111: Medical Management of Lung Transplant Patients

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.

In addition to pneumonia, bloodstream infections are common, occurring in up to 25% of patients.²² The most common bacterial pathogens are S. aureus and Pseudomonas. Candida spp. are the most common fungal organism identified. Lung transplant patients with indwelling central venous catheters are at greatest risk for these infections.

Although still uncommon, nontuberculous mycobacterial (NTM) infections occur more frequently in lung transplant recipients than in the general population.^23,24 In our program's experience, such organisms were isolated from 53 of 237 patients (22.4%) after lung transplantation, but the organisms were pathogenic in only six cases (unpublished data). Rapidly growing NTM were most likely to cause true infection.

Viral

The most frequently encountered viral infection in the transplant population is cytomegalovirus (CMV). The following table outlines the level of risk for the development of CMV infection depending upon the presence of CMV IgG in donor (D) and recipient (R) serum at the time of transplant:

• D+/R−: High risk.

• D+/R+: Intermediate.

• D−/R+: Intermediate.

• D−/R−: Low.

In our practice, we administer prophylactic therapy with valganciclovir for 6 to 12 months in intermediate and high-risk lung transplant recipients. Low-risk recipients receive valacyclovir for 6 to 12 months.

CMV active disease can present as either pneumonitis or systemic infection. Patients with CMV pneumonitis present with malaise, dyspnea, cough, and fever. The diagnosis is made when CMV is isolated from bronchoalveolar lavage or biopsy specimens, as well as by classic histopathologic changes demonstrating viral inclusion bodies. A positive CMV viral load in the blood provides supportive evidence of true infection. Additional studies suggest that new, more rapid, and less invasive techniques such as bronchoalveolar lavage viral load may add to the diagnostic yield.²⁵ Monitoring for systemic infection is achieved by serial studies of CMV antigenemia (as reflected by CMV antigen detected in peripheral leukocytes) or CMV viremia (demonstrated by CMV growth in shell vial culture). The development of antigenemia de novo or a marked increase in titers is consistent with systemic disease.²⁶ Other end-organ manifestations of CMV disease include retinitis, nephritis, hepatitis, enteritis, and neurologic disease. CMV disease also may be a risk factor for subsequent development of BOS.

The lung transplant patient is predisposed to other viral infections, including herpes simplex virus and Epstein-Barr virus, as well as respiratory viruses such as adenovirus, respiratory syncytial virus, and influenza.²⁷ We recommend annual influenza vaccine for all of our lung transplantation patients. Infection with Epstein-Barr virus is notable because it is thought to be a risk factor for later development of posttransplant lymphoproliferative disorder (PTLD).²⁸

Fungal

Aspergillus and Candida are the most common fungal pathogens in the transplant population.²⁹ Colonization with Candida spp. is common, and most patients who are colonized do not develop infection. However, for those who do develop disease, there is significant morbidity and mortality.³⁰ Candida presents most commonly as a bloodstream infection, at the anastomotic site, or as a mediastinitis.³¹ These infections can be treated with fluconazole or alternative azole therapy depending upon the candidal species and severity of disease.

Many patients are also colonized with Aspergillus; however, this colonization may pose an increased risk of invasive disease.³² Retrospective studies have demonstrated a decreased incidence of Aspergillus infection in patients treated with prophylactic nebulized amphotericin B or itraconazole.³³ All transplant recipients at our institution are placed on inhaled amphotericin postoperatively and remain on treatment for the duration of the initial inpatient stay. Topical prophylaxis may be extended if cultures reveal evidence of fungal colonization. In addition, all bilateral lung transplant recipients are started on micafungin at the time of transplant. IV antifungal therapy is either discontinued if intraoperative and posttransplant cultures are negative or is tailored to the fungal organism that is grown.

Aspergillus infection can take many forms, including disseminated and invasive disease, infection at the anastomotic site, aspergilloma, allergic bronchopulmonary aspergillosis, and semi-invasive tracheobronchitis. Invasive Aspergillus infection occurs mainly within the first year; however, up to 15% of cases can occur later in a patient's course, in contrast to other solid-organ transplant populations.³³ Surveillance bronchoscopy is used routinely to assess for infection, particularly at the anastomotic site. Aspergillus infections are treated with topical amphotericin B, voriconazole, or micafungin depending on the severity of disease and the site of infection.

Finally, all patients should receive prophylactic antibiotic treatment for Pneumocystis jirovecii particularly in the first year after transplantation. Our practice is to use single-strength trimethoprim-sulfamethoxazole daily or double-strength trimethoprim-sulfamethoxazole three times a week indefinitely. However, some feel that prophylaxis is needed only in the first year or when immunosuppression regimens are increased. For those with allergies to sulfa medications, alternatives include atovaquone, inhaled pentamidine, and dapsone.

Renal Complications

Renal dysfunction is common in lung transplant recipients, with recent data demonstrating a cumulative incidence of chronic renal insufficiency of 24.4% at 1 year, 34.7% at 5 years, and 41.5% at 10 years.¹ Some of these patients eventually require hemodialysis and on rare occasions undergo kidney transplantation for end-stage kidney disease. This high rate of renal dysfunction is largely a manifestation of calcineurin inhibitor toxicity. Calcineurin inhibitors are known to cause acute toxicity and more chronic changes in renal function. The acute toxicity is thought to be due to dysregulation of vascular tone mediators (i.e., endothelin, angiotensin II, and nitric oxide), which results in decreased renal blood flow and impaired glomerular filtration rate.³⁴ Acute calcineurin toxicity is dose-related and usually is reversible with a decrease in dose or discontinuation of the medication.

In contrast to the acute form, the chronic form of calcineurin toxicity is progressive and often results in end-stage renal disease. In addition to vascular changes, the chronic form is also associated with tubulointerstitial fibrosis and glomerulosclerosis. The chronic toxicity is not thought to be dose-dependent, but there is some evidence, derived from kidney and heart transplant populations, that switching the calcineurin inhibitor leads to some improvement of disease.³⁵ Both cyclosporine and tacrolimus have been associated with rare presentations of hemolytic-uremic syndrome. In the cases reported, the medication was discontinued and the patient underwent therapy for hemolytic-uremic syndrome. Once clinically stable, the patients were either rechallenged with the initial medication or given an alternative calcineurin inhibitor without return of symptoms of hemolytic-uremic syndrome.

Additional factors promoting renal dysfunction include hypertension, which is common in the posttransplant population. This may be exacerbated by medications, specifically glucocorticoids and calcineurin inhibitors. Furthermore, many of the lung transplant recipients have had exposure to aminoglycosides in both the pretransplant and posttransplant time periods, and most patients will receive ganciclovir or valganciclovir at some point in their treatment course. Both of these agents can be nephrotoxic and, over time, may contribute to the slow decline in glomerular filtration rate which is common in this patient population.

Neurologic Complications

Many of the neurologic complications observed after transplantation are secondary to medications. For example, it is estimated that 10% to 28% of patients who receive cyclosporine experience neurologic changes, and similar events have been described with tacrolimus.³⁶ Most patients present with mild complaints, such as headache, tremor, or peripheral neuropathy. However, more severe presentations, such as posterior leukoencephalopathy, also have been reported.³⁷ In these patients, temporary cessation of the specific calcineurin inhibitor or substitution of an alternative agent (e.g., cyclosporine vs. tacrolimus) may be helpful.

Patients who receive glucocorticoids are at risk for neuropsychiatric complications.³⁸ Patients can present with agitation, mania, or frank psychosis. Symptoms can recur with repeated high doses of steroids.³⁹ Therapy usually begins with decreasing the dosage, and if symptoms are sufficiently severe, treatment is pursued with lithium, valproic acid, neuroleptics, or other atypical antipsychotics.

Although no literature exists on the neurologic implications of cardiopulmonary bypass in the lung transplant population, there is ample evidence of cognitive impairment when cardiopulmonary bypass is used for patients undergoing cardiac surgery.⁴⁰ Many of the transplants in our institution are performed without cardiopulmonary bypass with a resulting decreased risk of neurocognitive effects.

Endocrine and Metabolic Complications

Glucocorticoids, as part of the immunosuppressive regimen, have multiple adverse metabolic effects, including glucose intolerance and diabetes mellitus. These effects are of particular concern in patients with cystic fibrosis, who may already have impaired pancreatic islet cell function. The use of calcineurin inhibitors has been corticosteroid-sparing with subsequent improved glucose control. It is interesting to note that tacrolimus is associated with an increased incidence of new-onset diabetes mellitus based on a meta-analysis of several studies.⁴¹ Glucocorticoids also predispose transplant patients to osteoporosis and decreased bone mineral density. The prevalence of osteoporosis after lung transplantation is as high as 57% to 73%, with a fracture incidence of 18% to 37%.⁴² Many patients will have decreased bone mineral density before transplant as a consequence of a smoking history, chronic decreased mobility, and steroid use. Cystic fibrosis patients have further risk factors, including decreased absorption of vitamin D and calcium. In a study of 100 lung transplant patients, the cumulative steroid dose appeared to be the strongest posttransplant determinant of osteoporosis and fracture.⁴³

Despite treatment with calcium, vitamin D, and bisphosphonates, many patients continue to have bone loss and are at risk for fracture.⁴⁴ In a study of 30 patients, despite aggressive medical management, 37% of patients in their first year posttransplant sustained an atraumatic fracture. Risk factors included female gender, pretransplant corticosteroid use, and low bone mineral density.⁴⁵ Our practice is to obtain a bone density study as part of the preoperative evaluation and to administer long-term supplemental vitamin D, calcium, and bisphosphonate.

Although not studied specifically in lung transplant patients, both calcineurin inhibitors and glucocorticoids can contribute to hyperlipidemia. A case-control study recently demonstrated markedly improved survival (91% vs. 54%) in lung transplant patients treated with a HMG-CoA reductase inhibitor for hyperlipidemia compared with patients without hyperlipidemia.⁴⁶ This appears to be a potential additional benefit with respect to the development of BOS, separate from its lipid-lowering effects.

Hematologic and Oncologic Complications

One of the most common hematologic complications is mild-to-moderate bone marrow suppression caused by medications. Often this sequela presents as a leukopenia, but thrombocytopenia and anemia are not uncommon. The agents most often associated with this phenomenon include the purine synthesis inhibitors (i.e., azathioprine and MMF), ganciclovir, and trimethoprim-sulfamethoxazole. A slightly increased rate of leukopenia with MMF compared with azathioprine has been reported, but both agents warrant monitoring of white blood cell counts.⁴⁷ Our standard of care is to withdraw purine synthesis inhibitors, when the total white blood cell count falls below 2000 or the absolute neutrophil count falls below 1000. Treatment with granulocyte colony-stimulating factor is also considered. During the early posttransplant course, leukopenia and thrombocytopenia are caused most commonly by one of the induction agents (i.e., OKT3, ATGAM, or antithymocyte globulin).

The most concerning hematologic/oncologic complication after transplantation is PTLD. This disorder describes a wide spectrum of B-cell dyscrasias ranging from benign hyperplasia to malignant non-Hodgkin's lymphoma. Most frequently, Epstein-Barr virus infection stimulates a proliferation of B cells that is unregulated in the setting of systemic immunosuppression. The incidence of PTLD in the lung transplant population is reported to be between 1.8% and 7.9%.⁴⁸ The presentation of the disease is protean and includes lung nodules and masses, liver lesions, small bowel wall thickening, and lymphadenopathy.⁴⁸ Because of the limited understanding of PTLD, therapies for this disorder are still in early stages. Treatment options include decreasing the immunosuppressive regimen and administration of rituximab (anti-CD20 antibody).⁴⁹ Refractory PTLD may require treatment with chemotherapy. Death from PTLD is relatively rare in lung transplant recipients (0.1% to 4.8%).¹

Gastrointestinal Complications

Lung transplant patients are at risk for several gastrointestinal issues related to medications, including peptic ulcer disease, gastritis, perforated bowel, and abdominal infections. Three particular issues deserve special attention.

The first is posttransplant GERD. As discussed earlier, there is emerging evidence of a connection between GERD and BOS. Recent evidence suggests an association between non-acid reflux and the development of BOS.⁵⁰ Additionally, improved lung function was noted after these patients were treated surgically with a fundoplication.¹⁹ Because of these findings, it is our practice to screen all patients for GERD preoperatively and to treat affected patients with pretransplantation laparoscopic fundoplication with encouraging results (Fig. 111-1).

The second area of interest is postoperative gastrointestinal disease in the patient with cystic fibrosis. These patients often have preexisting pancreatic insufficiency that may complicate medication absorption postoperatively. Additionally, there is an increased risk of distal intestinal obstruction syndrome, with one report showing an incidence as high as 20%.⁵¹ This is noteworthy because aggressive bowel regimens may prevent distal intestinal obstruction syndrome and eliminate the need for surgical treatment.

Colon and rectal complications are not frequently observed in lung transplant recipients in general.⁵² These complications can include abdominal perforation related to diverticulitis, as well as spontaneous perforation. Symptoms can be mild and atypical. Intra-abdominal complications should be suspected in the setting of unexplained abdominal pain, fever, or leukocytosis.

The authors acknowledge Dr. Patricia A. Kritek and Dr. Aaron Deykin, who contributed to this chapter in the first edition.

The lung, like the skin and the gut, is a portal of entry for potential pathogens. Not surprisingly, these organs have been resistant to successful transplantation. As a consequence of their aggressive immunosuppression, medical management of lung transplant recipients requires attention to common transplant-related infections as well as uncommon pulmonary infectious diseases.