Aspergillosis in liver transplant recipients: successful treatment and improved survival using a multistep approach.

ABSTRACT

Background. Invasive aspergillosis is a life-threatening complication in liver transplant recipients, with a reported mortality rate of more than 90%. Treatment is difficult, and no single agent is uniformly effective in treating this patient population.

Methods. We retrospectively reviewed all fungal cultures from 200 liver transplant patients between 1996 and 1999 at a single tertiary referral center.

Results. A diagnosis of aspergillosis was made in 6 patients. Five patients had pulmonary involvement; 1 presented with an inguinal mass. Time from transplant to infection ranged from 1 week to 34 months. Treatment included surgical intervention and medical treatment. All patients infected with Aspergillus fumigatus were treated with a sequential protocol of lipid complex amphotericin followed by itraconazole. The major side effect of treatment was worsening renal function. One patient died of intracranial hemorrhage during treatment.

Conclusion. Successful treatment of aspergillosis in liver transplant recipients should include early diagnosis, sequential medical treatment with lipid amphotericin B and itraconazole, and surgical intervention for invasive disease.

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LIVER TRANSPLANT RECIPIENTS are at high risk of infection with Aspergillus species, which may cause invasive disease and severe complications in this patient population. (1-3) Risk factors are a high degree of immunosuppression, use of muromonab-CD3 (OKT3), need for retransplantation, history of smoking, and renal insufficiency. (1) single-center studies report an aspergillosis prevalence of approximately 1.5%, (4) but the mortality rate has been reported to be higher than 90%. (3)

New antifungal agents are now available; in particular, lipid formulations of amphotericin B, such as amphotericin B colloidal dispersion, amphotericin B lipid complex, and liposomal amphotericin B, are equally effective and less toxic. The overall impact of treatment with these new antifungal agents on aspergillosis at a single transplant center is not known. We performed a study at our center to see whether a multistep approach, using combined treatment, was effective in improving the outcome of patients with this infectious complication.

MATERIALS AND METHODS

We retrospectively reviewed all charts and microbiology cultures obtained from 200 liver transplant recipients between July 1996 and July 1999. Postoperative surveillance fungal cultures from all fluids (blood, sputum, urine, biliary drainage) were performed twice a week in all patients for the duration of their hospital stays. Standard fungal cultures were obtained whenever clinically indicated. All patients received postoperative prophylaxis with fluconazole (200 mg/day). Those with culture results positive for Aspergillus species were referred and treated by an infectious-disease specialist. Infections were classified as definite, probable, or possible.

CASE REPORTS

Patient Demographics

Six patients were treated for aspergillosis (Table I). Four patients had definite infection, and 2 patients had probable infection. Three of the patients were male, and 3 were female, with ages ranging from 47 to 57 years. The etiology of liver disease was hepatitis C virus infection in 3 patients, autoimmune hepatitis in 1 patient, alcoholic cirrhosis in 1 patient, and fulminant hepatic failure of unknown etiology in 1 patient. One patient with hepatitis C had co-infection with hepatitis B virus. The time spans between the transplant date and infection were 1 week, 2 weeks, 3 weeks, 5 weeks, 4 months, and 34 months.

Diagnosis

Diagnosis was made by positive fungal culture results in all patients. Tissue diagnosis was also obtained in 2 patients, 1 by lung resection and 1 by lymph node biopsy. The sites from which culture results were positive are indicated in Table 2. Aspergillus fumigatus was isolated in 4 patients, and in 2 of these 4 patients it was also associated with Aspergillus niger. Aspergillus flavus was isolated from the sputum of 1 patient and A niger alone was isolated from the sputum of another.

Immunosuppressive Medications

All patients were receiving cyclosporine-based immunosuppression, together with prednisone (range, 5 to 20 mg/day), at the time of diagnosis. Two patients were also receiving mycophenolate mofetil, and 1 patient was receiving azathioprine. No patient received OKT3.

Risk Factors for Aspergillosis

Two patients had primary graft nonfunction and required retransplantation. One of these patients was also a smoker. One patient had chronic renal insufficiency. Four patients had concomitant infections: cytomegalovirus infection in 3, Klebsiella pneumonia in 1, Pneumocystis carinii pneumonia in 1, candida albicans sepsis in 1, and Staphylococcus aureus bacteremia in 1. No patient had rejection at the time of infection.

Treatment

Treatment protocols are summarized in Table 3. Combined surgical and medical treatment was done in 2 patients; 1 of them had a right middle lobectomy for pulmonary aspergillosis, and the other had surgical excision of a right inguinal mass. Both subsequently received intravenous amphotericin B lipid complex (Abelcet) at 5 mg/kg/day for 30 days, followed by oral itraconazole, 200 mg po qd, for 1 year. Two patients with pulmonary infiltrate on chest x-ray and sputum cytology results positive for A fumigatus were treated medically. They received liposomal amphotericin B followed by itraconazole, according to the same protocol as described. The 2 patients with culture results positive for A Flavus and A Niger were treated with oral itraconazole for 6 months.

Side Effects of Treatment

Treatment with itraconazole was well tolerated in all patients, and no side effects were noted. None of the patients discontinued the medication during therapy. The major side effect of lipid amphotericin B was worsening renal function in 2 patients; it was necessary to withhold the drug for 2 days from 1 patient, who then promptly recovered renal function. One patient eventually required hemodialysis during lipid amphotericin B treatment. No other major side effects of treatment were noted. Serum electrolyte levels remained stable in all patients.

Results

Of the 6 patients, 5 (83.3%) survived this infectious complication, and no direct mortality from aspergillosis was recorded at our center. One patient died of intracranial bleeding during treatment. All 5 surviving patients had remission and are currently free of disease, with follow-up times ranging from 11 months to 5 years (median, 2.46 years).

DISCUSSION

Invasive aspergillosis remains one of the most worrisome infectious complications after liver transplantation, occurring in about 1.5% to 5% of cases in the decade 1981 to 1990. (4,5) In a case series of 405 liver transplant recipients from Mayo Clinic, aspergillosis represented 13% of invasive fungal infections. (6) The mortality rate of invasive forms of aspergillosis is high, exceeding 90%. (1) Positive culture results for Aspergillus species may represent invasive disease in more than 70% of cases, and patients should, therefore, be aggressively treated. (4,7) In particular, respiratory isolates strongly correlate with the presence of invasive pulmonary disease. (8) Disseminated infection may lead to the development of endocarditis, which is often not found until autopsy. (9)

To date, there is no effective prophylaxis for invasive infection from Aspergillus species. Prophylaxis with fluconazole or amphotericin B at low doses, both intravenously and orally, was ineffective in liver transplant recipients, (5,10) as well as in patients with acute liver failure before transplantation. (11) In a recent study, however, treatment with fluconazole decreased overall fungal colonization and infections when administration was continued until 10 weeks after transplantation. (12) In that study, there was 1 case of aspergillosis among patients receiving fluconazole, compared with 4 cases in patients receiving placebo. (12) All of our patients had received postoperative prophylaxis with fluconazole.

The treatment of aspergillosis remains difficult in liver transplant recipients. Local amphotericin B may be effective in selected cases of localized wound infections. (10) Anecdotal long-term survival in a patient with cerebral aspergillosis treated with a combination of surgery and amphotericin B has been reported. (2) In a retrospective review from the United Kingdom, liposomal amphotericin B was ineffective when used alone to treat aspergillosis. (13)

Two of the patients we describe were successfully treated with combined surgical and medical treatment. Sequential treatment with lipid amphotericin B and itraconazole was effective in 3 patients with A fumigatus infection. Lipid amphotericin B offers the advantage of less nephrotoxicity than amphotericin B, and appears to be equally effective. It should be preferred in liver transplant recipients because of their risk of renal insufficiency.

Aspergillosis is an uncommon but severe complication after liver transplantation. Improved outcome may be obtained with combined surgical and medical treatment, associated with early diagnosis in the postoperative period and treatment of all patients with positive culture results and potentially invasive disease.

TABLE 1

Demographics of Liver Tranplant Patients With Aspergillosis

Patient                                                      Time from
  No.    Age/Sex    Etiology          Presentation           Transplant

   1      55/F    AIH         Pulmonary infiltrate           34 months
   2      47/M    HCV/HBV     Pulmonary infiltrate            5 weeks
   3      50/F    FHF         Inguinal lymphadenopathy        4 months
   4      49/M    HCV         Pulmonary infiltrate, pleural   3 weeks
                               effusion
   5      57/M    HCV         Pneumonia                       2 weeks
   6      56/F    ETOH        Pneumonia                       1 week

Patient
  No.    Outcome

   1     Survived
   2     Survived
   3     Survived
   4     Survived

   5     Survived
   6     Died of ICH

AIH = Autoimmune hepatitis

HCV = hepatitis C virus

HBV = hepatitis B virus

FHF = fulminant heptic failure of unknown etiology

ETOH = alcoholic cirrhosis

ICH = intracarnial hemorrhage
TABLE 2

Microbiology Data From Liver Transplant Recipients With Aspergillosis

Patient
  No.    Aspergillus Species  Site of Isolation

   1         A fumigatus      BAL, lung

   2         A flavus         BAL
   3         A fumigatus      Lymph node
   4         A fumigatus      BAL, urine
             A niger
   5         A niger          Sputum

   6         A fumigatus      sputum
             A niger

Patient                                   Immunosuppresive
  No.      Concurrent Infections             Medications

   1     None                        Cyclosporine, mycophenolate
                                      mofetil, prednisone
   2     Pneumocystis carinii, CMV   Cyclosporine, prednisone
   3     CMV                         Cyclosporine, prednisone
   4     Candida albicans,           Cyclosporine, mycophenolate
          Staphylococcus aureus       mofetil, prednisone
   5     Klebsiella pneumoniae, CMV  Cyclosporine, azathioprine,
                                      prednisone
   6     None                        Cyclosporine, mycophenolate
                                      mofetil, prednisone

BAL = Bronchial alveolar lavage

CMV = Cytomegalovirus
TABLE 3

Surgical and Medical Intervention in Liver Transplant Recipients With
Aspergillosis

Patient                             Lipid Complex
  No.            Surgery            Amphotericin B  Itraconazole

   1     Right middle lobectomy          Yes            Yes
   2     No                              Yes            Yes
   3     Excision of inguinal mass       Yes            Yes
   4     No                              Yes            Yes
   5     No                              Yes            Yes
   6     No                              Yes            Yes

Patient  Duration of
  No.     Treatment *

   1     1 mo/1 yr
   2     6 mo
   3     1 mo/1 yr
   4     3 mo/9 mo
   5     6 mo
   6     3 wk +

* Duration of treatment expressed as duration of lipid complex
amphotericin B treatment/duration of itraconazole treatment for patients
who received both.

+ Died of intracranial hemorrhage during treatment.

References

(1.) Singh N: Infections in the liver transplant recipient. Semin Gastrointest Dis 1998; 9:136-146

(2.) Iemmolo RM, Rossanese A, Rotilio A, et al: Cerebral aspergillosis in a liver transplant recipient: a case-report of long term survival after combined treatment with liposomal amphotericin B and surgery. J Hepatol 1998; 28:518-522

(3.) Singh N, Arnow PM, Bonham A, et al: Invasive aspergillosis in liver transplant recipients in the 1990s. Transplantation 1997; 64:716-720

(4.) Kusne S, Torre-Cisneros J, Ma-nez R, et al: Factors associated with invasive lung aspergillosis and the significance of positive Aspergillus culture after liver transplantation. J Infect Dis 1992; 166:1379-1383

(5.) Singh N, Mieles L, Yu VL, et al: Invasive aspergillosis in liver transplant recipients: association with candidemia and consumption coagulopathy and failure of prophylaxis with low-dose amphotericin B. Clin Infect Dis 1993; 17:906-908

(6.) Patel R, Portela D, Badley AD, et al: Risk factors of invasive candida and non-candida fungal infections after liver transplantation. Transplantation 1996; 62:926-934

(7.) Patterson TF: Approaches to fungal diagnosis in transplantation. Transpl Infect Dis 1999; 1:262-272

(8.) Horvath JA, Dummer S: The use of respiratory-tract cultures in the diagnosis of invasive pulmonary aspergillosis. Am J Med 1996; 100:171-178

(9.) Paterson DL, Dominguez EA, Chang FY, et al: Infective endocarditis in solid organ transplant recipients. Clin Infect Dis 1998; 26:689-694

(10.) Viviani MA, Tortorano AM, Malaspina C, et al: Surveillance and treatment of liver transplant recipients for candidiasis and aspergillosis. Eur J Epidemiol 1992; 8:433-436

(11.) Fisher NC, Cooper MA, Hastings JG, et al: Fungal colonization and fluconazole therapy in acute liver disease. Liver 1998; 18:320-325

(12.) Winston DJ, Pakrasi A, Busuttil RW: Prophylactic fluconazole in liver transplant recipients. a randomized double-blind, placebo-controlled trial. Ann Intern Med 1999; 131:729-737

(13.) Fisher NC, Singhal S, Miller SJ, et al: Fungal infection and liposomal amphotericin B (AmBisome) therapy in liver transplantation: a 2 year review. J Antimicrob Chemother 1999; 43:597-600

RELATED ARTICLE: KEY POINTS.

* Invasive aspergillosis is a life-threatening complication in liver transplant recipients.

* Patients can be successfully treated with a sequential regimen of lipid amphotericin B, followed by itraconazole.

* This multistep approach should be considered in immuno-suppressed patients with invasive aspergillosis.

From the Divisions of Gastroenterology and Hepatology, Infectious Diseases, and General Surgery and Transplantation, Scripps Clinic, La Jolla, Calif.

Reprint requests to John C. McHutchison, MD, Scripps Clinic, Division of Gastroenterology and Hepatology, 10666 N Torrey Pines Rd, La Jolla, CA 92037.