Changes in the epidemiology of invasive fungal disease in a Pediatric Hematology and Oncology Unit: the relevance of breakthrough infections

BMC Infectious Diseases volume 23, Article number: 348 (2023) Cite this article

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Invasive fungal disease (IFD) is a significant cause of morbimortality in children under chemotherapy or hematopoietic stem cell transplant (HSCT). The purpose of this study is to describe the changes in the IFD epidemiology that occurred in a Pediatric Hematology-Oncology Unit (PHOU) with an increasing activity over time.

Retrospective revision of the medical records of children (from 6 months to 18 years old) diagnosed with IFD in the PHOU of a tertiary hospital in Madrid (Spain), between 2006 and 2019. IFD definitions were performed according to the EORTC revised criteria. Prevalence, epidemiological, diagnostic and therapeutic parameters were described. Comparative analyses were conducted using Chi-square, Mann-Whitney and Kruskal-Wallis tests, according to three time periods, the type of infection (yeast vs mold infections) and the outcome.

Twenty-eight episodes of IFD occurred in 27 out of 471 children at risk (50% males; median age of 9.8 years old, [IQR 4.9-15.1]), resulting in an overall global prevalence of 5.9%. Five episodes of candidemia and 23 bronchopulmonary mold diseases were registered. Six (21.4%), eight (28.6%) and 14 (50%) episodes met criteria for proven, probable and possible IFD, respectively. 71.4% of patients had a breakthrough infection, 28.6% required intensive care and 21.4% died during treatment.

Over time, bronchopulmonary mold infections and breakthrough IFD increased (p=0.002 and p=0.012, respectively), occurring in children with more IFD host factors (p=0.028) and high-risk underlying disorders (p=0.012). A 64% increase in the number of admissions in the PHOU (p<0.001) and a 277% increase in the number of HSCT (p=0.008) were not followed by rising rates of mortality or IFD/1000 admissions (p=0.674).

In this study, we found that yeast infections decreased, while mold infections increased over time, being most of them breakthrough infections. These changes are probably related to the rising activity in our PHOU and an increase in the complexity of the baseline pathologies of patients. Fortunately, these facts were not followed by an increase in IFD prevalence or mortality rates.

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Invasive fungal disease (IFD) is one of the leading causes of morbidity and mortality among immunocompromised children. In recent years, there has been a significant increase in pediatric patients at risk, due to the extended use of immunosuppressive medications and a rising complexity of the baseline pathologies [1]. Children who receive chemotherapy for malignancy or undergo hematopoietic stem cell transplant (HSCT) are at the highest risk for an IFD, particularly invasive candidiasis and aspergillosis [1, 2]. In December 2019, the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC/MSGERC) published an update on the definitions of IFD, including specific considerations for pediatric patients [3]. Monitoring the local epidemiology is essential to understand the pediatric IFD burden to set up preventive measures, rationalize resources and implement institution-based infection control strategies [1, 4].

The management of IFD, especially mold infections, in immunocompromised children is a challenge. Signs and symptoms may be non-specific and often develop late during the disease progression [2]. Data on imaging tools for the diagnosis of IFD are scarce and the role of fungal biomarkers may differ from those used in adults [5,6,7,8]. Randomized clinical trials evaluating antifungal drugs rarely involve children; therefore, these drugs are often used "off-label" for compassionate use. Antifungal prophylaxis (AFP) has shown to improve outcomes of these patients, but, as well as for adults, breakthrough invasive fungal infections have emerged as a significant problem [9,10,11].

The Pediatric Hematology-Oncology Unit (PHOU) of Hospital General Universitario Gregorio Marañón (HGUGM) in Madrid (Spain) has experienced a rising activity and an increase in the complexity of patients’ pathologies in recent years. This study aims to describe IFD in children admitted to the PHOU, according to the latest EORTC criteria [3], analysing the breakthrough IFD rate and evaluating the changes over the study period. Secondary objectives were to compare yeast and mold infections and the characteristics of surviving and non-surviving patients.

Clinical data of all pediatric patients (from 6 months to 18 years old) diagnosed with IFD at the PHOU of the HGUGM from January 2006 to December 2019 were retrospectively reviewed. HGUGM is a tertiary hospital located in Madrid (Spain) with 120 pediatric beds and around 7000 pediatric inpatient admissions per year. The PHOU of HGUGM counts with 18 hospitalizations beds and has experienced a rising activity in recent years, due, partially, to the creation of an adolescent unit and the accreditation as a National Reference Center for hereditary erythropathologies. The number of admissions per year in the PHOU has progressively increased from 343 in 2006 to 853 in 2019.

The information collected from the patients included: demographics, underlying condition, IFD host factors, AFP, laboratory, microbiological and radiological findings, antifungal therapy and clinical outcome. Deaths observed during the IFD treatment period were analyzed.

Cases were defined as proven, probable and possible IFD based on the last update in 2019 of the consensus definitions of IFD from the EORTC/MSGERC. Proven disease required histopathologic or microbiologic documentation of infection from tissue obtained by biopsy or autopsy, or an isolation from a culture sample obtained from a normally sterile site. Probable disease was defined as the presence of host factors, clinical features and mycological evidence of an IFD. Possible disease required proper host factors and sufficient clinical evidence compatible with IFD [3].

Host factors for IFD were those defined by the EORTC/MSGERC consensus: a recent history of prolonged neutropenia (<500 neutrophils/µL for >10 days), hematologic malignancy, allogeneic HSCT or solid organ transplant, prolonged use of corticosteroids (≥0.3 mg/kg for ≥ three weeks in the past 60 days), treatment with B-cell o T-cell immunosuppressants, severe hereditary immunodeficiency and graft-versus-host disease (GVHD) [3].

The risk for IFD represented the probability of IFD for each underlying condition. Patients considered at high-risk (≥10%) for IFD were those with acute myeloid leukemia (AML), high-risk or relapsed or acute lymphoblastic leukemia (ALL), severe aplastic anemia, myelodysplastic syndrome or those who underwent an allogeneic HSCT or developed a GVHD. Patients with non-Hodgkin lymphoma, standard-risk ALL or autologous HSCT were considered at low-risk (≤5%) for IFD. In opposition, patients with solid organ tumors (SOT), like brain tumors or Hodgkin lymphoma, were classified as sporadic risk [12, 13].

The global prevalence of IFD was calculated dividing the number of IFD cases by the total number of patients at risk. Moreover, the ratio of IFD cases per 1000 admissions in the PHOU was calculated globally and by time periods. The activity in the PHOU was measured using the number of admissions and HSCT carried out among periods.

Breakthrough IFD was defined as any IFD occurring during exposure to an antifungal drug, according to the recent definitions by the MSGERC [11]. In our institution protocol, used along the study period, oral or intravenous posaconazole, with therapeutic drug monitoring, and intravenous micafungin are considered the first choices for AFP in patients at high-risk for IFD. Liposomal amphotericin B is usually used for empirical or pre-emptive treatment in the setting of persistent neutropenic fever over 96 hours of significant respiratory symptoms, and voriconazole is the treatment of choice if an invasive aspergillosis is proven or probable.

Descriptive analyses were performed using frequencies and proportions for categorical variables and medians and interquartile ranges (IQR) for continuous variables. Comparative analyses were conducted according to time periods (three 56-months periods: January 2006 to August 2010 vs September 2010 to April 2015 vs May 2015 to December 2019), the type of infection (yeast vs mold infections), and outcome (survivors vs non-survivors). Categorical variables were compared using the chi-square or the Fisher exact test, as appropriate. Continuous dicotomic variables were evaluated with the Mann-Whitney U test. Kruskal-Wallis test, followed by posthoc analyses, was used when comparing variables among the three time periods. Statistical analyses were performed using IBM SPSS Statistics software (Statistical Package for the Social Sciences) version 23.0. The statistical significance level was defined as a two-tailed p-value <0.05.

From January 2006 to December 2019, a total of 471 children at risk for an IFD were followed and 90 HSCT (65 allogeneic, 25 autologous) were carried out at the PHOU. The underlying condition of these children at risk were: 26 AML, 66 ALL, 333 SOT and 46 HSCT performed in non-malignant diseases. Twenty-six children had one episode of IFD and one child had two episodes separated by four years, corresponding to 28 episodes overall. The median age at diagnosis was 9.8 years (IQR 4.9-15.1 years) and 50% were males. The global prevalence of IFD was 5.9%, and differed according to the underlying condition: 23.1% (6/26) for AML, 12.1% (8/66) for ALL and 1.8% (6/333) for SOT. The prevalence in those who required a HSCT was 13.3% (12/90), being 16.9% (11/65) for allogeneic and 4% (1/25) for autologous HSCT. Twenty-three were mold and five were yeast infections, with a prevalence of 4.9% and 1.1%, respectively.

There was a global ratio of 4.1 cases of IFD per 1000 admissions in the PHOU and decreased by 25% (p=0.674) between the first and the last study periods (Table 1). In contrast, there was a significant rising activity in the PHOU, with a 64% increase in the number of admissions (p<0.001) and 277% in the number of HSCT carried out (p=0.008). In the last period, children had more IFD host factors (p=0.028) and high-risk underlying disorders (p=0.012), being the cases of breakthrough IFD more frequent (p=0.012). All yeast infections took place during the first period (55.6% of cases in period 1), whereas in the second and third periods all IFD episodes were mold infections (p=0.002).

Most episodes (71.4%) occurred in children with underlying conditions considered at high-risk for IFD. Fourteen (50%) corresponded to children with blood malignancies: ALL n=8 (standard-risk ALL n=2; relapsed ALL n=3; high-risk ALL n=3) and AML n=6. Eight (28.6%) occurred in children with non-malignant blood disorders, all of them after allogeneic HSCT (sickle cell disease n=4, aplastic anemia n=2, Fanconi anemia n=1, β-thalassemia major n=1), and six (21.4%) were children with SOT (neuroblastoma n=3, osteosarcoma n=2, sarcoma n=1). One of the IFD episodes in patients diagnosed with ALL occurred during the induction treatment (standard-risk ALL), and the 3 cases in high-risk ALL occurred after a HSCT. The most common host factors for IFD were blood malignancies (50%), prolonged use of corticosteroids (50%), allogeneic HSCT (39.3%; median time between HSCT and IFD 43 days [IQR 14 - 253 days]) and prolonged neutropenia (39.1%); median time of neutropenia 16 days [IQR 12.5 - 23 day]). Eight patients (28.6%) were not neutropenic at the time they developed the IFD. Other host factors were: treatment with T-cell immunosuppressants (28.6%), acute GVHD (17.9%) and chronic GVHD (14.3%). More than a third of the patients (39.3%) had three or four IFD host factors and 7.1% had five or more.

Twenty children (71.4%) were receiving AFP, including 19/20 high-risk children and 1/3 low-risk children. The characteristics of these 20 breakthrough IFD episodes are described in Table 2. Levels of posaconazole were subtherapeutic in both patients at the time they developed the IFD. The global prevalence of breakthrough IFD was 4.2%, and according to the underlying condition, it was 23.1%, 9.1%, 0.3% and 12.2% for AML, ALL, SOT and HSCT groups, respectively. All the breakthrough episodes were mold infections. Forty percent of these episodes were defined as probable and 60% as possible disease.

In 11 episodes (39.3%), a clinically relevant pathogen was identified by culture or polymerase chain reaction (PCR): five culture-positive yeast infections (Candida albicans n=2; C. parapsilosis n=2; C. kefyr n=1), one culture-positive mold infection (Aspergillus ustus) and five PCR-positive mold infections (Aspergillus spp n=3; Cunninghamella spp n=1; Myriangiales spp n=1). According to EORTC criteria, the final diagnosis was proven IFD in six episodes (21.4%; prevalence 0.2%), probable in eight (28.6%; prevalence 1.7%), and possible in 14 (50%; prevalence 3%).

Table 3 shows the differences between yeast and mold infections. All yeast infections were candidemia (n=5; 17.9%), whereas all mold infections caused bronchopulmonary disease (n=23; 82.1%), being associated with rhino-sinusitis in two cases. Children with mold infections had a higher number of IFD host factors (median 3 vs 1; p=0.001) and had more frequently underlying high-risk disorders (87% vs 0%; p=0.001). All yeast and only one mold infection met the criteria for proven IFD (100% vs 4.3%, p=0.001), the last one due to the findings in a necropsy compatible with an invasive aspergillosis. There was a non-significant trend towards higher mortality in mold than yeast infections (26.1% vs 0%, p=0.553). Table 4 shows the radiological and microbiological findings of mold IFD.

Liposomal amphotericin B and voriconazole were the first options for IFD treatment in 85.7% (n=24) and 25% (n=7) of cases, respectively, being used in combination in 14.2% of cases. Two-thirds of the children experienced a change of treatment (67.9%), mostly based on voriconazole (68.4%), and 10.7% needed a third-line option. The median duration of treatment was 43 days (IQR 19.5-69 days).

Regarding outcomes, 8 patients (28.6%) required admission to the Pediatric Intensive Care Unit (PICU), 4 (14.3%) needed mechanical ventilation and 3 (10.7%), inotropic support. One patient required pleural effusion drainage but no cases required surgery. Six patients (21.4%) died during the IFD episode, all of which had mold infections, although death was directly attributed to the IFD in only one of them. Other causes of mortality were: disease progression (n=2), refractory GVHD (n=2) and a bacterial sepsis with multi-organic failure (n=1). Table 5 compares the characteristics between surviving and non-surviving children.

The present study describes 28 episodes of IFD in 27 children out of 471 patients at risk in a PHOU during 14 years. Data about global prevalence, the breakthrough IFD rate, clinical characteristics, diagnosis and treatment of IFD in these children receiving chemotherapy or undergoing HSCT were described. Yeast infections decreased over time, whereas mold infections increased, being breakthrough IFD the majority of them, occurring in children with high-risk pathologies and numerous host factors. A rising activity in the PHOU and an increasing complexity of patients’ pathologies over the study period were not followed by an increase in the rate of IFD cases per 1000 admissions in the PHOU or in the mortality rates.

The global prevalence of IFD was 5.9%, being higher in children with AML (23.1%) and in those who underwent allogeneic HSCT (16.9%). The global prevalence of IFD in children with cancer and HSCT recipients ranges from 3.4-7.2% [1, 10, 14]. The wide variety of immune dysfunctions related to underlying conditions, institutional variations in diagnostic and supportive care practices and the inconsistencies in diagnostic criteria make the estimation of this prevalence very challenging [1, 3, 14,15,16,17,18,19]. Our study´s prevalence in different groups of patients was similar to that reported recently by Bartlett et al [16]. Other studies have also shown that AML, allogeneic HSCT and high-risk ALL have an exceptionally high risk for IFD [2, 10, 13, 19,20,21,22].

Several patients in our study, especially those with mold infections, had numerous host factors for developing an IFD. It is known that IFD in children rarely occurs in the presence of an isolated host factor [2]. Notably, we detected 20 episodes of breakthrough IFD, with an overall rate of 4.2%. All of them were bronchopulmonary mold infections and 80% of these patients were receiving a mold-active agent. Breakthrough IFD is an emerging significant problem in patients who receive systemic antifungals, ranging from 1.6 to 7.7% for proven and possible breakthrough infections [9, 23,24,25,26,27]. Nevertheless, the validity of fungal biomarkers may differ in such cases and rates can increase up to 13% when including possible infections [9, 28]. Invasive mold infection are the most common breakthrough IFD [23, 24, 26]. Primary AFP is mainly based on posaconazole, but the concern about pharmacological interactions and toxicity of triazoles has led to a search for alternatives [12, 13, 29]. Liposomal amphotericin and micafungin have been shown to be safe and effective options [12, 26, 27].

Prevalence of yeast and mold infections was 1.1% and 4.9%, respectively. We identified five episodes of proven bloodstream candidemia; all of them took place during the first study period in children with a central venous catheter, and 60% were non-C. albicans species. These findings are consistent with recent reports, which describe a decrease in yeast infections in the past decade, attributed to the extended use of AFP, improved environmental strategies and infection control measures during line emplacement. This fact, together with the increasing number of children under immunosuppressive medications or HSCT, have led mold infections to replace invasive candidiasis as the most frequent IFD [10, 15, 16, 18, 20, 29, 30]. The predominance of non-C. albicans in children has been attributed to the affinity of C. parapsilosis for central venous catheter [2, 14, 16, 29].

Twenty-three episodes were bronchopulmonary mold infections and two were associated with rhino-sinusitis. Most of them were possible or probable infections. The diagnosis of mold IFD in children is a challenge, as only 30-50% of cases meet the criteria for a proven or probable disease [14, 16, 19, 21]. In our study, pulmonary infiltrates and consolidations were the most frequent radiological signs whereas the halo sign and cavities appeared in 17.4% and 8.7% of cases. Other studies have shown that radiological findings in pediatric IFD are unspecific and adult hallmarks are less common, with the halo sign appearing in less than 15% of images and the air crescent sign being very rarely observed [7, 13,14,15, 18, 20].

In our study, only one child met the criteria for proven mold disease (based on necropsy findings), 8 were classified as probable disease (based on seric galactomannan [GM; 5/8 cases] or GM in bronchoalveolar lavage [BAL; 3/8]) and 14 as possible cases (including four children with a single positive PCR in BAL and two with positive serum (1-3)-β-D-glucan [BDG]). Reaching a proven mold disease diagnosis is generally unfeasible to pediatric patients [3]. BAL has positioned itself as a safe technique, useful for culture, GM and PCR testing [31, 32], but the detection of Aspergillus by PCR requires several positive tests to support the diagnosis of probable IFD [3]. The threshold of the promising BDG may vary according to the age, etiology, specimens and manufacturers, and it is not currently recommended to provide evidence of an invasive mold disease in pediatric patients [3, 8, 13, 29, 33]. The exposure to mold-active AFP reduces the sensitivity of GM assay and it may be a reason for the high proportion of possible IFD [3, 8, 13, 20, 31].

Antifungal agents and treatment duration in our study followed pediatric guidelines [13, 20, 31, 34,35,36,37,38]. The high variability in days of therapy may be explained because the length of treatment is not well defined in mold infections [20]. The prompt initiation of empiric antifungal therapy is critical in a suspected IFD to reduce mortality, being a pre-emptive treatment is a safe strategy to avoid overuse of antifungals [10, 13, 20, 39]. In our study, six patients (21.4%) died during antifungal treatment, all diagnosed with mold infections, one of these cases was directly related to the IFD. Despite the rising activity in the PHOU at HGUGM and an increase in the complexity of pathologies and in the breakthrough IFD rates, mortality rates did not increased. Mortality in the second period was higher but no differences in the comparison between groups were found. The overall case-fatality rate attributable to IFD is very variable, reaching 10-25% in yeast infections and 20-50% in mold infections [1, 10, 16, 19, 20]. The patients who died without completing treatment can explain the shorter duration of treatment in period 2.

This study has several limitations. First of all, it is a retrospective study and data are limited to the information available in medical records. Secondly, it is a single-center study with a relatively small sample size; however, these data are probably representative of the characteristics of IFD in pediatric oncohematologic patients, considering that it was done in a tertiary hospital during a long study period. The activity of the PHOU was analysed by non-specific measurements, as the total number of admissions and the HSCT performed. In addition, the incidence of IFD in each risk category was not calculated considering that the risk of each patient can change during the treatment, but prevalence was estimated according to the underlying condition. Finally, a multidisciplinary management between experts in pediatric oncologic and infectious diseases, that maintain a high level of suspicion of IFD in children with numerous host factors, could have led to an over-diagnosis of the cases of possible IFD, taking into account the low specificity of radiological findings in children. However, a prompt treatment of IFD suspected cases is justified given the severity and the mortality rates of this entity and can explain the stable mortality rates within the study period.

In conclusion, this study offers a good picture of IFD in children receiving chemotherapy or undergoing HSCT. We observed a decrease in yeast infections during the study time with an increase in the proportion of mold infections. The rising activity and complexity in our PHOU led to an increase in the breakthrough IFD rates, but not in the number of IFD/1000 admissions in the PHOU or in the mortality rates. Local epidemiology knowledge of IFD is essential to implement appropriate therapeutic interventions early and improve survival in these children.

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

antifungal prophylaxis

acute lymphoblastic leukemia

acute myeloid leukemia

bronchoalveolar lavage

(1-3)-β-D-glucan

C-reactive protein

European Organization for Research and Treatment of Cancer

galactomannan

graft-versus-host disease

hematopoietic stem cell transplant

hospital General Universitario Gregorio Marañón

invasive fungal disease

interquartile range

Mycoses Study Group Education and Research Consortium

polymerase chain reaction

pediatric Hematology-Oncology Unit

pediatric Intensive Care Unit

solid organ tumor

Pana ZD, Roilides E, Warris A, Groll AH, Zaoutis T. Epidemiology of Invasive Fungal Disease in Children. J Pediatr Infect Dis Soc. 2017;6:S3-11. https://doi.org/10.1093/jpids/pix046.

Article Google Scholar

King J, Pana Z-D, Lehrnbecher T, Steinbach WJ, Warris A. Recognition and Clinical Presentation of Invasive Fungal Disease in Neonates and Children. J Pediatr Infect Dis Soc. 2017;6:S12-21. https://doi.org/10.1093/jpids/pix053.

Article Google Scholar

Donnelly JP, Chen SC, Kauffman CA, Steinbach WJ, Baddley JW, Verweij PE, et al. Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Clin Infect Dis. 2020;71(6):1367–76. https://doi.org/10.1093/cid/ciz1008.

Article PubMed Google Scholar

Santiago-García B, Rincón-López EM, Ponce Salas B, de Aguilarla Red Y, Garrido Colino C, Martínez Fernández- Llamazares C, et al. Effect of an intervention to improve the prescription of antifungals in pediatric hematology-oncology. Pediatr Blood Cancer. 2020;67(4):27963. https://doi.org/10.1002/pbc.27963.

Article Google Scholar

Warris A and the European Paediatric Mycology Network (EPMyN). Towards a Better Understanding and Management of Fungal Infections in Children. Curr Fungal Infect Rep. 2016;10(1):7–9. https://doi.org/10.1007/s12281-016-0252-7.

Article Google Scholar

Ramos JT, Francisco L, Daoud Z. Invasive fungal infections in children: similarities and differences with adults. Rev Esp Quimioter. 2016;29:59–65.

PubMed Google Scholar

Katragkou A, Fisher BT, Groll AH, Roilides E, Walsh TJ. Diagnostic Imaging and Invasive Fungal Diseases in Children. J Pediatr Infect Dis Soc. 2017;6:S22-31. https://doi.org/10.1093/jpids/pix055.

Article Google Scholar

Huppler AR, Fisher BT, Lehrnbecher T, Walsh TJ, Steinbach WJ. Role of Molecular Biomarkers in the Diagnosis of Invasive Fungal Diseases in Children. J Pediatr Infect Dis Soc. 2017;6:S32-44. https://doi.org/10.1093/jpids/pix054.

Article Google Scholar

García-Vidal C, Vázquez L, Jarque I. Relevance of liposomal amphotericin B in the treatment of invasive fungal infections in patients with hematologic malignancies. Rev Iberoam Micol. 2021;38(2):61–7. https://doi.org/10.1016/j.riam.2021.03.001.

Article PubMed Google Scholar

Rahi MS, Jindal V, Pednekar P, Parekh J, Gunasekaran K, Sharma S et al. Fungal infections in hematopoietic stem-cell transplant patients: a review of epidemiology, diagnosis, and management. Ther Adv Infect Dis. 2021: 19(8) https://doi.org/10.1177/20499361211039050.

Cornely OA, Hoenigl M, Lass-Flör C, Chen SC-A, Kontoyiannis DP, Morrissey CO, et al. Defining Breakthrough Invasive Fungal Infection– Position Paper of the Mycoses Study Group Education and Research Consortium (MSG-ERC) and the European Confederation of Medical Mycology (ECMM). Mycoses. 2019;62(9):716–29. https://doi.org/10.1111/myc.12960.

Article PubMed PubMed Central Google Scholar

Ramos JT, Romero CA, Belda S, Candel FJ, Caarazo Gallego B, Fernández-Polo A, et al. Clinical practice update of antifungal prophylaxis in inmunocompromised children. Rev Esp Quimioter. 2019;32(5):410–25.

CAS PubMed PubMed Central Google Scholar

Lehrnbecher T. The clinical management of invasive mold infection in children with cancer or undergoing hematopoietic stem cell transplantation. Expert Rev Anti-infect Ther. 2019;17(7):489–99. https://doi.org/10.1080/14787210.2019.1626718.

Article CAS PubMed Google Scholar

Ozsevik SN, Sensoy G, Karli A, Albayrak C, Dagdemir A, Belet N, et al. Invasive Fungal Infections in Children With Hematologic and Malignant Diseases. J Pediatr Hematol Oncol. 2015;37(2):e69-72. https://doi.org/10.1097/MPH.0000000000000225.

Article CAS PubMed Google Scholar

Kumar J, Singh A, Seth R, Xess I, Jana M, Kabra SK. Prevalence and Predictors of Invasive Fungal Infections in Children with Persistent Febrile Neutropenia Treated for Acute Leukemia – A Prospective Study. Indian J Pediatr. 2018;85(12):1090–5. https://doi.org/10.1007/s12098-018-2722-0.

Article PubMed Google Scholar

Bartlett AW, Cann MP, Yeoh DK, et al. Epidemiology of invasive fungal infections in immunocompromised children; an Australian national 10-year review. Pediatr Blood Cancer. 2019;66(4):e27564. https://doi.org/10.1002/pbc.27564.

Article PubMed Google Scholar

De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, et al. Revised Definitions of Invasive Fungal Disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis. 2008;46(12):1813–21. https://doi.org/10.1086/588660.

Article PubMed Google Scholar

Burgos A, Zaoutis TE, Dvorak CC, Hoffman JA, Knapp KM, Nania JJ, et al. Pediatric Invasive Aspergillosis: A Multicenter Retrospective Analysis of 139 Contemporary Cases. Pediatrics. 2008;121(5):e1286-94. https://doi.org/10.1542/peds.2007-2117.

Article PubMed Google Scholar

Han SB, Kim SK, Bae EY, Lee JW, Yoon JS, Chung NG, et al. Clinical Features and Prognosis of Invasive Pulmonary Aspergillosis in Korean Children with Hematologic/Oncologic Diseases. J Korean Med Sci. 2015;30(8):1121–8. https://doi.org/10.3346/jkms.2015.30.8.1121.

Article CAS PubMed PubMed Central Google Scholar

Warris A, Lehrnbecher T, Roilides E, Castagnola E, Brüggemannn RJM, Groll AH. ESCMID-ECMM guideline: diagnosis and management of invasive aspergillosis in neonates and children. Clin Microbiol Infect. 2019;25(9):1096–113. https://doi.org/10.1016/j.cmi.2019.05.019.

Article CAS PubMed Google Scholar

Kobayashi R, Hori D, Sano H, Suzuki D, Kishimoto K, Kobayashi K. Risk Factors for Invasive Fungal Infection in Children and Adolescents With Hematologic and Malignant Diseases: A 10-year Analysis in a Single Institute in Japan. Pediatr Infect Dis J. 2018;37(12):1282–5. https://doi.org/10.1097/INF.0000000000002010.

Article PubMed Google Scholar

Ruijters VJ, Oosterom N, Wolfs TFW, van den Heuvel-Eibrink MM, van Grotel M. Frequency and Determinants of Invasive Fungal Infections in Children With Solid and Hematologic Malignancies in a Nonallogeneic Stem Cell Transplantation Setting: A Narrative Review. J Pediatr Hematol Oncol. 2019;41:345–54. https://doi.org/10.1097/MPH.0000000000001468.

Article PubMed Google Scholar

Chen X, Wang J, Wang S, Jin J, Li J, Gao S, et al. Real-world assessment of the effectiveness of posaconazole for the prophylaxis and treatment of invasive fungal infections in hematological patients. Medicine. 2021;100(30):e26772. https://doi.org/10.1097/MD.0000000000026772.

Article CAS PubMed PubMed Central Google Scholar

Yang E, Choi EJ, Park HS, Lee SO, Sang-Ho Choi SO, et al. Comparison of invasive fungal diseases between patients with acute myeloid leukemia receiving posaconazole prophylaxis and those not receiving prophylaxis. Medicine. 2021;100(20):e25448. https://doi.org/10.1097/MD.0000000000025448.

Article CAS PubMed PubMed Central Google Scholar

Gangneux JP, Padoin C, Michallet M, Saillio E, Kumichel A, de La Tour JP, et al. Outcomes of Antifungal Prophylaxis in High-Risk Haematological Patients (AML under Intensive Chemotherapy): The SAPHIR Prospective Multicentre Study. J Fungi. 2020;12(64):281. https://doi.org/10.3390/jof6040281.

Article CAS Google Scholar

Mendoza-Palomar N, Soques E, Benitez-Carabante MI, Gonzalez-Amores M, Fernandez-Polo A, Renedo B, et al. Low-dose liposomal amphotericin B for antifungal prophylaxis in paediatric allogeneic haematopoietic stem cell transplantation. J Antimicrob Chemother. 2020;75(8):2264–71. https://doi.org/10.1093/jac/dkaa149.

Article CAS PubMed Google Scholar

Rothe A, Claßen A, Carney J, Hallek M, Mellinghoff SC, Scheid C, et al. Bridging antifungal prophylaxis with 50 mg or 100 mg micafungin in allogeneic stem cell transplantation: A retrospective analysis. Eur J Haematol. 2020;104(4):291–978. https://doi.org/10.1111/ejh.13372.

Article CAS PubMed Google Scholar

Li W, Xia F, Zhou H, Qiu H, Wu D, Ma X, et al. Efficacy of Posaconazole Prophylaxis for Fungal Disease in Hematology Patients Treated With Chemotherapy and Transplantation: An Open-Label, Prospective Observational Study. Front Microbiol. 2020;11:349. https://doi.org/10.3389/fmicb.2020.00349.

Article PubMed PubMed Central Google Scholar

Mantadakis E, Tragiannidis A. Invasive Fungal Infections in the Pediatric Intensive Care Unit. Pediatr Infect Dis J. 2019;38(9):e216-8. https://doi.org/10.1097/INF.0000000000002394.

Article PubMed Google Scholar

Bays DJ, Thompson GR. Fungal Infections of the Stem Cell Transplant Recipient and Hematologic Malignancy Patients. Infect Dis Clin North Am. 2019;33(2):545–66. https://doi.org/10.1016/j.idc.2019.02.006.

Article PubMed Google Scholar

Patterson TF, Thompson GR, Denning DW, Fishman JA, Hadley S, Herbrecht R, et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63(4):e1-60. https://doi.org/10.1093/cid/ciw326.

Article PubMed PubMed Central Google Scholar

Chellapandian D, Lehrnbecher T, Phillips B, Fisher BT, Zaoutis TE, Steinbach WJ, et al. Bronchoalveolar Lavage and Lung Biopsy in Patients With Cancer and Hematopoietic Stem-Cell Transplantation Recipients: A Systematic Review and Meta-Analysis. J Clin Oncol. 2015;33(5):501–9. https://doi.org/10.1200/JCO.2014.58.0480.

Article PubMed Google Scholar

Ferreras-Antolín L, Sharland M, Warris A. Management of Invasive Fungal Disease in Neonates and Children. Pediatr Infect Dis J. 2019;38:S2–6. https://doi.org/10.1097/INF.0000000000002317.

Article PubMed PubMed Central Google Scholar

Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1-50. https://doi.org/10.1093/cid/civ933.

Article PubMed Google Scholar

Tissot F, Agrawal S, Pagano L, Petrikkos G, Groll AH, Skiada A, et al. ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients. Haematologica. 2017;102(3):433–44. https://doi.org/10.3324/haematol.2016.152900.

Article PubMed PubMed Central Google Scholar

Hope WW, Castagnola E, Groll AH, Roilides E, Akova M, Arendrup MC, et al. ESCMID guideline for the diagnosis and management of Candida diseases 2012: prevention and management of invasive infections in neonates and children caused by Candida spp. Clin Microbiol Infect. 2012;18:38–52. https://doi.org/10.1111/1469-0691.12040.

Article CAS PubMed Google Scholar

Vasileiou E, Apsemidou A, Vyzantiadis TA, Tragiannidis A. Invasive candidiasis and candidemia in pediatric and neonatal patients: A review of current guidelines. Curr Med Mycol. 2018;4(3):28–33. https://doi.org/10.18502/cmm.4.3.173.

Article PubMed PubMed Central Google Scholar

Ullmann AJ, Aguado JM, Arikan-Akdagli S, Denning DW, Groll AH, Lagrou K, et al. Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin Microbiol Infect. 2018;24:e1-38. https://doi.org/10.1016/j.cmi.2018.01.002.

Article PubMed Google Scholar

Santolaya ME, Alvarez AM, Acuña M, Avilés CL, Salgado C, Tordecilla J, et al. Efficacy of pre-emptive versus empirical antifungal therapy in children with cancer and high-risk febrile neutropenia: a randomized clinical trial. J Antimicrob Chemother. 2018;73(10):2860–6. https://doi.org/10.1093/jac/dky244.

Article CAS PubMed Google Scholar

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Authors express their gratitude to their colleagues and research personnel involved in the data collection for the study. They are also grateful for the kind support of the Clinical Microbiology and Infectious, the Radiology and the Pathological Anatomy Departments at Hospital General Universitario Gregorio Marañón, Madrid, Spain. This project has been carried out with the collaboration of the Pediatric IFD Study Group at HGUGM, composed by: Teresa Hernández-Sampelayo Matosac, María del Mar Santos Sebastiána, Jesús Saavedra Lozanoac, David Aguilera Alonsoa, Elena Cela de Juliánbc, Cristina Mata Fernándezb, Marina García Morínb, Jorge Huerta Aragonésb and Eduardo Bardón Canchob. Affiliations: a) Hospital General Universitario Gregorio Marañón (Pediatric Infectious Diseases Unit. Pediatrics Department) and CIBERINFEC, Instituto de Salud Carlos III, Madrid, Spain; b) Hospital General Universitario Gregorio Marañón (Pediatric Hematology and Oncology Unit. Pediatrics Department), Madrid, Spain; c) Complutense University of Madrid, Spain.

Authors have no financial or proprietary interests in any material discussed in this article. No funding was received for conducting this study.

Pediatric Infectious Diseases Section. Pediatrics Department. Hospital Materno, Infantil Gregorio Marañón. C/ O’, Donnell 48-50, 28009, Madrid, Spain

Laura Calle-Miguel, Martha Patricia Moreno Santos & Henar Gonzalo Pascual

Hospital General Universitario Gregorio Marañón (Pediatric Hematology and Oncology Unit. Pediatrics Department), Madrid, Spain

Carmen Garrido-Colino, Beatriz Ponce Salas & Cristina Beléndez Bieler

Complutense University of Madrid, Madrid, Spain

Carmen Garrido-Colino, Marisa Navarro Gómez & Jesús Guinea Ortega

Hospital General Universitario Gregorio Marañón (Pediatric Infectious Diseases Unit. Pediatrics Department), CIBERINFEC, Instituto de Salud Carlos III, Madrid, Spain

Begoña Santiago-García, Marisa Navarro Gómez & Elena María Rincón-López

Hospital General Universitario Gregorio Marañón (Clinical Microbiology and Infectious Diseases Department), Madrid, Spain

Jesús Guinea Ortega

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Conceptualization: EMR-L. Design of the work: BS-G and EMR-L. Acquisition of data: LC-M, MPMS, HGP and BPS. Analysis: LC-M and MPMS. Interpretation of data: LC-M, BS-G and EMR-L. Writing original draft LC-M and EMR-L. Supervision: CBB, CG-C, MNG and JGO. Final revision: BS-G, EMR-L and JGO. All authors read and approved the final manuscript.

Correspondence to Laura Calle-Miguel.

This study was conducted in accordance with the 1964 Declaration of Helsinki and its subsequent amendments. Ethics approval was obtained from the Clinical Research Ethics Committee at HGUGM. Informed consent was waived as archival data were retrospectively reviewed and no identifiable personal information is exposed. The waiver was granted by the Clinical Research Ethics Committee at HGUGM (date 5th October 2020/ Number IFI-HOI-2020).

Not applicable. The manuscript does not contain any identifiable personal data.

The authors declare no competing interests.

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Calle-Miguel, L., Garrido-Colino, C., Santiago-García, B. et al. Changes in the epidemiology of invasive fungal disease in a Pediatric Hematology and Oncology Unit: the relevance of breakthrough infections. BMC Infect Dis 23, 348 (2023). https://doi.org/10.1186/s12879-023-08314-9

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Received: 18 November 2022

Accepted: 08 May 2023

Published: 25 May 2023

DOI: https://doi.org/10.1186/s12879-023-08314-9

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