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 97-1 and detailed below.
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.
The most common site of bacterial infection is pulmonary, with an incidence of pneumonia ranging from 33% to 66%.15 A decrease in early pneumonia has been demonstrated with prophylactic use of antibiotics in the immediate postoperative period, particularly in patients with cystic fibrosis. Antibiotics should be directed at the organisms that were identified in the recipient's previous cultures or in cultures of the donor's lungs. The most common pathogens include gram-negative rods, specifically Pseudomonas spp. and Staphylococcus aureus. Empirical coverage should be broad and adequately cover both these organisms. 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,16 but we have rarely found this to be necessary.
In addition to pneumonia, bloodstream infections are common, occurring in up to 25% of patients.17 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.
Mycobacterial disease is relatively uncommon in the posttransplant population.18 Tuberculosis infection, originating either from the donor lung or from the recipient, can be reactivated in the setting of immunosuppression.15 Lung transplant patients have been reported to develop atypical mycobacterial infections as well. In a retrospective review, Kesten and colleagues found an incidence of mycobacterial disease in approximately 4% of 219 lung transplant recipients, all of whom responded well to traditional therapy.18 While we have seen a similar incidence of disease, we have found atypical mycobacterial disease difficult to eradicate and often associated with significant morbidity.
The most frequently encountered viral infection in the transplant population is cytomegalovirus (CMV). The greatest risk for active CMV disease occurs when a recipient who is without antibodies to CMV (CMV-) receives a graft from a donor who has been exposed to CMV and has developed antibodies (CMV+). In our practice, we administer prophylactic therapy with valganciclovir for 6 months to all RCMV-/DCMV+ patients as well as for all recipients who are CMV+.15 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. Recent studies suggest that new, more rapid, and less invasive techniques such as bronchoalveolar lavage viral load may add to the diagnostic yield.19 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.20 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.21 Infection with Epstein-Barr virus is notable because it is thought to be a risk factor for later development of posttransplant lymphoproliferative disorder (PTLD).22 We recommend annual influenza vaccine for all of our lung transplantation patients.
Aspergillus and Candida are the most common fungal pathogens in the transplant population.23 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.24Candida presents most commonly as a bloodstream infection, at the anastomotic site, or as a mediastinitis.15 These infections can be treated with fluconazole, itraconazole, or amphotericin B depending on the severity of disease.
Many patients are also colonized with Aspergillus; however, this colonization may pose an increased risk of invasive disease.25 Retrospective studies have demonstrated a decreased incidence of Aspergillus infection in patients treated with prophylactic nebulized amphotericin B or itraconazole.26 This information has changed our practice, and we now routinely treat all our patients with prophylactic nebulized amphotericin (20 mg twice daily) in the immediate postoperative period.
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.26 Surveillance bronchoscopy is used routinely to assess for infection, particularly at the anastomotic site. Aspergillus infections are treated with amphotericin B, voriconazole, or caspofungin depending on the severity of disease and the site of infection.
Finally, all patients should receive prophylactic antibiotic treatment for Pneumocystis carinii, 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 dapsone, inhaled pentamidine, and atovaquone.
Renal dysfunction is common in lung transplant recipients, with recent data demonstrating a cumulative incidence of chronic renal insufficiency in lung transplant patients of 2.9% at 1 year, 10% at 3 years, and 15.8% at 5 years.27 Many 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.28 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.29 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 these agents can be nephrotoxic and, over time, may contribute to the slow decline in glomerular filtration rate common in this patient population.
Many of the neurologic complications observed after transplantation are secondary to medications. For example, it is estimated that 10–28% of patients who receive cyclosporine experience neurologic changes, and similar events have been described with tacrolimus.30 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.31 In these patients, temporary cessation of the specific calcineurin inhibitor or substitution of an alternative agent (e.g., cyclosporine versus tacrolimus) may be helpful.
Patients who receive glucocorticoids are at risk for neuropsychiatric complications. Patients can present with agitation, mania, or frank psychosis. Symptoms can recur with repeated high doses of steroids.32 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.33 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.34 Glucocorticoids also predispose transplant patients to osteoporosis and decreased bone mineral density. 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.35
Despite treatment with calcium, vitamin D, and bisphosphonates, many patients continue to have bone loss and are at risk for fracture. 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.36 Our practice is to obtain a bone density study as part of the preoperative evaluation and to administer supplemental vitamin D, calcium, and pamidronate during the initial transplant admission.
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% versus 54%) in lung transplant patients treated with a HMG CoA reductase inhibitor for hyperlipidemia compared with patients without hyperlipidemia.37 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.38 Our standard of care is to withdraw purine synthesis inhibitors when the total white blood cell count falls below 4000. If the patient progresses to absolute neutropenia, we treat with granulocyte colony-stimulating factor. 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%.39 The presentation of the disease is protean and includes lung nodules and masses, liver lesions, small bowel wall thickening, and lymphadenopathy.39 Because of the limited understanding of PTLD, therapies for this disorder are still in early stages. Treatment options include decreasing the immunosuppressive regimen, radiation, and chemotherapy. Of special note is the successful treatment of a small number of patients with rituximab (anti-CD20 antibody), although additional studies are still needed.40
Lung transplant patients are at risk for several gastrointestinal issues related to medications, including peptic ulcer disease, gastritis, perforated bowel, and abdominal infections. Two particular issues deserve special attention.
The first is posttransplant GERD. As discussed earlier, there is emerging evidence that there may be a connection between GERD and BOS. In a retrospective study of 43 patients, there was a significant association between frequency and severity of GERD and decreasing FEV1. Additionally, improved lung function was noted after these patients were treated surgically with a fundoplication. 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 results14 (Fig. 97-1).
Average FEV1 values before and after fundoplication therapy in patients with GERD. (Adapted with permission from Davis RD Jr, Eubanks S, Lau CL.: Improved lung allograft function after fundoplication in patients with gastroesophageal reflux disease undergoing lung transplantation.J Thorac Cardiovasc Surg 125:533–42, 2003, Fig. 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%.41 This is noteworthy because aggressive bowel regimens may prevent distal intestinal obstruction syndrome and eliminate the need for surgical treatment.