When a liver transplant recipient develops a life-threatening infection, the tendency is to decrease or withhold immunosuppression.1 However, the risk of infection must be balanced against the risk of organ rejection in this context. Here we report 3 patients with fungal infections after liver transplantation whose immunosuppression was switched to a budesonide-based regimen by our transplant team. Budesonide is an oral corticosteroid with a high rate of first-pass metabolism by the isoenzyme cytochrome P450 3A4, so high intrahepatic concentrations and low systemic concentrations are achieved. This decreases the glucocorticoid activity of the parent compound to approximately a hundredth and leaves very little available systemically; thus, the risk of infection and other adverse steroid effects is potentially decreased.2 We chose budesonide because it has recently been shown to be a successful treatment for autoimmune hepatitis and to both prevent rejection and provide control over severe fungal infections.3
The first case was a 60-year-old man who underwent liver transplantation for hepatitis C in 2001 and underwent retransplantation for ischemic cholangiopathy in November 2010 with a Model for End-Stage Liver Disease score of 23. He developed a Saccharomyces cerevisiae infection according to peritoneal fluid and blood cultures 5 days after transplantation, and this infection was treated with caspofungin. The patient also developed Enterobacter aerogenes sepsis, which was treated with imipenem. Because of these infections, mycophenolate mofetil and tacrolimus were discontinued, and oral budesonide was initiated at 9 mg once a day. This dosage was chosen because it is the standard dose for Crohn's disease.2 The liver enzyme levels and the liver function remained stable with budesonide monotherapy 3 months later, and follow-up liver biopsy revealed cholestasis but no evidence of acute rejection (Fig. 1).
The second case was a 63-year-old man who underwent liver transplantation for hepatitis B cirrhosis and developed pericardial tamponade 4 days after transplantation, which required a pericardial window. He was diagnosed with fungal pericarditis due to Aspergillus flavus and was started on voriconazole and caspofungin. He was switched from tacrolimus and prednisone to budesonide monotherapy (3 mg by mouth 3 times a day). The patient developed a hemorrhagic stroke a few months after transplantation and died because of acute aspiration pneumonia. During his autopsy, extensive pericardial fibrosis was found with occasional fungal hyphae consistent with his history of Aspergillus pericarditis. The liver showed no evidence of cellular rejection, but mild hemosiderosis was seen.
The third case was a 34-year-old woman with liver failure secondary to steroid-resistant autoimmune hepatitis with a Model for End-Stage Liver Disease score of 38. After liver transplantation, she was given corticosteroids, tacrolimus, and mycophenolate mofetil as immunosuppression. Magnetic resonance imaging of the brain was performed because of decreased mental status on postoperative day 10, and it demonstrated lesions consistent with a fungal etiology. The patient was treated with amphotericin B for invasive cerebral aspergillosis on the basis of positive sputum. She was switched from mycophenolate mofetil and tacrolimus to 3 mg of oral budesonide twice daily; the dosage was titrated to a maximum of 9 mg daily 19 days after the diagnosis of aspergillosis. Her liver enzyme levels normalized over a period of 8 months while she was on budesonide monotherapy, and there was no evidence of organ rejection in a follow-up liver biopsy sample.
These 3 cases suggest that immunosuppression with budesonide could prevent rejection in liver transplant recipients who develop severe infections; in this scenario, rejection commonly occurs because immunosuppression is reduced or stopped. The efficacy of budesonide in decreasing inflammation is similar to the efficacy of prednisolone (as measured by its effect on the erythrocyte sedimentation rate after 8 to 12 weeks of treatment in a randomized controlled trial).2
Immunosuppression with budesonide after transplantation has been studied in rat models, in which it has successfully prevented acute rejection after liver transplantation4 and intestinal transplantation.5 In the field of hepatology, budesonide has been shown in a randomized controlled trial to be effective in the treatment of autoimmune hepatitis.3 Patients were randomized to azathioprine in combination with either budesonide or prednisone; a complete biochemical response was observed in 60% of the budesonide patients but in only 38% of the prednisone patients. Fewer patients in the budesonide group developed steroid-related adverse effects (46% versus 72%).
This case series illustrates the possibility of budesonide as an immunosuppressant for liver transplant recipients who develop severe infections. This potentially promising strategy warrants a randomized controlled study to confirm the benefits of budesonide as an immunosuppressant in this context.
This case series received a priori approval by the McGill University Health Centre institutional review committee.