In addition to representing a significant surgical challenge, successful medical management of the lung transplant patient is a very complex issue. The protocol for medical management has evolved over time. The focus of care in this patient population is fourfold: immunosuppression, graft rejection, complications arising from infection, and other medical complications.

To attenuate graft injury owing to immunologic rejection, all lung transplant patients require lifelong systemic immunosuppression. The morbidity associated with mandatory immunosuppression is a key to the complexity of medical care for this patient group.

Induction Therapy

The risk of acute rejection is 40% to 50% in the first posttransplant year, and 50% of patients will have developed chronic rejection by the fifth posttransplant year.¹ To ameliorate this risk, clinicians have adopted an early and aggressive postoperative immunosuppression strategy using prophylactic T-cell depletion, commonly referred to as induction therapy. Approximately 50% of lung transplant programs utilize some form of induction therapy.¹ In addition to mitigating the incidence of acute rejection, induction therapy also has the advantage of delaying the use of the traditional immunosuppressants (i.e., calcineurin inhibitors) in the immediate postoperative period when the nephrotoxicity induced by these medications is potentially more harmful to the patient.

The standard choices for induction include rabbit and equine polyclonal antithymocyte globulins (thymoglobulin and ATGAM, respectively), murine monoclonal anti-CD3 antibody (OKT3), and interluekin-2 (IL-2) receptor antagonists. Antithymocyte globulin and OKT3 act on the entire T-cell population. IL-2 receptor antibodies (e.g., basiliximab) target the IL-2 receptor alpha chain, which is found selectively on activated T cells. Both antithymocyte globulin and OKT3 work by depleting the number of circulating lymphocytes, resulting in a predictable lymphopenia. Both antibodies are also associated with thrombocytopenia and flu-like illness with fever and chills. A more dramatic release of cytokines (i.e., tumor necrosis factor, IL-2, and γ-interferon) with subsequent cardiovascular collapse has been described with the use of OKT3. All of the induction agents increase the risk of infection. In one study comparing the three main agents, there was no difference in episodes of acute rejection, episodes of bronchiolitis obliterans syndrome (BOS), or survival at 2 years, although there was a statistically significant risk of increased infection with OKT3.²

Maintenance Therapy

Long-term immunosuppression is a core component of medical care. Most lung transplant patients are maintained on a three-medication regimen consisting of an oral corticosteroid, a calcineurin inhibitor (i.e., cyclosporine or tacrolimus), and a purine synthesis inhibitor (i.e., azathioprine or mycophenolate mofetil [MMF]).

Most clinicians initiate corticosteroids in the early postoperative period. Intravenous (IV) dosing of moderate-to-high levels of drug is administered during the first week, and patients are thereafter transitioned to oral glucocorticoids, traditionally prednisone. Although lung transplant patients are maintained on glucocorticoids for the long term, attempts are made to minimize the dose to reduce the risk of infection, osteoporosis, glucose intolerance, and mood effects. In our practice, we reduce the corticosteroid dose to 0.5 mg/kg daily on the fifth postoperative day and to 0.3 mg/kg by 3 months posttransplant. Patients are typically maintained on 5 mg prednisone daily.

Calcineurin inhibitors include cyclosporine and tacrolimus. Cyclosporine, a fungal peptide, acts by binding to cytoplasmic proteins and by inhibiting calcineurin. This inhibition causes decreased transcription of many cytokines (IL-2, IL-3, IL-4, IL-5, γ-interferon, and tumor necrosis factor) and decreased activation of T cells. Cyclosporine has a narrow therapeutic window and is highly nephrotoxic. For this reason, close monitoring of cyclosporine blood levels is essential. The published data suggest that the optimal time for this measurement is 2 hours after a dose, although trough levels obtained immediately prior to the dose are more commonly used in clinical practice. The preferential use of tacrolimus over cyclosporine has increased, given recent evidence that tacrolimus is associated with fewer acute episodes of rejection.³ An additional retrospective study of 29 patients revealed a survival benefit in patients treated with MMF and tacrolimus over those treated with cyclosporine and azathioprine.⁴ Tacrolimus appears to have similar nephrotoxicity to cyclosporine but an increased risk of associated glucose intolerance. Both tacrolimus and cyclosporine are metabolized by the cytochrome P450 system. Caution should be used in administering these drugs in combination with other agents affected by this system, particularly azoles and macrolides, which are the commonly used lung transplant recipients.

The third agent, most patients receive is a purine synthesis inhibitor, specifically azathioprine or MMF. These agents decrease B- and T-cell proliferation and result in decreased circulating lymphocytes. The most common toxicities of these agents are bone marrow suppression, gastrointestinal upset, and liver toxicity. Small studies in lung transplantation suggest that MMF may be associated with lower rates of acute rejection than azathioprine.^5–7

Acute Rejection

Despite systemic immunosuppression, acute rejection is common, with studies demonstrating up to 50% of lung transplant recipients having biopsy-proved rejection within the first year.¹ Hypoxemia, fever, infiltrates, lymphocytic pleural effusions, and/or worsening lung function can be seen with acute rejection; however, it also can be clinically silent. Because of an association between episodes of acute rejection and later BOS, many clinicians believe that it is important to diagnose and treat acute rejection in a timely fashion.

In most clinical settings, transbronchial biopsy is the best procedure for establishing the histologic diagnosis. An analysis of 1235 lung biopsies revealed an excellent diagnostic yield when 10 to 12 biopsies were taken either as part of a routine surveillance protocol or in response to clinical changes of concern for acute rejection.⁸ Currently, the International Society for Heart and Lung Transplantation has standardized the histologic grading of acute and chronic rejection based on the intensity and distribution of perivascular mononuclear cell infiltrates and bronchiolar and bronchial inflammation.⁹ Many institutions, including our own, perform regular surveillance bronchoscopy to evaluate for clinically silent rejection.

Transbronchial biopsies are invasive and do carry a small risk of serious bleeding or infection. Consequently, there have been continued efforts to develop a noninvasive method to diagnose acute rejection. Although many programs use forced expiratory volume in 1 second (FEV₁) values, these are neither sensitive nor specific enough to reliably diagnose acute rejection. A 10% decrease in FEV₁ yields a sensitivity of approximately 50% and a specificity of approximately 70%, with slight variations observed based on the underlying lung disease.¹⁰ Novel techniques including exhaled nitric oxide and serum hepatocyte growth factor have been studied but have not been established as effective clinical tools.

Acute rejection generally is treated with a pulse dose of parenteral corticosteroids, followed by tapering oral corticosteroids over several weeks. Our practice is to administer methylprednisolone (1000 mg) daily for 3 days, followed by tapering oral prednisone over 2 weeks.

Antibody-mediated rejection (AMR) is a newly emerging complication of solid organ transplantation and its relevance and approach to management continue to be elucidated.^11,12 No formal diagnostic criteria have been formulated in lung transplantation, and the approach to this entity is generally extrapolated from kidney transplant literature. The finding of circulating donor-specific antibody in the setting of deteriorating organ function should lead to the suspicion of AMR. Classic pathologic findings include parenchymal vasculitis. The significance of C4 d staining in lung specimens remains controversial. Plasmapheresis and IVIG treatment, along with rituximab therapy, can be considered in the management of AMR.

Chronic Rejection

Chronic allograft rejection manifests pathologically as bronchiolitis obliterans. It occurs in up to 50% of transplant recipients who survive at least 5 years.¹ Patients usually present with progressive dyspnea and obstruction on spirometry without evidence of an alternative diagnosis. Transbronchial biopsy, if performed, can show vascular changes of accelerated atherosclerosis and airway changes indicative of bronchiolitis obliterans. However, in contrast to acute rejection, biopsy is often unrevealing despite a clinical scenario consistent with chronic rejection. Therefore, in 2002, the International Society for Heart and Lung Transplantation updated already established diagnostic and grading guidelines based on changes in FEV₁ in order to establish the diagnosis of BOS in the absence of pathology.¹³ For this reason, surveillance spirometry, both in clinic and at home, is an important component of the long-term management of these patients. AMR may also contribute to the development of chronic allograft dysfunction, though the diagnostic and therapeutic approach to this entity remains to be elucidated.

The treatment of BOS is challenging because few of the pathologic features of the syndrome are reversible. The mainstays of therapy traditionally have included changing immunosuppressants within a class, adding a new medication, or initiating novel therapies such as photopheresis.^14,15 A single-center study suggests beneficial effects of alemtuzumab in the treatment of recurrent acute rejection and BOS in antithymocyte globulin refractory patients.¹⁶ Recently, promising data have been published that demonstrate lung function improvements in patients with established BOS after treatment with azithromycin (250 mg three times a week).^17,18 Finally, the importance of occult gastroesophageal reflux disease (GERD) in the propagation of BOS and the beneficial effects of surgical treatment of this problem have been elucidated recently.¹⁹ Our current clinical approach to BOS incorporates both the use of azithromycin and preoperative assessment for the presence of reflux. ECP or alemtuzumab is considered in select patients.

In addition to graft rejection, transplant recipients are predisposed to other infectious and noninfectious complications that affect all of the major organ systems. These are summarized in Table 111-1 and detailed later.

Infectious Complications

The mandatory use of high-level immunosuppression and constant exposure of the allograft to the environment predisposes lung transplant recipients to increased risk of infection.

Bacterial

The most common site of bacterial infection is pulmonary, and commonly implicated organisms include Staphylococcus aureus and Pseudomonas.²⁰ A decrease in early pneumonia has been demonstrated with prophylactic use of antibiotics in the immediate postoperative period, particularly in patients with cystic fibrosis. The upper airways and sinuses can serve as reservoirs for pulmonary infection with colonizing organisms after transplant. We recommend Pneumococcal vaccination for all transplant recipients. Antibiotics should be directed at the organisms that were identified in the recipient’s previous cultures or in cultures of the donor’s lungs. Empirical coverage should be broad, and tapered rapidly on the basis of available microbiological data. If a patient develops a new infiltrate, early bronchoscopy with bronchoalveolar lavage for Gram stain and culture should be performed for a specific diagnosis. Some advocate for the addition of transbronchial biopsy or protected brush specimens to increase the diagnostic yield,²¹ but we have rarely found this to be necessary.