Pediatr Blood Cancer 2009;52:470475

Invasive Fungal Infections in Pediatric Leukemia Patients Receiving

Fluconazole Prophylaxis
Zuhre Kaya,

1 ,{
MD, *

Turkz Gursel, MD,1{ Ulker Kocak, MD,1 Yusuf Ziya Aral,

Ayse Kalkanci, MD,2{ and Meryem Albayrak, MD1

Background. Children with acute leukemia have increased risk

for invasive fungal infections (IFI) but the role of long term antifungal
prophylaxis (AFP) in morbidity and mortality of IFI is not well-known.
Procedure. Medical records of 154 children with acute leukemia
who received AFP with fluconazole during intensive chemotherapy
were retrospectively reviewed to determine risk factors, clinical
characteristics and outcome of IFI. Results. The overall incidence of
IFI was 13.6%. Frequencies of proven, probable and possible
infections were 7.2%, 2.6%, and 3.8%, respectively. The causative
agent was Candida in 12 (57.2%) and Aspergillus in 9 (42.8%)
children. There were 10 children with candidemia (47.6%), 7 with
pulmonary aspergillosis (33.4%), 2 with hepatosplenic candidiasis
(10.0%), one with sinopulmonary aspergillosis (4.5%) and one with

Key words:

MD,

sinus aspergillosis (4.5%). IFI was twice as common in acute myeloid

leukemia (AML) (20.7%) than in acute lymphoblastic leukemia (ALL)
(10.2%). Duration of profound neutropenia (P 0.01) and steroid
medications (P 0.001) were significantly associated with IFI in
univariate but not in multivariate analysis. Liposomal amphotericin
B (L-AMB) was successful in 15 of 21 children as a single agent.
Voriconazole produced complete response in four children with
invasive aspergillosis and two with hepatosplenic candidiasis, who
were unresponsive to L-AMB. The rate of IFI attributable death was
5%. Conclusions. Our results indicate that AFP with fluconazole and
early empirical antifungal therapy may be effective in reducing the
incidence and mortality of IFI in children with acute leukemia.
Pediatr Blood Cancer 2009;52:470475. 2008 Wiley-Liss, Inc.

antifungal therapy; invasive fungal infections; leukemia

INTRODUCTION
Invasive fungal infections (IFIs) pose a serious threat to
patients with acute leukemia undergoing chemotherapy or stem
cell transplantation (SCT) [14]. They are difficult to diagnose due
to nonspecific clinical manifestations and trouble with obtaining
appropriate material to document infection, especially in sick
children resulting in high mortality rates. Autopsy studies revealed
fungal infections in 2531% of patients with leukemia with the
incidence varying considerably among countries [57].
Few data are available on the epidemiology and clinical
characteristics of IFI in children with leukemia. The incidence rate
varies between 4.9% and 29% in leukemic children not receiving
antifungal prophylaxis (AFP) and between 2% and 4% in those
given systemic AFP during intensive chemotherapy [813].
Fluconazole prophylaxis has been shown to reduce the incidence
and mortality of IFI in adult leukemia patients undergoing
chemotherapy [14] but little is known about its use in childhood
leukemia, especially in the developing world, where infections are
still the leading cause of death in such patients [15]. The purpose of
this study was to determine the incidence, risk factors, clinical
characteristics, and outcome of IFI in children with leukemia who
received prophylactic fluconazole during intensive chemotherapy.

METHODS
Clinical records of 154 children (age  16 years) with acute
leukemia (106 with ALL and 48 with AML) treated at our institution
from 1998 to 2007 were retrospectively reviewed. Children with
ALL were treated according to the BFM 95 protocol, as described
previously [16]. Patients with AML received a Medical Research
Council (MRC)10 based protocol which contained two instead of
one intensification course with Mid ARA-C (Cytosine arabinoside
1.5 g/m2/day bid on days 13 and mitoxantrone 10 mg/m2/day
on days 15) in the original protocol. Risk classification was made
according to BFM95 protocol for ALL and MRC10 for AML.

2008 Wiley-Liss, Inc.

DOI 10.1002/pbc.21868
Published online 4 December 2008 in Wiley InterScience
(www.interscience.wiley.com)

During intensive chemotherapy, children were isolated in single

rooms with en suite facilities but no air filtration system at the
general pediatric ward. Per oral fluconazole 46 mg/kg/day and
ciprofloxacin 15 mg/kg/day were started at the beginning of each
chemotherapy cycle until neutrophil recovery in AML and only
during severe neutropenia (absolute neutrophil count <500/ml)
in ALL. Bacterial and fungal surveillance cultures were
obtained weekly from the central venous line (CVL), throat, urine,
and stool, and also from peripheral blood, and any wounds at the
beginning of each febrile episode. Empirical antifungal therapy with
liposomal amphotericin B (L-AMB) was started at a dose of 3
5 mg/kg in children with fever persisting beyond 7 days of broad
spectrum antibiotic therapy (BSAT). Treatment adverse effects were
monitored with daily clinical assessments, blood counts, renal and
hepatic function tests at least twice a week. Abdominal ultrasound,
CT scans and/or magnetic resonance imaging (MRI) of the chest,
sinuses, abdomen, and brain were performed as soon as clinical
suspicion for IFI was raised. High resolution computerized
tomography (HRCT) became regularly available after year 2000
and was performed in patients with persistent respiratory symptoms
with or without abnormal chest X-rays. Panfungal, Aspergillus, and
Candida polymerase chain reaction (PCR) tests were added to

Pediatric Hematology Unit of the Department of Pediatrics, Medical

School of Gazi University, Ankara, Turkey; 2Department of
Microbiology, Medical School of Gazi University, Ankara, Turkey

Assistant Professor of Pediatric Hematology.

Professor of Pediatric Hematology.

Fellow in Pediatric Hematology.

Associate Professor of Microbiology.

*Correspondence to: Zuhre Kaya, Birlik mahallesi 68. sokak No: 18/4,
Cankaya, Ankara 06610, Turkey. E-mail: zuhrekaya@gazi.edu.tr
Received 26 June 2008; Accepted 20 October 2008

Invasive Fungal Infections in Leukemia

471

fungal screening after year 2002. These tests were performed using
DNA extraction kits from Metis Biotechnology (Ankara, Turkey)
and primers from TibMolbiol (Berlin, Germany) according to the
manufacturers instructions.

Definition of IFI
The criteria set by the European Organization for Research and
Treatment of Cancer/Invasive Fungal Infections Cooperative Group
were used for the definition and classification of proven, probable,
and possible IFI [17].

Statistical Analysis
Statistical analysis was performed using SPSS 11.5 by means of
MannWhitney U test in comparison of data and, chi-square
analysis and multivariate analysis with logistic regression to
evaluate associations between categorical variables.

RESULTS

Risk Factors

Incidence
Demographic data, frequency of each category for IFI are
summarized in Table I. IFI was identified in 21 (13.6%) of
154 children with acute leukemia. The incidence of proven,
probable, and possible IFI was 7.2% (n: 11), 2.6% (n: 4), and
3.8% (n: 6), respectively. The cause of infection was Candida in
12 (57.2%) and Aspergillus in 9 (42.8%) of the 21 cases with IFI.
The overall incidence of invasive candidiasis (IC) and invasive
aspergillosis (IA) was 7.7% and 5.8%, respectively. There was a
mild but statistically not significant increase in the biannual
incidence of IFI throughout the 10-year study period (P 0.37)
(Fig. 1).
TABLE I. Demographic Data, Distribution of Proven, Probable
and Possible Fungal Infections According to the Type of Leukemia
ALL
Characteristics

Fig. 1. The incidence rate of invasive fungal infections (IFI) in

children with leukemia over the study period (The number of cases with
IFI (prov: proven; prob: probable; poss: possible)).

Number of patients
106
Age (years)
7.5  4.4*
Gender (F/M)
36/70
Infection type
Proven
7
Probable
2
Possible
2
Total
11
Candida spp
Proven
7
Probable
1
Possible

Total
8
Aspergillus spp
Proven

Probable
1
Possible
2
Total
3*

AML
%

Total
%

48
9.3  4.4*
18/30

Clinical and Laboratory Characteristics

%

154
8.1  4.5
54/100

4
2
4
10

8.3
4.1
8.3
20.7

11
4
6
21

7.2
2.6
3.8
13.6

6.6
0.9

7.5

3
1

6.2
2.1

6.4
1.3

8.3

10
2

12

0.9
1.8
2.8

1
1
4
6*

2.1
2.1
8.3
12.5

1
2
6
9

0.7
1.3
3.9
5.8

Pediatr Blood Cancer DOI 10.1002/pbc

Clinical details, antifungal therapy and outcome in 21 cases with

IFI are shown in the Table III.

Proven IFI

6.6
1.8
1.8
10.2

*P < 0.05.

IFI was more common (20.7%) in AML than (10.2%) in ALL

(P 0.13). It occurred more often during induction therapy than in
consolidation with high dose chemotherapy both in ALL (81.8% vs.
18.2%) and in AML (70.0% vs. 30.0%). At the time of diagnosis of
IFI, 90.4% (19/21) of children had CVLs and all cases had been
receiving BSAT for more than 1 week, 61.9% (13/21) had been
severely neutropenic for more than 2 weeks, and 42.8% (9/21) in
patients with ALL had received steroids within the previous 4 weeks
(P 0.001) (95% confidence interval (CI) (1.6921.2)). Severe
prolonged neutropenia was more common in AML (90.0%) than in
ALL (36.3%) (P 0.03) (95% CI (1.1235.3)), with a mean
duration of 4.5  1.7 weeks (range 37 weeks) in AML and of
2.0  0.6 weeks (range 13 weeks) in ALL (P 0.01) (95% CI
(2.63.9)) However, none of these risk factors were significantly
associated with IFI in multivariate analysis (Table II).

7.7

Of the 11 children with proven IFI, 10 had Candida fungemia

(C. albicans in 7 and non-albicans Candida in 3 cases) and one had
IA, documented histopathologically in resected lung tissue. All
cases with Candida fungemia had CVL which was infected with the
same Candida species in five.

Probable IFI
There were two children with HSC and one with SA and one with
SPA in the probable IFI group. In one of the children with HSC,
the diagnosis could be established 6 months after the onset of a
prolonged fever which remained unresponsive to treatment with
several combinations of BSAT and 5 mg/kg L-AMB. Results of
microbiological, radiological and histopathological (liver biopsy)

472

Kaya et al.
TABLE II. Risk Factors for Developing Invasive Fungal Infections in Cases With Leukemia
ALL
n
Number of patients with IFI
Phase of chemotherapy
Induction
Consolidation
Maintenance
Severe neutropenia* (>2 weeks)
Steroid therapy**
Antibiotic usage
Central venous line

AML
%

11
9
2

4*
9**
11
10

Total
%

10

21

81.8
18.2

7
3

70.0
30.0

16
5

76.1
23.8

36.3
81.8
100.0
90.9

9*

10
9

90.0

100.0
90.0

13
9
21
19

61.9
42.8
100.0
90.4

*P 0.03, relative risk (95% confidence interval) 5.51 (1.1235.3); **P 0.001, relative risk (95%
confidence interval) 6.12 (1.6921.2).

examinations remained negative during the febrile period and the

patient eventually developed disseminated liver microabscesses in
which no fungal element could be demonstrated but Candida PCR
was positive.

Except for moderate nephrotoxicity in a case with HSC (Case 11)

(Table III) probably due to prolonged administration of multiple
antibiotics and antifungal, no significant adverse effect requiring
cessation of antifungal therapy was seen.

Possible IFI

Mortality

The diagnosis of PA depended on HRCT with halo sign in 5 and

air crescent sign in one child. A further case of PA developed diffuse
pneumonia during the severe neutropenia after induction therapy for
AML, did not respond BSAT and 5 mg/kg L-AMB and died on the
8th day of infection. Post mortem cultures revealed Aspergillus
flavus in sputum and E. coli in blood.

Thirty-four (22.1%) of 154 children died, 14 (9.1%) due to

relapse or refractory disease and 20 (12.9%) due to infections.
Overall infection related mortality was 22.7% (11/48) in AML and
8.4% (9/106) in ALL. Death could be attributed to IFI in only one
(5%) of the 20 infection related deaths.

DISCUSSION
Screening With Fungal PCR
Fungal PCR was positive in seven of 15 cases with proven/
probable IFI, including three with Candida fungemia, both cases
with HSC, and the cases with SA and SPA. Sensitivity, specificity,
positive and negative predictive value of the PCR test in these cases
was 47%, 100%, 100%, and 57%, respectively.

Antifungal Treatment
Of the 154 children with acute leukemia, 80 (51.9%) received
at least one course of empirical antifungal treatment. All of the
21 children with IFI was on empirical antifungal therapy at the time
of diagnosis and received pre-emptive or targeted treatment
according to the method of diagnosis.
L-AMB was successful in 15 of 21 children as a single agent
(Table III). All cases with candidemia responded to L-AMB within a
median period of 14 days (range 1021 days) with no recurrence,
deep tissue involvement or need to remove CVL. Four of the seven
cases with PA showed complete response to 5 mg/kg L-AMB within
a median period of 25 days (range 742 days) while three cases with
PA, one case with SPA and one with HSC were unresponsive to LAMB and treated with VRC. The other case with HSC (Case 11)
(Table III) did not respond alone 5 mg/kg LAMB for 7 weeks and
treated with sequential administration of VRC for 8 weeks followed
by L-AMB plus high dose (12 mg/kg) fluconazole for 4 weeks. The
case of isolated SA was treated with L-AMB plus itraconazole.
Surgery was performed in one case for resection of a residual fungus
ball because SCT was contemplated.
Pediatr Blood Cancer DOI 10.1002/pbc

In the present study, the overall incidence of IFI was found to be

13.6% in children with leukemia who received fluconazole
prophylaxis during intensive chemotherapy. Although a control
group without AFP is lacking to evaluate the efficacy of fluconazole
prophylaxis, the incidence of proven IFI in our study group was
(7.2%) close to the proven IFI incidence (210%) found in the
fluconazole arms of clinical trials in adult patients with leukemia
undergoing chemotherapy or SCT [14,1821].
Similar to other reports, Candida and Aspergillus were the
main pathogens accounting for 57.2% and 42.8%, respectively
[8,9,15,22]. Over the 10-year study period, infection rate for
Candida remained unchanged while there was a notable increase in
Aspergillus (Fig. 1). Although several studies suggested that nonalbicans Candida species is becoming more common than C.
albicans in children with cancer [9,22] C. albicans predominated
non-albicans Candida (7 vs. 3) in our study. However, the number of
culture positive cases is too small to reflect the trends in invasive
Candida infections in leukemia cases receiving fluconazole
prophylaxis.
Candida fungemia was the most common infection occurring in
10 of 21 cases and associated with CVL infection with Candida in a
half of them. The incidence of deep fungal infections was (7.2%)
less than that (15.5%) found in a recent retrospective study in
children with hematological malignancies treated without AFP [12].
Deep Candida infections were represented by HSC which had an
overall incidence of 1.3%. No data are available about the frequency
of HSC in the other pediatric series, whereas it has been reported in
27% of adult patients with leukemia [2325].The diagnosis of

Pediatr Blood Cancer DOI 10.1002/pbc

3/F

6/M
7/F
8/M
14/M
10/M
12/M

14/F

14/M
6/M

6/F
12/F
5/M
3/F
2/M
6/M
3/M
13/F
16/M
3/M

3
4
5
6
7
8

10
11

12
13
14
15
16
17
18
19
20
21

ALL-MR
ALL-MR
ALL-SR
ALL-SR
ALL-SR
ALL-MR
ALL-SR
AML-PR
AML-SR
AML-GR

AML-PR
ALL-HR

ALL-MR

ALL-MR
AML-PR
ALL-HR
AML-PR
AML-SR
AML-SR

AML-GR

AML-SR

Consolidation
Consolidation
Induction
Induction
Induction
Induction
Induction
Induction
Induction
Consolidation

Consolidation
Induction

Induction

Induction
Consolidation
Induction
Induction
Induction
Induction

Induction

Induction

Fungemia*
Fungemia*
Fungemia*
Fungemia*
Fungemia*
Fungemia**
Fungemia*
Fungemia**
Fungemia*
Fungemia**

HSC
HSC

SA #

PA
PA
PA
PA
PA
SPA #

PA

PA

Proven
Proven
Proven
Proven
Proven
Proven
Proven
Proven
Proven
Proven

Probable
Probable

Probable

Possible
Possible
Possible
Possible
Possible
Probable

Possible

Proven

Blood
Blood
Blood
Blood
Blood
Blood
Blood
Blood
Blood
Blood

culture
culture, PCR
culture
culture
culture
culture, PCR
culture
culture
culture
culture, PCR

PCR, US
PCR, US

Cytology, culture, PCR, CT

HRCT
HRCT
HRCT
HRCT
HRCT
Cytology, culture, PCR, HRCT

HRCT

Cytology, HRCT

Diagnosis of fungal infection

L-AMB
L-AMB
L-AMB
L-AMB
L-AMB
L-AMB
L-AMB
L-AMB
L-AMB
L-AMB

L-AMB/VRC
L-AMB/VRC/5-FU

L-AMB/ITC

L-AMB/VRC
L-AMB
L-AMB
L-AMB
L-AMB
L-AMB/VRC

L-AMB/VRC

L-AMB/VRC

Antifungal
treatment

Mild hepatotoxicity
Mild nephrotoxicity

hypokalemia
hypokalemia
Urticaria

Hypokalemia
hypokalemia
Headeche, visual
hallusinations hypokalemia
Hypokalemia, peripheral
neuropathy
hypokalemia
Moderate nephrotoxicity,
hypokalemia

Rash, abnormal vision, Mild

nephrotoxicity
Mild nephrotoxicity,
hypokalemia
Hypokalemia

Adverse effects

132/Survived
104/Survived
125/Survived
118/Survived
89/Survived
13/Survived
46/Survived
43/Survived
61/Survived
17/Survived

24/Survived
50/Survived

48/Survived

10/Survived
84/Survived
62/Survived
Died
16/Survived
17/Survived

25/Survived

19/Survived

Follow up/
outcome
(months)

PA, pulmonary aspergillus; SA, sinus aspergillus; SPA, sinopulmoner aspergillus; HSC, hepatosplenic candidiasis; HRCT, high resolution computerized tomography; US, ultrasonography; CT,
computerized tomography; L-AMB, liposomal amphoterisin B; VRC, voriconazole; ITC, itraconazole; 5-FU, fluorocytosine; SR, standard risk; MR, medium risk; HR, high risk; GR, good risk; PR,
poor risk; *, Candida albicans, **, Candida nonalbicans, # SA, aspergillus fumigatus; SPA, aspergillus flavus.

15/M

Underlying
Phase of
Type of fungal Degree of
Age/sex disease/risk groups chemotherapy
infection
certainty

Patient
no

TABLE III. Clinical Data of Children With Invasive Fungal Infections

Invasive Fungal Infections in Leukemia

473

474

Kaya et al.

HSC is difficult in the absence of characteristic radiological lesions

in liver and/or spleen [26]. Candida PCR was positive while culture
was negative in both of our cases supporting that it is more sensitive
in the diagnosis of HSC [27]. The incidence of IAwas (5.8%) similar
to that (6.8%) reported by Groll et al. [28] in children with leukemia
during a 5-year observation period. Similar to other reports, IA was
more common in AML (12.5%) than in ALL (2.8%) and the lungs
were the most frequently affected site (80%), followed by the
sinuses (25%) [7,2931].
In an accord with previous reports, prolonged severe neutropenia
and corticosteroid treatment were associated with increased IFI risk
[7,8,22,2833]. In ALL, the presence of steroids in induction
chemotherapy may explain more frequent occurrence of IFI at this
phase than during intensification with high dose methotrexate
(HDMTX), which is often complicated by severe mucositis, another
risk factor for invasive candidiasis [34]. However, our data did not
confirm that high dose ARA-C (HDARA-C) increases the risk of IFI
[35,36]. It seems that mucositis associated with HDARA-C or
HDMTX therapy is probably not a risk factor in patients receiving
fluconazole prophylaxis. Rate of CVL related to candidemia among
our study group is (3.17 per 1,000 catheter days) higher than the
general infection rate in the literature (2.86 per 1,000 catheter days)
emphasizing the importance of hand hygiene and appropriate care of
CVLs in the prevention of IFI [37]. Previous antibiotic usage and
quinolone prophylaxis were present in all of our cases and may also
have contributed to the development of IFI.
L-AMB in doses of 35 mg/kg is effective in majority of patients
with IFI but its efficacy is lower, at around 2030% in patients with
IA and resistant Candida infections [38]. We found it to be
successful in two thirds of all cases with IFI, with a 100.0% response
rate in candidemia and 36.4% in deep fungal infections. VRC
produces a response rate over 45% in IFI associated with pediatric
cancers [39]. It was successful in four of seven cases with PA who
were unresponsive or responding slowly to L-AMB. It should be
noted that sequential administration of VRC followed by L-AMB
plus high dose fluconazole treatment led to complete resolution of
HSC (Case 11) (Table III) that was unresponsive to monotherapy
with L-AMB [40]. Caspofungin may provide an effective
therapeutic option in children with invasive Candida or Aspergillus
infections but further data are needed for its use in children
refractory or intolerant to other antifungal therapies [41].
Although IFI related mortality range between 28% and 85% in
earlier reports [8,15,2831], two recent studies have shown that
2.1% children with AML treated according to MRC-AML-10 trial
and 0.45% children with ALL treated according to BFM-95 protocol
died in the context of IFI. We could identify only one death in
conjunction with a possible IFI despite our patients treated with
these treatment protocols. Obviously, it does not reflect the true
mortality rate of IFI since detailed post mortem examination could
be performed in only a few cases. In fact, the overall infection
related mortality was higher in our study group than those found in
MRC-AML-10 trial and ALL-BFM-95 Study Group (22.7% vs.
9.1% in AML and 8.4% vs. 2.1% in ALL) [42,43]. Nevertheless, the
fact that 20 of our 21 cases with IFI were cured and alive illustrates
the importance of early diagnosis by means of novel diagnostic
methods such as fungal PCR and/or HRCT and pre-emptive
treatment in reducing IFI related mortality. Empirical antifungal
therapy was needed in half of the children with leukemia and may
also influence morbidity and mortality of IFI. Neither prophylaxis
nor treatment with antifungal agents caused a significant side effect.
Pediatr Blood Cancer DOI 10.1002/pbc

In conclusion, our results show that deep Candida infections are

rare but IA remains an important problem in neutropenic children
with acute leukemia receiving fluconazole prophylaxis. Broad
spectrum antifungal agents, active against both Aspergillus and
Candida species and suitable for long-term oral use would be more
appropriate during neutropenic periods at induction and intensification therapy of leukemia at institutions with high IFI risk. L-AMB
is effective in the majority of children with invasive Candida
infections while VRC seems to be a better choice in the primary
therapy of IA.

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