DISCUSSION
The present study describes 28 episodes of IFD in 27 children out of 471
patients at risk in a PHOU during 14 years. The global prevalence of IFD
was 5.9% and the rate of cases per 1 000 admissions decreased
throughout the study. IFD prevalence was higher in children with AML
(23.1%) and in those requiring allogeneic HSCT (16.9%). Prevalence of
yeast and mold infections was 1.1% and 4.9%, respectively. Yeast
infections decreased over time, whereas all IFD cases in the last two
periods were mold infections and they were mostly probable and possible
disease. Mold infections occurred in older high-risk children, with
numerous host factors and mostly receiving AFP. A rising activity in the
PHOU and the increasing complexity in patients’ pathologies did not
produce an increase in mortality rates.
The global prevalence of IFD in children with cancer and HSCT recipients
ranges from 5-7.2%1,11. The wide variety of immune
dysfunctions related to underlying conditions, institutional variations
in diagnostic and supportive care practices and inconsistencies in
diagnostic criteria make determining this prevalence very
challenging1,3,11-16. Our study´s prevalence in
different cohorts was similar to that reported recently by Bartlettet al 13. Other studies have also shown that AML
and high-risk ALL have an exceptionally high risk for
IFD2,10,16-18. In the same line, the risk of IFD after
allogeneic HSCT is considerably higher than after autologous
HSCT2,13,19.
Several patients in our study, especially those with mold infections,
had numerous host factors for developing an IFD. It is known that IFD in
children rarely occurs in the presence of an isolated host
factor2. Notably, we detected 20 episodes of
breakthrough IFD in children receiving AFP, all of which were
bronchopulmonary mold infections. The AFP consisted of a mold-active
agent in 80% of them (mostly micafungin), and fluconazole in 20%. In
agreement with international guidelines, micafungin and liposomal
amphotericin B are considered the first choices for AFP in our
institution protocols; broad-spectrum triazoles are alternatives for
AFP, considering the high incidence of drug interactions and potential
adverse effects9,10,20. Non-Aspergillus molds
are being diagnosed with increased frequency in patients receiving anAspergillus -active AFP1,2.
We identified five episodes of proven bloodstream candidemias; all of
them took place during the first study period in children with a central
venous catheter (CVC), and 60% were non-C. albicans species.
These findings are consistent with recent reports, which describe a
decrease in yeast infections in the past decade, attributed to the
extended use of AFP, improved environmental strategies and infection
control measures during line emplacement. As a consequence, mold
infections have replaced IC as the most frequent
IFD12,13,15,17,20,21. The predominance of
non-C. albicans in children has been attributed to the
affinity of C. parapsilosis for
CVC2,11,13,20.
Twenty-three episodes were bronchopulmonary mold infections, two of
which were associated with rhino-sinusitis. The diagnosis of mold IFD in
children is challenging, as only 30-50% of cases meet the criteria for
a proven or probable disease11,13,16,18. In our study,
pulmonary infiltrates and consolidations were the most frequent
radiological signs whereas the halo sign and cavities appeared in 17.4%
and 8.7% of cases. Other studies have shown that radiological findings
in pediatric IFD are unspecific and adult hallmarks are less common,
with the halo sign appearing in less than 15% of images and the air
crescent sign being very rarely observed7,10-12,15,17.
According to EORTC classification3, a proven mold IFD
diagnosis requires a sample obtained from sterile material, which is
generally unfeasible to pediatric patients. The diagnosis of a probable
IFD requires either a direct microbiological test from a non-sterile
specimen –such as bronchoalveolar lavage (BAL)-, or a positive
biomarker result -such as galactomannan (GM) in plasma, serum, BAL or
cerebrospinal fluid. BAL has positioned itself as a safe technique,
useful for culture, GM and PCR testing22,23. The
detection of Aspergillus by PCR in serum, plasma or BAL requires
two or more positive tests to support the diagnosis of probable
IFD3. The threshold of the promising (1-3)-β-D-glucan
(BDG) may vary according to the age, etiology, specimens and
manufacturers, and it is not currently recommended to provide evidence
of an invasive mold disease3,8,10,20,24. In our study,
only one child met the criteria for proven mold IFD, based on necropsy
findings, and eight children were classified as probable IFD based on
seric GM (5/8 cases) or GM in BAL (3/8). The remaining 14 children were
possible IFD cases, including four children with a single positive PCR
in BAL and two with positive serum BDG. The exposure to mold-active AFP
reduces the sensitivity of GM assay and it may be a reason for the high
proportion of possible IFD3,8,10,17,22. A better
comprehension of the role of these novel mycological biomarkers is
needed to guide clinical decision-making in children.
The prompt initiation of empiric antifungal therapy is critical for
treating children with a suspected IFD10. A
pre-emptive treatment is a safe strategy to avoid overuse of
antifungals17,25 and it is the standard strategy used
in our institution. In our study, yeast infections were mostly treated
with caspofungin or voriconazole, mold infections with liposomal
amphotericin B or voriconazole, and 25% of patients received a
combination of antifungals as first or second-line therapy. Antifungal
agents in pediatrics are limited and no specific antifungal drug regimen
is superior in terms of mortality, whereas combination therapy may
increase adverse events10,15,17.26. Echinocandins are
the first-line agents for candidemia in children and adults, but
liposomal amphotericin B and voriconazole may be a suitable option if
additional mold coverage is desired20,27-30.
Antifungal agents and treatment duration in our study followed pediatric
guidelines10,17,22,28,31. The high variability in days
of therapy may be explained because the length of treatment is not well
defined and depends on clinical response, degree of immunosuppression
and recovery from predisposing factors17.
In our study, six patients (21.4%) died during antifungal treatment,
all diagnosed with mold infections. Despite the rising activity in the
PHOU at HGUGM and an increase in the complexity of pathologies,
mortality rates did not increased. Mortality in the second period was
higher but no differences in the comparison between groups were found.
The overall case-fatality rate attributable to IFD is very variable,
reaching 10-25% in yeast infections and 20-50% in mold
infections1,13,16,17. Patients who died without
completing treatment can explain the shorter duration of treatment in
period 2. A multidisciplinary management between experts in pediatric
oncologic and infectious diseases that maintain a high level of
suspicion of IFD in children with numerous host factors allowing for a
prompt diagnosis can explain the lower number of proven infections in
the third period and the stable mortality rates within the study period.
This study has several limitations. It is a retrospective study and data
are limited to the information available in medical records. It is a
single-center study with a relatively small sample size; however, the
study is probably representative considering that it was done in a
tertiary hospital during a long study period. A high level of suspicion
in patients with several risk factors could have led to an
over-diagnosis of the cases of possible IFD.
In conclusion, this study offers a good picture of IFD in children
receiving chemotherapy or undergoing HSCT and may improve the current
knowledge of IFD in these patients. We observed a decrease in yeast
infections during the study time. The rising activity and complexity in
our PHOU did not produce an increase in the prevalence of IFD or
mortality rates. Local epidemiology knowledge of IFD is essential to
implement appropriate therapeutic interventions early and improve
survival in these children.