopenia and anemia) may occur. Other effects include interstitial pneumonitis and hepatotoxicity. Sirolimus has a boxed warning regarding immediate use after lung transplant, as it has been associated with bronchial anastomotic dehiscence. It can be safely used later (after anastomotic healing), but caution is warranted if other surgeries are required.
Monitoring: Monitoring is essential as target levels also depend on whether CsA or tacrolimus is used.
Interleukin-2 Receptor Antagonists
IL-2 receptor antagonists are chimeric murine–human monoclonal antibodies. They bind the IL-2 receptor on the surface of activated T lymphocytes and inhibit proliferation and differentiation of T cells. Basiliximab is a true chimeric antibody (25% mouse) used for induction immunosuppression. Daclizumab is a humanized antibody (10% mouse) that is no longer available.
Basiliximab has a half-life of ∼14 days. It is given as a 20-mg IV infusion once before transplant and then again on the fourth day posttransplantation.
Adverse effects: Basiliximab is fairly well tolerated, much better than predecessors OKT3 and muromonab-CD3. Side effects are generally similar to placebo but there remains a theoretical risk for infection and posttransplant lymphoproliferative disorder (PTLD). A severe, acute hypersensitivity syndrome (including a pulmonary edema/acute respiratory distress [ARDS]-like picture) can occur with basiliximab and is a contraindication to continued use.
Antithymocyte globulin (ATG) is a polyclonal antilymphocyte globulin used for treatment of rejection and also for induction immunosuppression in some centers. Atgam is derived from horses, whereas thymoglobulin is of rabbit origin. There is profound B- and T-cell depletion after administration owing to complement-mediated cytolysis of antibody-coated cells.
Dosing: Atgam: 10–20 mg/kg IV infusion. Thymoglobulin: 1–1.5 mg/kg IV infusion. Atgam has a half-life of 6 days, whereas thymoglobulin has a half-life of 30 days. Thymoglobulin is ∼10 times more potent than atgam.
Adverse drug reactions: There are numerous reactions, including flu-like symptoms secondary to cytokine release syndrome (IL-1, IL-6, tumor necrosis factor-α). These symptoms can be attenuated with premedication (using a combination of prednisone, acetaminophen, diphenhydramine, and IV fluids). There is a potential risk of infection and PTLD, but the data in lung transplantation are variable. Leukopenia is the most serious complication of therapy. Thrombocytopenia may complicate therapy and anaphylaxis is documented but rare.
Monitoring: Some centers monitor CD3+ levels to gauge adequacy of therapy.
Alemtuzumab (anti-CD52) has been used by a few centers for induction immunosuppression or for treatment of rejection. However, this drug is no longer widely available and is used under a special distribution program.
Azithromycin is a macrolide antibiotic that has demonstrated efficacy to delay the development of bronchiolitis obliterans syndrome (BOS) and chronic rejection in several studies. Dosing schedules are usually three times per week.
Leflunomide is an antimetabolite that blocks pyrimidine synthesis and lymphocyte proliferation, similar to purine synthesis inhibitors.
Rituximab (anti-CD20) is a chimeric monoclonal antibody that destroys B cells and commonly used for connective tissue diseases, such as lupus. It is also used in the treatment of antibody-mediated rejection (AMR) in some centers.
Bortezomib is a proteasome inhibitor used in the treatment of multiple myeloma. Given the effect on plasma cells, some centers have used bortezomib in patients with severe AMR.
Immediate response due to preformed circulating antibodies to donor antigens (HLA, ABO, and other antigens) that bind the vascular endothelium and initiate the host immunologic response and lead to thrombus formation, inflammatory cell infiltrates, and fibrinoid necrosis of the vessels.8
Clinically, this results in fulminant allograft failure, although there have been reported cases of successful management with intensive immunosuppression and plasma exchange.
This complication has become exceedingly rare in recent years because of sensitive screening methods to avoid donors with reactivity to preformed anti-HLA antibodies in potential transplant recipients.