8th European Conference on Infections in Leukaemia. 2020 guidelines for the diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or post-haematopoietic cell transplantation

Policy Review
8th European Conference on Infections in Leukaemia:

2020 guidelines for the diagnosis, prevention, and
treatment of invasive fungal diseases in paediatric patients
with cancer or post-haematopoietic cell transplantation
Andreas H Groll, Dorothea Pana, Fanny Lanternier, Alessio Mesini, Roland A Ammann, Dina Averbuch, Elio Castagnola, Simone Cesaro,
Dan Engelhard, Carolina Garcia-Vidal, Jukka Kanerva, Nicole Ritz, Emmanuel Roilides, Jan Styczynski, Adilia Warris, Thomas Lehrnbecher, on
behalf of the 8th European Conference on Infections in Leukaemia
Paediatric patients with cancer and those undergoing allogeneic haematopoietic cell transplantation have an Lancet Oncol 2021; 22: e254–69
increased susceptibility to invasive fungal diseases. In addition to differences in underlying conditions and Published Online
comorbidities relative to adults, invasive fungal diseases in infants, children, and adolescents are unique in terms March 31, 2021
https://doi.org/10.1016/
of their epidemiology, the validity of current diagnostic methods, the pharmacology and dosing of antifungal
S1470-2045(20)30723-3
agents, and the absence of phase 3 clinical trials to provide data to guide evidence-based interventions. To re-
For the full scientific faculty of
examine the state of knowledge and to further improve invasive fungal disease diagnosis, prevention, and the 8th European Conference on
management, the 8th European Conference on Infections in Leukaemia (ECIL-8) reconvened a Paediatric Group Infections in Leukaemia meeting
to review the literature and to formulate updated recommendations according to the European Society of Clinical see Online for appendix p 6
Microbiology and Infectious Diseases (ESCMID) and European Confederation of Medical Mycology (ECMM) Infectious Disease Research
grading system, which are summarised in this Review. Program, Center for Bone
Marrow Transplantation,
and Department of Pediatric
Introduction complications in immunocompromised patients after Hematology and Oncology,
Invasive fungal diseases are important causes of morbidity HCT, with leukaemia, or with other malignancies as University Children’s Hospital
and mortality in patients with cancer who are immuno previously described.6,7 Münster, Münster, Germany
(Prof A H Groll MD);
compromised or those undergoing allogeneic haemato Because a substantial amount of time has elapsed since Department of Medicine,
poietic cell transplantation (HCT). Although (relative to the completion of the first paediatric-specific guideline in European University of Cyprus,
adults) paediatric patients are similarly susceptible to 2011, the group was reconvened in Jan 16, 2019, for an Nicosia, Cyprus (D Pana MD);
Infectious Diseases Unit,
invasive fungal diseases, relevant differences exist in the update. The ECIL Paediatric Group consisted of
Necker-Enfants Malades
biology and treatment of underlying conditions and age- 16 independent international experts, identified by the two Hospital, Assistance Publique—
dependent comorbidities, the populations at risk and the designated group leaders (AHG and TL) on the basis of Hôpitaux de Paris, University
exact epidemiology of invasive fungal diseases, the knowledge and publications in the field of paediatric of Paris, Paris, France
(Prof F Lanternier MD);
performance and usefulness of diagnostic tools, the invasive fungal diseases, methodological expertise, and
Infectious Diseases Unit,
pharmacology and dosing of systemic antifungal agents, geographical location. Under the guidance of the Department of Pediatrics,
and the availability of evidence generated by interventional group leaders, relevant issues, questions, and outcomes IRCCS Istituto Giannina Gaslini,
phase 3 studies.1–4 addressed in the ECIL-4 guideline were evaluated ahead of Genoa, Italy (A Mesini MD,
Prof E Castagnola MD); Pediatric
In view of these differences, recommendations for the the consensus conference through a systematic literature
Hematology and Oncology,
diagnosis, prevention, and treatment of invasive fungal review. Recommendations were formulated or adapted Department of Pediatrics,
diseases in patients with cancer and recipients of allogeneic after discussion of the literature review within the group Inselspital, Bern University
HCT, which are made for adults, might not be directly and graded according to the European Society of Clinical Hospital, Bern, Switzerland
(Prof R A Ammann MD);
transferable to infants, children, and adolescents. To adapt Microbiology and Infectious Diseases (ESCMID) and
Department of Pediatrics,
such guidelines to the relatively small, but relevant popu European Confederation of Medical Mycology (ECMM) Hebrew University Medical
lation of paediatric patients, the 4th European Conference grading system (panel).8,9 This system differs from the Center, Jerusalem, Israel
on Infections in Leukaemia (ECIL) convened, in 2011, a grading system used for ECIL-4, in that it contains the (Prof D Averbuch MD,
Prof D Engelhard MD); Pediatric
Paediatric Group that developed the first international option for an explicit recommendation against an Hematology Oncology,
guideline solely dedicated to the diagnosis, prevention, and intervention and annotations of level II evidence. Department of Mother and
treatment of invasive fungal diseases in paediatric patients The consensus development conference was convened Child, Azienda Ospedaliera
with cancer and those who had undergone allo geneic on Sept 19–21, 2019, and attended by 56 experts from Universitaria Integrata, Verona,
Italy (Prof S Cesaro MD);
HCT.5 The 8th ECIL (ECIL-8) reconvened a Paediatric Australia, Israel, Saudi Arabia, Turkey, USA, and Department of Infectious
Group to review the current state of knowledge and to 16 European countries. Delegates were specialists in Diseases, Hospital Clinic of
formulate updated recommendations for this population. haematology, oncology, microbiology, infectious diseases, Barcelona
and clinical research, and selected on the basis of (Prof C Garcia-Vidal MD),
IDIBAPS
Methods expertise and active participation in the host organisations (Prof C Garcia-Vidal MD),
Guideline development overview (appendix p 19). The group presented the findings of the University of Barcelona,
The objective of the ECIL is to develop evidence- literature review and the proposed recommendations to Barcelona, Spain; Division of
based guidelines for the management of infectious the faculty in an initial plenary session. Similarly to and Hematology-Oncology and
www.thelancet.com/oncology Vol 22 June 2021 e254

Policy Review
Stem Cell Transplantation, diagnostic interventions, the group assumed potential

New Children’s Hospital, Panel: European Society of Clinical Microbiology and differences in children and, therefore, adult data were
University of Helsinki and Infectious Diseases and European Confederation of used merely as supportive and not as major evidence for
Helsinki University Hospital, Medical Mycology grading system for ranking
Helsinki, Finland useful performance in children. After a panel debate
(Prof J Kanerva MD); Pediatric
recommendations moderated by two of the experts (DE and ER), the
Infectious Diseases and recommendations were revised as necessary, rediscussed
Vaccinology, University of
Grade of recommendation
Basel Children’s Hospital, Basel, Grade A in a second moderated plenary session, and a final
Switzerland (N Ritz MD); The guideline group strongly supports a recommendation for consensus reached on the quality of evidence and the
Infectious Diseases Unit, use. strength of each recommendation. Consensus was
3rd Department of Pediatrics, defined as simple majority (more than 50% agreement);
Faculty of Health Sciences, Grade B
and Hippokration Hospital,
however, all faculty members had to find the resolu
The guideline group moderately supports a recommendation
Aristotle University of tion acceptable. The final version was approved on
for use.
Thessaloniki, Thessaloniki, Oct 11, 2019, and the slide set was made available without
Greece (Prof E Roilides MD); Grade C restriction on the ECIL website on Dec 2, 2019.
Department of Pediatric
The guideline group marginally supports a recommendation For information on the intended use of the guideline,
Hematology and Oncology,
Collegium Medicum, Nicolaus for use. and an overview of risk factors, clinical epidemiology,
Copernicus University Torun, Grade D and antifungal agents in paediatric patients with cancer
Bydgoszcz, Poland or after HCT, see appendix pp 1–10. For a narrative
(Prof J Styczynski MD);
The guideline group supports a recommendation against use.
MRC Centre for Medical
summary of the recommendations and the changes
Mycology, University of Exeter,
Level of evidence relative to the previous version, see appendix pp 16–19.
Exeter, UK (Prof A Warris MD); Level I
Great Ormond Street Hospital Evidence from at least one properly designed randomised, Recommendations for the diagnosis of invasive
London, London, UK controlled trial
(Prof A Warris); Pediatric fungal diseases
Hematology and Oncology, Level II Early recognition and prompt antifungal treatment are
Hospital for Children and Evidence from at least one properly designed clinical trial, crucial for the control of invasive fungal diseases.
Adolescents, Johann Wolfgang
without randomisation; from cohort or case-controlled Standard diagnostic procedures include blood cultures
Goethe University, Frankfurt,
Germany analytical studies (preferably from more than one centre); for yeasts and some moulds, cultures and microscopic
(Prof T Lehrnbecher MD) from multiple time series; or from striking results of examination of appropriate liquid and solid specimens,
Correspondence to: uncontrolled experiments. Added index for source of level II and imaging studies as mandated by clinical findings.
Prof Andreas H Groll, Infectious evidence: Indications, validity, advantages, and disadvantages of
Disease Research Program,
• r: meta-analysis or systematic review of a randomised these diagnostic procedures in paediatric patients are
Center for Bone Marrow
Transplantation and Department controlled trial similar to those for adults. All appropriate efforts should
of Pediatric Hematology and • t: transferred evidence (ie, results from different patient be made to identify the causative pathogen and to do
Oncology, University Children’s cohorts, or similar immune status situation resistance testing.5,14,15
Hospital, Münster 48149,
• h*: historical control as a comparator group Major advances in the early detection of invasive fungal
Germany
[email protected] • u*: uncontrolled trials diseases have been made with the development of non-
See Online for appendix • a*: published abstract presented at an international culture assays for fungal antigens or nucleic acids and
symposium or meeting with high-resolution CT imaging of the chest. Although
Level III these diagnostic tools are included in the European
Evidence from opinions of respected authorities, based on Organisation for Research and Treatment of Cancer and
clinical experience, descriptive case studies, or reports of Mycoses Study Group Education and Research
expert committees Consortium (EORTC/MSGERC) definitions of invasive
fungal diseases,16 their validity and usefulness in
*Not used in this Policy Review because not applicable to any recommendation of this paediatric patients require a separate assessment.3,5,17
guideline.
Detection of fungal antigens

consistently with the ECIL-4 guideline5 and with Galactomannan, a cell wall component released by all
paediatric drug development regulations and guidelines Aspergillus species, is detected with high specificity by an
from the European Medicines Agency,10,11 the recom enzyme immunoassay (Platelia Aspergillus Ag, Bio-Rad ,
mendations for interventions were based on four Hercules, CA, USA). Galactomannan positivity in serum,
essential components: evidence of efficacy from adult bronchoalveolar lavage fluid, and cerebrospinal fluid is,
phase 2 and phase 3 trials corresponding to current adult on the basis of multiple studies in adults, accepted as a
ECIL recommendations,12,13 existence and quality of mycological criterion for the diagnosis of invasive
paediatric pharmacokinetic data and dosing recommen aspergillosis in the EORTC/MSGERC definitions of
dations; specific paediatric safety data and supportive invasive fungal diseases.16 A systematic literature review
efficacy data; and regulatory approval for use in paediatric and meta-analysis identified 18 studies that assessed the
patients by the European Medicines Agency. For presence of galactomannan in serum in the paediatric
e255 www.thelancet.com/oncology Vol 22 June 2021

Policy Review
cancer and HCT setting and that included adequate of non-Aspergillus moulds, absence of validation in
information for individual patients and use of EORTC/ patients without granulocytopenia, and several potential
MSGERC diagnostic criteria.3 Among the ten studies in causes of false-positive test results.3
which galactomannan in serum was used as a screening Data from studies in adult patients21,22 and two retro
test during periods of granulocytopenia or in the context spective studies in paediatric patients23,24 support the use
of graft-versus-host disease, wide ranges were seen for of the galactomannan test in bronchoalveolar lavage
specificity, sensitivity, and positive predictive value, fluid, with an optical density index threshold of 1·0, as an
whereas the negative predictive value was narrow and adjunctive tool for conventional microbiological studies
ranged from 85% to 100%. In the other eight studies that for the diagnosis of invasive pulmonary aspergillosis
assessed serum galactomannan as a diagnostic tool in (grade A recommendation, level of evidence IIt).
children with symptoms potentially suggestive of invasive Similarly, there is data to support the utility of
fungal disease, and in a further study published in the galactomannan testing in the cerebrospinal fluid (optical
interim,18 similar observations were made for specificity, density index threshold 1·0) of both adults and paediatric
sensitivity, and positive predictive value, whereas the patients to assess involvement of the CNS (grade A
negative predictive value ranged from 70% to 100%. recommendation, level of evidence II; table 1).25–28
Considering the pooled sensitivity (81% [95% CI 69–89]) β-D-glucan can be detected in the serum of patients
and specificity (88% [95% CI 75–95]) of all 18 studies,3 the with invasive fungal disease caused by Aspergillus spp,
data are consistent with the results from a meta-analysis Candida spp, Fusarium spp, Trichosporum spp or
of galactomannan testing in adults (sensitivity 82% Saccharomyces spp, and Pneumocystis jirovecii, but also in
[95% CI 73–90] and specificity 81% [95% CI 72–90]),19 patients with some bacterial infections. The presence of
suggesting that the performance of galactomannan β-D-glucan in the serum is a mycological criterion for
testing in children is similar to that in adults. probable invasive candidiasis and probable pneumo
On the basis of these data, prospective monitoring of cystosis (but not for aspergillosis) in the revised EORTC/
galactomannan in serum twice per week should, in MSGERC invasive fungal disease definitions.16 Although
principle, be considered for early diagnosis of invasive a meta-analysis of studies in adults showed that β-D-
aspergillosis in paediatric patients at high risk of invasive glucan testing has good diagnostic accuracy for the early
fungal disease (grade A recommendation, level of diagnosis of invasive fungal disease,29 data on β-D-glucan
evidence II; table 1). However, because administration of testing in paediatric patients at high risk of invasive
systemic mould-active antifungal prophylaxis has been fungal diseases using a similar threshold for positivity
shown (in adults) to decrease the performance of the (80 pg/mL) are very scarce.3,30–32 Considering that the
galactomannan assay,20 prospective monitoring of optimal threshold for positivity in paediatric patients
galactomannan in serum is discouraged in patients on remains undefined,3,33 the poor predictive value (17–49%)
mould-active prophylaxis (grade D recommendation, level of a positive test result in the available paediatric studies,
of evidence IIt) and, thereby, has a restricted role in most and the absence of a clinically important discrimination
high-risk patients. In contrast to the previous version between yeasts and moulds, β-D-glucan testing in serum
of the guideline5 and to a paediatric Clinical Practice is currently discouraged for prospective monitoring or
Guideline,17 the galacto mannan assay is now strongly diagnostic use in paediatric patients at high risk of
recommended as a diagnostic tool in paediatric patients invasive fungal disease (grade D recommendation, level
at high risk of invasive fungal disease with symptoms of evidence II; table 1). Data on β-D-glucan testing in
potentially suggestive of invasive fungal disease, cerebrospinal fluid in patients with suspected CNS
including prolonged fever during granulocytopenia and involvement are too scarce34 to make any recommendation,
abnormalities on CT imaging of the chest (grade A and its use as a diagnostic adjunct in bronchoalveolar
recommendation, level of evidence II). This difference in lavage fluid is discouraged due to the frequent
recommending the galactomannan assay as a diagnostic colonisation or contamination of this anatomical site by
tool is due to the results of the meta-analysis3 and to the Candida spp from the oropharynx, which results in false-
different methods used for the development of the positive results (no grading).
guideline.17 Consistent with the threshold used in adults,3,25
the threshold for a positive test result in serum is an Detection of fungal nucleic acids
optical density index of 0·5 or higher (grade B Standardised PCR-based diagnostic methods for blood or
recommendation, level of evidence II). This clinical bronchoalveolar lavage fluid35,36 are now included in the
threshold is based on the meta-analysis and not necessarily EORTC/MSGERC consensus group criteria as diagnostic
identical to the threshold used in the revised EORTC/ methods to confirm the microbiological diagnosis of
MSGERC invasive fungal disease definitions.16 Careful invasive aspergillosis, and are also accepted for species
interpretation of test results is necessary due to the test’s identification in frozen tissue and when moulds or yeasts
inherent limitations, including poor positive predictive are seen in formalin-fixed paraffin-embedded tissue.16
values with potential for unnecessary treatment, high Four studies investigating multifungal or Aspergillus-
negative predictive values that do not rule out the presence specific PCR screening in serum, plasma, or whole blood

Policy Review
Grade of Level of Comments References

evidence recommendation
Prospective monitoring of galactomannan in serum twice A II Performance of galactomannan assay in children is similar to that in adults; careful 3,18,19
per week or for early diagnosis of invasive aspergillosis in interpretation is necessary because of limitations such as poor positive predictive
paediatric patients at high risk of invasive fungal disease and values, high negative predictive values, assay not being validated in patients
not receiving mould-active prophylaxis without granulocytopenia patients, and several potential causes of false-positive
galactomannan test results
Prospective monitoring of galactomannan in serum is D IIt Administration of systemic mould-active antifungal prophylaxis decreases the 3,20
discouraged in patients on mould-active prophylaxis performance of the galactomannan assay
Diagnostic utility of detecting galactomannan in serum of A II Performance of galactomannan assay in children is similar to that in adults; careful 3
paediatric patients with prolonged febrile neutropenia, interpretation is necessary due to limitations such as poor positive predictive
abnormalities in chest CT imaging, or both values, high negative predictive values, assay not being validated in non-
granulocytopenic patients, and several potential causes of false-positive
galactomannan test results
Optical density index of ≥0·5 as a threshold for a positive B II None 3,19
result of galactomannan in serum testing
Galactomannan in bronchoalveolar lavage with an optical A IIt Supported by data from studies in adults and two retrospective paediatric studies 21–24
density index threshold for a positive test of 1·0 is an
adjunctive tool for diagnosis of invasive pulmonary
aspergillosis
Galactomannan in cerebrospinal fluid with an optical density A II Supported by data from studies in adults and a few paediatric patients with 25–28
index threshold for a positive test of 1·0 is an adjunctive probable and proven CNS aspergillosis (assay not validated in cerebrospinal fluid)
method for diagnosis of central nervous system aspergillosis
Beta-D-glucan testing in serum is not recommended for D II Poor positive predictive values in patients at high risk with fever and 3,16,21,29–
prospective monitoring or diagnostic use granulocytopenia; although included as a mycological criterion in the 33
EORTC/MSGERC definitions of invasive fungal diseases, data in children are very
scarce and the optimal threshold for positivity of beta-D-glucan testing in children
is unknown
Beta-D-glucan testing in cerebrospinal fluid (no grading) NA NA No grading because of extremely scarce data in adults and children 34
Detection of fungal nucleic acids in plasma, serum, or whole NA NA No grading due to the inexistence of validated data 3,16,32,35–
blood for prospective monitoring (no grading) 37
Detection of fungal nucleic acids in plasma, serum, or whole B IIt Standardised, PCR-based methods in plasma, serum, or whole blood included in 16
blood for diagnostic use the 2019 revised EORTC/MSGERC invasive fungal disease definitions
Detection of fungal nucleic acids in bronchoalveolar lavage, A IIt Should be done preferentially in a reference laboratory; supported by well 23,38–41
cerebrospinal fluid, body fluids, and tissue specimen is documented cases and case series
recommended whenever these specimens are obtained
High-resolution CT scan of the chest should be performed in A II Signs considered typical of invasive fungal diseases in adults (eg, halo sign, 42–44
patients at high risk with febrile granulocytopenia that air crescent sign, and cavities) are not seen in the majority of children with
persists beyond 96 h or with focal clinical findings pulmonary mould infections; radiographic findings are often unspecific,
in particular in children younger than 5 years; optimal timing of initial and
repeated imaging in children not known
Typical and non-typical pulmonary infiltrates might be A II None 18,45–49
indicative of pulmonary invasive fungal disease and should
prompt further diagnostic testing and initiation of
mould-active antifungal treatment
CT of the paranasal sinuses should only be performed in B III Few studies directly address the utility of routine CT of the sinuses 17
patients with localising signs or symptoms
Appropriate cranial imaging (MRI preferred) should be B II CNS involvement in pulmonary mould infections is frequent; a retrospective 50–52
considered in patients with probable or proven pulmonary analysis of 29 children with mould infection in the CNS showed that 8 (28%) did
mould infection, even when neurologically asymptomatic not have neurological symptoms
EORTC=European Organisation for Research and Treatment of Cancer. MSGERC=Mycoses Study Group Education and Research Consortium. NA=not applicable (no grading).
Table 1: Recommendations for the use of non-culture diagnostic tools for early diagnosis of invasive fungal diseases in paediatric patients with cancer or after haematopoietic cell
transplantation
found specificity to range between 43% and 85%, was 88–100%. In the only study in which mould-active
sensitivity between 11% and 80%, the positive predictive antifungal prophylaxis was given to all patients, the positive
value between 20% and 50%, and the negative predictive predictive value of Aspergillus-specific PCR was not
value between 60% and 96%.3,37 In nine studies in determined.3,32 Although data synthesis in the screening
which PCR-based assays were used for diagnosis in setting was not possible in the meta-analysis because of
patients with suspected invasive aspergillosis, specificity the low number of appropriate studies, six studies
was 36–83%, sensitivity was 0–100%, the positive predictive evaluating PCR-based assays as a diagnostic test showed a
value was 0–71%, and the negative predictive value pooled sensitivity of 76% (95% CI 62–86%) and a pooled

Policy Review
specificity of 58% (95% CI 42–72%).3 On the basis of this the paranasal sinuses should only be done in patients
analysis and due to the absence of validated data, with localising signs and symptoms (grade B recom
unfortunately, no recommendation can be made for the mendation, level of evidence III). CNS involvement in
use of PCR for prospective monitoring of paediatric pulmonary mould disease is frequent in both paediatric
patients at high risk of developing invasive fungal diseases. and adult patients.50,51 A comprehensive retrospective
Despite the remaining interinstitutional variations in test analysis in paediatric patients with cancer or after
performance and the overall suboptimal specificity of the allogeneic HCT and with mould infections of the CNS
test, PCR-based assays in plasma, serum, or whole blood showed that 8 (28%) of 29 patients did not have
can be recommended for diagnostic use only, with neurological signs and symptoms.52 Despite the low level
moderate support (grade B recommendation, level of of evidence for potential benefit in the individual patient,
evidence IIt; table 1). appropriate cranial imaging should be evaluated in
The use of PCR and other molecular methods on patients with probable or proven pulmonary mould
bronchoalveolar lavage fluid,23,27,38,39 diagnostic aspirates, disease, even in the absence of neurological signs and
or tissue specimen40,41 is supported by case series and symptoms (grade B recommendation, level of evidence II;
is strongly recommended whenever the respective table 1).
specimens are obtained (grade A recommendation, level
of evidence IIt). If molecular diagnostics are not available, Recommendations for prophylaxis of invasive
specimens should be sent to an appropriate reference fungal diseases
laboratory. Primary antifungal chemoprophylaxis
Paediatric guidelines strongly recommend primary
Diagnostic imaging antifungal prophylaxis in patients who are at high risk of
In adults, systematic CT imaging of the chest allows earlier developing invasive fungal diseases to reduce disease-
diagnosis of invasive pulmonary aspergillosis and, thereby, related morbidity and mortality (invasive fungal diseases
improves prognosis.42,43 CT imaging of the chest also is a with an incidence of ≥10% are usually considered of high
useful tool for early response prediction.44 Pulmonary risk).5,14,15 However, although the paediatric patient popu
nodules, in particular those with the halo sign, the air lation at high risk is well characterised and unchanged
crescent sign, cavitation, wedge-shaped, and segmental or over time (appendix pp 3–7), the local epidemiology is an
lobar consolidations are considered typical findings for important additional consideration for designing an
mould-associated pneumonia in adults with cancer or institutional prophylaxis strategy that is ideally embedded
HCT recipients and are included as clinical criteria in the into an antifungal stewardship programme.53 Further
EORTC/MSGERC definitions of invasive fungal diseases.16 more, low or sporadic risk is not equal to a null risk, and
However, the available studies in paediatric patients with a personalised assessment might be indicated for
cancer who present with persistent fever, granulocytopenia, individual patients based on specific individual risk
and proven pulmonary invasive fungal disease indicate factors and on new anticancer treatments.54
that imaging findings are often non-specific in this A considerable number of retrospective and prospective
population.45–49 In children younger than 5 years in observational paediatric studies have been done with
particular, signs considered typical of pulmonary mould different mould-active and mould non-active agents.55–58
infection in adults are not usually observed; instead, Two randomised, double-blind studies of antifungal
multiple nodules or fluffy masses and mass-like lesions chemoprophylaxis, in which approximately 10% of
have been reported as the two main types of abnormalities.17 patients were infants, children, or adolescents, compared
Because of the pivotal role of early diagnosis, either micafungin or voriconazole to fluconazole in the
CT imaging of the chest is strongly recommended in setting of allogeneic HCT. These two studies provided
children at high risk of invasive fungal disease presenting important safety data for micafungin and voriconazole
with fever and granulocytopenia that persists beyond and no suggestion of different efficacy relative to adults.59,60
96 h, or in those with focal clinical findings (grade A A large multicentre, randomised, open-label trial that
recommendation, level of evidence II). Because typical enrolled 517 patients (of whom 508 completed the trial)
signs of pulmonary invasive fungal disease are often with acute myeloid leukaemia, aged between 3 months
missing, even non-typical pulmonary infiltrates might be and 30 years, compared caspofungin with fluconazole and
indicative of pulmonary invasive fungal disease and showed a significant reduction in the incidence of proven
should prompt further diagnostic investigation and or probable invasive fungal disease with caspofungin
initiation of mould-active antifungal treatment (grade A (3·1% in the caspofungin group vs 7·2% in the fluconazole
recommendation, level of evidence II; table 1). group; HR 0·37 [95% CI 0·15–0·94]; p=0·03) and proven
Other imaging studies might be indicated depending or probable invasive aspergillosis (0·5% vs 3·1%, HR 0·16
on clinical signs and symptoms and on the symptomatic [95% CI 0·02–1·27]; p=0·046).61 However, there was no
region. Based on the small number of studies addressing effect on overall survival and interpretation is limited by
the utility of routine sinus imaging in patients with early termination due to an unplanned interim analysis.61
persistent fever and granulocytopenia,17 a CT or MRI of In a systematic review and meta-analysis of randomised,

Policy Review
controlled trials, mould-active prophylaxis compared with Contraindications, drug–drug interactions, and specific
fluconazole prophylaxis significantly reduced proven or warnings for each compound must be considered.
probable invasive fungal diseases, invasive aspergillosis, Special caution should be exerted with the concomitant
and invasive fungal disease-related mortality in cancer use of antifungal triazoles with immunosuppressants,
patients receiving chemotherapy or HCT, but did not vincristine, and other anticancer agents.4,62 For recom
affect overall mortality.57 A recently published clinical mendations for secondary antifungal prophylaxis, see
practice guideline based on a systematic review of appendix pp 10–11.
systemic antifungal prophylaxis in children and adults
with cancer and HCT recipients, including 68 randomised Recommendations for empirical and pre-
trials of which six (9%) were done in an exclusively emptive (diagnostic-driven) antifungal therapy
paediatric population, concluded with a strong recom Whereas the results of early clinical trials done
mendation to administer systemic antifungal prophylaxis 30 or 40 years ago are difficult to interpret in the current
to paediatric patients with acute myeloid leukaemia, to medical context,5 a meta-analysis comparing empirical
those undergoing allogeneic HCT pre-engraftment, and antifungal treatment with no treatment in adults with
to those receiving systemic immunosuppression for graft- persistent febrile granulocytopenia concluded that
versus-host disease treatment. A strong recommendation antifungal treatment significantly decreased the incidence
was made in this guideline to administer a mould-active of invasive fungal diseases, but did not alter mortality.84
agent with an echinocandin or a mould-active azole when Although no comparable data exist for the paediatric
systemic antifungal prophylaxis is warranted.58 population, empirical antifungal therapy has been a
Considering the conceptual framework of the guideline common practice in children with granulocytopenia and
outlined in the methods section and recommendations persistent or recurrent fever despite appropriate empirical
made for adults,12 table 2 summarises recommendations antibacterial therapy.2 Three prospective ran domised
for primary antifungal prophylaxis in paediatric patients clinical trials compared different anti fungal agents as
at high risk of invasive fungal diseases. Primary empirical antifungal therapy in children (mostly with
antifungal prophylaxis is strongly recommended for leukaemia or after allogeneic HCT).85–87 In these com
patients receiving intensive chemotherapy for acute parisons, caspofungin was equally85 or better86 tolerated
myeloid leukaemia, high-risk acute lymphoblastic than liposomal amphotericin B, and liposomal
leukaemia, and recurrent acute leukaemia, especially amphotericin B was less nephrotoxic than amphotericin B
during prolonged courses of glucocorticosteroids or deoxycholate.87 No difference in efficacy was observed
phases of long-lasting and profound granulocytopenia;5 between caspofungin and liposomal amphotericin,85,86 and
for those undergoing allogeneic HCT in the pre- the efficacy of liposomal amphotericin B was slightly better
engraftment and in the post-engraftment phases until than that of amphotericin B deoxycholate.87 Overall, the
attainment of immune reconstitution; or in situations of paediatric safety and efficacy data are in line with those
augmented immunosuppressive treatment in the context reported in much larger randomised datasets in adults.88,89
of graft-versus-host disease (grade A recommendation, According to the approach used in the clinical registration
level of evidence IIt).5,12 trials, empirical antifungal therapy (if chosen as a strategy)
Whereas the previous guideline made separate should be initiated in children with granulocytopenia at
recommendations for patients with allogeneic HCT high risk of invasive fungal disease after 96 h of fever of
before engraftment, patients with allogeneic HCT after unclear cause that is unresponsive to broad-spectrum
engraftment and graft-versus-host disease, and patients antibacterial agents, and should be continued until
with acute leukaemia, the revised guideline has adopted resolution of granulocytopenia in the absence of suspected
uniform recommendations for all patients at high or documented invasive fungal disease (grade B
risk for reasons of practicability (table 2). In patients recommendation, level of evidence II; table 3). Empirical
who had allogeneic HCT, post-engraftment antifungal antifungal therapy can also be considered in patients with
prophylaxis can be continued until discontinuation of persistent fever, low-risk conditions, profound and long-
immunosuppression and immune recovery. In the lasting granulocytopenia, and severe mucosal damage (no
presence of graft-versus-host disease with augmented grading). The options include either caspofungin or
immunosuppression (including, but not limited to, the liposomal amphotericin, both of which are approved for
use of glucocorticosteroids in therapeutic dosages this indication without age restriction in paediatric patients
[≥0·3 mg/kg per day prednisone equivalent] or of anti- (grade A recommendation, level of evidence I). A similar
inflammatory antibodies), prophylaxis against mould approach can be chosen in patients with granulocytopenia
and yeast infections is recommended. In patients with who develop recurrent fever after defervescence after the
acute leukaemia, prophylaxis is usually given during initiation of broad-spectrum antibacterial agents (no
prolonged courses of glucocorticosteroids (for patients grading). Although no data are available for patients
with acute lymphoblastic leukaemia) and phases of already receiving mould-active antifungal prophylaxis,
prolonged and profound granulocytopenia (for patients switching to a different class of mould-active antifungal
with acute lymphoblastic or acute myeloid leukaemia).5 agents seems reasonable when empirical therapy is

Policy Review
indicated. Of note, other antifungal agents have been empirical antifungal therapy (itraconazole, voriconazole,
investigated for empirical antifungal therapy in adults, and micafungin), their use cannot be recommended for
including itraconazole,95 voriconazole,96 and micafungin.97 the paediatric population (grade D recommendation, level
However, because these compounds are not approved in of evidence IIt). Similarly, the use of amphotericin B
paediatric patients (itraconazole) or not approved for deoxycholate is discouraged on the basis of its
Dose and administration route Grade of Level of Comments References

recommendation evidence
Primary antifungal ·· A IIt Includes patients with acute myeloid leukaemia, recurrent Inference from randomised
prophylaxis is strongly leukaemia, high-risk acute lymphoblastic leukaemia, and those studies in adults with
recommended for undergoing allogeneic HCT in the pre-engraftment and in the non-absorbable antifungal
paediatric patients at post-engraftment phase until immune reconstitution, or in agents as comparator4,12,58,62
high risk situations of augmented immunosuppressive treatment in the
(≥10% estimated context of graft-versus-host disease; augmented
natural incidence) of immunosuppression refers to the use of additional
invasive fungal disease immunosuppressive interventions to control overt graft-
versus-host disease and includes, but is not limited to, the use
of glucocorticosteroids in therapeutic doses (≥0·3 mg/kg per
day prednisone equivalent) or anti-inflammatory antibodies;
attention to drug–drug interaction is needed, particularly with
immunosuppressive agents and vincristine
Fluconazole for patients Single dose of 8–12 mg/kg (max A IIt Fluconazole is active only against yeasts and should only be Clinical trials in adults;57,63–67
with leukaemia and 400 mg) per day intravenously or used if the institutional incidence of invasive mould infections pharmacokinetic and safety
allogeneic HCT in the orally is low, or if there are active diagnostic and therapeutic and efficacy studies in
pre-engraftment phase algorithms for mould infections paediatric patients*
Fluconazole for ·· D IIt Allogeneic HCT post-engraftment: fluconazole not ··
patients with recommended because of to the predominant role of mould
allogeneic HCT in the infections in this setting
post-engraftment
phase
Posaconazole Patients aged 13 years or older: A IIt Spectrum includes both yeasts and moulds; approved for Clinical trials in adults;68,69
delayed-release tablets, 300 mg in adults; a novel delayed-release oral suspension is under pharmacokinetic and safety
one single daily dose (2 × 300 mg evaluation, and no dosing recommendations exist for the and efficacy studies in
on day 1); patients aged 1 month to intravenous formulation, but until approval of the delayed- paediatric patients*;
12 years: oral suspension, starting release suspension, adult doses of the delayed-release tablets TDM dosing target70
dose 6 mg/kg three times daily can be prescribed to paediatric patients aged 13 years and older
(oral suspension is discouraged in this age group); TDM is
suggested (dosing target: trough concentration of ≥0·7mg/L)
Itraconazole Patients aged 2 years or older: B IIt Spectrum includes both yeasts and moulds; approved Clinical trials in adults;71–74
5 mg/kg per day orally in indication, but not approved in patients younger than 18 years; TDM dosing target;70
two divided doses TDM is suggested (dosing target: trough concentration of pharmacokinetic and safety
≥0·5 mg/L) and efficacy studies in
paediatric patients*
Liposomal 1 mg/kg every other day B IIt Spectrum includes both yeasts and moulds; alternative option Clinical trials in adults;75–78
amphotericin B intravenously for patients who do not tolerate or have contraindications to pharmacokinetic and safety
triazoles (not approved for prophylaxis) and efficacy studies in
Liposomal 2·5 mg/kg twice per week B II ·· ··
amphotericin B intravenously
Voriconazole Patients aged 2–12 years, or aged B IIt Spectrum includes both yeasts and moulds; approved for Clinical trials in adults;60,79
12–14 years and weighing less than patients older than 2 years; TDM is suggested (dosing target: TDM dosing target70,80,81
50 kg: 8 mg/kg (9 mg/kg on day 1) trough concentration of 1·0–5·0 mg/L) pharmacokinetic and safety
twice a day intravenously or and efficacy studies in
9 mg/kg twice a day orally; patients paediatric patients*
aged 12–14 years and weighing
50 kg or more, or aged 15 years and
older: 4 mg/kg (6 mg/kg on day 1)
twice a day intravenously or
200 mg twice a day orally
Micafungin 1 mg/kg per day (max 50 mg) C I Spectrum of includes Candida and Aspergillus spp; once daily Clinical trials in adults;59,82
once daily intravenously regimen approved for prophylaxis of invasive Candida spp pharmacokinetic and safety
infections in patients with granulocytopenia and efficacy studies in
Micafungin 4 mg/kg twice weekly C II Twice weekly dosing supported by pharmacokinetic and ··
observational data
(Table 2 continues on next page)

Policy Review

(Continued from previous page)
Aerosolised liposomal 12·5 mg on 2 consecutive days per NA NA Targeted against pulmonary mould infections; non-approved Clinical trial in adults83
amphotericin B week route of administration, appropriate doses and dose schedule
unknown in patients younger than 18 years (no grading)
Caspofungin 50 mg/m² per day (70 mg/m² NA NA Potential new option for mould-active prophylaxis (no grading Clinical trial in paediatric and
on day 1) intravenously in because data published after the meeting and non-approved young adults;61
one single dose indication) pharmacokinetic and safety
and efficacy studies in
Isavuconazole 10 mg/kg (maximum 372 mg total NA NA No approved indication and not approved in paediatric No controlled studies in
dose) isavuconazonium sulfate patients. Suggested dose corresponds to that under adults; pharmacokinetic
intravenously once daily (every 8 h investigation in a paediatric phase 2 trial (EudraCT number study in paediatric patients*
on days 1–2) 2018-003975-36) conducted as part of the European
Medicines Agency’s Paediatric Investigation Plan (no grading)
HCT=haematopoietic cell transplantation. NA=not applicable (no grading). TDM=therapeutic drug monitoring. *Appendix pp 22–25.
Table 2: Recommendations for primary chemoprophylaxis of invasive fungal diseases in paediatric patients with cancer or after haematopoietic cell transplantation
Grade of Level of Comments References

Empirical antifungal therapy: if chosen as a B II Randomised clinical trials with both caspofungin and liposomal Clinical trials in paediatric
strategy, it should be initiated in paediatric amphotericin B done in paediatric patients show safety and efficacy patients;85–87 clinical trials in
patients with granulocytopenia at high risk after similar to that of much larger trials in adults with similar study design; adults;88,89 pharmacokinetic and
96 h of fever of unclear cause that is unresponsive both compounds are approved for empirical antifungal therapy in both safety and efficacy studies in
to broad-spectrum antibacterial agents children and adults paediatric patients*
Caspofungin (50 mg/m² per day, 70 mg/m² on A I For liposomal amphotericin B, approved doses differ in different ··
day 1) or liposomal amphotericin B (1–3 mg/kg per countries, with data being stronger for the 3 mg/kg dose
day)
Pre-emptive (diagnostic driven) therapy B II Rapid availability of pulmonary CT and galactomannan assay results is a Clinical trials in adults;90–92
prerequisite and capability of performing bronchoscopies with recommendations in adults;8,93
bronchoalveolar lavage is desirable; note that the sensitivity of clinical trials in paediatric
galactomannan in serum might be lower in patients on mould-active patients94
prophylaxis
NA=not applicable (no grading). *Appendix pp 22–25.
Table 3: Recommendations for antifungal therapy in paediatric patients with cancer or after haematopoietic cell transplantation
nephrotoxicity and high rates of infusion-related reactions favour of the pre-emptive therapy cohort, supporting the
(grade D recommendation, level of evidence I).87,88 feasibility of the pre-emptive, diagnostic-driven approach
The intention of pre-emptive (or diagnostic-driven) in the paediatric population.94 Based on this study, pre-
antifungal therapy, which uses clinical, mostly non- emptive therapy might be applied as an alternative
culture-based, microbiological and radiographic para strategy to the empirical antifungal approach in paediatric
meters to determine whether or not to start antifungal patients (grade B recommendation, level of evidence II),
therapy in patients with granulocytopenia, is to reduce although it requires rapid availability of pulmonary
the exposure to potentially unnecessary antifungal CT imaging and of galactomannan-assay results, and,
treatment. The feasibility of this strategy has been shown ideally, the ability to perform diagnostic bronchoscopies
in adults90–92 and it has been accepted as an alternative to with bronchoalveolar lavage (table 3).
the empirical approach in a subset of adult patients with
granulocytopenia at high risk of invasive fungal disease.8,93 Recommendations for targeted treatment of
In the meantime, a multicentre, randomised clinical trial invasive fungal diseases
comparing the efficacy of pre-emptive versus empirical Treatment recommendations for invasive Candida
antifungal therapy in 149 children with granulocytopenia infections
and persistent fever has been completed.94 Although no The general principles of management of invasive Candida
differences were found in overall mortality, invasive spp infections in paedatric patients have not changed and
fungal disease-related mortality, and the incidence of continue to be similar to those for adults. They include the
proven or probable invasive fungal diseases, a significant prompt initiation of antifungal therapy, resistance testing
reduction in the use of antifungal drugs was observed in of all invasive isolates, control of predisposing conditions,

Policy Review
surgery as appropriate, and the removal of indwelling In comparison with other Candida spp, echinocandins
intravenous catheters and other prosthetic devices. In all have higher minimum inhibitory concentrations for
cases of candidaemia, clinical evaluation of deep sites of Candida parapsilosis;120 however, no diminished clinical
infection, including an ophthalmological examination, is efficacy of echinocandins against these species has been
required. The optimal duration of therapy for uncom noted in randomised clinical trials (appendix pp 24–25),
plicated candidaemia is 14 days after blood cultures have and an observational study reported no differences in
become sterile and the patient has recovered from 30 day mortality and persistent candidaemia at 72 h with
neutropenia. For tissue-invasive candidiasis, the affected echinocandin-based verus azole-based therapy for patients
site, the patient’s response, and resolution of predisposing with candidaemia caused by C parapsilosis.121 Treatment
conditions determine the duration of treatment.5,13,14,98 with fluconazole is not recommended for infections
On the basis of the adult ECIL guidelines updated in with Candida krusei and Candida glabrata because C krusei
2017,13 a patient-level quantitative review of seven published is inherently resistant and C glabrata is variably sus
randomised trials on invasive candidiasis,99 a systematic ceptible to fluconazole (no grading).122 Because of the high
review of 17 randomised clinical trials focusing on invasive pharmacokinetic variability of voriconazole, therapeutic
candidiasis in granulocytopenic patients,100 a randomised drug monitoring is recommended when this compound
comparison of liposomal amphotericin versus mica is being used.70,80,81
fungin,101 quality pharmacokinetic and safety data, and
regulatory approval for paediatric patients for this Treatment recommendations for invasive Aspergillus
indication, echinocandins or liposomal amphotericin B infections
are strongly recommended for the first-line treatment of The general principles of management of invasive
invasive Candida spp infections before species identifi Aspergillus spp infections in paediatric patients have not
cation (table 4). The grading (grade A, level of evidence IIt) changed and continue to be similar to those for adults,
is the same for anidulafungin, caspofungin, micafungin, and include the prompt initiation of antifungal therapy,
and liposomal amphotericin B, and applies to all patients, control of predisposing conditions (eg, colony-stimulating
regardless of their absolute neutrophil count and factors for patients with granulocytopenia, and reduction
haemodynamic status. However, the safety profile of each of immunosuppressive therapy, parti cularly discon
of these agents needs to be taken into account for each tinuation or tapering of gluco corticosteroids), and
individual patient. surgical interventions on a case-by-case basis using a
Voriconazole and fluconazole are secondary options for multidisciplinary approach. Granulocyte transfusions can
first-line treatment (grade B recommendation, level of be considered in individual patients with profound and
evidence IIt).13 Voriconazole is not approved for patients persistent granulocytopenia. A thorough evaluation for
with granulocytopenia, and there is now a strong further sites of infection, particularly the CNS, is required.
recommendation against the use of fluconazole for initial The optimal duration of therapy is not defined but will be
treatment in patients with granulocytopenia or haemo determined by the resolution of all signs and symptoms
dynamic instability (grade D recommendation, level of and reversal of the underlying deficit in host defences.5,13,15
evidence IIt). Isavuconazole is not approved for paediatric Recommendations for initial antifungal treatment of
patients or for primary treatment of invasive candidiasis invasive aspergillosis (table 4) are similar in their ranking
on the basis of inferiority compared with caspofungin in to the ECIL-4 guideline and include intravenous
a randomised registration trial.102 voriconazole coupled with therapeutic drug monitoring
Amphotericin B lipid complex is another option with (grade A recommendation, level of evidence IIt;
lower grading (grade C, level of evidence II) because of limited to children aged 2 years or older),107,108 liposomal
the absence of completely published phase 3 clinical ampho tericin B (grade B recommendation, level of
trials data and of the limited paediatric pharmacokinetic evidence IIt),109 and amphotericin B lipid complex
studies available. Finally, combination antifungal therapy (grade C recom mendation, level of evidence II).106
(eg, amphotericin B plus flucytosine and other Whereas the grade A, level of evidence IIt recom
combinations) can be considered in special situations mendation for voriconazole is based on two phase 3 trials
(eg, severe, life-threatening infection, compromised drug in adults,107,108 the weaker grade B, level of evidence IIt
penetration in CNS infection, complicated bone and recommendation for liposomal amphotericin B is due to
joint infections, and urinary tract and intra-abdominal the fact that the pivotal phase 3 trial was a comparison
infections; no grading).5,14 between two different dosing strategies and not a head-
A switch in class should be considered in patients to-head comparison with the reference agent.109 However,
with breakthrough infections on antifungal prophylaxis liposomal amphotericin B is the first option for treatment
or empirical therapy (no grading). When the isolate is when azole resistance is suspected or confirmed (no
azole-susceptible, a stepdown to fluconazole can be grading). The results of a randomised, comparative
considered in stable patients without granulocytopenia, clinical trial of voriconazole plus anidulafungin110 showed
after a minimum of 5 days of intravenous therapy (no no difference in the primary endpoint, providing
grading).103–105 marginal support for its use in primary treatment of

Policy Review
invasive aspergillosis (grade C recommendation, level of although there are no specific data, a switch in class
evidence IIt). No data of adequate quality are available to should be considered in patients with breakthrough
support other forms of combination therapy. Of note, infections on antifungal prophylaxis or empirical therapy

Invasive candidiasis
Caspofungin Single dose 50 mg/m² per day (70 mg/m² on A IIt Consider for patients with granulocytopenia and Clinical trials in adults;102
day 1) intravenously haemodynamic instability; higher minimum inhibitory appendix p 26;
concentrations against Candida parapsilosis but no pharmacokinetic and
diminished efficacy against these species noted in safety and efficacy studies
randomised clinical trials in adults in paediatric patients*
Liposomal amphotericin B Single dose 3 mg/kg per day intravenously A IIt Consider for patients with granulocytopenia and Clinical trials in adults;103
haemodynamic instability pharmacokinetic and
safety and efficacy studies
in paediatric patients*
Micafungin Single dose 2–4 mg/kg per day A IIt Consider for patients with granulocytopenia and Clinical trials in adults;103
intravenously (100–200 mg for patients haemodynamic instability; higher minimum inhibitory appendix p 26;
weighing 50 kg or more) concentrations against C parapsilosis but no diminished pharmacokinetic and
efficacy against these species noted in randomised safety and efficacy studies
clinical trials in adults in paediatric patients*
Voriconazole Patients aged 2–12 years, or aged B IIt Only approved for patients without granulocytopenia, Clinical trials in adults;103
12–14 years and weighing less than 50 kg: not approved for patients younger than 2 years; relative TDM dosing target;70,80,81
8 mg/kg (9 mg/kg on day 1) twice a day to fluconazole, spectrum extends to Candida glabrata pharmacokinetic and
intravenously or 9 mg/kg twice a day orally; and Candida krusei; TDM is suggested for all patients safety and efficacy studies
patients aged 12–14 years and weighing (dosing target: trough concentration of between in paediatric patients*
50 kg or more, or aged 15 years and older: 1·0 and 5·0 mg/L)
4 mg/kg (6 mg/kg on day 1) twice a day
intravenously or 200 mg twice a day orally
Fluconazole Single dose 12 mg/kg (maximum 800 mg) B IIt Consider only for patients with no granulocytopenia or Clinical trials in adults;104
per day intravenously or orally (stepdown haemodynamic instability; not recommended for appendix p 26;
only) infections by C krusei and C glabrata; maximum pharmacokinetic and
approved dose advised; option to stepdown after safety and efficacy studies
minimum of 5 days of intravenous therapy for stable in paediatric patients;*
patients for the stepdown103–105
Fluconazole Single dose 12 mg/kg (maximum 800 mg) D IIt Not recommended for patients with granulocytopenia ··
per day intravenously and haemodynamic instability
Amphotericin B lipid Single dose 5 mg/kg per day intravenously C II Lower grading because of absence of completely Clinical trials in adults;106
complex published first-line phase 3 data and few paediatric appendix p 26;
pharmacokinetic studies; can be used in patients with pharmacokinetic and
granulocytopenia and haemodynamic instability safety and efficacy studies
Anidulafungin Single dose 1·5 mg/kg (3 mg/kg on day 1) A IIt Consider for patients with granulocytopenia and Clinical trials in adults;104
per day intravenously haemodynamic instability higher minimum inhibitory pharmacokinetic and
concentrations against C parapsilosis, not associated safety and efficacy studies
with diminished efficacy; regulatory approval for in paediatric patients*
paediatric patients recently granted by the European
Medicines Agency
Invasive aspergillosis
Voriconazole Patients aged 2–12 years, or aged A IIt Approved for patients older than 2 years; Clinical trials in
12–14 years and weighing less than 50 kg: TDM suggested (target:trough concentration of adults;107,108 TDM dosing
8 mg/kg (9 mg/kg on day 1) twice a day between 1·0 and 5·0 mg/L); current treatment of target;70,80,81
intravenously or 9 mg/kg twice a day orally; choice for infections involving the CNS; a switch in pharmacokinetic and
patients aged 12–14 years and weighing class is to be considered in patients with breakthrough safety and efficacy studies
50 kg or more, or aged 15 years and older: aspergillosis on mould-active azole prophylaxis in paediatric patients*
4 mg/kg (6 mg/kg on day 1) twice a day
intravenously or 200 mg twice a day orally
Liposomal amphotericin B Single dose 3 mg/kg per day intravenously B IIt Pivotal phase 3 trial compared two different doses but Clinical trials in adults;109
no head-to-head comparison to the reference agent at pharmacokinetic and
the time of its conduct (ie, voriconazole); first option if safety and efficacy studies
azole resistance is suspected or confirmed in paediatric patients*
Amphotericin B lipid Single dose 5 mg/kg per day intravenously C II No controlled first-line data available, but there are Clinical trials in adults;106
complex solid second-line data from treatment-naive patients pharmacokinetic and
receiving the compound on the basis of its improved safety and efficacy studies
safety profile relative to amphotericin B deoxycholate in paediatric patients*
(Table 4 continues on next page)

Policy Review

recommendation evidenc
(Continued from previous page)
Combination therapy ·· C IIt Randomised clinical trial of voriconazole plus 110,111
(voriconazole or liposomal anidulafungin versus voriconazole in adults showed no

amphotericin B plus differences in the primary endpoint; randomized
echinocandin) clinical trial of liposomal amphotericin B plus
caspofungin was underpowered
Isavuconazole 10 mg/kg (maximum 372 mg) A† IIt† Equivalent to voriconazole in randomised phase 3 Clinical trials in adults;108
isavuconazonium sulfate intravenously clinical trial in adults; paediatric development ongoing pharmacokinetic studies
once daily (every 8 h on days 1–2) in phase 2 trials in paediatric patients*
Mucormycosis
Liposomal amphotericin B Single dose 5–10 mg/kg per day A IIt Preferred first-line therapy, particularly for infections Clinical trials in
intravenously involving the CNS or in patients with renal failure adults;70,112–115
pharmacokinetic and
Amphotericin B lipid Single dose 5·0–7·5 mg/kg per day B II Solid data from treatment-naive patients receiving the Clinical trials in
complex intravenously compound on the basis of its improved safety profile adults;106,116
relative to amphotericin B deoxycholate pharmacokinetic and
Combination therapy ·· C III No conclusive data for or against a benefit of the Clinical data in adults;117,118
(lipid amphotericin B combination preclinical data (appendix
formulation plus p 27)
caspofungin or
posaconazole)
Isavuconazole 10 mg/kg (maximum 372 mg) B† IIt† Approved for adults as first-line therapy if amphotericin Clinical trials in adults;119
isavuconazonium sulfate intravenously B treatment is not appropriate; paediatric development pharmacokinetic studies
once daily (every 8 h on days 1–2) ongoing, no paediatric efficacy data in paediatric patients*
NA=not applicable (no grading). TDM=therapeutic drug monitoring. *Appendix pp 22–25. †Provisional recommendation, pending regulatory approval for paediatric patients by the Europeans Medicine Agency.
Table 4: Recommendations for antifungal therapy of proven or probable invasive fungal diseases in paediatric patients with cancer or after haematopoietic cell transplantation
(no grading). Isavuconazole, a newer second-generation evidence IIt)112–115,125 and, with lesser strength, ampho
antifungal triazole, was equivalent to voriconazole in a tericin B lipid complex (grade B recommendation, level
phase 3 clinical trial in adults108 and is approved by the of evidence II).106,116 For pharmacokinetic and pharma
European Medicines Agency for the first-line treatment codynamic reasons,127 liposomal amphotericin B is the
of invasive aspergillosis in adults. While paediatric preferred drug to treat CNS infections, and, because of its
development is ongoing, the group agreed on a lower renal toxicity, for patients with renal failure.128 Due
provisional grade A, level of evidence IIt recommendation to the absence of adequate data, combination therapies of
that is contingent on regulatory approval of isavuconazole lipid amphotericin B plus caspofungin or posaconazole
for paediatric patients by the European Medicines can be recommended with marginal strength only
Agency. For recommendations for second-line treatment, (grade C recommendation, level of evidence III).117,118,123
see appendix pp 11–15. On the basis of a single-arm, open-label trial using
amphotericin B as comparator in a matched case–control
Treatment recommendations for mucormycosis analysis,119 isavuconazole has been approved for the
General principles in the management of mucormycosis treatment of mucormycosis in adults when treatment
are similar to those outlined for invasive aspergillosis.13,123 with amphotericin B in not appropriate. Since paediatric
In patients with mucormycosis, no recommendation for development of isavuconazole is ongoing, no recom
or against the use of hyperbaric oxygen can be made mendations can be made for first-line treatment of
(no grading); on the basis of a randomised pilot trial, the mucormycosis (no grading). For recommendations for
adjunctive use of deferasirox is not recommended second-line treatment, see appendix pp 12–15.
(grade D recommendation, level of evidence IIt).123
Independently of age, the outcome of mucormycosis Treatment recommendations for infections by rare
crucially depends on the prompt initiation of treatment filamentous fungi and rare yeasts
with amphotericin B and surgery.124–126 Recommendations Recommendations for rare filamentous fungi are based
for the first-line treatment of mucormycosis are similar on preclinical in-vitro and in-vivo data and few case series,
to those in adults (table 4) and include liposomal and generally do not differ between paediatric and adult
amphotericin B (grade A recommendation, level of patients. Differentiated recommendations for the different

Policy Review
DE and ER moderated the panel debate about the findings of the

Search strategy and selection criteria literature review and the proposed recommendations. All authors
revised the manuscript and provided final approval for its publication.
Medical subject heading terms and free-text terms were used
Declaration of interests
in combination as keywords to search the MEDLINE, PubMed, AHG reports research support from Gilead Sciences, Merck Sharp and
and Cochrane databases for articles published in English Dohme, and Pfizer; is a consultant for Amplyx, Astellas, Basilea, F2G,
between Jan 1, 2010, and June 30, 2019. Abstracts presented Gilead Sciences, Merck Sharp and Dohme, and Pfizer; and served at the
between 2017 and 2019 at international infectious diseases speakers’ bureau of Astellas, Basilea, F2G, Gilead Sciences, Merck Sharp
and Dohme, and Pfizer. FL served at the speakers’ bureau of Gilead
meetings, including European Society of Clinical Sciences and Basilea. DA reports research support from Merck Sharp
Microbiology and Infectious Diseases meetings and IDWeek, and Dohme; was a consultant for Pfizer; and served at the speakers’
were also screened but used only as preliminary and bureau of GlaxoSmithKline. EC is a consultant for Angelini Pharma and
supporting data. Used search terms were “paediatric”, “child”, Ferrer. CG-V reports research grants from Gilead Sciences and Merck
Sharp and Dohme; and served at the speakers’ bureau of Gilead Sciences,
“children”, “haematology”, “cancer”, “leukaemia”, “stem cell Merck Sharp and Dohme, Novartis, Pfizer, Jannsen, and Lilly. JK is a
transplantation”, “mycoses”, “invasive fungal diseases”, consultant for Bayer. ER reports research grants from Astellas, Gilead
“aspergillosis”, “candidiasis”, “mucormycosis”, “risk factors”, Sciences, Merck Sharp and Dohme, and Pfizer; and is a scientific advisor
“epidemiology”, “diagnosis”, “galactomannan”, and member of speakers’ bureaus for Astellas, Gilead Sciences, Merck
Sharp and Dohme, and Pfizer. JS reports scientific grants or serving at
“beta-D-glucan”, “polymerase chain reaction”, “computed the speakers’ bureau of Merck Sharp and Dohme, Gilead Sciences,
tomography”, “magnetic resonance imaging”, “antifungal”, Roche, Pfizer, and Astellas; and participated in the advisory board of
“prophylaxis”, “therapy”, “empirical”, “pre-emptive”, Gilead Sciences, Merck Sharp and Dohme, Roche, and Pfizer. AW reports
“diagnostic-driven”, and “treatment”. Retrieved publications research support from Gilead Sciences; and served at the spearker’s
bureau of Gilead Sciences. TL reports unrestricted research support from
were manually screened for additional references. Gilead Sciences; is a consultant for Gilead Sciences, Merck Sharp and
Dohme, Pfizer, Astellas, and Roche; and serves at the speakers’ bureau of
Gilead Sciences, Merck Sharp and Dohme, Astellas, Pfizer, and
entities is beyond the scope of these guidelines, and the GlaxoSmithKline. All other authors declare no competing interests.
reader is referred to existing international European Acknowledgments
Confederation of Medical Mycology guidelines129 that The ECIL is a joint initiative of the following groups or organisations: the
Infectious Diseases Working Party of the European Society for Blood and
include paediatric-specific considerations.
Marrow Transplantation, the former Infectious Diseases Group of the
Similarly, rare yeasts and cryptococcosis are sporadic European Organisation for Research and Treatment of Cancer, the
causes of invasive fungal diseases. Although treatment International Immunocompromised Host Society, and the European
recommendations do not necessarily differ to those Leukaemia Net. We thank Geraldine Bezamat and the staff of GL events,
Lyon, France, for the organisation of the meeting, and Sandra Kunz for
made for the adult population, the reader is referred to her invaluable support in the editing of the final manuscript. The ECIL-8
the existing international guidelines for cryptococcosis130 meeting (Sept 19–21, 2019) was supported by unrestricted educational
and infections by rare yeast,131 which also include grants from Basilea Pharmaceuticals, Cidara Therapeutics, F2G, Gilead
recommendations for paediatric patients. Sciences, Merck Sharp and Dohme, and Takeda. Basilea Pharmaceuticals,
Cidara Therapeutics, F2G, Gilead Sciences, Merck Sharp and Dohme, and
Takeda had no role in the selection of experts and the design of the
Conclusion guideline, in the collection, analysis, and interpretation of the data at any
The updated ECIL-8 guidelines are intended to improve time including the consensus conference, or in the writing and editing of
prevention, diagnosis, and treatment of invasive fungal the guideline and in the decision to submit it for publication.
diseases in paediatric patients with cancer or undergoing References
1 Fisher BT, Robinson PD, Lehrnbecher T, et al. Risk factors for
allogeneic HCT. Although there are individual differences invasive fungal disease in pediatric cancer and hematopoietic stem
in specific recommendations in comparison with existing cell transplantation: a systematic review. J Pediatric Infect Dis Soc
clinical practice guidelines,3,17,58 these differences originate 2018; 7: 191–98.
in the different metho dological approach used in the 2 Lehrnbecher T, Groll AH. Pre-emptive versus empirical antifungal
therapy in immunocompromised children.
clinical practice guidelines and are not necessarily Lancet Child Adolesc Health 2019; 3: 518–20.
contradictory. For a comprehensive narrative summary of 3 Lehrnbecher T, Robinson PD, Fisher BT, et al. Galactomannan,
the updated recommendations and the changes relative to β-d-glucan, and polymerase chain reaction-based assays for the
diagnosis of invasive fungal disease in pediatric cancer and
the previous version, see appendix pp 16–19. The updated hematopoietic stem cell transplantation: a systematic review and
guidelines should be integrated into algorithms that are meta-analysis. Clin Infect Dis 2016; 63: 1340–48.
tailored to the specific patient population and the fungal 4 Lestner JM, Smith PB, Cohen-Wolkowiez M, Benjamin DK Jr,
Hope WW. Antifungal agents and therapy for infants and children
epidemiology of each institution, and they should ideally with invasive fungal infections: a pharmacological perspective.
be implemented within an antifungal stewardship pro Br J Clin Pharmacol 2013; 75: 1381–95.
gramme.53 Nevertheless, personalised assessment might 5 Groll AH, Castagnola E, Cesaro S, et al. Fourth European
Conference on Infections in Leukaemia (ECIL-4): guidelines for
be indicated in individual patients based on specific diagnosis, prevention, and treatment of invasive fungal diseases in
individual risk factors and new treatments. paediatric patients with cancer or allogeneic haemopoietic stem-cell
transplantation. Lancet Oncol 2014; 15: e327–40.
Contributors
6 Cordonnier C, Calandra T. The first European conference on
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8th European Conference on Infections in Leukaemia:

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Stem Cell Transplantation, diagnostic interventions, the group assumed potential

Detection of fungal antigens

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Grade of Level of Comments References

NA=not applicable (no grading). *Appendix pp 22–25.

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(voriconazole or liposomal anidulafungin versus voriconazole in adults showed no

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