Groll, A.H., Castagnola, E., Cesaro, S., Dalle, J.H., Engelhard, D., Hope, W., ... & Lehrnbecher, T. (2014). Fourth European Conference on Infections in Leukaemia (ECIL-4): Guidelines for diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or allogeneic hematopoietic stem-cell transplantation. Lancet Oncology, 15, e327–e340. 

Guidelines divided into four categories: Recommendations for diagnosis of IFDs, prophylaxis of IFDs (primary and secondary), empirical and pre-emptive antifungal therapy, and targeted treatments of IFDs, with the exception of rare yeasts and cryptococcosis, which were not addressed. A grading system similar to the one developed by IDSA for adults but specific to address pediatric concerns was used. Four components for grading of recommendation: evidence for efficacy from adult phase 2 and 3 trials, existence and quality of pediatric pharmacokinetic data and dosing recommendations, specific pediatric safety data and supportive efficacy data, and regulatory approval for use in pediatric age groups.

Diagnosis: Cultures, imaging studies; for aspergillus spp, galactomannan monitoring and serial screening two times weekly in pediatrics at a high risk for IFD (index of 0.5 or higher as +); data were too scarce in pediatrics to recommend β-D-Glucan testing; no general recommendation exists for the use of PCR because of the absence of standardization and validation. CT imaging recommended for high-risk pediatrics with febrile granulocytopenia persistenting beyond 96 hours or focal clinical findings.

Primary prophylaxis: In patients undergoing HSCT, prophylaxis is recommended during granulocytopenic phase until engraftment. Options include fluconazole (A-I), itraconazole or voriconazole (B-I), micafungin (C-I), and liposomal amphotericin B (C-III). Considerations for liposomal amphotericin B and posaconazole in children older than age 13 years. In the presence of graft-versus-host disease (GVHD), treatment with immunosuppression prophylaxis is recommended. Options include posaconazole for children aged 13 years or older (B-I), voriconazole for children aged 2 years or older (B-I), and itraconazole (C-III). In high-risk patients with de-novo or recurrent acute leukemia primary, itraconazole plus TDM (B-I), posaconazole  plus TDM 13 years or older, or liposomal amphotericin B (B-II) and fluconazole (C-I) is recommeded.

Secondary Prophylaxis: Bo data available for patients receiving mold-active antifungal prophylaxis, switching to a different class of mold-active antifungal agents seems reasonable. Patients receiving antifungal prophylaxis without mold activity should be given either caspofungin or liposomal amphotericin B for empirical therapy (no grading).

Targeted treatment: Candidemia treatments are caspofungin (B-II), fluconazole (B0IIU), liposomal amphotericin B (B-II), micafungin (B-11), voriconazole (B-II; restricted to children older than age 2 years and amphotericin B lipid complex [C-II]). A switch in class should be considered in patients with breakthrough infections. Aspergillus treatments are IV voriconazole coupled with TDM (A-I; restricted to patients older than age 2 years), liposomal amphotericin B (B-I), and amphotericin B lipid complex (B-II). Second-line treatment liposomal amphotericin B in amphotericin B naïve patients (B-I) and voriconazole plus TDM in voriconazole naïve patients (A-1: children older than age 2 years). No recommendation for or against hyperbaric oxygen to treat mucorales can be made; adjunctive use of deferasirox is not recommended; recommend initiation of amphotericin B and surgery.

Some recommendations were not graded because of lack of evidence in pediatrics, and some recommendations were based upon adult trials. In addition, there was an assumption that the same principals for pre-emptive therapy in adults could be applied in children.

Additional research is needed in epidemiology and surveillance of resistance, imaging and molecular diagnostics, exposure of antifungal agents in prophylaxis and treatment, and safety of antifungal drugs in the pediatric population.