Antifungal prophylaxis of patients undergoing allogenetic hematopoietic stem cell transplantation in China: a multicenter prospective observational study
Gao et al. Journal of Hematology & Oncology
Antifungal prophylaxis of patients undergoing allogenetic hematopoietic stem cell transplantation in China: a multicenter prospective observational study
Lei Gao 0 4
Yuqian Sun 2 4
Fanyi Meng 1 4
Mingzhe Han 3 4
He Huang 4 7
Depei Wu 4 6
Li Yu 4 5
Hanyun Ren 4 8
Xiaojun Huang 2 4
Xi Zhang 0 4
0 Xinqiao Hospital, Third Military Medical University , Chongqing 400037 , China
1 Nanfang Hospital, Nanfang Medical University , Guangzhou , China
2 Peking University Institute of Hematology, Peking University People's Hospital, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation , Beijing 100044 , China
3 Institute of Hematology and Blood Diseases Hospital
4 Chinese Academy of Medical Sciences , Tianjin , China
5 Chinese PLA General Hospital (301 Hospital) , Beijing , China
6 The First Affiliated Hospital of Soochow University , Suzhou , China
7 The First Affiliated Hospital of Medical School of Zhejiang University , Hangzhou , China
8 The First Hospital of Peking University , Beijing , China
Background: Antifungal prophylaxis is currently regarded as the gold standard in situations with allo-genetic hematopoietic stem cell transplantation (allo-HSCT). However, the epidemiological information regarding prophylaxis of invasive fungal diseases (IFDs) is not clear in China. Methods: We report the first large-scale (1053 patients) observational study of the prophylaxis and management of IFDs among patients with allo-HSCT in China. Results: The incidence rates of IFD after primary antifungal prophylaxis (PAP), secondary antifungal prophylaxis (SAP), and non-prophylaxis were 22.7 vs. 38.6 vs. 68.6 %, respectively (P = 0.0000). The median time from transplantation to IFD was 45 days in PAP patients, 18 days in SAP patients, and 12 days in non-prophylaxis patients. Aspergillus spp. represents the most common type of fungal infection. Independent risk factors for IFD in allo-HSCT patients with PAP were age, having human leukocyte antigen (HLA)-haploidentical or matched unrelated donor, decreased albumin levels, and the use of itraconazole as the prophylactic antifungal agent. Among SAP transplant recipients, there was no significant risk factor for IFDs. The incidence rates of overall survival (OS) in the PAP, SAP, and no prophylaxis groups were 85.07, 78.80, and 74.82, respectively (P = 0.01). Conclusions: This observational study indicates that prophylaxis of IFD is helpful to reduce the incidence of IFDs and improve the OS of patients after allo-HSCT.
Invasive fungal diseases; Allogenetic; Stem cell; Transplantation; Prophylaxis; China
Although the control of bacterial infections in patients
with hematological malignancies has been significantly
improved with broad-spectrum antibiotics in the past
decades, treating invasive fungal diseases (IFDs) is still a
major problem in these patients, especially in patients
undergoing allogenetic hematopoietic stem cell
transplantation (allo-HSCT) [1–3]. Epidemiological data from
the USA, China, and parts of Europe have shown that
the incidence of IFDs in patients after allo-HSCT has
increased dramatically in the past several years,
substantially increasing the morbidity and mortality rates [4–9].
The diagnosis and treatment guidelines for IFDs,
including some that are specific to HSCT patients, have
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been developed by academic societies in different world
regions [10–12]. Notwithstanding the guidance and new
forms of antifungal agents, treatment is often delayed
because of nonspecific disease presentation and a lack of
reliable diagnostic techniques, leading to poor clinical
outcomes. Prophylaxis of IFDs is currently regarded as
the gold standard in situations with allo-HSCT. Over the
years, different scientific societies have established a series
of recommendations for antifungal prophylaxis based on
prospective studies performed with different drugs [13–17].
However, until recently, data on the prophylaxis of
IFDs and real-world management of IFDs in patients
with allo-HSCT have been gleaned primarily from
single-center and retrospective studies in China. Here,
we report the first large-scale observational study of the
prophylaxis and management of IFDs among adults and
children who have undergone allo-HSCT in China. Data
came from the China Assessment of Antifungal Therapy
in Hematological Disease (CAESAR) study.
The CAESAR study was a multicenter, prospective,
observational study performed in 35 hematology centers across
China, including two children’s hospitals. Subjects were
consecutive patients of any age with a hematological
malignancy who were hospitalized during the study period
either after allogeneic or autologous HSCT or to receive
intravenous chemotherapy. The overall study methods
have been described previously [7, 18]. This observational
study was conducted as a part of the CAESAR study and
focused on the prophylaxis of IFDs in 1053 patients who
underwent allo-HSCT in 31 HSCT centers.
All patients in each study center who were
hospitalized and had undergone allo-HSCT between January 1,
2011 and October 30, 2011 were enrolled in this study.
Data were collected by chart reviews and included the
following parameters: demographic characteristics,
antecedent hematologic disease, type of HSCT, conditioning
regimen, IFD risk factors, clinical features suggestive of
IFD, laboratory findings such as imaging, histopathology,
and fungal cultures, treatment outcome of IFD, and
mortality. Each IFD was categorized as proven, probable,
or possible, according to 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) 2008 criteria . Patients were
diagnosed as having suspected IFD if they had IFD risk
factors; were observed to have symptoms, radiological
abnormalities, or indirect microbiological evidence of
fungal infection; and were treated empirically with
antifungal agents but could not be diagnosed with proven,
probable, or possible IFD according to the EORTC/MSG
2008 criteria . Patients were followed for 6 months
after the date of transplantation; the follow-up was
completed on April 30, 2012. In all, 18 patients were lost to
In accordance with common practice and to maximize
diagnostic accuracy, the incidence of IFD was mainly
calculated based on proven and probable cases
combined. The cumulative incidence was calculated as the
incidence of proven plus probable IFD for the first
187 days after transplantation, divided by the number of
cases at risk. Data were grouped according to primary
antifungal prophylaxis (PAP) or secondary antifungal
prophylaxis (SAP). PAP refers to patients without a
history of fungal infection and need to be protected to
avoid fungal infection after HSCT . SAP is a rational
strategy for patients with proven or probable IFD within
6 months before transplantation . In particular, all
allo-HSCT patients (n = 1045) in the CAESAR study
were included in the analysis of overall survival (OS) for
comparison of the OS differences in the PAP, SAP, and no
prophylaxis groups. The characteristics of all of the
alloHSCT patients were described in the CAESAR study .
Statistics were primarily descriptive and were
compared using analysis of variance, the Wilcoxon rank-sum
test, or the chi-squared test, as appropriate. Risk factors
for IFD were analyzed using univariate analysis followed
by multivariate logistic regression. Kaplan-Meier analysis
and the log-rank test were used to compare OS between
different groups of patients. A two-sided P value of less
than 0.05 was denoted as statistically significant. All
statistical analyses were performed with SAS software
version 9.1 (SAS, Cary, NC, USA).
Patient characteristics and antifungal prophylaxis
A total of 1053 patients who underwent allo-HSCT were
enrolled from 31 HSCT centers across China. Their
baseline demographic and clinical characteristics at the
time of admission for transplantation are shown in
Table 1. Among them, 906 patients received prophylactic
antifungal treatment before or after transplantation.
Previous IFDs were noted in 88 patients (8.4 %, 88/1053),
including 7 with proven IFDs and 81 with probable IFDs.
The average duration of antifungal prophylaxis before
HSCT was 10.9 ± 6.56 days (10.8 ± 6.57 days in the PAP
group and 12.0 ± 6.43 days in the SAP group). Single
antifungal agents were the most common prophylaxis
regimen (667/818 in the PAP group and 69/88 in the SAP
group). Fluconazole (429/818, 64.9 %) and voriconazole
(32/88, 46.4 %) were the most widely used agents for
PAP and SAP, respectively (Table 1). All antifungal
Table 1 Patient characteristics and antifungal prophylaxis regimen
Characteristic PAP (N = 818)
Age, mean (range/%)/case 28.5 (1–63)
0–6 33 (4 %)
>6–16 129 (15.8 %)
>16–40 488 (59.7 %)
>40–65 168 (20.5 %)
Male 505 (61.7 %)
Female 313 (38.3 %)
0 227 (27.8 %)
1 438 (53.5 %)
2 89 (10.9 %)
3 51 (6.2 %)
4 13 (1.6 %)
Acute myeloid leukemia 289 (35.3 %)
Acute lymphocytic leukemia 241 (29.5 %)
Chronic myeloid leukemia 100 (12.2 %)
Aplastic anemia 69 (8.4 %)
Myelodysplastic syndrome 62 (7.6 %)
Non-Hodgkin’s lymphoma 23 (2.8 %)
Chronic lymphocytic leukemia 4 (0.5 %)
Multiple myeloma 2 (0.2 %)
Hodgkin’s disease 2 (0.2 %)
Myeloprolififerative neoplasms 2 (0.2 %)
Solid tumor 1 (0.1 %)
Hereditary and metabolic disorders 9 (1.1 %)
Paroxysmal nocturnal hemoglobinuria 1 (0.1 %)
Othersa 13 (1.6 %)
HLA-matched related (sibling) 335 (41.0 %)
Haploidentical 269 (32.9 %)
Unrelated 213 (26.0 %)
Source of stem cells
PB 417 (51.0 %)
BM + PB 348 (42.5 %)
BM 33 (4.0 %)
CB 15 (1.8 %)
BM + CB 3 (0.4 %)
BM + PB + CB 2 (0.2 %)
Yes 729 (89.1 %)
No 89 (10.9 %)
Table 1 Patient characteristics and antifungal prophylaxis regimen (Continued)
E-COG Eastern Cooperative Oncology Group, PAP primary antifungal prophylaxis, SAP secondary antifungal prophylaxis, BM bone marrow, PB peripheral blood,
CB cord blood, CMV cytomegalovirus, aGVHD acute graft versus host disease, cGVHD chronic graft versus host disease, IFD invasive fungal diseases, HSCT
hematopoietic stem cell transplantation
aOthers include chronic myelomonocytic leukemia (n = 3), T lymphoblastic lymphoma leukemia (n = 2), mixed-lineage leukemia (n = 10), aggressive NK cell
leukemia (n = 3), myeloid sarcoma (n = 1), plasmablasticlymphoma (n = 3)
bOthers include infectious disease (n = 18), digestive system diseases (n = 10), cholecystolithiasis (n = 7), mouth disease (n = 8), urological diseases (n = 6), intestinal
diseases (n = 7), endocrine diseases (n = 7), surgery (n = 5), cerebrovascular disease (n = 4), tumor (n = 2)
agents were given in accordance with the recommended
doses and schedule.
Efficacy of PAP and SAP on the prophylaxis of IFD
In the 1053 patients, 321 (30.5 %) patients were
identified as having an IFD, including 13 (1.2 %) with proven
IFD, 81 (7.7 %) with probable IFD, and 227 (21.6 %) with
possible IFD. The incidence rates of proven, probable,
and possible IFD in the PAP, SAP, and non-prophylaxis
groups were 0.7 vs. 0.0 vs. 4.8 %, 7.0 vs. 11.4 vs. 9.5 %,
and 15.0 vs. 27.3 vs. 54.4 %, respectively (Table 2). The
median time from transplantation to IFD was 45 days in
the PAP group (interquartile range (IQR), 16 to 75),
18 days in the SAP group (IQR, 7 to 26), and 12 days in
the non-prophylaxis group (IQR, 0 to 93), respectively.
Table 2 The recurrence rates of IFD in patients from the PAP, SAP, and non-prophylaxis groups
Patients without IFD
Characteristics of patients with IFD occurrence
Thirteen patients were diagnosed with proven IFD (6 in
the PAP group and 7 in the non-prophylaxis group), and
81 patients were diagnosed with probable IFD (57 in the
PAP group, 10 in the SAP group, and 14 in the
nonprophylaxis group). Among the 94 patients with IFD, 56
were male and 38 were female. The underlying diseases
were acute myeloid leukemia (n = 32), acute lymphocytic
leukemia (n = 32), myelodysplastic syndrome (n = 10),
chronic myeloid leukemia (n = 8), non-Hodgkin’s
lymphoma (n = 5), aplastic anemia (n = 5), and others (n = 2).
Twenty patients received human leukocyte antigen
(HLA)-matched sibling HSCT, 42 patients received
HLA-haploidentical HSCT, and 32 patients received
HLA-matched unrelated HSCT.
Detailed data regarding the distribution of fungal
pathogens and the methods of microbiological diagnoses of
Table 3 Identified etiological pathogens in IFD cases
IFDs are shown in Table 3. Of the 89 etiological
pathogens identified in patients with proven or probable IFDs,
62 (69.7 %) were Aspergillus, including 19 that were
exclusively diagnosed with two positive galactomannan
tests. Unspecified Aspergillus was the most common
mold (31 cases), followed by Aspergillus flavus (5 cases),
and Aspergillus fumigatus (2 case) isolates.
The infection sites of all categories of IFD were also
analyzed. Of all the 54 infection sites identified in
patients with IFDs, the most common location of
infection was the lower respiratory tract (64.8 %, 35/54),
followed by blood stream infections only (13.0 %, 7/
54), central nervous system (5.6 %, 3/54), spleen
(1.9 %, 1/54), and three other sites (14.8 %, 8/54).
Further analysis showed that Aspergillus is the main
pathogen of lower respiratory tract fungal infection
(85.7 %, 30/35). In other infection sites, there was no
Positive GM tests only
aIncluding cases with yeasts identified in tissue but negative cultures
bIncluding cases with hyphae identified in tissue but negative cultures
Table 4 Risk factors for proven/probable IFD among allo-HSCT patients in the PAP group
Factor Univariate analysis
Patients with proven/ Incidence of proven/
probable IFD (n/N) probable IFD (%)
Table 4 Risk factors for proven/probable IFD among allo-HSCT patients in the PAP group (Continued)
Drugs for IFD prophylaxis
Fluconazole/fluconazole + itraconazolee
significant difference in the infection rate between
Aspergillus and Candida.
Risk factors for proven and probable IFD
The risk factors for proven and probable IFDs among
PAP and SAP transplant recipients are presented in
Tables 4 and 5. Univariate analyses revealed that
HLAhaploidentical HSCT, HLA-matched unrelated HSCT,
the use of antithymocyte globulin, prolonged profound
neutropenia (>14 days), renal impairment, decreased
albumin levels, and Epstein-Barr virus and
cytomegalovirus viremia were independent risk factors for proven
Table 5 Risk factors for proven/probable IFD among allo-HSCT patients in SAP group
Patients with proven/ Incidence of proven/ Comparison (P value) SE
probable IFD (n/N) probable IFD (%)
OR (95 % CI)
Comparison (P value)
HLA-matched related (sibling) 1/35
Prolonged, profound neutropenia
ANC > 500/mm3
ANC < 500/mm3, <10 days
ANC < 500/mm3, 10–14 days
ANC < 500/mm3, >14 days
Time of IFD prophylaxis
Drugs for IFD prophylaxis
Fluconazole + itraconazoleb
aIncluding voriconazole + caspofungin and fluconazole + caspofungin + voriconazole
bCompared with others
The italicized data reflected significant difference
1.77 2.48 (0.08–79.46) 0.61
1.77 2.24 (0.07–72.11) 0.65
1.68 2.49 (0.09–67.66) 0.59
1.13 5.90 (0.65–53.89) 0.12
0.74 2.07 (0.49–8.79)
0.76 1.10 (0.25–4.86)
0.96 0.87 (0.13–5.64)
0.91 1.50 (0.25–8.96)
and probable IFDs in allo-HSCT patients with PAP (P <
0.05). Among the allo-HSCT patients with SAP, the use
of antithymocyte globulin was the only obviously
significant risk factor (P = 0.043).
Multivariate analyses demonstrated that independent
risk factors for proven and probable IFDs in allo-HSCT
patients with PAP were age >18 years (odds ratio (OR),
2.78; 95 % confidence interval (CI), 1.18–6.55; P < 0.05),
having an HLA-matched unrelated donor (OR, 8.07;
95 % CI, 2.50–26.10; P < 0 .01), having an
HLAhaploidentical donor (OR, 6.08; 95 % CI, 1.69–21.86; P
< 0.01), decreased albumin levels (OR, 1.98; 95 % CI,
1.08–3.62; P < 0.05), and the use of itraconazole as the
antifungal prophylactic agent (OR, 3.41; 95 % CI, 1.11–
8.86; P < 0 .05) (Table 4). Among the SAP transplant
recipients, there was no significant risk factor for proven
or probable IFD.
Overall antifungal therapy
A total of 321 IFD patients were provided therapeutic
antifungal treatment. A single antifungal agent was used
for treatment in 116 (36.1 %) patients; 144 (44.9 %)
patients required two agents, and 61 (19.0 %) patients
required three or more agents during the course of their
treatment. Among the PAP transplant recipients,
itraconazole (34.4 %, 64/186 in all-category IFD; 46.1 %, 29/63
in proven or probable IFD) was the most popular agent
for the initial therapy. Among the SAP and
nonprophylaxis transplant recipients, voriconazole (36.3 %,
49/135 in all-category IFD; 25.8 %, 8/31 in proven or
probable IFD) was the most common agent for the
initial therapy. Whether the patients in PAP, SAP, or
nonprophylaxis groups, voriconazole as a single agent or in
combination with other agents (35.8 %, 115/321) was the
most popular agent for antifungal treatment.
The median overall treatment duration in patients
who started and completed antifungal treatment while
hospitalized was 36 days (IQR, 21–65) for PAP
transplant recipients, 39 days (IQR, 24–58) for SAP
transplant recipients, and 35 days (IQR, 20–67) for
nonprophylaxis transplant recipients. A total of 175 patients
(54.5 %, 94 in the PAP group, 20 in the SAP group, and
61 in the non-prophylaxis group) continued treatment
after leaving the hospital.
Outcomes including mortality
At the end of follow-up, 171 patients had died, resulting
in an overall mortality rate of 16.2 % (171/1053).
Compared with the overall study population, the mortality
rate was markedly higher in patients with proven (5/13;
38.5 %), probable (19/81; 23.5 %), or possible (58/227;
25.6 %) IFDs. Furthermore, the mortality rate among
patients treated for suspected IFD despite failing to meet the
EORTC/MSG diagnostic criteria  (25/166; 15.1 %) was
higher than that among patients who were not suspected
of having IFD and, therefore, not treated with antifungal
agents (64/566; 11.3 %) (Fig. 1, P < 0.001). In addition, we
compared the incidence of OS in the PAP, SAP, and no
prophylaxis groups. There was a significant difference
among the three groups (85.07 vs. 78.80 vs. 74.82 %,
respectively, Fig. 2, P = 0.01).
Invasive infections remain major infectious threats to
patients undergoing allo-HSCT and are associated with
high fatality rates [23–28]. The diagnosis of IFDs
continues to be difficult to establish because they do not
manifest with specific clinical or radiographic signs or
symptoms . In the recent years, there has been a
concerted effort to identify alternative procedures for
the future diagnosis of fungus. They include the
targeting of fungal antigens by enzyme-linked immunosorbent
assay (ELISA) or lateral flow devices (LFDs) ,
detection of siderophores , and amplification of fungal
nucleic acids from tissue and body fluids  as well as
application of matrix-assisted laser desorption ionization
TOF mass spectrometry (MALDI-TOF MS) . Each
of the above methods has advantages and disadvantages,
and not all of which have entered clinical practice .
The difficulty in obtaining a timely diagnosis as well as
the high morbidity and mortality rates associated with
IFDs provide a rationale for antifungal prophylaxis in
patients undergoing allo-HSCT. Nonetheless, antifungal
prophylaxis remains a topic of some controversy, with
no clear consensus among different centers [35–37].
The CAESAR study is the first population-based and
the largest prospective observational study of the
incidences of IFDs in patients receiving HSCT . This
Fig. 1 Overall survival of patients with proven/probable IFD, possible
IFD, or suspected IFD and who received antifungal therapy; those
with no suspected IFD and who did not receive antifungal therapy;
and those without any IFD (proven, probable, or possible)
Fig. 2 Overall survival of allo-HSCT patients receiving PAP, SAP, or
observational study was conducted as a part of the
CAESAR study and focused on the prophylaxis of IFDs in
patients who underwent allo-HSCT. In the present analysis
of adults and children at risk for IFD due to allo-HSCT,
non-prophylaxis transplant recipients had a higher
incidence of proven/probable/possible IFD than PAP and
SAP transplant recipients at 6 months (68.6 vs. 22.7 and
38.6 %, P = 0.0000). This result was in accord with the
classic randomized clinical trials on PAP in HSCT
recipients and patients with hematological malignancies [38–
40]. Furthermore, the OS was significantly different
among PAP, SAP, and no prophylaxis patients. It was
revealed that antifungal prophylaxis was helpful to reduce
the incidence of IFD and improve the survival of
patients after transplantation.
The most recently published European guidelines
pointed out that SAP should be administered to patients
with a previous IFD to prevent recurrence of the
previous IFD or onset of a new IFD during a new at-risk
phase, mainly referring to a prolonged neutropenic
period induced by chemotherapy or a phase of severe
immunosuppression after allo-HSCT . Several
studies have reported success rates for SAP, which was
proven to be effective in preventing IFD recurrence [41,
42]. In the study, the cumulative incidence of IFD
increased particularly rapidly during the first month after
transplantation in the SAP group and non-prophylaxis
group, suggesting that this is a high-risk period during
which health care providers should pay particularly close
attention to signs of emerging IFD in SAP and
nonprophylaxis patients. On the contrary, the median time
of IFD occurrence in the PAP group was 45 days after
HSCT. This finding indicated that patients who had a
previous IFD and had no antifungal prophylaxis were
more likely to experience a breakthrough fungal
infection in the early stage after transplantation.
As 22.7 % of patients treated with PAP and 38.6 % of
patients treated with SAP in the study went on to
develop proven, probable, or possible IFD, there remains
an unmet need for education about the appropriate
timing and choice of antifungal agent for prophylaxis in
China. Among PAP transplant recipients, the most
commonly prescribed prophylactic agents were fluconazole
and itraconazole, which may be less effective than
posaconazole . The use of itraconazole as the antifungal
prophylactic agent also proved the independent risk
factor for IFD occurrence in our study. An update to the
cost-effectiveness of posaconazole vs. fluconazole or
itraconazole in the prevention of IFD among neutropenic
patients in the USA has shown that posaconazole is a
cost-effective alternative to fluconazole or itraconazole
in the prevention of IFD among neutropenic patients
. Among SAP transplant recipients, there was no
significant risk factor for proven or probable IFD. The
characteristics of the observational study and the small
sample size of the patients treated with SAP may be the
main reasons. Prospective and randomized studies
assessing the risk factors for SAP are needed in the future.
The epidemiological characteristics of IFD continue to
evolve in transplant patients. A major contributor is the
widespread use of azole prophylaxis since the early
1990s, which results in less candidiasis but more
frequent mold infections in hematologic malignancies [25,
45]. In most [46–48] but not all  cases, Aspergillus
spp. represent the most frequent cause of fungal-related
morbidity in patients with HSCT. In our study,
Aspergillus spp. also predominated in culture-proven or
histologically proven pathogens and was more than two times as
common as Candida spp. The mortality among patients
who developed IFD (24.1 %) was almost double than
that in the overall population of HSCT patients (15.0 %),
and regression analysis confirmed that the development
of IFD is a significant independent risk factor for death,
highlighting the grave prognosis of those with IFD and
the need for a timely diagnosis and prompt treatment.
The incidence rates of invasive aspergillosis, however,
need to be interpreted with caution as establishing
this diagnosis often requires invasive procedures that
are difficult to perform in severely ill patients. The
low rate of proven/probable IFD in the present study
suggests the need to improve diagnostic techniques to
treat IFD as early and accurately as possible. Under
the existing conditions, in order to reduce the
IFDrelated mortality of allo-HSCT patients, preemptive
antifungal therapy should be given to patients with
possible or suspected IFD.
The current study has several limitations. The main
limitation was its observational nature. Confounding
factors cannot be controlled effectively in observational
studies, frequently due to biased selection of patients or
treatment protocols. In the analysis of mortality by
antifungal therapy, the uncontrolled study design means that
no firm conclusions can be drawn regarding the relative
effect of different treatments. Another limitation was the
relatively short duration. The fact that the overall
treatment duration was not recorded in patients who were still
taking antifungal treatment after discharge from the
hospital further limited data analysis. A longer follow-up
would have allowed a more comprehensive analysis of
patients who developed IFD after discharge. Procedures for
diagnosis, prophylaxis, and treatment of IFD were not
prespecified in the protocol but were performed according to
usual practice and local clinical guidelines .
Furthermore, in some centers, diagnostic procedures were
conducted only among patients with suspected clinical signs
or symptoms of IFD. The observational study also meant
that the diagnosis of specific infections, although guided
by EORTC/MSG 2008 criteria, was limited to the data
collected according to local hospitals’ usual practice; there
was no mandatory requirement for diagnostic
microbiological testing or the use of a centralized laboratory to
validate the results.
In conclusion, the results of the present observational
study indicate that prophylaxis of IFD among patients
receiving allo-HSCT for hematological malignancy in
China is broadly in line with the recommended practice
and is helpful to reduce the incidence of IFD and
improve the OS of patients after transplantation. For
patients with a history of IFD, active and effective
prevention of fungal infections is particularly important
because these patients have a higher incidence of IFD
occurrence and a shorter incubation period. Different
from the traditional view, for the allo-HSCT patients
with PAP, itraconazole was a less effective treatment
than other antifungal drugs. Aspergillus spp. represents
the most common type of fungal infection in patients
with allo-HSCT. Due to the limited diagnostic
techniques, it is necessary to give antifungal therapy to
patients who do not meet the EORTC/MSG 2008 criteria
but show clinical evidence of fungal infection.
allo-HSCT: Allo-genetic hematopoietic stem cell transplantation;
CAESAR: China Assessment of Antifungal Therapy in Hematological Disease;
ELISA: Enzyme-linked immunosorbent assay; EORTC/MSG: 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; HLA: Human leukocyte antigen;
IFDs: Invasive fungal diseases; LFDs: Lateral flow devices; MALDI-TOF
MS: Matrix-assisted laser desorption ionization TOF mass spectrometry;
OS: Overall survival; PAP: Primary antifungal prophylaxis; SAP: Secondary
The authors would like to thank the patients and investigators at each study site,
without whom this study would not have been possible. The CAESAR study group
investigators not listed as authors were as follows: Jing Chen, Shanghai Children’s
Medical Center, Shanghai; Zhixiang Shen, Rui Jin Hospital Affiliated to Shanghai Jiao
Tong University School of Medicine, Shanghai; Juan Li and Waiyi Zou, The First
Affiliated Hospital of Sun Yat-Sen University, Guangzhou; Chun Wang, Jun Yang,
and Yu Cai, The First People’s Hospital of Shanghai, Shanghai; Yang Xiao and
Yonghua Li, The General Hospital of Guangzhou Military Command of PLA,
Guangzhou; Yongping Song and Yuewen Fu, Henan Tumor Hospital affiliated to
Zhengzhou University, Zhengzhou; Kang Yu, Xudong Hu, and Xingzhou Ren, The
First Affiliated Hospital of Wenzhou Medical College, Wenzhou; Huisheng Ai and
Jianhui Qiao, Chinese PLA 307 Hospital, Beijing; Jianmin Wang and Xianmin Song,
Changhai Hospital of the Second Military Medical University, Shanghai; Hai Bai and
Chunbang Wang, The General Hospital of Lanzhou Military Area, Lanzhou; Yongmin
Tang and Heping Shen, Children’s Hospital of Zhejiang University Medical school,
Hangzhou; Jianyong Li and Xiaoyan Zhang, Jiangsu Province Hospital, Nanjing; Xin
Du and Chengwei Luo, Guangdong General Hospital, Guangzhou; Jian Ouyang
and Yong Xu, Nanjing Drum Tower Hospital, Nanjing; Huo Tan and Runhui Zheng,
The First Affiliated Hospital of Guangzhou Medical University, Guangzhou; Ting Liu
and Juan Xu, West China Hospital, Sichuan University, Chengdu; Jin Zhou and
Liming Li, The First Hospital of Harbin Medical University, Harbin; Jun Ma, Harbin
Hematologic Tumor Institution, Harbin; Zhuogang Liu, Shengjing Hospital of China
Medical University, Shenyang; Jianda Hu, Fujian Medical University Union Hospital,
Fuzhou; Ping Zou and Yong You, Wuhan Union Hospital, Huazhong University of
Science and Technology, Wuhan; Lin Liu and Li Wang, The First Affiliated Hospital
of Chongqing Medical University, Chongqing; Yan Li and Ran Gao, The First
Affiliated Hospital of China Medical University, Shenyang; Zhanxiang Liu, Chinese
PLA General Hospital (301 Hospital), Beijing; Mangju Wang, The First Hospital of
Peking University, Beijing; Guopan Yu, Nanfang Hospital, Nanfang Medical University,
Guangzhou; Ling Wang, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University
School of Medicine, Shanghai; Jun Wang, The First Affiliated Hospital of Soochow
University, Suzhou; Guixin Zhang, Institute of Hematology and Blood Diseases
Hospital, Chinese Academy of Medical Sciences, Tianjin; Xia Qin, Shanghai Children’s
Medical Center, Shanghai; Liya Ma and Wangzhuo Xie, The First Affiliated Hospital
of Medical School of Zhejiang University, Hangzhou, China.
This work was supported by Merck Sharp & Dohme (China), who sponsored
the study. The support for the manuscript development was provided by
Merck & Co., Inc. (Whitehouse Station, NJ).
XH and XZ contributed to the conception and design of the study. FM, MZ,
HH, DW, LY, and HR were involved in the development of the methodology
and participated in the analysis. LG and YS interpreted the data and drafted
the paper. All authors contributed in the writing, review, and revision of the
article and final approval for submission.
Consent for publication
The authors declare that they have no competing interests.
Ethics approval and consent to participate
This observational study was conducted in accordance with the Declaration
of Helsinki, International Conference on Harmonization Good Clinical
Practice, and nationally mandated ethical requirements. The study protocol
and informed consent document were reviewed and approved by the ethics
committee of Peking University People’s Hospital. All participating
institutions obtained ethical approval separately before initiation of the
study. All study participants provided informed consent.
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