Discussion
IFI is an important condition in patients with hematological malignancies due to devastating effects.5 Despite timely diagnosis and treatment, IFI can result in serious morbidity and mortality.1 Previous studies of pediatric IFI are quite inadequate, and most knowledge regarding the treatment of IFI is gathered from studies in adults.16,17 Because of the difficulty of performing prospective studies in this vulnarable patient group, data were obtained retrospectively in almost all of the limited number of studies.17 Considering the difficulties in planning studies in pediatric patient group and limited data about IFI treatment, the value of any study that contributes to the literature is obvious. This study is remarkable in the light of the limitations that have been accepted in this regard.
IFI-related mortality rates range from 45% to 90%, and treatment success for IFI is reported to be around 60% in various reports.1,5,19,20 Since the advantages and disadvantages have not been determined compared to monotherapy, CAT in IFI is still unclear. However, thanks to increased drug synergy and efficacy, and decreased resistance to antifungal drugs, the expectation that CAT may improve the outcome of the patients occurs. Due to the absence of prospective and randomized controlled clinical trials with an adequate statistical power, combined antifungal use in IFI treatment is included in current international guidelines as a low level of evidence and recommendation.17,18 Although the CAT approach in IFI has weak foundations, it is frequently applied in daily practice14 , and there are even reports emphasizing that this choice has reached 90%.21
In previously published studies, overall response to CAT was reported at rates ranging from 35% to 60% (8). The 12-week survival rate was generally reported at higher than the overall response rate.8-12 Previous studies reported that CAT appears helpful especially in patients with poor prognostic features.8 In our results, considering that patients generally consist of children with poor prognostic factors such as prolonged neutropenia and relapse leukemia, the overall response to CAT can be interpreted as good although there is no control group. However, ultimately the mortality rate attributed to IFI was found to be quite high. Neutropenia is an important risk factor for IFI, and the duration of neutropenia affects the treatment response and mortality rates.2 In our patient group, the mean duration of neutropenia was found to be 42.87 ± 35.5 days, and this neutropenia duration was detected longer than previous studies.19,22 Although the duration of neutropenia was not statistically different in the episodes with/without death, was the main determinant in the high IFI attributable mortality rate, as our opinion.
In our results, LamB was found to be the most preferred first line agent in monotherapy due to the inability to distinguish invasive aspergillosis and mucormycosis on the day of diagnosis. Monotherapy was switched to CAT in approximately two weeks in all episodes and voriconazole-based combination regimen was applied most frequently. Although in vitro studies have reported that caspofungin and voriconazole have a synergistic effect against Aspergillus spp 23,24 and this combination reduces fungal burden in animal tissues compared to single echinocandin or triazole administration11, the combination regimen preferences may vary in practice.8,14,15 In our experience, the choice of antifungal combination was found to vary according to the first antifungal chosen in monotherapy, and LamB plus voriconazole were the most common preference. The total mortality rate in combination regimens was around 60% in our patients, and the highest mortality rate was seen in the voriconazole plus caspofungin combination with 80%. When evaluating this result, it should be kept in mind that there is not a patient group receiving monotherapy for comparison, and there was not a control group. In response to the expectation of improvement in patients’ outcomes, there are reports claimed that CAT is ineffective in general patient outcomes6,14,22,25, despite clinical trials with positive results.6,12 In our study, CAT could not be compared with monotherapy due to absence of a control group, but the combination regimen type was found to be ineffective on mortality. This study demonstrated once again that the uncontrolled underlying disease was one of the most important factors affecting the mortality rate.1,2
When the previous studies are evaluated, it is seen that both in the transition time from monotherapy to CAT and in the duration of CAT do not have a standard, and varies widely.6,8,10,12-15 In this study, the mean duration of therapy was 42.36 ± 36.4 days, and unchanged according to combination regimen type. The main determinant of the duration of CAT seems to be the combination of clinical, radiological and microbiological response of the patient. Due to individual differences in determining the treatment reflection, CAT durations can be very short or very long.6,12-15
CAT was generally reported as associated with an increased risk of adverse events.14,22 Although it variables according to the type of antifungal drug used, the most common side effects of CAT were reported as liver, renal, and neurologic toxicity.12,13 Despite reports indicating increased risk of side effects, there are also studies that proved CAT does not cause significant side effects other than mild or moderate events.6,26 In our experience, CAT resulted as well tolerated generally. Namely, as a positive result, CAT has been found to be safe in IFI episodes of pediatric leukemia.
This study has some limitations. Our study is a retrospective study reporting data from only one institute. Due to the small number of patients, the power of statistical comparisons decreased. Furthermore, due to quite low number of proven IFI, it is not clear which combined antifungal regimen is administered for IFI, which fungal agent is caused. Despite the limitations, we think that the data of this study may contribute to the analysis of combined antifungal use in daily clinical practice, tolerability and results in haematological patients with IFI.
Optimal therapy for IFI in pediatric hematological malignancy patients is unknown, some clinicians use the CAT approach as an alternative choice to improve the outcome of these critically ill patients. However, while various pre-clinical studies suggest the possibility of this preference, there is no definite accepted recommendation yet. Well-designed and randomized trials are required to define the role of combined antifungal use in pediatric haematological patients.
Disclosure: The authors declare no conflict of interests.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.