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mycoses
Diagnosis,Therapy and Prophylaxis of Fungal Diseases
Original article
Mucormycosis in paediatric patients: demographics, risk factors and
outcome of 12 contemporary cases
Jan Däbritz,1 Andishe Attarbaschi,2 Kathrin Tintelnot,3 Nina Kollmar,4 Bernhard Kremens,5
Friederike D. v. Loewenich,6 Lothar Schrod,7 Friedhelm Schuster,8 Uwe Wintergerst,8 Michael Weig,9
Thomas Lehrnbecher10 and Andreas H. Groll1
1
Infectious Disease Research Program, Department of Pediatric Hematology/Oncology and Center for Bone Marrow Transplantation, University Hospital of
Münster, Münster, Germany, 2St. Anna Kinderspital, Vienna, Austria, 3Robert-Koch-Institute, Berlin, Germany, 4Department of Pediatrics, University Hospital
of Göttingen, Göttingen, Germany, 5Department of Pediatrics, University Hospital of Essen, Essen, Germany, 6Department of Medical Microbiology, University
Hospital of Freiburg, Freiburg, Germany, 7Municipal Hospital Frankfurt-Hoechst, Frankfurt, Germany, 8Department of Pediatrics, University Hospital of
München, München, Germany, 9Department of Medical Microbiology and National Reference Center for Systemic Mycoses, University Hospital of Göttingen,
Göttingen, Germany and 10Department of Pediatric Hematology/Oncology, University Hospital of Frankfurt, Frankfurt, Germany
Summary
Mucormycosis is associated with high morbidity and mortality and is perceived as an
emerging fungal infection. However, contemporary paediatric data are limited. We
present a series of paediatric cases of mucormycosis reported from Germany and
Austria collected within a voluntary epidemiological survey through standardised,
anonymized case report forms. Twelve cases were reported between January 2004 and
December 2008 (six men; mean age: 12.6 years, range: 0.1–17 years). Mucormycosis
was proven in nine, and probable in three cases. Isolates included Lichtheimia (syn.
Absidia pro parte, Mycocladus) (five), Rhizopus (three) and Mucor (one) species. Infection
was limited to soft tissue in three cases, the lung in two cases, and an infected
thrombus in one case; rhinocerebral disease was found in three cases, and pulmonarymediastinal, pulmonary-cerebral and soft tissue-cerebral involvement in one case each.
All three patients with isolated soft tissue infection were cured, whereas seven of the
remaining patients died (one patient without follow-up). The overall mortality rate was
67%. While these data cannot provide conclusive data on incidence and disease burden
of mucormycosis in paediatric patients, they reflect the continuing threat of these
infections to immunocompromised patients and the need for improved diagnosis and
management.
Key words: Mycoses, mucormycosis, children, neonates, epidemiology, outcome.
Introduction
Zygomycoses are among the less prevalent invasive
fungal infections but have exceedingly high fatality
rates.1 They are increasingly being recognised in
immunocompromised patients, in particular during
the recent 5–10 years. This trend is coincident with
Correspondence: Andreas H. Groll, MD, Infectious Disease Research
Program, Center for Bone Marrow Transplantation and Department of
Pediatric Hematology ⁄ Oncology, ChildrenÕs University Hospital of Münster,
Albert-Schweitzer-Strasse 33, 48129 Münster, Germany.
Tel.: +49 0 251 834 7742. Fax: +49 0 251 834 7828.
E-mail: [email protected]
Accepted for publication 31 January 2011
2011 Blackwell Verlag GmbH • Mycoses 54, e785–e788
an increased awareness of mucormycosis and the wider
use of voriconazole and members of the echinocandins
for prophylaxis and empirical therapy in this population. The rhinocerebral, pulmonary, and disseminated
forms are usually seen in patients with underlying
haematological malignancies, such as leukaemia or
lymphoma, in patients receiving immunosuppressive
therapy or corticosteroids and in patients with diabetes.
Skin and soft tissue infections are often the result of
trauma or burns. Even with early diagnosis and
appropriate surgical and medical therapy, the mortality
rate is high.1–6 For this reason, a high degree of
suspicion is needed, to initiate treatment promptly.
Although mucormycosis is associated with high
morbidity and mortality and is perceived as an emerging
doi:10.1111/j.1439-0507.2011.02025.x
J. Däbritz et al.
fungal infection, contemporary data on demographics,
risk factors, management and outcome particularly in
paediatric patients are limited.4,5,7–9 In 2004, the
European Confederation for Medical Mycology (ECMM)
has initiated a prospective survey to collect data on
mucormycosis in Europe as a first step to planning
strategies for improved diagnostic and therapeutic
interventions and outcome of these infections. Herein
we present a series of paediatric cases reported to the
registry from Germany and Austria from January 2004
until December 2008.
Patients and methods
The survey was initiated in 2004 by members of the
European Confederation for Medical Mycology (ECMM;
ECMM Working Group on Zygomycosis) with the aim to
prospectively collect cases of mucormycosis throughout
Europe to obtain more information on demographics,
organisms, risk factors, management, and outcome of
this emerging fungal infection. The survey was based on
the voluntary reporting of cases of all age categories by
clinicians and laboratories via national coordinators to
the ECMM study centre using a standardised, pseudonymized case report form (CRF). Submission of isolated
fungal organisms or infected tissue specimen for further
biological investigations was encouraged.
Data collected by the CRFs included demographic
characteristics, underlying medical conditions and predisposing factors, use of antifungal agents prior to
diagnosis, clinical presentation, methods of diagnosis,
microbiological species identification, treatment, and
outcome of the infection. Minimum data requirements
for the inclusion of a case in this analysis were
paediatric age, origin in Germany or Austria, information on demographics, underlying condition, clinical
presentation, and diagnosis of mucormycosis. Proven
mucormycosis was defined by compatible clinical
and ⁄ or radiographic findings, conventional microbiological identification of the organism, and histopathological evidence in case of lung and paranasal sinus
infection; and probable mucormycosis by compatible
clinical and ⁄ or radiographic findings plus microscopic
detection in biopsy specimens without microbiological
identification of the organism.10 One case that was
included on the basis of molecular detection of a
zygomycete from bronchoalveolar lavage fluid (BAL)
was classified as probable infection. All cases were
reviewed and adjudicated as necessary by the national
coordinator (AHG). Prior to the surveyÕs start, data
collection, and data handling were approved by the
Ethics Committee of the University Hospital Münster. Of
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note, the ECMM survey has been completed in the
interim, and the combined analysis of all 230 adult and
paediatric cases has been presented elsewhere.11
Results
Twelve cases of proven or probable mucormycosis from
nine centres were reported between January 2004 and
December 2008 (2004: 3; 2005: 4; 2006: 1; 2007: 3
and 2008: 1). The demographic and clinical characteristics of the 12 paediatric patients with mucormycosis
are presented in Table 1.
Six patients were male, and six were female; the
median age was 14.5 years (range: 0.1–17). The
majority of patients (67%) was either treated for acute
myeloid leukaemia (3), acute lymphatic leukaemia (2),
non-Hodgkin lymphoma (1), and severe aplastic anaemia (1), or had received an allogeneic hematopoietic
stem cell transplant (HSCT 1; during the aplastic phase).
Other conditions included insulin-dependent diabetes
mellitus (2), soft tissue trauma, and premature birth
with lung hypoplasia and extracorporal membrane
oxygenation (one patient each). With respect to potentially predisposing factors, six of 12 evaluable patients
had received glucocorticosteroids, six of 11 were neutropenic (absolute neutrophil count <500 ll)1), and
seven of 10 had received broadspectrum antibacterial
agents within 4 weeks prior to the diagnosis of the
fungal infection; in addition, four of 12 evaluable
patients were on antifungal therapy with either caspofungin or voriconazole at the time of diagnosis.
Mucormycosis was proven in nine, and probable in
three cases. Isolates included Lichtheimia (syn. Absidia
pro parte, Mycocladus) (5), Rhizopus (3) and Mucor (1)
species. Infection was limited to the soft tissues in three
cases, the lung in two cases, and an infected central
thrombus in one case. Sinoorbital-cerebral disease was
found in three cases, and pulmonary-mediastinal, pulmonary-cerebral and soft tissue-cerebral involvement in
one case each. The sources of the isolate in cases of
proven disease were the paranasal sinuses (n = 3),
infected soft tissue (n = 3), lung tissue (2), and an
implanted catheter material (1). While in three patients,
the diagnosis had been made within 24 h prior to death
and no antifungal therapy was initiated, nine of the 12
patients were treated with antifungal agents (lipid
formulations of amphotericin B, six; amphotericin B
deoxycholate, two; consolidation ⁄ maintenance with
posaconazole, four); four of these patients underwent
surgical debridement or resection of affected tissue.
Overall mortality was 67% (eight of 12 patients with
follow-up). Three of the four survivors included the
2011 Blackwell Verlag GmbH • Mycoses 54, e785–e788
Mucormycosis in paediatric patients
Table 1 Demographic and clinical characteristics of 12 paediatric patients with mucormycosis.
Age
Patient ID ⁄ year Gender (years) Underlying condition
Corticosteroids Neutropenia Antibacterials
(yes ⁄ no)
(yes ⁄ no)
(yes ⁄ no)
Site of infection
Histopathology
Proven cases
GE 13 ⁄ 2004
GE 18 ⁄ 2004
AT 17 ⁄ 2004
GE 03 ⁄ 2005
GE 23 ⁄ 2005
GE 26 ⁄ 2005
GE 27 ⁄ 2007
GE 33 ⁄ 2007
Paranasal sinus
Paranasal sinus
Paranasal sinus
NA
NA
Lung
NA
NA
GE 38 ⁄ 2008
Probable cases
GE 30 ⁄ 2005
GE 16 ⁄ 2006
AT 14 ⁄ 2007
Patient ID ⁄ year
Proven cases
GE 13 ⁄ 2004
GE 18 ⁄ 2004
AT 17 ⁄ 2004
GE 03 ⁄ 2005
GE 23 ⁄ 2005
GE 26 ⁄ 2005
GE 27 ⁄ 2007
GE 33 ⁄ 2007
GE 38 ⁄ 2008
Probable cases
GE 30 ⁄ 2005
GE 16 ⁄ 2006
AT 14 ⁄ 2007
Female
Female
Male
Male
Male
Male
Male
Male
11
15
17
14
16
8
10
0.1
Yes
No
Yes
Yes
Yes
No
No
Yes
Yes
No
Yes
Yes
No
NR
No
No
Yes
No
Yes
Yes
NR
NR
No
Yes
Female 15
Severe aplastic anaemia
IDDM ⁄ ketoacidosis
AML ⁄ allo HSCT
T-ALL
T-ALL
AML
Soft tissue trauma
Prematurity ⁄ lung
hypoplasia
IDDM ⁄ ketoacidosis
No
Rhinocerebral
Rhinocerebral
Rhinocerebral
Soft tissues
Soft tissues
Lung
Soft tissues
Thrombosed
ECMO canula
Lung ⁄ mediastinum
No
No
Lung
Female 16
Female 15
Female 14
AML
T-NHL
AML
No
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
Lung ⁄ brain
Soft tissues ⁄ brain
Lung
Brain
Soft tissues ⁄ brain
NA
Microbial culture
Prior
antifungals
Antifungal
treatment
Antifungal
agents
Surgical
treatment
Outcome
Follow-up
(days)
Lichtheimia corymbifera
Rhizopus spp.
Rhizopus oryzoe
Mucor spp.
Lichtheimia corymbifera
Lichtheimia ramosa
Lichtheimia corymbifera
Rhizopus spp.
Lichtheimia corymbifera
FCZ, CAS
No
No
No
NR
VCZ, CAS
No
No
No
Yes
Yes
No
Yes
Yes
Yes
Yes
No
Yes
LFAB
AMB, PCZ
No
LFAB
AMB
LFAB
LFAB, PCZ
No
LFAB, PCZ
Debridement
No
No
Resection
Debridement
NR
Debridement
No
No
Death
Cure
Death
Cure
Cure
Unknown
Cure
Death
Death
201
609
1
20
44
NA
34
1
7
NA
NA
Mucor by PCR
VCZ
No
VCZ
No
Yes
Yes
No
LAMB
LAMB, PCZ
No
No
No
Death
Death
Death
1
3
120
IDDM, insulin-dependent diabetes mellitus; AML, acute myeloid leukaemia; ALL, acute lymphatic leukaemia; NHL, non-Hodgkin lymphoma; HSCT, haematopoietic stem cell transplantation; PCR, polymerase chain reaction; ECMO, extracorporal membrane oxygenation;
FCZ, fluconazole; VCZ, voriconazole; PCZ, posaconazole; CAS, caspofungin; LFAB, lipid formulation of amphotericin B; AMB, amphotericin
B; NR, not reported ⁄ unknown; NA, not available ⁄ not done.
patients with soft tissue infection who had received
combined antifungal and surgical treatment; for nonsoft tissue infections, the outcome was particularly
dismal with 88% mortality.
Discussion
Invasive mucormycosis is a life-threatening infection in
children and neonates and has both similarities to and
differences from that in adults. Prematurity is a major
underlying factor among neonatal cases and the most
common reported manifestations of mucormycosis here
are gastrointestinal and cutaneous. In contrast, older
children and adults typically present with pulmonary
or sinuorbitocerebral patterns. Overall mortality is 64%
in neonates and 56% in children. Dissemination and
2011 Blackwell Verlag GmbH • Mycoses 54, e785–e788
young age (<1 year) were independent risk factors for
death in children. Similar to adults, surgery combined
with antifungal therapy is a protective factor against
death in neonates and children.7–9 The vast majority of
adult patients with malignancy have pulmonary disease, whereas the majority of patients with diabetes
have disease originating in the paranasal sinuses.
Dissemination is seen in one-fourth of cases in adults
and mortality varies with the site of infection. Survival
is 70% for cases treated with antifungal therapy and
surgery compared with 3% for cases that were not
treated, 61% for cases treated with amphotericin B, and
57% for cases treated with surgery alone.4
In agreement with previously published risk factors
for mucormycosis,2,4–7,12 the underlying conditions in
our patients were haematological malignancies (58%),
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J. Däbritz et al.
diabetes mellitus (17%), haematopoietic stem cell transplantation, soft tissue trauma and prematurity (8%
each). While this study cannot yield conclusive information on incidence rates of invasive mucormycosis in
different patient groups, frequency of registration may
suggest epidemiological tendencies. In the largest subgroup of patients with haematological malignancies, the
lung and brain could be confirmed as the typical site of
infection, as reported previously.3,4 Disseminated disease was also associated with high mortality in our
cohort (100%), whereas all patients with localised soft
tissue trauma survived. Similar to larger, mostly literature-based case series,4,7,8 treatment with surgery and
antifungal therapy was associated with a lower mortality in our cohort, when compared with cases that were
not treated, or treated with antifungal medication alone.
Cleary, these statements are limited by the small
number of patients. In previous reports on genus and
species distribution Rhizopus spp., Mucor spp. and
Cunninghamella bertholletiae have been mentioned as
the most frequently isolated genus in studies from North
America and Italy, whereas Lichtheimia corymbifera (syn.
Absidia corymbifera, Mycocladus corymbifer),13 was the
most commonly identified isolate in a registry study
from central Europe and Asia.4 In agreement with this
analysis, Lichtheimia was also the most commonly
isolated agent of mucormycosis in our study, followed
by Rhizopus spp. and Mucor spp.
In conclusion, mucormycosis is a life-threatening and
often fatal disease in immunocompromised paediatric
patients and a variety of underlying diseases. While
these data cannot provide the full extent of disease
burden of mucormycosis in paediatric patients in
Germany or Austria, they reflect the continuing threat
of these infections to immunocompromised patients and
the need for improved diagnosis and management.
Acknowledgments
The ECMM survey has been supported by an unrestricted grant from Gilead Sciences. Gilead Sciences was
not involved in data collection, data analysis and the
writing or reviewing of this manuscript.
Conflict of interest
AHG has served on the speakerÕs bureau and as a
consultant to Astellas Pharma, Cephalon, Gilead Sciences, Merck & Co., Pfizer, Schering-Plough, and
Vicuron Pharmaceuticals. He has received research
grants from Gilead Sciences and Merck & Co. TL has
received grants from Gilead; is a consultant to Gilead,
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Merck, Sharp & Dohme and Schering-Plough, and
served at the speakersÕ bureau of Astellas, Gilead,
Merck, Sharp & Dohme and Schering-Plough. All other
authors: none to declare.
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