Anti-Aspergillus Prophylaxis in Lung Transplantation: A Systematic Review and Meta-analysis

Abstract

Aspergillus is the most common cause of invasive fungal infection in lung transplant recipients. Most transplant centers employ routine antifungal prophylaxis to prevent the development of invasive aspergillosis (IA). We identified 22 studies from the literature to perform a systematic review and meta-analysis, in order to assess the development of IA and Aspergillus colonization with and without antifungal prophylaxis. Similarly, differences in the toxicities of different formulations of amphotericin-B and azoles were analyzed. Nineteen of 235 (8.1 %) and 28 of 196 (14.3 %) developed IA in the universal prophylaxis and no-prophylaxis arms, respectively (RR: 0.36, CI: 0.05-2.62). We did not find a significant reduction in IA or Aspergillus colonization with universal anti-aspergillus prophylaxis. There was no difference in the adverse events of inhaled amphotericin-B deoxycholate and lipid formulations of inhaled amphotericin-B. However, voriconazole was more hepatotoxic than itraconazole. These results should be interpreted with caution due to heterogeneity of the studies. A multicenter randomized controlled trial is warranted to assess the efficacy of anti-aspergillus prophylaxis in lung transplant recipients.

Antifungal Prophylaxis in Lung Transplant Recipients

“…7,15,20,22,31,[33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49]51 Although inhaled formulations of amphotericin B remain the most widely studied agent for antifungal prophylaxis, their optimal dosages, formulations, and durations of therapy remain unknown. [52][53][54] In pharmacokinetic studies performed in lung transplant recipients, inhaled deoxycholate amphotericin B achieves high concentrations in the lower airways of transplanted lungs, but concentrations at the bronchial anastomosis and in native lungs (in the case of single-lung transplant) are lower. 55 Most available studies have used daily administration of inhaled amphotericin B.…”

“…7,32 The results of several comparative studies of inhaled formulations of amphotericin B suggest a lack of significant differences between the deoxycholate and lipid formulations in reducing the incidence of IA, when used as single agents. 31,35,51,52 Although the role of fluconazole appears limited, due to its lack of activity against Aspergillus, the role of several newer azoles with activity against Aspergillus has been explored. Although itraconazole 20,33,34,37,38,[44][45][46]50 and voriconazole, 20,37,40,41,48,50 have proved effective in comparative trials, neither has achieved superiority against comparator agents in the reduction of IFIs.…”

“…Although itraconazole 20,33,34,37,38,[44][45][46]50 and voriconazole, 20,37,40,41,48,50 have proved effective in comparative trials, neither has achieved superiority against comparator agents in the reduction of IFIs. 37,40,48,50,52 In addition, long-term use of itraconazole and voriconazole is not optimal due to unpredictable pharmacokinetics, 33,48 drug-drug interactions via cytochrome P450 enzyme system inhibition, 59 and adverse effects (described below). 20,37 Current data suggest that flaws exist with all currently studied prophylactic strategies.…”

“…The heterogeneity of the studies included in this meta-analysis limited the conclusions that could be made. 52 Despite the lack of a clearly defined optimal prophylactic agent, most adult lung transplantation centers use antifungal prophylaxis and treat Aspergillus airway colonization, although not in all patients, and there are substantial variations in clinical practice between centers. Based on data from surveys published in 2004, 2011, and 2015 of centers using prophylaxis, the preferred agent has shifted from itraconazole to inhaled amphotericin B and most recently, to voriconazole, alone or in combination with inhaled amphotericin B.…”

“…57,61 A recent meta-analysis of available studies was unable to compare adverse events of the inhaled deoxycholate and lipid formulations of amphotericin, due to nonuniform reporting of data; however, discontinuation rates due to adverse effects were similar between formulations. 31,35,51,52 Regarding the azole antifungals, fluconazole is very well tolerated. All azoles can cause hepatotoxicity, 62 but the risk is greatest with itraconazole and voriconazole, 63 and hepatotoxicity is more common with voriconazole than itraconazole in lung transplant recipients.…”