Preliver Transplant Aspergillus Colonization: An Ounce of Prevention

Invasive Aspergillus (IA) remains the second most common invasive fungal infection among liver transplant recipients, with an estimated incidence ranging between 1% and 9%.1 Risk factors are reasonably well established and include perioperative renal replacement therapy, model for end-stage liver disease (MELD) >30 at transplant, cytomegalovirus infection, and retransplantation, the latter being the highest risk for IA posttransplant.1-4 Initially described as an early opportunistic infection, more recent epidemiological studies have revealed a shift toward the later postoperative period (>3 mo). Although uncommon, IA is associated with significant morbidity and mortality, especially when occurring early after transplant.5 Targeted prophylaxis among patients at risk has been studied, using a variety of antifungal agents such as echinocandins or azoles, and appears effective in preventing or at least in delaying onset of IA.6,7 Recent guidelines recommend such approach for liver transplant candidates at risk.1 In this issue of Transplantation, Winston et al report on the outcome of 27 postliver transplant patients with pretransplant Aspergillus colonization during a 5-year period in a single center.8 All patients, except 1, were found to be colonized in the respiratory tract shortly before transplant. While only 6 patients received treatment for this before transplant, all received antifungal prophylaxis with activity against Aspergillus postoperatively, most with voriconazole, for a median of 85 days. After transplant, only 3 patients developed IA, 2 within 6 days of transplant, and shortly after being initiated on prophylaxis, perhaps indicating that the patients could have had active infection going into the transplant. Overall, 1-year survival was 66.7% (21/27 patients), and only 1 death was attributed directly to IA. Meanwhile, a control group of liver transplant recipients with a similar MELD score but not colonized had a 1-year survival of 81.5% (P = 0.01). Despite this difference, the authors conclude that these patients can still undergo successful transplantation if given adequate prophylaxis. Evidence is accumulating that voriconazole prophylaxis is safe and effective for high-risk patients undergoing liver transplant, and this article is an important contribution to that literature.6,7 There were no reported adverse events due to voriconazole, and patients seem to have tolerated it well. More importantly, this study also highlights the potential feasibility of proceeding with transplant even when Aspergillus colonization has been identified. For patients with cystic fibrosis who are colonized with Aspergillus pretransplant, studies have shown that outcomes are similar to those who are not colonized.9 Certainly, these results may be due to source control (ie, removing colonized lungs) as much as antifungal therapy. Nevertheless, such data have not been previously available in liver transplant, leading to the potential denial of life-saving procedure due to a perceived high risk of infectious complications afterward. Given that, this study provides important information for transplant clinicians in that prophylaxis seems to decrease the rate of IA, or at least postpones it to a time when the recipient is possibly stronger. This study requires careful interpretation, however. Since there was no routine testing for fungal colonization, some patients with colonization could have been missed. Similarly, defining IA in retrospective studies may be problematic and cases may have been either missed or incorrectly diagnosed. As the authors suggest, the small sample size significantly limited further analysis and further identification of risk factors for the lower 1-year survival was not possible. More importantly, although the comparison group used for analysis was matched for MELD score, the groups were otherwise markedly different including a much higher rate of patients undergoing retransplantation and on associated pretransplant immunosuppression, renal disease requiring dialysis and longer ICU stay in the colonized group. These are important factors because they most likely impacted the survival rate in the colonized group, particularly those undergoing retransplants. As a reference, 1-year survival rates in patients undergoing retransplantation have been reported to be near 75%, which would be similar to the colonized patients.10 Therefore, it may be that, for patients undergoing retransplantation, Aspergillus colonization does not significantly impact survival beyond baseline outcomes, whereas it may be an important marker, among other risk factors, for poor outcomes in surrogate patients undergoing the first transplant. As such, screening for Aspergillus colonization in liver transplant candidates is an intriguing question. Further studies on who should be tested and how they should be managed are much needed. As organ transplantation remains a scarce resource, recipient selection to maximize the potential benefit of each donor graft remains of primary concern to the transplant community. As infection remains among the most common causes of morbidity and mortality following liver transplant, there has been increased attention paid to the evaluation of pretransplant colonization with both fungi and multidrug-resistant bacteria with subsequent targeted prophylaxis in the perioperative period. Such initiatives, and further research, seem worthwhile in that they open the way for candidates with complex medical histories to safely proceed with transplantation.