Incidence and Risk Factors for Invasive Mold Infections in Children During First-Line Chemotherapy for Primary Acute Leukemia: Protocol for a National Retrospective Cohort Study
Conditions: Leukemia, Myeloid, Acute, Acute Lymphoblastic Leukemia
Sponsor: University of Southern Denmark

_____________________________________________________ 
Incidence and Risk Factors for Invasive Mold Infections in Children During 
First-Line Chemotherapy for Primary Acute Leukemia:  
Protocol for a National Retrospective Cohort Study 
_____________________________________________________ 
 
Rasmus Moeller Duus, MD1,2,3 
Dorthe Grosen, MD, PhD1,2 
Flemming Schoenning Rosenvinge, MD4,5 
Robin Christensen, BSc, MSc, PhD6,7 
Jesper Bonnet Moeller, MSc, PhD3,8 
Mathias Rathe, MD, PhD1,2 
 
1Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark;  
2Research unit of Paediatrics, University of Southern Denmark, Odense, Denmark;  
3Department of Cancer and Inflammation Research, University of Southern Denmark;  
4Department of Clinical Microbiology, Odense University Hospital, Odense, Denmark;  
5Research Unit of Clinical Microbiology, University of Southern Denmark, Odense, Denmark;  
6Section for Biostatistics and Evidence-Based Research, the Parker Institute, Bispebjerg and Frederiksberg Hospital, 
Copenhagen  
7Research Unit of Rheumatology, Department of Clinical Research, University of Southern Denmark, Odense University 
Hospital, Denmark;  
8Danish Institute for Advanced Study (D-IAS), University of Southern Denmark. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
May 9th, 2023 
NCT number (clinicaltrials.gov): NCT05774990 
 

 
2 
INTRODUCTION 
Background 
Children treated with chemotherapy are immunocompromised, making them susceptible to 
infections, including devastating invasive mold infections (IMI), of which Aspergillus spp. are the major 
pathogenic group. The at-risk population for IMI in children with acquired immunodeficiency is 
patients with prolonged granulocytopenia due to hematologic malignancies treated with 
chemotherapy or allogeneic hematopoietic stem cell transplantation (HSCT) recipients and children 
receiving long-term corticosteroid treatment (1). Incidence in at-risk patients may be influenced by 
the choice of prophylactic strategy, outbreaks related to local factors such as hospital renovation, or 
reflecting changing epidemiology of mold infections (2). 
Few studies have examined the incidence according to the currently used “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) 
guidelines for a proven, probable, or possible IMI (3). An Australian 10-year epidemiological study, 
however, indicates an incidence of invasive aspergillosis in patients treated for acute myelogenous 
leukemia (AML) and acute lymphoblastic leukemia (ALL) of (14/232) 6%, (33/1216) 2.7 %, respectively 
(4, 5). Only few epidemiologic reports have been performed in Denmark or Scandinavia (6). 
Despite progress in the diagnosis, prevention, and management of IMI, the reported 
mortality rates are often high. In an epidemiologic multicenter study, the main proportion of molds 
was A. fumigatus, with a mortality rate of 30% (7). A number of risk factors have been associated with 
IMI, among these, corticosteroid exposure, neutropenia, as well as different chemotherapy and 
conditioning regimens. However, few studies have addressed this in children with cancer, and 
knowledge regarding individual risk prediction for developing IMI in immunosuppressed children 
remains sparse (8, 9). Besides established risk factors for IMI, other treatment-related toxicities, 
including metabolic changes and gastrointestinal toxicity, may also be related to infectious morbidity 
(10-12).  
Our aim is to obtain an epidemiological overview of IMI in children receiving first-line 
treatment for ALL or AML in Denmark and identify possible risk factors, including treatment-related 
adverse effects.  
 
Objectives 
1. To determine and compare the incidence of IMI in childhood AML and ALL during first-line 
chemotherapy in Denmark. 
2. To determine and compare the mortality of IMI in childhood AML and ALL during first-line 
chemotherapy in Denmark. 
3. To explore risk factors for IMI in childhood AML and ALL during first-line chemotherapy in Denmark. 
 
 
 

 
3 
METHODS 
Study design  
A retrospective nationwide multicenter, open cohort study of all children who received first-line 
chemotherapy against acute leukemia from January 1st, 2008, to December 31st, 2022, in a Danish 
pediatric oncology unit; this includes data from the four Danish tertiary pediatric oncology units at 
Rigshospitalet, Aarhus University Hospital, Odense University Hospital, and Aalborg University 
Hospital. 
 
Study population 
Any patient (<18 years) who initiated first-line chemotherapy against primary ALL or AML at any of 
the four Danish departments of pediatric oncology from January 1st, 2008, to December 31st, 2022 
(Figure 1). The eligible sample of children has been estimated to correspond to approximately 800 
individuals who will be included in the cohort and subsequently be referred to as the intention-to-
survey (ITS) population.  
 
Data sources 
Patients from the four Danish departments of pediatric oncology treating pediatric ALL and AML will 
be identified by searching the Danish Childhood Cancer Registry. The register holds data since 1985 on 
all children < 15 years with cancer and all children 15-17 years of age treated at a pediatric oncology 
department (13). 
After cohort inclusion, data will be collected from the databases below, including the patient's 
medical records, hospital administrative databases, and national databases when applicable. The data 
for all cohort patients will be collected as listed in Table 2. For IMI patients only, additional data for a 
qualitative synthesis is collected, as detailed in Table 3. 
 
• The Danish Microbiology Database is a nationwide database carrying all microbiology test 
results. We will search the database to identify factors that fulfill the criteria of direct or 
indirect proof of mold infection (Table 1). 
• The Danish Pathology Register is a nationwide database carrying all pathology test results. We 
will search the database to identify histopathologic proof of mold infection. 
• We will search the regional radiology databases for proof of mold infection, as this is not a 
nationwide database. We will explore the databases for radiologic interpretations of 
computed tomographies and magnetic resonance imaging to identify the IMI criteria (Table 1).  
• Regional databases of blood test results will be searched to identify the neutrophilic count at 
the time of mold diagnosis in the IMI group and further to find proof of pancreatitis or 
hyperlipidemia.  
• Patient records will be scrutinized to identify pre-leukemia comorbidities, leukemia diagnosis, 
and risk group, among other information, as listed in table 2 and table 3. 
Data collection will start in April 2023. 
 
Outcome variables 
The primary outcome is defined as IMI. To identify patients who develop IMI, all cohort patients will 
have their pathology, microbiology, and radiology records reviewed for documentation, qualifying for 
EORTC/MSG criteria for either proven or probable disease. As recommended for epidemiological 
studies, the possible disease category has been left out (3). In brief, IMI is classified as proven when 
there is tissue damage and histopathologic, cytopathologic, or microscopic documentation of 
infection; a fungal DNA amplification by polymerase chain reaction (PCR) in paraffin-embedded tissue; 
or culture samples from a normally sterile site suspicious of infection. 

 
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The probable IMI requires the presence of a host factor (hematologic malignancy, 
among others), clinical features, and mycological evidence. Clinical features comprise specific clinical, 
bronchoscopic, and/or radiologic findings showing signs of tracheobronchitis, pulmonary, sino-nasal, 
or central nervous system (CNS) infection. The mycological documentation is either direct, usual 
cultures from a non-sterile site (i.e., mold found in sputum) or indirect detection of Aspergillus 
galactomannan antigen. The criteria for “possible disease” are identical to “probable disease” but 
without the presence of mycological evidence (3) (see table 1). The outcome variable is binary (i.e., 
IMI yes or no), but an additional analysis will be made for the IMI subgroups (i.e., IMI proven or 
probable). 
 
Exposure variables 
The putative risk factors, referred to as ‘exposures’, are obtained from the patient's medical charts 
and corresponding paraclinical databases. These include antifungal medication, its type, dosing, and 
duration. It will be registered whether this was given as primary prophylaxis, treatment, or as 
secondary prophylaxis (after treated IMI). Also, preleukemic morbidities, treatment protocol, 
neutrophil granulocyte count at leukemia diagnosis, concomitant infections, and blood transfusion 
history, as a means of generalized toxicity, will be registered. Furthermore, therapy-related adverse 
effects, including gastrointestinal toxicity, neutropenic colitis, and treatment-related metabolic 
changes, including hyperglycosemia, pancreatitis, and hyperlipidemia (Table 2). 
 
Observational period 
The period of IMI risk is defined as the period of active anticancer treatment. Exposure data from 
cohort subjects are collected from the date of cancer diagnosis until finished first-line chemotherapy, 
IMI occurrence, death, emigration, switching to a non-first-line treatment (e.g., treatment for 
induction failure or relapse), or 31st December 2022 (end of the study period), whichever comes first. 
For the IMI patients, we will also collect IMI outcome (cured, deceased, or emigrated) data after the 
IMI diagnosis for a narrative description of this group and to calculate the fatality rate. 
 
 

 
5 
Figure 1. STROBE flow diagram presenting the study design. ITS, intention to survey; ALL, acute 
lymphoblastic leukemia; AML, acute myelogenous leukemia (AML); IMI, invasive aspergillus. 
Patient assessment for eligibility 
• Age <18 years at the time of inclusion 
• First-line treatment for ALL or AML 
• Treatment at a Danish tertiary pediatric oncology unit 
(Rigshospitalet, Aarhus University Hospital, Odense University 
Hospital, and Aalborg University Hospital) 
• Treatment initiation January 1st, 2008, to December 31st, 2022 
Exclusion 
• Not meeting inclusion criteria 
• Chemotherapy initiated before January 1st, 2008 
• Therapy other than protocolized first-line 
chemotherapy (i.e., non-protocolized treatment, 
treatment against induction failure and relapse) 
• Treated in an adult hematology department 
• Other reasons 
Analysis 
• Inclusion for analysis 
• Exclusion from analysis 
Loss to follow-up 
• Death 
• Emigration 
 
Patient observational period 
• Starts at the date of ALL diagnosis 
• Ends at the date of stopping the first-line 
chemotherapy (planned or switching to a 
non-first-line treatment protocol) 
• End of this study (July 31st, 2022) 
Enrolment with ALL 
Loss to follow-up 
• Death 
• Emigration 
 
Patient observational period 
• Starts at the date of AML diagnosis 
• Ends at the date of stopping the first-line 
chemotherapy (planned or switching to a 
non-first-line treatment protocol) 
• End of this study (July 31st, 2022) 
Enrolment with AML 
Analysis 
• Inclusion for analysis 
• Exclusion from analysis 
ITS Population 
Analysis 
Follow-Up 
Enrolment 
Enrollment 

 
6 
Bias and limitations 
As the cohort study is observational and retrospective, the study relies on data extracted from 
medical charts. To avoid imprecise documentation, the predominant amount of data is exact (i.e., 
blood values), whereas more loosely medical chart statements will be avoided as far as possible. 
There is no risk of ‘recall bias,’ as no patients or health care professionals will be contacted. 
Another limitation in our study could be a small number of IMI patients and exposures; 
this would yield a low power and could be the reason for inconclusive findings. To avoid this and type 
1 errors, we will report measures of association with confidence intervals; if these exclude measures 
of clinical interest, we will assume that our study is not limited by sample size and number of events 
(say, if the 95% confidence intervals around the Hazard Ratio reasonably precise [95%CI: 0.80 to 
1.25]). 
During the 15 years of study, the treatment protocols have changed. We will apply the 
analyses to the whole population and do subgroup analyses for patients according to their specific 
treatment protocols. 
 
Statistical methods 
The primary analyses will be based on the Intention to Survey (ITS) population, i.e., based on the Full 
Analysis Set (see Figure 1 illustrated above). To assess distributions and check for errors, variables will 
be summarized before analysis. The frequency of IMI in the cohort will be determined by calculating 
the cumulative incidence. 
Hazard ratios (HR) for ALL relative to AML will be estimated, with two-sided 95% 
confidence intervals, based on a Cox proportional-hazards model, with AL-type as the primary 
covariate. Equivalence will be shown if the limits of the two-sided 95% confidence interval exclude 
(less than) 0.80 and (more than) 1.25. Crude incidence rates will be expressed in patients with IMI 
events per 100 patient-years, with two-sided 95% confidence intervals. No multiplicity adjustments 
will be applied. P values, without adjustment for multiplicity, will be produced for all listed objectives. 
To identify independent risk factors for the development of IMI, regression models will be applied to 
explore which children were more likely to develop IMI (e.g., AL-type, sex, age at diagnosis, and 
related toxicities, see table 2).  
All P values and 95% confidence intervals will be two sided. We will not apply explicit 
adjustments for multiplicity, rather we will analyze the secondary objectives in a prioritized order: The 
analyses of these will be performed in sequence until one of the analyses fails to show the statistically 
significant difference, or until all analyses have been completed at a statistical significance level of 
0.05. The key secondary statistical tests will be reported with P values for hypothesis tests and claims 
of statistical significance.  
Analyses will be performed using STATA software version 17 (StataCorp. 2021. Stata 
Statistical Software: Release 17. College Station, TX: StataCorp LLC.). 
 
Patient and public involvement statement 
As all data will be retrieved from patients no longer in active treatment, patients are not actively 
involved and were unfortunately not included in designing this study. 
 
Ethics and dissemination 
The relevant Danish authorities have approved the study, including the regional research legislation 
office “Regionssekretariat og jura, Syddanmark” (journal no. 22/7692), “Region Syddanmarks Interne 
Fortegnelse” (journal no. 22/15850), and by the involved departments. Other ethics approval has not 
been required for this study. 
The study will be registered at Clinical.Trials.gov. The study acts under the Declaration of Helsinki. No 
patient will be contacted and is not exposed to any inconvenience. All data are confidential and will 

 
7 
be processed in accordance with the General Data Protection Regulation (GDPR) and The Danish Data 
Protection Act. 
Data management is carried out in OPEN Odense Patient Data Explorative Network, 
Odense University Hospital, Clinical Institute, University of Southern Denmark 
https://www.sdu.dk/da/ki/open. Data is stored in an electronic database in RedCap, 
http://www.project-redcap.org., according to the EU GDPR https://www.eugdpr.org/. The findings 
are reported according to the guidelines for reporting observational studies as outlined in the 
Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement (14). 
Anonymized raw data will be published as an appendix to the finished article. After five 
years, the data will be offered to The Danish National Archives. 
The projects’ results (whether positive, negative, or inconclusive) are submitted for 
publication in a scientific peer-reviewed journal; alternatively, results are published another way 
(possibly on www.clinicalstudyresults.org). Data are published according to the Act on Processing of 
Personal Data. 
 
 
 

 
8 
Table 1. Criteria for proven, probable, and possible mold infections.  
Modified from the EORTC/MSG guidelines (4). 
CRITERIA FOR PROVEN DISEASE - moldsa: one of the following 
Microscopic analysis (sterile material): Histopathologic, cytopathologic, or direct microscopic examinationb of a specimen obtained by needle aspiration or biopsy 
in which hyphae or melanized yeast-like forms are seen accompanied by evidence of associated tissue damage 
Culture (sterile material): Recovery of a hyaline or pigmented mold by culture of a specimen obtained by a sterile procedure from a normally sterile and clinically 
or radiologically abnormal site consistent with an infectious disease process, excluding BAL fluid, a paranasal or mastoid sinus cavity specimen, and urine 
Blood: Blood culture that yields a moldc (eg, Fusarium species) in the context of a compatible infectious disease process 
Tissue Nucleic Acid Diagnosis: Amplification of fungal DNA by PCR combined with DNA sequencing when molds are seen in formalin-fixed paraffin-embedded 
tissue 
CRITERIA FOR PROBABLE DISEASE: Host factors + clinical features + mycological evidence 
Host factors 
Hematologic malignancyd 
Clinical features 
Pulmonary aspergillosis  
The presence of 1 of the following 4 patterns on CT:  
Dense, well-circumscribed lesions(s) with or without a halo sign  
Air crescent sign  
Cavity  
Wedge-shaped and segmental or lobar consolidation  
Other pulmonary mold diseases 
As for pulmonary aspergillosis but also including a reverse halo sign 
Tracheobronchitis  
Tracheobronchial ulceration, nodule, pseudomembrane, plaque, or eschar seen on bronchoscopic analysis 
Sino-nasal diseases  
Acute localized pain (including pain radiating to the eye)  
Nasal ulcer with black eschar  
Extension from the paranasal sinus across bony barriers, including into the orbit  
Central nervous system infection  
1 of the following 2 signs:  
Focal lesions on imaging  
Meningeal enhancement on magnetic resonance imaging or CT  
Mycological evidence  
Any mold, for example, Aspergillus, Fusarium, Scedosporium species or Mucorales recovered by culture from sputum, BAL, bronchial brush, or aspirate 
Microscopical detection of fungal elements in sputum, BAL, bronchial brush, or aspirate indicating a mold  
Tracheobronchitis  
Aspergillus recovered by culture of BAL or bronchial brush  
Microscopic detection of fungal elements in BAL or bronchial brush indicating a mold  
Sino-nasal diseases  
Mold recovered by culture of sinus aspirate samples  
Microscopic detection of fungal elements in sinus aspirate samples indicating a mold  
Aspergillosis only  
Galactomannan antigen  
Antigen detected in plasma, serum, BAL, or CSF  
Any 1 of the following:  
Single serum or plasma: ≥1.0  
BAL fluid: ≥1.0  
Single serum or plasma: ≥0.7 and BAL fluid ≥0.8  
CSF: ≥1.0  
Aspergillus PCR  
Any 1 of the following:  
Plasma, serum, or whole blood 2 or more consecutive PCR tests positive  
BAL fluid 2 or more duplicate PCR tests positive  
At least 1 PCR test positive in plasma, serum, or whole blood and 1 PCR test positive in BAL fluid  
Aspergillus species recovered by culture from sputum, BAL, bronchial brush, or aspirate  
CRITERIA FOR POSSIBLE DISEASE: Host factors + clinical features + no mycological evidence 
Probable invasive mold infection (IMI) requires the presence of at least 1 host factor, a clinical feature, and mycologic evidence and is proposed for 
immunocompromised patients only, whereas proven IMI can apply to any patient, regardless of whether the patient is immunocompromised. Probable IMI 
requires the presence of a host factor, a clinical feature, and mycologic evidence. Cases that meet the criteria for a host factor and a clinical feature but for which 
mycological evidence has not been found are considered possible IFD. (1,3)-beta-D glucan was not considered to provide mycological evidence of any invasive 
mold disease.  
 
Abbreviations: BAL, bronchoalveolar lavage; CSF, cerebrospinal fluid; CT, computed tomography; PCR, polymerase chain reaction; IMI, invasive mold infection. 
 
aIf culture is available, append the identification at the genus or species level from the culture results.  
bTissue and cells submitted for histopathologic or cytopathologic studies should be stained using Grocott-Gomori methenamine silver stain or periodic acid Schiff 
stain to facilitate inspection of fungal structures. Whenever possible, wet mounts of specimens from foci related to invasive fungal disease should be stained with a 
fluorescent dye (eg, calcofluor or blankophor). 
cRecovery of Aspergillus species from blood cultures rarely indicates endovascular disease and almost always represents contamination. 
dHematologic malignancy refers to active malignancy, in receipt of treatment for this malignancy, and those in remission in the recent past. These patients would 
comprise largely acute leukemias and lymphomas, as well as multiple myeloma, whereas patients with aplastic anemia represent a more heterogeneous group of 
individuals and are not included. The list of host factors has been shortened. 
 
 
 

 
9 
Table 2. Characteristics and putative risk factors to be collected from all cohort patients. 
 
VARIABLE 
Age (number in years) 
Numerical  
Sex (male/female) 
Binary  
Treating facility (Copenhagen/Århus/Odense/Aalborg) 
Categorical 
Pre-leukemia comorbidities 
Categorical 
ALL diagnosis: treatment protocol, risk group and CNS-status 
Categorical 
AML diagnosis: treatment protocol, risk group, FAB, and CNS-status 
Categorical 
Date of malignancy diagnosis 
- 
Name of treatment protocol 
Categorical 
Criteria met for IMI (proven/probable) 
Categorical 
Localization of IMI 
Categorical 
Neutrophil granulocyte count at leukemia diagnosis 
Numerical 
Anemia and red blood cell transfusion requirement (quantity) 
Numerical 
Thrombocytopenia and platelet transfusion requirement (quantity) 
Numerical 
Primary antifungal prophylaxis (type/dose/duration) 
Categorical 
Fungal infection other than IMI (fungi in a sterile site) (localization and type) 
Categorical 
Concomitant infections (bacteria in a sterile site) (localization and type)  
Categorical 
Neutropenic colitis (only radiological evidence: MRI, CT, plain film of the abdomen, US: bowel wall thickening > 4 mm, mesenteric stranding, 
bowel dilatation, mucosal enhancement, or pneumatosis) (yes/no) 
Binary 
Pancreatitis (> x3 upper limit of amylase/lipase) (yes/no) 
Binary 
Therapy related hyperlipidemia (triglycerides/cholesterol blood concentrations greater than upper normal limit (UNL). Grading: Mild: 
triglycerides/cholesterol <10 times UNL; Moderate: triglycerides/cholesterol 10–20 times UNL; Severe: triglycerides/cholesterol >20 times 
UNL.) (mild/moderate/severe) 
Categorical 
Therapy related diabetes (insulin dependent) (yes/no) 
Binary 
Therapy related diabetes (insulin dependent) (duration) 
Numerical 
Outcome cancer (finishing anticancer therapy, death, hematopoietic stem-cell transplantation (HSCT), emigration, or 31st December 2022 
(end of the study period)) (cured, recurrence, deceased) 
Categorical 
 
Table 3. Qualitative description of identified invasive aspergillus patients. 
Patient data collection 
Type of mold 
Mold resistance pattern 
Treatment day (days since the date of malignancy diagnosis) 
Corticosteroid therapy (duration, type, mg/m2, time since) 
Immunosuppressive therapy type/treatment phase 
Neutropenia (severe: < 0,5 x 109/l) (days prior to IMI diagnosis/neutrophilic count at day of diagnosis) 
Primary antifungal prophylaxis before IA (type/dose/duration) 
Antifungal IA treatment (type/dose/duration) 
Secondary antifungal prophylaxis after IA treatment (type/dose/duration) 
Preceding and concomitant antimicrobial therapy (type / duration prior to IMI) 
Diagnostic procedures (culture, galactomannan assay, radiologic findings, etc.) 
Intravenous access at time of diagnosis (central venous / port-a-cath) 
Anticancer treatment delays/modifications 
ICU stay (yes/no/duration) 
Outcome fungal (cured, ongoing, deceased) 
 
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Footnotes 
Authors' contributions 
The principal investigator (RD) is the first author in all publications. RD, MR, and RC designed the 
study. RD, MR, RC, SH, JB, DG, and UH will participate in conducting and analyzing the research and 
manuscript writing. The first author assumes responsibility for all practical issues, applications, and 
first drafts of all articles. Articles are written, and authorship is decided according to guidelines by the 
International Committee of Medical Journal Editors 
http://www.icmje.org/recommendations/browse/roles-and-responsibilities/.  
 
Funding statement 
This research received no specific grant from any funding agency in the public, commercial or not-for-
profit sectors. 
 
Competing interests 
All authors report no conflicts of interest.