J Antimicrob Chemother 2012; 67: 2731 – 2738
doi:10.1093/jac/dks266 Advance Access publication 31 July 2012
Indications and outcomes of antifungal therapy in French patients
with haematological conditions or recipients of haematopoietic stem
cell transplantation
Raoul Herbrecht1*, Denis Caillot2, Catherine Cordonnier3, Anne Auvrignon4, Anne Thiébaut5, Benoı̂t Brethon6,
Mauricette Michallet7, Nizar Mahlaoui8, Yves Bertrand 9, Paul Preziosi10, Fabrice Ruiz10, Norbert-Claude Gorin11
and Jean-Pierre Gangneux12
1
Pôle d’oncologie et d’hématologie, Hôpital de Hautepierre, Strasbourg, France; 2Service d’hématologie clinique, Complexe Hospitalier Le
Bocage, Dijon, France; 3Service d’hématologie, Hôpital Henri Mondor, and Université Paris XII, Créteil, France; 4Service d’hématologie et
oncologie pédiatrique, Hôpital Armand Trousseau, Paris, France; 5Service d’hématologie, Hôpital A. Michallon, Grenoble, France; 6Service
de pédiatrie à orientation hématologique, Hôpital St Louis, Paris, France; 7Service d’hématologie, Pavillon Marcel Bérard 1G, Centre
Hospitalier Lyon Sud, Pierre Bénite, France; 8Service d’immuno-hématologie pédiatrique, Hôpital Necker-Enfants Malades, AP-HP, Paris,
France; 9Institut d’hématologie et d’oncologie pédiatrique, Hôpital Debrousse, Lyon, France; 10ClinSearch, Bagneux, France; 11Service
d’hématologie clinique, Hôpital St Antoine, Paris, France; 12Laboratoire de parasitologie-mycologie, CHU Rennes/INSERM U1085-IRSET,
Université Rennes 1, Rennes, France
*Corresponding author. Tel: +33-3-88-12-76-88; Fax: +33-3-88-12-76-81; E-mail: [email protected]
Received 7 March 2012; returned 24 March 2012; revised 23 May 2012; accepted 16 June 2012
Objectives: Invasive fungal disease (IFD) remains a major concern in patients with haematological conditions.
We describe diagnoses, therapeutic management and outcomes in unselected consecutive patients from
haematological facilities treated for suspected or documented IFD.
Methods: In this observational prospective study, children/adults with haematological conditions or haematopoietic stem cell transplantation (HSCT) were recruited upon start of non-prophylactic systemic antifungal
treatment in 37 French haematological facilities (December 2007 to December 2008). IFD episodes were classified according to the 2008 EORTC/MSG criteria.
Results: The cohort included 419 patients (298 adults and 121 children): 88% haematological malignancies,
28% HSCT recipients and 68% neutropenic. Patients had 423 IFD episodes: 21% mycologically documented
(59% probable/proven aspergillosis, 32% proven candidiasis and 9% probable/proven other IFD) and 20% classified as possible IFD. The remaining cases were assigned to two groups: febrile neutropenia (34%) and unclassified (25%), 9% of which were classified as possible/probable/proven IFD by day 7. Treatment was thus
initiated early in 59% of patients; liposomal amphotericin B and caspofungin were the most common
single-agent therapies. The 12 week mortality was 18% for probable/proven aspergillosis, 15% for proven candidiasis, 10% for probable/proven other IFD, 9% for possible IFD, 3% for febrile neutropenia and 12% for unclassified episodes (log rank P ¼0.016); it was dependent on age, complete remission of underlying
haematological disease and mechanical ventilation.
Conclusions: In this comprehensive sample of haematological patients receiving antifungal treatment, we
observe a widespread resort to early therapy and a low mortality rate, including in patients with probable or
proven IFD.
Keywords: invasive fungal disease, haematology, haematopoietic stem cell transplantation, mortality, invasive aspergillosis, invasive
candidiasis
Introduction
Invasive fungal disease (IFD) remains a major concern in patients
with haematological conditions, especially in those with
chemotherapy-induced neutropenia or in recipients of haematopoietic stem cell transplantation (HSCT). Several recent changes
were observed in the epidemiology of IFD,1 – 4 and outcomes
have improved in haematological patients.5 – 7 These changes
# The Author 2012. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
For Permissions, please e-mail: [email protected]
2731
Herbrecht et al.
may be due to an evolution in the management of underlying
conditions or to the availability of a widened antifungal
arsenal, but also to a shift in practice towards early antifungal
therapy.8 – 11 Although a lot of work has been devoted to IFD in
the last 20 years, many studies have focussed on selected highrisk patients or on specific fungal agents. The purpose of this
work was to describe diagnoses, therapeutic management and
outcomes in unselected consecutive patients from haematological facilities treated for suspected or documented IFD.
Patients and methods
This was an observational prospective study. French haematological
centres, including all those performing one or more HSCT per month,
were offered participation. Patients were children or adults with haematological conditions or HSCT therapy. They were recruited upon start of nonprophylactic systemic antifungal treatment and followed-up thereafter for
12 weeks. No other selection criterion was applied. Written informed
consent was obtained from all patients or their parents. Assent was
given by children old enough to understand. In accordance with French
law, Ethics Committee approval was not required as the protocol was
strictly observational and usual practice was unchanged; approvals from
the national review boards Comité consultatif sur le traitement de l’information en matière de recherche dans le domaine de la santé and Commission nationale de l’informatique et des libertés were obtained.
Medical histories, haematological conditions and recent or ongoing
treatments were collected at inclusion. Clinical signs, imaging and microbiological results and antifungal treatments were recorded retrospectively at inclusion and prospectively throughout the follow-up. Clinical
evolution was recorded 6 and 12 weeks after inclusion. Cause of death
was judged by the investigators. All data were recorded through a
secure online case-report form. Independent monitoring was provided
by a contract research organization during the whole study period.
Study documents and data collection were designed with pre-coded
answers matching the IFD criteria definitions published in 2002 by the
European Organization for Research and Treatment of Cancer/Invasive
Fungal Infections Cooperative Group and the National Institute of
Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) consensus group, and also the revised criteria published in 2008 but made
available before publication to allow public comment.12 – 14
IFD episodes were subsequently classified by an expert committee
according to the 2008 criteria13 upon initiation of treatment (day 0)
and 1 week later (day 7). All diagnostic procedures performed up to
the given day were taken into account, regardless of the availability of
their results at that date. The decision to limit this evaluation to the
first 7 days was motivated by a desire to avoid confusion between the
original episode and a subsequent IFD episode.
Episodes insufficiently documented to be classified as possible, probable or proven IFD were labelled febrile neutropenia where persistent
fever and neutrophil count below 0.5×109 cells/L were the only
grounds for suspecting an IFD, or unclassified episodes if these criteria
were not satisfied (e.g. no severe neutropenia) or if other signs were
reported but did not meet the criteria for possible IFD.
Mortality rates were determined using Kaplan–Meier estimates, and
groups were compared using the log rank test. A Cox regression multivariate analysis was performed to identify prognostic factors for death in this
population among the following selected variables: sex, age, mechanical
ventilation, aspergillosis/mould infection, candidiasis/yeast infection,
amphotericin B at day 0, combination therapy at day 0, azole agents at
day 0, caspofungin at day 0, neutropenia (,0.5×109 cells/L), low creatinine
clearance (,50 mL/min), malignancy status, antifungal prophylaxis, allogeneic HSCT, autologous HSCT and possible IFD at day 7. All analyses
were carried out using SAS 9.2 (SAS Institute Inc., Cary, NC, USA).
2732
Results
Patients
Of the 81 French haematological facilities invited to participate,
41 accepted, of which 37 included 419 patients (298 adults
and 121 children) between December 2007 and December
2008. Two of these patients experienced two IFD episodes
during the study period, and one experienced three episodes.
Thus 423 episodes are described.
The characteristics of the patients are summarized in Table 1.
Most patients (88%) were treated for haematological malignancies, and 40 (10%) and 74 (18%) were recipients of autologous
or allogeneic HSCT, respectively. Neutropenia (,0.5×109 cells/L)
was present at day 0 in 284 patients (68%), and had lasted
.10 days in 222 patients (53%). Overall, 184 patients (44%)
were receiving antifungal prophylaxis at the time of the
episode, reported as fluconazole (148/261 treatments, 57%),
posaconazole (49/261, 19%), amphotericin B (32/261, 12%),
voriconazole (13/261, 5%), itraconazole (12/261, 5%) or caspofungin (4/261, 2%). Prophylactic treatment was administered
either orally or intravenously, in approximately equal amounts.
Antifungal prophylaxis was used in 27 of the 48 proven infections
(56%) as follows: fluconazole in 16 cases, amphotericin B in 5
cases, voriconazole in 3 cases and posaconazole in 3 cases.
IFD diagnoses
IFD diagnoses are shown in Table 2, while species identified in
proven infections are detailed in Table 3. Proven and probable
aspergilloses were the most common IFD classifications, representing 12.5% of the episodes (53/423) at day 0. Invasive candidiasis accounted for 7% of the episodes (29/423), while 59%
of mycologically documented episodes (53/90) were invasive aspergillosis, diagnosed in most cases by detection of galactomannan antigen in serum or bronchoalveolar lavage fluid, and 32%
(29/90) were invasive candidiasis. All Candida infections were
proven by isolation of Candida species from blood cultures in
28 cases, from biopsy material in 4 cases and from peritoneal
fluid in the remaining 3 cases. Fifty-nine percent of episodes
(249/423) did not meet EORTC/MSG criteria for possible, probable
or proven IFD. This rate was as high as 77% (93/121) in children
at day 0.
Antifungal therapy
Initial and day 7 antifungal therapy received by patients is
detailed in Table 4. Combination therapy was given for 61
(14%) episodes at day 0, mostly in patients with febrile neutropenia, unclassified episodes or possible IFD. This high number
of combination therapies may be explained in part by continuation of antifungal prophylaxis after day 0 in 40 patients. In
nine patients, this prophylaxis was still ongoing at day 7. Antifungal therapy was changed before day 7 in 159 patients (38%).
Over the 12 week follow-up, it was changed once or more in
49% of patients. Treatment change was more frequent in
patients with probable or proven aspergillosis (median, two
changes per patient) compared with patients with possible IFD,
proven candidiasis or probable/proven other IFD (one change
per patient); there were no changes in the remaining patients.
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Invasive fungal disease in haematology
Table 1. Characteristics of patients (n¼419)
Children (n¼121)
Adults (n¼298)
Gender (male)
55 (45)
Age (years), median (range)
7.1 (0.1 –17.9)
Underlying condition
acute lymphoblastic leukaemia
acute myeloid leukaemia
acute biphenotypic leukaemia
acute undifferentiated leukaemia
myelodysplastic syndrome
lymphoproliferative syndrome
chronic myeloproliferative syndrome
solid tumour
aplastic anaemia
inherited bone marrow dysfunction
inherited immunodeficiency
other immunodeficiency
other
38 (31)
35 (29)
2 (2)
0
2 (2)
13 (11)
0
7 (6)
8 (7)
2 (2)
7 (6)
5 (4)
2 (2)
35 (12)
156 (52)
2 (1)
1 (0.3)
15 (5)
54 (18)
31 (10)
0
4 (1)
0
0
0
0
73 (17)
191 (46)
4 (1)
1 (0.2)
17 (4)
67 (16)
31 (7)
7 (2)
12 (3)
2 (1)
7 (2)
5 (1)
2 (1)
HSCT
autologous
allogeneic
6 (5)
28 (23)
34 (11)
46 (15)
40 (10)
74 (18)
3 (11)
0
1 (4)
9 (20)
1 (2)
8 (17)
12 (16)
1 (1)
9 (12)
Malignancy status (if applicable and available, n¼370)
complete remission
partial remission
stable
progression
51 (46)
11 (10)
37 (33)
12 (11)
97 (38)
46 (18)
35 (14)
81 (31)
148 (40)
57 (15)
72 (20)
93 (25)
Neutropenia (,0.5×109 cells/L for more than 10 days) (available n ¼ 416)
74 (61)
148 (50)
222 (53)
Prolonged use of corticosteroids (.3 weeks) (available n ¼ 416)
21 (17)
37 (13)
58 (14)
Treatment with T cell immunosuppressants (available n ¼ 416)
25 (21)
67 (23)
92 (22)
Central venous line (available n ¼ 388)
103 (92)
248 (90)
351 (91)
Parenteral feeding (available n ¼ 382)
55 (50)
107 (40)
162 (42)
9 (8)
13 (5)
22 (6)
Graft versus host diseasea
acute, grade I-II
acute, grade III-IV
chronic
Mechanical ventilation (available n ¼ 375)
180 (60)
All (n ¼419)
56 (18 –85)
235 (56)
47 (0.1 –85)
Data are n (%) unless otherwise specified.
Percentages among recipients of allogeneic HSCTs.
a
Overall, median treatment duration was 29 days: 15 days for
patients with febrile neutropenia, 23 days for unclassified episodes, 68 days for possible IFD, 32 days for proven candidiasis,
and .12 weeks for probable or proven aspergillosis.
Mortality
Before week 12, 41 patients died. Of these, 12 (29%; 9 before
week 6) were considered related to IFD by investigators. Most
of the other deaths were related to the underlying haematological condition and/or to bacterial infections. The 12 week mortality rate was 3% for febrile neutropenia, 12% for unclassified
episodes, 9% for possible IFD, 18% for probable/proven aspergillosis, 15% for proven candidiasis and 10% for probable/proven
other IFD (log rank P ¼ 0.016, Figure 1). Out of 10 patients with
other IFD, 1 with a proven Rhodotorula mucilaginosa infection
died at week 10 from his underlying condition.
Multivariate analysis for risk factors associated with a higher
mortality in the overall population showed that older age
[hazard ratio (HR) 1.4/10 years; 95% CI 1.2– 1.7; P,0.001],
absence of underlying malignancy remission at antifungal
therapy onset (HR 5.3; 95% CI 1.6–17.5; P ¼ 0.007) and mechanical ventilation at antifungal therapy onset (HR 2.8; 95% CI 1.1 –
7.1; P¼ 0.037) were significant determinants of mortality.
2733
Herbrecht et al.
Table 2. IFD diagnosis at day 0 and day 7 of antifungal treatment (EORTC/MSG 2008 definitions, n ¼423 episodes in 419 patients)
Day 0 \ day 7
Febrile
neutropenia
Febrile
neutropenia
Unclassified
episode
Possible IFD
Probable
aspergillosis
Proven
aspergillosis
Proven candidiasis
Probable/proven
other IFDa
All (day 7)
Unclassified
episode
Possible
IFD
Probable
aspergillosis
Proven
aspergillosis
Proven
candidiasis
Probable/
proven
other IFDa
All (day 0)
119
8
8
5
0
2
0
142 (34)
0
97
5
3
0
1
1
107 (25)
0
0
0
0
68
0
12
49
0
3
3
0
1
0
84 (20)
52 (12)
0
0
0
0
1
0
0
1 (0.2)
0
0
0
0
0
0
0
0
0
0
29
0
0
8
4 (1)
35 (8)
119 (28)
105 (25)
81 (19)
69 (16)
10 (2)
29 (7)
8 (2)
423 (100)
Data are n (%) of episodes.
One patient had both a proven other IFD and a probable aspergillosis and has been classified in the group ‘Probable/proven other IFD’ for all
analyses.
a
Table 3. Species identified by day 7 of antifungal treatment (n ¼48
patients with proven IFD)
Species
Yeasts
Candida albicans
Candida glabrata
Candida krusei
Candida parapsilosis
Candida kefyr
Candida guilliermondii
Candida lambica
Candida tropicalis
Candida spp.
Candida albicans and Candida glabrata
Candida albicans and Candida parapsilosis
Candida albicans, Candida glabrata and Candida zeylanoides
Rhodotorula mucilaginosa
unidentified yeasta
Moulds
Aspergillus fumigatus
Aspergillus flavus
Fusarium solani
Fusarium spp.
Mucor spp.
unidentified moulda
n (%)
14 (29)
5 (10)
4 (8)
3 (6)
2 (4)
1 (2)
1 (2)
1 (2)
1 (2)
1 (2)
1 (2)
1 (2)
1 (2)
2 (4)
3 (6)
1 (2)
1 (2)
2 (4)
2 (4)
1 (2)
a
Diagnosis by microscopy on biopsy material, no culture growth.
Discussion
This work provides a comprehensive picture of patients treated
for a suspected or documented IFD with their treatments and
2734
outcomes, in a large number of haematological facilities,
across the whole French territory.
Only 47% of these episodes met the criteria for possible, probable or proven IFD according to EORTC/MSG criteria by day 7 of
antifungal treatment. More than half of the other episodes
could be classified as febrile neutropenia since they had persistent fever, neutrophil count ,0.5×109 cells/L and no other clinical
or mycological sign of IFD, matching this well-defined condition
in haematological patients. Although many haematology
departments have developed various preemptive strategies, it
is still widely accepted that these patients should receive empirical antifungal treatment after failure of broad-spectrum antibiotherapy.15 Several clinical trials have been conducted to
assess such empirical antifungal therapies and have led to the
approval of liposomal amphotericin B and caspofungin for this
indication.11,16
Overall, 25% of episodes remained unclassified, either
because they lacked a host-specific criterion or because they presented with non-specific clinical or radiological signs, thus not
satisfying EORTC/MSG criteria. This work shows that, in practice,
patients who do not fit into any of the classical categories
make up a significant proportion of patients who receive antifungal therapy, indicating that in the physicians’ opinion there is
some ground to suspect an IFD. Whether such an approach
should be considered as an empirical therapy similarly to the
treatment of a febrile neutropenia, or as a pre-emptive therapy
similarly to the treatment of a possible IFD, remains debatable.
In our study, most of the patients treated for an unclassified
episode received liposomal amphotericin B or caspofungin, in
proportions similar to those for the group of patients with
febrile neutropenia.
The IFD criteria revised in 2008 by the EORTC/MSG consensus
group are more stringent than the criteria published in 2002,12 – 14
excluding from the possible IFD group cases with minor or nonspecific clinical signs such as cough, dyspnoea and pleural rub.
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Invasive fungal disease in haematology
Table 4. Antifungal treatments at day 0 and 7 of treatment, according to IFD diagnosis (n ¼423 episodes in 419 patients)
Day 0
Day 7
age ,18 years (n¼121)
age ≥18 years (n¼302)a
age ,18 years (n¼121)
age ≥18 years (n ¼300)a,b
Febrile neutropenia
N
amphotericin B deoxycholate
liposomal amphotericin B
fluconazole
voriconazole
posaconazole
caspofungin
combinationc
no antifungal treatment
63
3 (5)
38 (60)
0
2 (3)
0
17 (27)
3 (5)
0
79
2 (3)
16 (20)
8 (10)
4 (5)
0
28 (35)
21 (27)
0
57
0
27 (47)
0
1 (2)
1 (2)
15 (26)
1 (2)
12 (21)
62
0
13 (21)
5 (8)
7 (11)
2 (3)
21 (34)
8 (13)
6 (10)
Unclassified episode
N
amphotericin B deoxycholate
liposomal amphotericin B
fluconazole
voriconazole
posaconazole
itraconazole
caspofungin
combinationc
investigational drug
no antifungal treatment
30
2 (7)
21 (70)
2 (7)
0
0
0
5 (17)
0
0
0
77
1 (1)
12 (16)
9 (12)
14 (18)
2 (3)
1 (1)
25 (32)
13 (17)
0
0
27
1 (4)
14 (52)
0
0
0
0
5 (19)
3 (11)
0
4 (15)
77
0
9 (12)
8 (10)
14 (18)
2 (3)
0
21 (27)
9 (12)
1 (1)
13 (17)
Possible IFD
N
liposomal amphotericin B
fluconazole
voriconazole
posaconazole
caspofungin
combinationc
investigational drug
no antifungal treatment
17
7 (41)
1 (6)
3 (18)
0
4 (24)
2 (12)
0
0
67
7 (10)
3 (4)
33 (49)
3 (4)
13 (19)
7 (10)
1 (1)
0
17
6 (35)
0
3 (18)
0
1 (6)
6 (35)
0
1 (6)
64
9 (14)
0
24 (38)
1 (2)
15 (23)
5 (8)
6 (9)
4 (6)
Probable/proven aspergillosis
N
liposomal amphotericin B
voriconazole
posaconazole
caspofungin
combinationc
investigational drug
no antifungal treatment
5
2 (40)
1 (20)
0
1 (20)
0
1 (20)
0
48
5 (10)
24 (50)
1 (2)
6 (13)
8 (17)
4 (8)
0
10
4 (40)
0
0
2 (20)
3 (30)
1 (10)
0
62
7 (11)
24 (39)
2 (3)
7 (11)
12 (19)
9 (14)
1 (2)d
Proven candidiasis
N
liposomal amphotericin B
fluconazole
voriconazole
caspofungin
combinationc
investigational drug
5
1 (20)
0
0
4 (80)
0
0
24
3 (13)
1 (4)
0
13 (54)
5 (21)
2 (8)
9
3 (33)
1 (11)
0
3 (33)
2 (22)
0
26
1 (4)
3 (11)
1 (4)
9 (35)
6 (23)
6 (23)
Continued
2735
Herbrecht et al.
Table 4. Continued
Day 0
Day 7
age ,18 years (n¼121)
age ≥18 years (n¼302)a
age ,18 years (n¼121)
age ≥18 years (n ¼300)a,b
1
0
0
0
0
1 (100)
0
7
2 (29)
0
2 (29)
1 (14)
1 (14)
1 (14)
1
0
0
0
0
1 (100)
0
9
1 (11)
1 (11)
2 (22)
0
4 (44)
1 (11)
Probable/proven other IFDa
N
liposomal amphotericin B
fluconazole
voriconazole
caspofungin
combinationc
investigational drug
Data are n (%).
One patient had both a proven other IFD and a probable aspergillosis and has been classified in the group ‘Proven/probable other IFD’ for all analyses.
b
Two patients died before day 7: one with an unclassified episode, the other with probable aspergillosis.
c
Combined treatments include 40 cases where antifungal prophylaxis was not immediately stopped upon introduction of a non-prophylactic treatment. In nine of these cases, prophylaxis was continued after day 7.
d
All but palliative treatment had been stopped for this patient, who died shortly after day 7.
a
0.4
Febrile neutropenia
Unclassified episode
Possible IFD
Cumulative mortality rate
0.3
Probable/proven aspergillosis
Proven candidiasis
Probable/proven other IFD
0.2
0.1
0.0
0
14
28
42
56
Follow-up time (days)
70
84
Figure 1. Cumulative mortality rate 12 weeks after initiation of a non-prophylactic antifungal therapy according to classification at day 7 (n¼419
patients, 4708 patient-weeks). Log rank, P¼0.016.
Also excluded from the possible IFD group were cases with a
positive mycology but no clinical or radiological sign, which
more likely reflect a false positive serological test or colonization
than a fungal disease. Over half of our unclassified episodes
would have been accepted as possible IFD or probable aspergillosis by the 2002 criteria. The main reason for disqualification
from the 2008 criteria was deletion of the items ‘persistent
fever for .96 h refractory to appropriate broad-spectrum antibacterial treatment in high-risk patients’ and ‘recent or current
use of significant immunosuppressive agents in previous 30
days’. In addition, a significant number of episodes did not
2736
qualify for the 2008 criteria as the lower respiratory tract signs
were not adequately documented by a CT scan.
While the appropriateness of the updated 2008 criteria is
recognized for patient inclusion in clinical trials, these criteria
were never intended for guiding initiation (or not) of antifungal
therapy in clinical practice.13 It is therefore not surprising that
clinicians started antifungal therapy in a significant set of
patients not fulfilling the definitions of possible, probable or
proven IFD.
Interestingly, 9% (10/107) of the episodes that were unclassified at day 0 were documented as possible, probable or proven
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Invasive fungal disease in haematology
IFD by day 7. Nine additional episodes, still unclassified at day 7,
were documented as probable or proven IFD beyond day 7. Additionally, the 12 week mortality rate in those who remained unclassified at day 7 was very close to that observed in patients
with possible IFD. The heterogeneity of this group shows, nevertheless, that in some patients, mycological confirmation of an
IFD came after day 7, while in others antifungal therapy was discontinued early, indicating that suspicion seemed no longer
justified.
Although providing interesting information on patients receiving antifungals in haematology wards, our study has some limitations, mainly due to its design. We collected data only on
patients who, at inclusion, were receiving antifungals. Therefore,
we cannot provide reliable incidence rates of IFD in the whole
population of the participating wards. Additionally, inclusions
may not have been consecutive, as some investigators may
have hesitated to include the less founded suspicions, resulting
in an underestimated rate of early treatment. This may partly
explain the fairly high relative frequency of proven or probable
IFD (21%) compared with other series. Conversely, they may
have been reluctant to request consent from a dying patient
and include the most serious cases.
The same design issues may account for the low mortality
rate observed in this study. More than 80% of patients with probable or proven invasive aspergillosis were alive at week 12. This
result seems in line with the decrease in IFD mortality observed
over the last 10 years,7,17 – 19 although caution should be exerted
in comparing studies performed in overlapping but not strictly
similar patient populations. The low number of deaths observed
in this work did not allow for a conclusive analysis of mortality
risk factors for each subgroup. However, mortality in the whole
patient population was, as shown in other studies, dependent
on age and complete remission of the underlying haematological disease.20 – 23
Overall, in this comprehensive sample of haematological
patients receiving antifungal treatment, we observe a widespread resort to early therapy, as already noted in a recent
report,7 and a low mortality rate, including in patients with probable or proven IFD.
Acknowledgements
Preliminary findings were presented at the European Hematology
Association (EHA) Congress 2010 (poster P254) and the Interscience
Conference on Antimicrobial Agents and Chemotherapy (ICAAC) 2010
(poster 1547).
We would like to thank the investigators: Rosa Adaeva, Paris; André
Baruchel, Paris; Lotfi Benboubker, Tours; Stephane Blanche, Paris; Pascale
Blouin, Tours; Giovanna Cannas, Lyon; Jean-Hugues Dalle, Paris; Stéphane
De Botton, Villejuif; François Demeocq, Clermont Ferrand; Evelyne
D’Incan-Corda, Marseille; Daniel Espinouse, Pierre Bénite; Marie-Pierre
Gourin-Chaury, Limoges; Gaëlle Guillerm, Brest; Norbert Ifrah, Angers;
Maud Janvier, Saint Cloud; Stéphane Lepretre, Rouen; Aude
Marie-Cardine, Rouen; Jean Michon, Paris; Noel Milpied, Pessac; Cécile
Molucon, Clermont Ferrand; Mario Ojeda-Uribe, Mulhouse; Sylvie Parer,
Montpellier; Jean-Michel Pignon, Dunkerque; Isabelle Plantier-Colcher,
Roubaix; Oumédaly Reman, Caen; David Sibon, Paris; Marc Simon,
Valenciennes; Anne Sirvent, Nice; Dominique Valteau-Couanet, Villejuif;
Anne Vekhoff, Paris; Brigitte Witz, Vandoeuvre Les Nancy; and Ibrahim
Yakoub-Agha, Lille. We thank mycologists from participating centres and
ClinSearch for their contribution to the monitoring and the data collection.
Funding
This work was supported by an unrestricted grant from MSD France,
which was not otherwise involved in the work.
Transparency declarations
R. H. has been a consultant to Astellas, Gilead, MSD, Pfizer and
Schering-Plough. D. C. has been a consultant to Pfizer, MSD and
Schering-Plough. C. C. has received grants and research support from
Gilead, MSD, Pfizer and Schering-Plough, and has been a consultant to
Gilead, Pfizer, Schering-Plough and Zeneus Pharma. A. T. has been a consultant to MSD, Schering-Plough, Gilead and Pfizer. J.-P. G. has received
research support from and has been a consultant to Astellas, Gilead,
MSD and Pfizer. A. A., B. B., M. M., N. M., Y. B., P. P., F. R. and N.-C. G.: no
potential conflicts of interest.
References
1 Marr KA, Carter RA, Crippa F et al. Epidemiology and outcome of mould
infections in hematopoietic stem cell transplant recipients. Clin Infect Dis
2002; 34: 909–17.
2 Richardson MD. Changing patterns and trends in systemic fungal
infections. J Antimicrob Chemother 2005; 56 Suppl 1: i5– 11.
3 Sandven P, Bevanger L, Digranes A et al. Candidemia in Norway (1991
to 2003): results from a nationwide study. J Clin Microbiol 2006; 44:
1977– 81.
4 Lortholary O, Gangneux JP, Sitbon K et al. Epidemiological trends in
invasive aspergillosis in France: the SAIF network (2005–2007). Clin
Microbiol Infect 2011; 17: 1882 –9.
5 Upton A, Kirby KA, Carpenter P et al. Invasive aspergillosis following
hematopoietic cell transplantation: outcomes and prognostic factors
associated with mortality. Clin Infect Dis 2007; 44: 531– 40.
6 Pagano L, Caira M, Candoni A et al. The epidemiology of fungal
infections in patients with hematologic malignancies: the SEIFEM-2004
study. Haematologica 2006; 91: 1068 –75.
7 Pagano L, Caira M, Candoni A et al. Invasive aspergillosis in patients with
acute myeloid leukemia: a SEIFEM-2008 registry study. Haematologica
2010; 95: 644–50.
8 Pappas PG, Kauffman CA, Andes D et al. Clinical practice guidelines for
the management of candidiasis: 2009 update by the Infectious Diseases
Society of America. Clin Infect Dis 2009; 48: 503–35.
9 Walsh TJ, Anaissie EJ, Denning DW et al. Treatment of aspergillosis:
clinical practice guidelines of the Infectious Diseases Society of
America. Clin Infect Dis 2008; 46: 327–60.
10 Morrell M, Fraser VJ, Kollef MH. Delaying the empiric treatment of
Candida bloodstream infection until positive blood culture results are
obtained: a potential risk factor for hospital mortality. Antimicrob
Agents Chemother 2005; 49: 3640 –5.
11 Cordonnier C, Pautas C, Maury S et al. Empirical versus preemptive
antifungal therapy for high-risk, febrile, neutropenic patients: a
randomized, controlled trial. Clin Infect Dis 2009; 48: 1042 –51.
12 Ascioglu S, Rex JH, de Pauw B et al. Defining opportunistic invasive
fungal infections in immunocompromised patients with cancer and
hematopoietic stem cell transplants: an international consensus. Clin
Infect Dis 2002; 34: 7 –14.
2737
Herbrecht et al.
13 De Pauw B, Walsh TJ, Donnelly JP et al. Revised definitions of invasive
fungal disease from the European Organization for Research and
Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the
National Institute of Allergy and Infectious Diseases Mycoses Study Group
(EORTC/MSG) Consensus Group. Clin Infect Dis 2008; 46: 1813–21.
fungal infections in France during 1998 –1999. J Antimicrob Chemother
2004; 54: 456–64.
14 de Pauw BE, Patterson TF. Should the consensus guidelines’ specific
criteria for the diagnosis of invasive fungal infection be changed?. Clin
Infect Dis 2005; 41 Suppl 6: S377–80.
20 Cornely OA, Maertens J, Bresnik M et al. Liposomal amphotericin B as
initial therapy for invasive mold infection: a randomized trial comparing a
high-loading dose regimen with standard dosing (AmBiLoad trial). Clin
Infect Dis 2007; 44: 1289 –97.
15 Marchetti O, Cordonnier C, Calandra T. Empirical antifungal therapy
in neutropaenic cancer patients with persistent fever. Eur J Cancer
Supplements 2007; 5: 32 –42.
16 Goldberg E, Gafter-Gvili A, Robenshtok E et al. Empirical antifungal
therapy for patients with neutropenia and persistent fever: systematic
review and meta-analysis. Eur J Cancer 2008; 44: 2192 –203.
17 Barnes PD, Marr KA. Risks, diagnosis and outcomes of invasive
fungal infections in haematopoietic stem cell transplant recipients. Br J
Haematol 2007; 139: 519–31.
18 Lortholary O, Charlemagne A, Bastides F et al. A multicentre
pharmacoepidemiological study of therapeutic practices in invasive
2738
19 Marr KA, Carter RA, Boeckh M et al. Invasive aspergillosis in allogeneic
stem cell transplant recipients: changes in epidemiology and risk factors.
Blood 2002; 100: 4358– 66.
21 Cornely OA, Maertens J, Bresnik M et al. Efficacy outcomes in a
randomised trial of liposomal amphotericin B based on revised EORTC/
MSG 2008 definitions of invasive mould disease. Mycoses 2011; 54:
e449–55.
22 Nivoix Y, Velten M, Letscher-Bru V et al. Factors associated with overall
and attributable mortality in invasive aspergillosis. Clin Infect Dis 2008;
47: 1176– 84.
23 Zaoutis TE, Prasad PA, Localio AR et al. Risk factors and predictors for
candidemia in pediatric intensive care unit patients: implications for
prevention. Clin Infect Dis 2010; 51: e38– 45.