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.