Liver transplantation

Due to the high incidence of invasive aspergillosis (IA) in liver transplant recipients, reportedly 4-42% at some centers, there has been extensive work delineating potential risk factors for disease in this patient population (Singh et al, 1997; Castaldo et al, 1991; Grauhan et al, 1994; Steffen et al, 1994; Briegel et al, 1995; Kusne et al, 1992; Patel et al, 1996; Collins et al, 1994). However, it is difficult to interpret longitudinal studies over many years as the practice of post-transplantation management, specifically the immunosuppressive regimens employed, has changed. For instance, in one study patients from 1990-1995 were compared to those from 1998-2001 (Singh, 2003). The earlier cohort was significantly more likely to have disseminated disease, central nervous system involvement, and a higher mortality rate (92% vs. 60%). One proposed possibility is the greater use of tacrolimus (FK506) as the major immunosuppressant in the later group, compared to earlier use of cyclosporine.

 

The mortality of IA in liver transplant recipients is approximately 90% (Singh et al, 1997; Castaldo et al, 1991; Grauhan et al, 1994; Steffen et al, 1994; Briegel etal, 1995; Kusne et al, 1992; Patel et al, 1996; Collins et al, 1994). Invasive pulmonary aspergillosis is most common but disseminated disease occurs in ~50% of liver transplant recipients affected. Infection confined to the skin (or the surgical wound or other intra-abdominal site) has been described. More recent data suggests a lower frequency of disease.

Akin to hematopoietic stem cell transplant recipients, it appears that the epidemiology of IA in liver transplant recipients is changing.  While earlier studies had repeatedly shown that the peak incidence of IA was while the patients were still in the intensive care unit after surgery (approximate mean of 17 days), more recent data suggest a swing towards a peak more than 100 days post-transplantation (Fortun, 2001).  Perhaps, as postulated for other transplant recipients, this is due to increased use of antifungal prophylaxis or the improved prophylaxis and treatment of CMV disease.  This incidence may be changing due to these and other technical changes in transplantation practices (Singh, 2002).  One study showed that re-transplantation (odds ratio 29.9) and dialysis after transplantation (OR 24.5) were both extremely associated with a higher incidence of IA (Fortun, 2001).

Diagnostic tools and differential diagnoses may be different in liver transplant recipients compared with other immunocompromised patients.  Pulmonary infiltrates have a wide differential diagnosis after liver transplantation, including IA (Singh, 1999; Knollmann, 2000)  For instance, liver transplant recipients may have different results related to the use of the galactomannan assay compared to hematopoietic stem cell transplant recipients.  There has been little published experience with liver transplantation, and one study revealed a lower sensitivity of 55.6% (Fortun, 2001). Another study showed that a positive test was a good predictor for death (Kwak, 2004). There is more work ongoing to examine this and other diagnostic issues, and it is likely that the differing immunologic milieus in these various transplant recipients will require separate diagnostic and therapeutic markers.

Prophylaxis

Most cases of invasive aspergillosis after liver transplantation occur within 3 months of operation. Additional risk factors include renal failure, poor graft-function, re-operation and CMV infection which could allow focussing of prophylactic efforts. Fluconazole prophylaxis is ineffective in reducing Aspergillus infections after liver transplantation. A study comparing oral itraconazole solution with fluconazole had few infections and so itraconazole was not shown to prevent IA (Winston & Busuttil, 2002), but compared to placebo it was superior (Sharpe, 2003). Low dose intravenous amphotericin B and liposomal amphotericin have been used as prophylaxis against fungal infections in liver transplant recipients, but not wholly successfully (Lorf, 1999; Singh, 2001; Biancofiore, 2002; Fortun, 2003). The number of patients in these studies is too small to demonstrate any prophylactic benefits. At least three patients have been reported who developed invasive aspergillosis while receiving intravenous amphotericin B at a dose of 0.5 mg/kg/day.

Treatment

There have been no large clinical trials specifically focused on liver transplant recipients, so clinicians are relegated to use the larger collection of data on all types of immunocompromised patients.  While studies have shown the benefit of pre-emptive therapy for IA (Singh, 2001) with lipid amphotericin B products, there is little data on the newer antifungal agents.

Antifungal therapy should be started when microscopy of any body fluid (BAL, would drainage etc) reveals hyphae or when Aspergillus is cultured. Although some patients are 'colonized' there is a strong association between isolation of the organism and subsequent development of invasive disease. As renal function is often tenuous and patients are receiving cyclosporine or tacrolimus, a lipid associated formulation of amphotericin B is appropriate (if affordable) as initial therapy for invasive aspergillosis. Singh et al, (1997) showed that the mean time to death after initiation of therapy was 20 and 43 days in patients who received amphotericin B deoxycholate or lipid-associated amphotericin respectively (p=0.11). However, 23 of 24 patients so treated died. If hepatic function and renal function are reasonable, voriconazole would be a better choice, but with therapeutic drug monitoring to prevent accumulation. Caspofungin might be an acceptable alternative in those with reasonable hepatic function (reduce daily dose if Child-Pugh score shows moderate impairment of liver function), but poor renal function.

David Paterson
Professor of Infectious Diseases at the University of Queensland
Consultant Infectious Diseases Physician and Microbiologist at the Royal Brisbane and Women's Hospital, 
Australia

David W. Denning FRCP FRCPath FIDSA FMedSci
Professor of Medicine and Medical Mycology
Director, National Aspergillosis Centre
Education and Research Centre
University Hospital of South Manchester (Wythenshawe Hospital)
Southmoor Road
Manchester M23 9LT UK

June 2004