Download Suspected infections in children treated for ALL

Acta Pædiatrica ISSN 0803–5253
REGULAR ARTICLE
Suspected infections in children treated for ALL
Sólveig Hafsteinsdóttir1, Kristján Jónasson2, Guðmundur K Jónmundsson1,3, Jón R Kristinsson1,3, Ólafur Gísli Jónsson1,3, Inga Huld Alfreðsdóttir3,
Corrado Cilio4, Thomas Wiebe5, Ásgeir Haraldsson ([email protected])1,3
1.Children’s Hospital Iceland, Landspı́tali – University Hospital, Reykjavı́k, Iceland
2.Faculty of Engineering, University of Iceland, Iceland
3.Faculty of Medicine, University of Iceland, Iceland
4.Department of Paediatrics, University Hospital Malmö, Sweden
5.Department of Paediatrics, Haematology ⁄ Oncology, University Hospital Lund, Sweden
Keywords
ALL, Infection, Leukaemia, Treatment
Abstract
Correspondence
Ásgeir Haraldsson, Children’s Hospital Iceland,
Landspı́tali Hringbraut, 101 Reykjavı́k, Iceland.
Tel: +354 543-1000 |
Fax: +354 543-3021 |
Email: [email protected]
treated for ALL and to analyse which patients have an enhanced infection risk.
Methods: Episodes of suspected or confirmed infections were evaluated during the first 12 months
Received
2 November 2008; revised 8 February 2009;
accepted 3 March 2009.
episodes (31.8%), the most common being coagulase-negative staphylococci. The number of
DOI:10.1111/j.1651-2227.2009.01286.x
Aim: The aim of our study was to get epidemiological information on bacterial infections in children
of treatment for childhood acute lymphoblastic leukaemia (ALL).
Results: The number of patients was 73 (43 boys). The median age was 4.6 years. A total of 179
episodes occurred, varying from none in six patients to eight in one. Bacteria were cultured in 57
episodes fell significantly with increasing age for suspected and confirmed infections (p < 0.001 and
p ¼ 0.03). The proportion of confirmed infections was significantly higher (p < 0.001) in the first
episodes. The average number of suspected infections was higher in girls than in boys (p ¼ 0.03),
but confirmed infections were not.
Conclusion: Most of the serious infections occur early in the treatment and the number of suspected and
confirmed infections falls with age. Suspicion of infection is more likely in girls, but the number of confirmed
infections is equal in both sexes. Coagulase-negative staphylococcus was most commonly isolated, highlighting
the importance of careful handling of central venous devices.
INTRODUCTION
Malignant diseases in children are relatively rare yet lifethreatening. In western societies, malignant diseases are the
second most common cause of death in children older than
one year after accidents (1,2). Despite remarkable progress
in the treatment of childhood malignancies, much work still
needs to be done. Understanding the main complications of
the treatment is important in order to further improve the
survival of children with malignancies.
Survival of children diagnosed with malignant diseases
has improved substantially during the last decades. This
progress is mainly attributed to more accurate diagnosis,
improved treatment and follow-up (2–6). The treatment
is complicated, involving substantial immune suppression
(2,7,8), making the children prone to severe infections,
including bacteraemia and sepsis (9–13). Approximately
2–3% of children, treated for malignant diseases, die of
infectious complications (9,14). In addition to the temporary immune suppression and frequent surgical procedures,
these patients are prone to mucositis and almost all have
indwelling catheters increasing the infection risk (15–19).
Furthermore, it has become evident that some children are
burdened with recurrent infections during their treatment,
whereas others experience fewer complications. The reason
for this still remains unknown. It is urgent to analyse which
factors make children prone to infections and why some
children seem to suffer from these complications more often than others.
The annual incidence of acute lymphoblastic leukaemia
(ALL) in children aged 0–14 years in the Nordic countries
is around 4.0 per 100 000 and has remained relatively stable
during the last decades (20). The total number of children
diagnosed annually with acute lymphoblastic leukaemia in
the Nordic countries is therefore approximately 170.
More than 25 years ago the Nordic countries – Iceland,
Sweden, Norway, Denmark and Finland – founded the
Nordic Society of Paediatric Haematology and Oncology
(NOPHO) in order to improve and coordinate registration,
treatment and monitoring of results for children with malignant diseases. This cooperation has been very successful.
The 5-year survival of acute lymphoblastic leukaemia, standard risk or intermediate risk in the NOPHO cooperation,
is continuously improving (5,21,22).
Treatment of infectious complications in children undergoing chemotherapy for malignancies is complicated. Use of
broad-spectrum antibiotics is often necessary but can at the
same time be a confounding factor (9,23,24). In addition, the
incidence, types of bacteria and their antimicrobial susceptibility, is continuously changing (17,25–28). It is therefore
necessary to know the infectious agents in various places
and at different times.
Although long-term survival of children with malignant
diseases has improved substantially, infections are still a
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Suspected infections in ALL
Hafsteinsdóttir et al.
MATERIAL AND METHODS
All children 0–18 years of age with acute lymphoblastic
leukaemia, standard risk or intermediate risk, diagnosed
in Iceland and southern Sweden during the 10-year period
1996–2005, were enrolled in the study.
Diagnosis, gender, country of residence, as well as other
underlying diseases or disorders were recorded from hospital records. From the patients’ registry, information was
collected on blood results at diagnosis and during fever or
suspected infectious episodes according to treatment protocols. The blood results retrieved were bacterial cultures,
white blood cell (WBC) count, leukocyte differential count,
capsular reactive protein (CRP) and tests indicating disease
activity. Neutropenia was defined as the number of neutrophils in peripheral blood less than 0.5 · 109 ⁄ L. The length
and type of antibiotic treatment was recorded as well as adjustments or changes in antibiotic treatment during the period. Data were collected for the first 12 months after initial
diagnosis.
All patients were treated according to existing NOPHO
protocols for this disease (NOPHO ALL-92 and NOPHO
ALL-2000) (5,21,29).
Suspected infectious episodes were defined as fever of
more than 38.5C during leukopenia or when the responsible paediatrician suspected bacterial infection and started
antibiotic treatment according to protocol. The number of
suspected infectious episodes was recorded for each patient
as well as the number of positive blood or fungal cultures.
The bacteria or fungi cultured from blood on all the occasions were noted and blood results during these episodes
were recorded. Other suspected bacterial or fungal infections were also recorded. When blood cultures grew bacteria
or fungi, the infection was regarded as confirmed.
Statistical analysis was done using generalized linear models with Poisson distribution (Poisson regression) and also
with binomial distribution. In addition t-tests of normalized
data were used in comparison of means. A result was considered significant if the p-value was less than 0.05.
Appropriate approval was obtained from the Icelandic
and Swedish National Bioethics Committees and the privacy
and data protection authorities in both countries and the
study was approved by the local hospital authorities.
RESULTS
The total number of patients involved in the study was
73 in the age range 1.5)17 years, 43 boys and 30 girls,
with a gender ratio of 1.43. The median age at diagnosis was 4.6 years overall, 4.4 years for boys and 4.8 years
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Table 1 Suspected and confirmed infectious episodes according to age and
gender
Average number of infections
Boys
Girls
p-value (two-tailed)
Number of cases (children)
complicating factor in the treatment and a significant threat
to these children. In our study of 73 children treated for
ALL, we aim to get better epidemiological information on
infections of these children and an attempt is made to analyse which patients might be more prone to infections than
others. The main purpose of the study is to try to define
patients needing special attention or follow-up because of
increased risk of infection.
Average age (year)
Suspected
Confirmed
5.76
5.18
>0.10
2.02
3.07
0.03
0.77
0.80
>0.10
boys (43 in all)
girls (30 in all)
14
12
10
8
6
4
2
0
0
1
2
3
4
5
6
7
8
Number of suspected infections within 1 yr
Figure 1 Distribution of the number of suspected infectious episodes according
to gender.
for girls (corresponding means were 5.5, 5.2 and 5.8 years)
(Table 1). The number of patients from Sweden was 65 and
from Iceland eight. Two patients died during the study.
The 73 patients had a total of 179 episodes with suspected
infection. Of the 73 patients, 67 had one or more episodes
with suspected infection; the number of suspected infectious
episodes varied from none in six patients to eight in one patient (Fig. 1 and Table 2), the average number of episodes being 2.45. The number of patients with three or more episodes
of suspected infections was 29, the number of periods with
positive culture ranging from one to four in this group
(Table 2).
Of the 73 patients, 68 had already a Port-A-Cath (PAC)
system or a central venous device at the time of their first
episode. All patients had a central venous device, most
often a PAC, during the treatment period. Seven of the
73 patients were started on antimicrobial treatment within
48 h of the first admission, either before or very soon after
insertion of a central venous device. Only a few of the children received antibacterial prophylactic therapy, but 40 of
the 73 children received nystatin treatment. The PAC was
removed because of suspected infection in 35 of the 179
episodes. Of the 57 culture-confirmed bacterial infections,
the PAC was removed on 27 occasions. The PAC was removed after 8 of the 122 episodes of suspected infections
that were not confirmed with positive blood cultures.
Of the 179 suspected infectious episodes, blood cultures
were negative in 122 (68.2%) but bacteria was cultured in
57 (31.8%). The bacteria most often cultured was coagulasenegative staphylococcus (CNS) that was found in 23 of
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Hafsteinsdóttir et al.
Suspected infections in ALL
Table 2 Pattern of infections for children with three or more episodes of suspected infection and removal of PAC
Suspected infection episode
No.
Gender
Age
1st
2nd
3rd
4th
5th
6th
7th
8th
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Boy
Girl
Girl
Girl
Girl
Girl
Girl
Boy
Boy
Girl
Boy
Girl
Girl
Girl
Boy
Girl
Girl
Girl
Girl
Girl
Boy
Boy
Boy
Boy
Boy
Boy
Girl
Boy
Boy
4
3
7
2
4
3
4
2
3
6
3
2
4
5
4
6
4
3
15
6
4
5
2
6
3
3
7
4
6
E. coli
*
CNS
CNS(#)
CNS(#)
*
*
CNS
CNS(#)
Vir strept(#)
E. coli
*
*
*
E. faec
CNS
Proteus sp
E. coli
*
*
*
*
*
*
GNR
CNS
Mor(#)
St aur(#)
CNS
*
S. marc
*
CNS
*
*
*
*
CNS
*
*(#)
*(#)
*
*
H. infl
E. coli
*
CNS(#)
*(#)
*(#)
*
*
*
Pseud
*
C. par(#)
*
St aur(#)
*
CNS(#)
*
*
CNS(#)
*
*
CNS(#)
*
*
*
*
*(#)
*
*
CNS
E. coli(#)
*
*
*
*
*
*
CNS
*
*
CNS(#)
CNS
*
*
*
CNS(#)
*
*
*
*
*
*
*(#)
*
*
*
*
*
CNS(#)
*
Cor sp
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
CNS(#)
*
¼ suspected but not confirmed infection; (#) ¼ removal of PAC; CNS ¼ coagulase-negative staphylococcus; S. marc ¼ Serratia marcescens; Vir strept ¼
Streptococcus viridance; E. faec ¼ Enterobacter faecalis; H. infl ¼ Haemophilus influenzae; Proteus sp ¼ Proteus species; Cor sp ¼ Corynebacterium species;
Pseud ¼ Pseudomonas species; GNR ¼ Gram-negative rod; C. par ¼ Candida parapsilosis; Mor ¼ moraxella; St aur ¼ Staphylococcus aureus.
the culture-positive cases (40.4%), followed by Staphylococcus aureus in eight cases (14.0%) and Esherichia coli was
cultured on five occasions (8.8%). Pseudomonas, betahaemolytic streptococcus group A and pneumococci were
cultured three times each, other bacteria were less common.
In the 179 episodes of suspected infection, X-ray confirmed pneumonias were diagnosed on 32 occasions. Some
of the patients had pneumonias more than once, thus the
number of patients was 26. In 7 of the 32 pneumonias,
Pneumocystis jiroveci infection was suspected but only confirmed in one. Respiratory syncytial virus (RSV) was confirmed twice. In 8 of the 32 episodes, a positive blood culture was obtained at the time of the pneumonia diagnosis.
In four instances, CNS was cultured, once concomitantly
with an RSV virus. In addition, E. coli, Candida parapsilosis, S. aureus and Enterococcus faecalis were cultured. It
remained questionable if these microbes were the causative
agents of the pneumonia. In three patients, cellulitis was diagnosed during these episodes and two had complicated
colitis. Two patients developed abscesses causing severe
complications, one of whom had a positive blood culture growing pseudomonas as was found in an abdominal
abscess. Some patients might have had other complications
during their treatment period with various results of bacterial cultures.
The most common bacteria were coagulase-negative
staphylococci, cultured in 17 patients on 23 occasions. The
bacteria were most common in the induction phase when it
was cultured 14 times, 6 times in the consolidation phase,
once in the reinduction and twice in the maintenance phase.
In 13 (56%) of these episodes, the PAC was removed and
later replaced.
On one occasion a C. parapsilosis was cultured.
Patients with three or more episodes of suspected infection were 29. Seven patients had a total of 19 successively positive cultures (Table 2). In those cases, 12
cultures grew coagulase-negative staphylococcus and two
grew S. aureus. In 9 of these 14 episodes with staphylococcus the PAC was removed. Repeated positive cultures,
that is episodes when in the next episode bacteria or fungi
were also grown, were analysed (Table 2). These episodes
were 12; in eight of them coagulase-negative staphylococcus and in one S. aureus were grown. Five cultures grew
the same bacteria as was detected in the previous episode;
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Average number of suspected / confirmed
infections in each age group
Suspected infections in ALL
Hafsteinsdóttir et al.
3.5
suspected
confirmed
3
2.5
2
28 children
1-4yr
1.5
30 children
4-7yr
10 children
7-11yr
1
5 children
11-18yr
0.5
0
2
4
6
8
10
12
14
16
Age, yr
(the dots are at average age in age group)
Figure 2 Suspected and confirmed infections according to age.
in two of these the central venous device had been removed. In three of the 12 cases of repeated infections the
central venous catheter had been removed before the repeated infection.
The number of infectious episodes by gender is given
in Table 1. There were significantly more suspected infections in girls than in boys (3.07 vs. 2.02), but there was
no noticeable difference in confirmed infections. Figure 2
shows the number of infections by age. Experiments with
a few different canonical link functions with Poisson regression for these data gave the models: logðksusp Þ ¼ 1:844
0:629 logðageÞ and logðkconf Þ ¼ 0:651 0:595 logðageÞ,
where ksusp and kconf are the expected numbers of suspected
and confirmed infections. The coefficients of log (age) were
both significantly negative with p ¼ 0.00011 for suspected
infections and p ¼ 0.038 for confirmed infections. Thus, both
suspected and confirmed infection numbers fell significantly
with age. An overdispersion parameter was estimated to be
1.0, confirming that overdispersion was not present. The average number of suspected infections for the youngest age
group (1–4 years) was 3.29 but 1.20 for the oldest group (11–
18 years) (Fig. 2). Corresponding numbers for confirmed
infections were 1.20 and 0.40 (Fig. 2).
The fraction of infections confirmed remains around onethird for all age groups (it is in fact 33, 31, 31 and 33% in
the four groups).
At the initial diagnosis the median total WBC count was
5.3 (mean 10.4; range 0.95–41.0), the median neutrophil
count was 0.40 (mean 0.64; range 0.08–3.80), and the median number of blasts in peripheral blood was 1.30 (mean
5.46; range 0.0–36.3). In suspected infectious episodes when
blood cultures grew bacteria, the average CRP value was
63.7 mg ⁄ L but 45.5 when cultures were negative, the difference being statistically significant (p ¼ 0.02). The total
WBC count or number of neutrophils was not significantly
different. The total WBC count, number of neutrophils and
lymphoblasts at diagnosis or at the start of suspected infectious episodes had no significant correlation with the
number of suspected infections or outcome of bacterial
cultures.
In the 179 episodes of suspected infection, the patients
were neutropenic (number of neutrophils <0.5 · 109 ⁄ L)
on 139 occasions or 78%. In the 57 episodes when bacteria
were cultured, the patients were neutropenic in 48 (84%). In
the 122 episodes when cultures were negative, the patients
were neutropenic 91 times (75%).
Bacterial infection was confirmed by a positive bacterial
culture in 34 of 67 episodes (51%) in the first event after diagnosis. In subsequent episodes of suspected infections, the infections were confirmed relatively less often
(Table 3). Taken together, 53% of the episodes occurred
in the induction phase, 10% in the consolidation phase,
3% in the reinduction and 34% in the maintenance phase
(Table 3). Some differences in these figures were noted between different risk groups of ALL and different protocols
(Table 3). There were altogether 10 episodes that were the
sixth, seventh or eighth episode that a patient had, and of
these only one was confirmed (Fig. 3). The reduction in
the proportion of confirmed infection is significant with p <
0.001 according to a binomial distribution generalized linear
model.
Table 3 Number of episodes (percentages) with suspected infections according to treatment protocol and phase of treatment, that is induction, consolidation,
reinduction (delayed intensification) and maintenance therapy and total number of confirmed bacterial infections
Induction
Consolidationc
Reinductiond
Maintenancee
Total
SI (N ¼ 9)a
Number of episodes
II (N ¼ 15)a
Number of episodes
SR (N ¼ 32)b
Number of episodes
IR (N ¼ 17)b
Number of episodes
Total
number of episodes
Total
number of confirmed bacterial infections
8 (33)
2 (8)
–
14 (58)
24
18 (46)
3 (8)
4 (10)
14 (36)
39
43 (54)
12 (15)
–
25 (31)
80
26 (72)
1 (3)
1 (3)
8 (22)
36
95 (53)
18 (10)
5 (3)
61 (34)
179 (100)
45 (25)
5 (3)
3 (2)
4 (2)
57 (32)
a
SI and II refer to patients without unfavourable features according to NOPHO-ALL 2000 standard intensive protocol (SI) and intermediate intensive protocol (II).
SR and IR refer to standard risk and intermediate risk according to NOPHO-ALL 1992 treatment protocol.
c
Starting on day 50 for SI, II and SR but on day 106 for IR.
d
None in SI and SR, starts on day 120 for II and on day 169 for IR.
e
Starting on days 120, 211, 99 and 225, respectively.
b
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Proportion of suspected
infections which are confirmed
Hafsteinsdóttir et al.
Suspected infections in ALL
50%
40%
30%
20%
total 67
conf. 34
total 47
conf. 11
10%
0%
1st
2nd
total 29
conf. 8
3rd
total 26
conf. 3
total 10
conf. 1
4th-5th
6th-8th
Suspected infection episode (the numbers inside
the bars give total / confirmed episode count)
Figure 3 Suspected and confirmed infections according to whether it is the 1st,
2nd, 3rd, etc., time that suspicion arises and treatment is instigated.
Antibiotic treatment was altered or changed in 60 (47
patients) of the 179 episodes (33.5%).
DISCUSSION
Bacterial infection in children treated for malignant diseases
can be a complicating factor in the treatment and a serious life-threatening event (10–13). For some reason, some
children experience greater number of episodes with fever
and suspected infections than others. Our study attempts to
identify some of the underlying factors causing this.
In our study, 179 suspected infections in 73 children
treated for ALL were analysed. The patients experiencing
frequent episodes with suspected infections were mainly the
younger patients in our study. This has been described earlier (9). The male–female ratio in our study was 1.43. Interestingly, girls had more suspected infectious episodes although positive bacterial cultures were equally common in
both sexes. The higher number of suspected infections in
girls has not been reported earlier and the reason for this is
unclear. However, one study found that girls were at a higher
risk of treatment-related death, mostly because of infection
(9).
In 68% of the episodes with suspected infections in our
study, no bacteria could be cultured from the blood. However, one must bear in mind that on many occasions only
one blood sample could be drawn for culture before initiating antibiotic treatment. One must also keep in mind that
these children tend to be severely ill, not allowing for series
of blood cultures to be drawn. It can therefore be expected
that the study underestimates the number of bacteraemias
in the patient group. In addition, several other factors may
cause infections in this group of patients, including viral and
fungal infections. Immunological disturbances as well as activity of the underlying disease in addition to drugs may also
cause clinical symptoms and fever, leading to a suspicion of
infections.
Only six patients had no episode of suspected infection.
The all remaining patients had suspected infections and 29
had three or more episodes. On several occasions, the same
bacteria were cultured repeatedly, in particular coagulasenegative staphylococcus, sometimes despite removal of the
central venous catheter. This does not come as a surprise
but underlines the need for careful handling of these devices. Nevertheless, although removal of PAC almost always
requires a new central venous catheter, the reappearance of
CNS in some patients is a concern and might raise the question of the effect of the procedure.
Coagulase-negative staphylococci were the most common bacteria cultured. This is in agreement with other
studies reporting an increasing incidence of Gram-positive
bacteria in children with malignant diseases, in particular
coagulase-negative staphylococci (10,15,17,25–28,30). This
is related to more intensive chemotherapy and increased use
of indwelling central venous catheters (26–28). Although
coagulase-negative staphylococci can frequently be regarded
as contamination during blood sampling, this is certainly
not as simple in children receiving cancer treatment. Infections caused by coagulase-negative staphylococci must be
taken into consideration as potential pathogens in this patient group.
Our study also indicates that most of the serious infections involving life-threatening pathogens occur early in the
treatment period. This may be partly explained by the fact
that the patients are the most immunocompromised during induction treatment. In addition, patients with recurrent
episodes of fever with suspected infections tended to have
negative blood cultures in the second half of their treatment
period. The cause of this remains uncertain but may reflect
increased awareness of severe infections in this subgroup of
patients.
In our study, infection parameters from blood, that is
WBC count, number of neutrophils and CRP, were recorded
when antibiotic treatment was started. The WBC and number of neutrophils were frequently low as was expected in
this patient group. The ratio between neutropenic and nonneutropenic patients was similar in patients with positive
or negative cultures. We found that CRP was significantly
higher in the febrile periods when blood cultures revealed
bacteria compared to those that did not. CRP has been studied extensively in cancer patients in order to detect bacterial infections (18,31). Although studies, including ours,
find higher CRP in patients with proven bacterial infections,
these results should be evaluated with caution. CRP can
certainly be raised due to other reasons than bacterial infections and, more importantly, low CRP does not exclude
severe infections.
The initial antibiotic treatment in the two study centres is
somewhat different as is often the case in different countries
(15,30,32,33). In Iceland, the initial treatment is piperacillin
and aminoglycoside, whereas the empirical treatment in
southern Sweden is usually imipenem or ceftazidime. The
treatment needed to be adjusted or altered in one-third of the
episodes; usually antibiotics with extended spectrum toward
Gram-positive bacteria were often added to the treatment.
Colony-stimulating factors are at this time not included in
the empirical therapy, but beneficial effects of this treatment
has been reported (15,30,33). Apparently, the treatment regimens in both centres seem to be appropriate considering the
types of bacteria cultured. Prophylactic antibacterial treatment was rarely used in our cohort, in particular in southern
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Hafsteinsdóttir et al.
Sweden, but prophylactic treatment against fungi was common. There is clearly a difference between various centres
in terms of antimicrobial prophylactic therapy in this patient group. Awareness is needed for increasing number of
Gram-positive bacteria, but at the same time complications
of over usage or wrong use of antibiotics must be kept in
mind (23,24).
Our study provides important information regarding
patients with recurrent episodes of suspected bacterial
infections. The results are helpful in deciding on initial
antibiotic treatment in this patient group. The study also
provides interesting background for further research into
suspected infections in patients treated for malignant
diseases.
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