The lung is a mediator of many immunologic processes, serving as an interface between the exogenous and endogenous environments. Consequently, lung transplant patients have required higher levels of immunosuppression than recipients of kidney, heart, or liver. The immunosuppression strategy can be conceptualized as two overlapping phases: (1) induction and (2) maintenance. While there are some variations in the medications used at different lung transplant programs, the approach to immunosuppression is fairly similar. The general concepts are discussed here but are better defined in Chapter 111 by Drs. Goldberg and Camp.
The goal of induction therapy in lung transplantation is to deplete or inactivate the host T cells. The original goal of early aggressive immunosuppression was simply to induce a state of immunologic unresponsiveness or tolerance. In most cases, polyclonal antibodies (e.g., antilymphocyte globulin and antithymocyte globulin) or monoclonal antibodies (e.g., anti-CD3, OKT3, and anti-interleukin 2 receptor) were used to inactivate (or bind) T-lymphocyte antigens. The ability of induction agents to achieve immunologic unresponsiveness, however, proved to be very disappointing. Nonetheless, there remains a practical use for induction therapy in lung transplantation. Because the lungs are relatively edematous after transplantation, aggressive diuresis is commonly used in the postoperative lung transplant recipient to maintain effective gas exchange. In this setting, induction therapy permits potentially nephrotoxic maintenance therapies, such as cyclosporine or tacrolimus, to be minimized during the first postoperative week. Further, during this time following ischemic insult to the donor lungs, the ability of the immune system to multiply the inflammatory result is blunted.
The general approach to maintenance immunosuppression is based on a multiagent regimen composed of calcineurin inhibitors (e.g., cyclosporin A or tacrolimus), cell cycle inhibitors (e.g., azathioprine or mycophenolate), and steroids (Table 108-1). The regimen generally is started at a relatively high dose and tapered over the first 3 months after transplantation. The rate at which the dose of maintenance therapy is tapered depends on the presence and severity of acute rejection episodes experienced by the patient.
Table 108-1Immunosuppressive Agents ||Download (.pdf) Table 108-1Immunosuppressive Agents
Cyclosporin A (CSA) and its intracellular receptor form a complex that binds and inhibits calcineurin. Calcineurin is a component of the lymphocyte signal transduction pathway that regulates interleukin 2 expression. The starting dose is 8 mg/kg/day in two divided doses.
Tacrolimus (FK-506) is a macrolide compound with a mechanism of action similar to CSA. FK-506 is given intravenously with dosing adjusted to blood levels. Toxicity includes reversible renal dysfunction, hypertension, and neurotoxicity.
Azathioprine is a purine analog that is converted to several active metabolites, including 6-mercaptopurine. These metabolites inhibit lymphocyte proliferation. Azathioprine is started at a dose of 2 to 2.5 mg/kg/day, and the dose is adjusted to maintain a total white blood cell count of 4000 cells/mm3.
Mycophenolate mofetil (MMF) blocks de novo purine synthesis. MMF selectively inhibits lymphocyte proliferation because lymphocytes, in contrast to other cells that use salvage pathways, use only the de novo pathway in purine biosynthesis. MMF is usually given at 1 g PO bid, and the dose is titrated to a white blood cell count greater than 4000 cells/mm3.
Corticosteroids have a variety of immunosuppressive effects that are not well understood. Methylprednisolone, prednisolone, and prednisone are all used for transplant immunosuppression.
Acute rejection generally is treated with high-dose steroids. A typical episode of acute rejection is treated with 1 g/day of IV steroids (Solu-Medrol) × 3 doses, followed by a modest taper of oral prednisone to baseline levels.
The immune-mediated destruction of the transplanted lung occurs both acutely and chronically. Acute rejection in the lung is often characterized by hypoxemia, fever, and radiographic infiltrates. The presentation of acute rejection can be virtually indistinguishable from acute infection. In contrast, chronic rejection is associated with a slow and progressive decline in pulmonary function.
Acute rejection is an inflammatory reaction initially confined to the perivascular zones. Untreated, the acute rejection will progress to involve not only blood vessels but also airways and interstitium. This pathophysiologic process is reflected in the generally accepted classification of lung allograft rejection (Table 108-2).9
Table 108-2Revised Working Formulation for Histopathologic Classification and Grading of Pulmonary Allograft Rejection ||Download (.pdf) Table 108-2Revised Working Formulation for Histopathologic Classification and Grading of Pulmonary Allograft Rejection
|A: ||Acute rejection |
|B: ||Airway inflammation |
Grade 1R—low grade
Grade 2R—high grade
|C: ||Chronic airway rejection—obliterative bronchiolitis |
|D: ||Chronic vascular rejection—accelerated graft vascular sclerosis |
Because the signs and symptoms of acute rejection are nonspecific, the diagnosis is often triggered by clinical suspicion and requires histologic confirmation. Many transplant teams use surveillance bronchoscopy, bronchoalveolar lavage, and transbronchial biopsy to evaluate the lung parenchyma and environment. In addition to signs of acute rejection, the lung tissue is evaluated for other sources of inflammation. For example, cytologic inclusion bodies suggest a viral infection, polymorphonuclear leukocytes indicate a possible bacterial infection, and necrosis or hyphae are suggestive of fungal infection.
What has become clear in the past 5 to 10 years is the fact that acute rejection is a much more complex and diverse set of immunologic processes that are both cellular and noncellular mediated and are poorly understood. The recognition of subtle states of rejection has become a very hotly debated topic and which therapeutic modalities, and when, are not yet clearly understood. This topic is of keen interest as there are strong associations between the number and severity of acute rejection episodes, and the development of bronchiolitis obliterans syndrome (BOS) (see below), the common pathologic endpoint of chronic rejection. Early use of newer therapies beyond pulsed doses of maintenance medications are more commonly used including targeted immunolytic therapies (Antithymocyte, anti-IL2 receptor, anti-CD3), and extracorporeal photopheresis (ECP) to name a few.
Ongoing immune destruction of the lung leads to scarring of the terminal airways, a process known as bronchiolitis obliterans. This end-stage process is characterized by the presence of intraluminal polypoid plugs of granulation tissue in the terminal and respiratory bronchioles that cause partial or total obliteration of the lumen of the airway. BOS is the irreversible and final common pathway of a number of lung diseases.
Chronic airway inflammation may be owing to a combination of effects. In some cases, the acute rejection is superimposed on an underlying bronchiolitis obliterans. The ongoing destruction of the airways promotes frequent colonization by bacteria and fungi, and thus a component of inflammatory response actually may reflect infection.
Confirmation of BOS by histologic examination of a transbronchial biopsy is relatively insensitive (60%). However, the histologic severity of bronchiolitis obliterans correlates strongly with airflow obstruction measured by spirometry. Hence the classification system for BOS is based on spirometry (Table 108-3).10 Patients with bronchiolitis obliterans have a characteristic “scooped” expiratory flow histogram with a marked absolute reduction in forced expiratory volume in 1 second (FEV1) (Fig. 108-2). Chest radiographs may show hyperinflation secondary to chronic small airway obstruction (Fig. 108-3), and CT scan can show signs of delay in airspace emptying.
Table 108-3BOS Classification System: 2002 ||Download (.pdf) Table 108-3BOS Classification System: 2002
|BOS 0 ||FEV1 >90% of baseline and FEF25%–75% >75% of baseline |
|BOS 0p ||FEV1 81%–90% of baseline and/or FEF25%–75% ≤75% of baseline |
|BOS 1 ||FEV1 66%–80% of baseline |
|BOS 2 ||FEV1 51%–65% of baseline |
|BOS 3 ||FEV1 ≤50% of baseline |
Characteristic “scooped” expiratory flow histogram of patients with BOS, with marked absolute reduction in FEV1.
Chest radiograph demonstrating hyperinflation secondary to chronic small airway obstruction.
Approximately one-third of patients develop histologic evidence of bronchiolitis obliterans within 12 months of lung transplant. Although the coincidence of bronchiolitis and chronic infection complicates the analysis, approximately two-thirds of patients ultimately experience a progressive and unrelenting loss of pulmonary function owing to chronic rejection. Multiple therapies are used to arrest or slow this process with varied success. Bronchiolitis obliterans remains the primary obstacle to widespread long-term graft function and survival.