The risk of invasive fungal infection after HSCT is greater in allogeneic HSCT recipients than in autologous HSCT recipients.9-19
The incidence of invasive fungal infection in pediatric allogeneic HSCT recipients is reported to be 1.3-13% for Candida infection and 3-14% for mold infection, while, the incidence is 5-6% for Candida infection and 0.3-3% mold infection in autologous HSCT recipients.17,20-25
Nationwide data of 152,231 immunocompromised children in the United States, including 822 autologous HSCT recipients, show that 0.3% of autologous HSCT recipients had invasive aspergillosis.17
Therefore, although less frequent than in allogeneic patients, serious invasive fungal infections can still occur in autologous HSCT recipients.13,19,26-29
Very limited data are available on the effects of antifungal prophylaxis in autologous HSCT recipients, particularly in pediatric recipients with high-risk sold tumors. In a meta-analysis of antifungal prophylaxis reported by Robenshtok, et al.30
antifungal prophylaxis reduced all-cause mortality, fungal-related mortality, and invasive fungal infections in allogeneic recipients. For autologous HSCT, effect estimates of antifungal prophylaxis [RR 0.27, 95% confidence interval (CI) 0.08-0.95 for all-cause mortality; RR 0.28, 95% CI 0.06-1.28 fungal-related mortality; RR 0.36, 95% CI 0.13-1.01 for invasive fungal infection] were similar to those for allogeneic HSCT recipients (RR 0.62, 95% CI 0.45-0.85 for all-cause mortality; RR 0.52, 95% CI 0.27-0.99 for fungal-related mortality; RR 0.33, 95% CI 0.18-0.63 for invasive fungal infection]. However, in this study, the samples lacked the power to reach significance, so that the data were insufficient to determine whether antifungal prophylaxis should be recommended for patients with solid tumors undergoing autologous HSCT. Therefore, the topic of whether antifungal prophylaxis should be recommended for autologous HSCT recipients is still under debate. While many transplantation centers have used antifungal prophylaxis for allogeneic HSCT recipients, no standard guidelines or consensus about the use of antifungal prophylaxis in autologous HSCT recipients have been established. In this context, we investigated the efficacy of prophylactic itraconazole by comparing with that of empirical treatment in pediatric autologous HSCT recipients with high-risk solid tumors.
Since no case of fungal infection occurred in either study group, we could not determine the efficacy of antifungal prophylaxis for the prevention of invasive fungal infection. However, the duration of fever was significantly shorter in the prophylaxis group compared to the empirical group, while no differences were observed between the two groups in the frequency of factors that might increase the chance of infection. In addition, patients in the itraconazole prophylaxis group required a shorter duration of antibacterial treatment, and fewer prophylaxis patients needed second- and third-line antibiotic regimens. These findings suggest that undiagnosed subclinical fungal infections could have occurred in many of our patients, and that the antifungal agent was beneficial for the patients in the prophylaxis group. In this way, the antifungal prophylaxis may have influenced the requirement for second- or third-line antibacterial agents.
Invasive fungal infections in autologous HSCT recipients occur most frequently during the pre-engraftment period.31
During pre-engraftment neutropenia, mucositis and the presence of indwelling central venous catheters are important risk factors. Multivariate analysis indicated that treatment with thiotepa-containing regimens and the prophylactic use of itraconazole were independent factors associated with fever duration. Since mucositis facilitates the development of fungal infection, mainly from Candida species, via damaged mucosal barriers, we expected that the benefit from antifungal prophylaxis would be greater in patients with severe mucositis than in patients without mucositis. A subgroup analysis of patients who received thiotepa and developed severe mucositis showed that the prophylaxis group had a shorter duration of fever than did the empirical treatment group. However, in patients without severe diarrhea, the prophylaxis group also had a shorter duration of fever. These findings suggest that antifungal prophylaxis could have contributed to a reduced duration of fever regardless of the severity of the gross mucositis.
A meta-analysis of randomized-controlled trials comparing fluconazole and itraconazole for antifungal prophylaxis in patients with neutropenia and hematological malignancies suggested that, even though itraconazole might be more effective than fluconazole for preventing fungal infections, its association with more adverse effects may limit its use.7
In contrast, a study that compared posaconazole and fluconazole or itraconazole prophyalxis in patients with neutropenia showed that itaconazole did not have a significantly increased frequency of serious adverse events compared to fluconazole or posaconazole.32
In the present study, no difference in serious adverse events was observed between the prophylaxis group and the empirical treatment group, even though the prophylaxis group received itracon hematopoiazole for a longer duration. Itraconazole was safely used in both groups without serious adverse effects.
One limitation of this study is that the drug levels of itraconazole were not measured. However, since all the patients received intravenous itraconazole, we assumed that the itraconazole concentration reached the therapeutic range reported in the literature, and that bioavailability was less variable than with the oral capsular form of itraconazole.33,34
A possible cefepime-associated neurotoxicity has been recognized.35-38
However, our study population showed no incidence of suspected neurotoxicity due to cefepime. Quality-adjusted life years and cost-effectiveness of transplantation are important issues when determining antifungal prophylaxis.39
Although we did not observe a significant difference in duration of hospitalization or cost-related transplantation/antimicrobial agents between the prophylaxis and empirical groups, we did observe a tendency for lower total treatment costs in the prophylaxis group than for the empirical treatment group. The issue of cost-effectiveness of antifungal prophylaxis requires further attention.
The above findings suggest that some autologous HSCT recipients might benefit from antifungal prophylaxis without increased toxicity, although the incidence of invasive fungal infection is low in autologous HSCT recipients. However, patients with prophylaxis received a longer duration of antifungal treatment than those in the empirical treatment group, so that the benefits from prophylaxis must be weighed with caution against a potential increase in the risk of drug toxicity, increased cost, and selection for resistant and rare fungal pathogens. The above factors are associated with longer use of antifungal agents, although they were not observed in this study.
In summary, this study was the first prospective double-blinded randomized trial to examine the efficacy of prophylactic antifungal use in pediatric autologous HSCT recipients with high-risk solid tumors. Although some beneficial effects, including a shorter duration of fever and reduced need for antibiotic use were observed for the prophylaxis group, this study could not definitely conclude if antifungal prophylaxis should be routinely recommended for pediatric autologous HSCT recipients with high-risk solid tumors. Further investigation with a larger cohort of patents is needed.