Clinical practice update of antifungal prophylaxis in immunocompromised children

Rev Esp Quimioter 2019;32(5): 410-425 410 ©The Author 2019. Published by Sociedad Española de Quimioterapia. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)(https://creativecommons.org/licenses/by-nc/4.0/). in children and to provide a comprehensive proposal for each type of patient. Key-words: antifungal prophylaxis, children, pediatric patients, HIV, primary immunodeficiency, Solid organ transplantation, haematopoietic stem cell transplantation. Revisión de estrategias de profilaxis antifúngica en niños inmunodeprimidos RESUMEN Las infecciones fúngicas invasoras (IFI) constituyen un problema creciente en adultos y niños inmunodeprimidos, acompañándose de una elevada morbimortalidad. El número de niños inmunodeprimidos va en aumento. Los grupos de riesgo de IFI en pediatría incluyen a los grandes prematuros, que se benefician de profilaxis con fluconazol, pacientes hemato-oncológicos sometidos a quimioterapia o trasplante de precursores hematopoyéticos con neutropenias prolongadas, en quienes la profilaxis frente a hongos filamentosos suele recomendarse en situaciones de alto riesgo. En niños sometidos a trasplante de órgano sólido, la profilaxis depende del tipo de trasplante y factores de riesgo asociados. En pacientes con inmunodeficiencias primarias o adquiridas como la infección VIH o tratamiento inmunosupresor prolongado, la profilaxis antifúngica dependerá del tipo de inmunodeficiencia primaria y del grado de inmunosupresión. La enfermedad granulomatosa crónica tiene riesgo particularmente elevado de IFI y requiere siempre profilaxis frente a hongos filamentosos. En cambio, en niños con ingresos prolongados en cuidados intensivos la profilaxis frente a IFI habitualmente no está indicada. El tipo de profilaxis está limitado por la diferente aprobación de antifún- ABSTRACT Due to the rise in the number and types of immunosuppressed patients, invasive fungal infections (IFI) are an increasing and major cause of morbidity and mortality in immunocompromised adults and children. There is a broad group of pediatric patients at risk for IFI in whom primary and/or secondary antifungal prophylaxis (AFP) should be considered despite scant evidence. Pediatric groups at risk for IFI includes extremely premature infants in some settings, while in high-risk children with cancer receiving chemotherapy or undergoing haematopoietic stem cell transplantation (HCT), AFP against yeast and moulds is usually recommended. For solid organ transplanted, children, prophylaxis depends on the type of transplant and associated risk factors. In children with primary or acquired immunodeficiency such as HIV or long-term immunosuppressive treatment, AFP depends on the type of immunodeficiency and the degree of immunosuppression. Chronic granulomatous disease is associated with a particular high-risk of IFI and anti-mould prophylaxis is always indicated. In contrast, AFP is not generally recommended in children with long stay in intensive care units. The choice of AFP is limited by the approval of antifungal agents in different age groups and by their pharmacokinetics characteristics. This document aims to review current available information on AFP Clinical practice update of antifungal prophylaxis in immunocompromised children 1Department of Public and Mother-Child Health. Hospital Clínico San Carlos, Complutense University. Madrid. 2Department of Salud Pública y Materno-Infantil.Complutense University. Neonatology Unit. Hospital 12 de Octubre. Madrid 3Department of Pediatrics. Intensive Care Unit. Hospital 12 de Octubre. Madrid. Complutense University. Madrid. 4Clinical Microbiology and Infectious Diseases Department. Transplant. Coordination Unit. IdISSC and IML Health Institutes. Hospital Clínico San Carlos. Madrid. Spain. 5Department of Pediatrics. Sección de Enfermedades Infecciosas. Hospital Carlos Haya, Málaga. 6Pharmacy Department. Hospital Universitari Vall d’Hebron. Barcelona. 7Department of Pediatrics. Infectious Diseases Unit. Saint George Hospital Londres. 8Department of Pediatrics. Sección de Hemato-oncología. Hospital Gregorio Marañón. Madrid. 9Department of Pediatrics. Sección de Enfermedades Infecciosas. Hospital Gregorio Marañón. Madrid. 10Department of Pediatrics. Sección Infectología, Reumatología e Inmunología Pediátrica. Hospital Universitario Virgen del Rocío, Sevilla. 11Department of Pediatrics. Hospital 12 de Octubre. Madrid. Complutense University. Madrid. 12Pediatric Infectious Diseases and Immunodeficiencies Unit. Hospital Universitari Vall d’Hebron. Barcelona. José Tomás Ramos1 Concepción Alba Romero2 Sylvia Belda3 Francisco Javier Candel4 Begoña Carazo Gallego5 Aurora Fernández-Polo6 Laura Ferreras Antolín7 Carmen Garrido Colino8 María Luisa Navarro9 Olaf Neth10 Peter Olbrich10 Elena Rincón-López9 Jesús Ruiz Contreras11 Pere Soler-Palacín12 on behalf of the Fungal Infection Study Group of Spanish Society of Paediatric Infectious Disease (SEIP); Traslational Research Network in Pediatric Infectious Diseases (RITIP). Correspondence: José T. Ramos Amador Departmento de Salud Pública y Materno-Infantil. Complutense University. Madrid. Hospital Clínico San Carlos. IdISSC Health Research Institute Madrid. Spain. Avda Profesor Martín Lagos s/n. 28040. Phone: + 34 91 330 3486 E-mail: [email protected] Review Article history Received: 31 July 2019; Revision Requested: 18 August 2019; Revision Received: 30 August 2019; Accepted: 3 September 2019 Clinical practice update of antifungal prophylaxis in immunocompromised childrenJ. T. Ramos, et al. Rev Esp Quimioter 2019;32(5): 410-425 411 able in neonatal intensive care units (NICU) ranging from 3% to 23% in extreme premature infants, depending on the complexity of the NICU and whether surgery is involved or not. This patient population has a high risk of dissemination to the central nervous system (up to 15-20% in extreme premature babies), even before presenting overt clinical signs of infection, and high mortality rates. Despite high variations among NICU, Candida albicans is the most frequent isolated species, followed by C. parapsilosis [3-6]. Risk factors for IC in preterm infants include immaturity of the immune system (especially low levels of maternal IgG transmission and impaired functions of opsonization and complement) and epithelial barriers, frequent rupture of these barriers by invasive procedures, such as catheters, intubation or surgery, and the increase in the density of colonization by Candida spp. promoted mostly by the frequent use of broad-spectrum antibiotics. In addition, H2-receptor blockers and steroids may facilitate intestinal translocation leading to Candida spp. invasion and secondary systemic infection. Transmission through peripartum colonization and horizontal transmission through health-care professionals colonized by Candida spp. may also occur [3-6]. Due to its bad prognosis, prophylactic strategies to prevent IF are warranted [7]. General strategies include hand hygiene; individual room for families and newborns; reduction of risk factors for colonization and infection for IC, such as limitation of H2-recep- tor blockers, steroids and broad-spectrum antibiotics, mainly carbapenems and third-generation cephalosporins; minimizing the use of invasive devices including minimal manipulation of central venous catheters, as well as early introduction of mother´s milk. Although some experts advocate for using lactoferrin alone or combined with probiotics in order to reduce intestinal Candida spp. colonization and late onset sepsis in neonates weighing < 1,500 g, evidence is still scarce [7] (CII). The indication of AFP, although controversial, is generally recommended in preterm babies <1,000 g., in NICU with a prevalence of Candida spp. infection above 5-10%. Oral nystatin suspension (1ml: 100.000 U/ml) has been considered as an option, when fluconazole is not available or azole resistance is suspected, but evidence is low [7] (CII). When indicated fluconazole is the recommended option, starting either in the first 24 or 72 hours of life at a dose 3-6 mg/kg i.v. (until catheter withdrawal) or orally twice weekly for 6 weeks. Multiple clinical trials have been performed with several regimens of fluconazole showing the impact of fluconazole in high-risk preterm babies in the incidence of IC, morbidity and mortality [8-12]. Twice weekly regimens do not seem to be inferior to the same daily dose [10]. According to the IDSA guidelines prophylaxis with fluconazole is indicated in admitted neonates with birth weight < 1000 gr when the prevalence of IC is higher than 10% [1]. Similarly, above this threshold in Spain, different Spanish scientific societies (Spanish Society of Infectious Diseases and Clinical Microbiology -SEIMC- and Spanish Society of Paediatric Infectious Diseases-SEIP) advocate fluconazole prophylaxis at 3 mg/kg/day in newborns with birth weight < 1,500 g, continuing it for all the period at risk [4,13]. The ESC- gicos a distintas edades. Este documento pretende revisar la información actual disponible respecto a profilaxis antifúngica en niños, con propuesta para la estrategia más apropiada en cada tipo de paciente. Palabras clave: profilaxis antifúngica, niños, pacientes pediátrico, VIH, inmunodeficiencia primaria, trasplante de órgano sólido, trasplante de precursores hematopoyéticos Invasive fungal infection (IFI) is considered an opportunistic infection that occurs almost exclusively in immunocompromised and critically ill children. The impact of an IFI can be devastating and is associated with a high rate of morbimortality despite the availability of new antifungal drugs in recent years. The number of paediatric patients at risk for IFI is increasing and include: extremely premature infants (especially those with weight less than 1,500 g), children with cancer, undergoing haematopoietic stem cell transplantation (HSCT) or solid organ transplant, neutropenic children, those with long stay in intensive care units (ICU) and children with primary or acquired immunodeficiency such as HIV or long-term immunosuppressive treatment [1-4]. Timely diagnosis and initiation of appropriate antifungal therapy is a key point to improve outcomes. Thus, it is mandatory to consider antifungal prophylaxis (AFP) in most of these situations. Herein, a comprehensive proposals for each patient´s group based on an updated review of AFP strategies in children is provided. The strength of recommendations and the quality of evidence are graded according to the scoring system proposed by the Infectious Diseases Society of North America (IDSA) [1]. In the process of providing recommendations, we have taken into account the paediatric development regulations and guidelines from the European Medicines Agency (EMA). The EMA accepts the requirement for extrapolation of evidence for efficacy from studies in adults to paediatric patients or from older to younger paediatric patients when the following criteria are met: (a) underlying condition and cause of targeted disease and expected response to therapy are similar; (b) data from clinical studies on pharmacokinetics, safety and tolerance are available for paediatric patients; and (c) supportive paediatric efficacy data exists [2]. In this scoring system, the strength of the recommendation is rated as follows: A: strongly recommended; B: moderately recommended; C: weak author support; D: not recommended by the authors. The quality of evidence is evaluated on a 3-lev- el scale as follows: I: data from at least 1 well-designed and conducted randomized controlled trial; II: data from at least 1 well-designed and conducted clinical trial, without randomization, cohorts or case-control analyses (preferably multicenter), multiple retrospective series, or major findings of noncontrolled studies; III: expert opinions based on clinical experience, descriptive case series, or expert committee reports [1]. 1.- ANTIFUNGAL PROPHYLAXIS IN NEWBORNS The prevalence of invasive candidiasis (IC) is highly vari- Clinical practice update of antifungal prophylaxis in immunocompromised childrenJ. T. Ramos, et al. Rev Esp Quimioter 2019;32(5): 410-425 412 and Candida spp. positive urine cultures [20, 21]. However, these criteria might not be fully applicable to children. Several studies have tried to identify risk factors for invasive candidemia in non-immunocompromised critically ill children. In one population-based, case-control study in a large tertiary care paediatric center, the following risk factors for Candida spp. bloodstream infections were identified: presence of central venous catheter, underlying malignant conditions, and having received vancomycin or an anti-anaerobic antibiotic for more than 3 days. The predicted risk for candidemia for patients with some of these three risk factors in different combinations ranged between 10% and 46%. In this study, the authors concluded that these patients could be candidates for antifungal prophylaxis [4]. Another observational study in 24 Spanish PICUs recorded 125 invasive Candida spp. infections and determined that previous bacterial infection, chronic metabolic disease, digestive surgery, pre-PICU stay longer than 15 days, previous colonization, parenteral nutrition and invasive devices were risk factors [22]. Central venous catheters, immunosuppression (including long-term steroids), damage of gastrointestinal tract, broad-spectrum antibiotics, parenteral nutrition, renal failure requiring hemodialysis, mechanical ventilation and genetic susceptibility have been described in other studies as important risk factors [23-25]. Children younger than one year of age have a higher incidence of candidemia [26]. In addition to risk factors, the local incidence of invasive Candida spp. infections should be considered to decide whether or not to start AFP. An incidence of 10% is considered the threshold to use prophylaxis with an acceptable risk-benefit analysis. Some authors suggest that in PICUs with rates of invasive candidiasis higher than 5%, AFP may be considered in selected patients with several risk factors (CII). There are few studies about the benefits of AFP in PICU. Reduction on invasive candidemia incidence with fluconazole prophylaxis has been studied in adult intensive care patients in four meta-analyses, though the incidence of both candidemia and mortality decreased only in two of these studies. Even though evidence is scarce especially in children, prophylaxis may be an option in selected critically ill children, other than immunocompromised and oncological patients, considering the high mortality of these infections. A personalized assessment may be warranted for individual PICU patients based on the presence of specific individual risk factors and local epidemiology The difficulty to identify risk factors for invasive Candida spp. infections and the lack of evidence about the benefits of AFP, make early empirical treatment a preferred strategy for children with a high likelihood of fungal infection in order to decrease the high mortality rates [14] and minimizing the selection of antifungal resistances. Empiric therapy for non-neu- tropenic patients with risk factors for fungal infections without documented invasive candidiasis is still controversial [27]. Decision should be based on colonization data, presence of risk factors, surrogate markers of fungal infection and ongo- MID strongly recommends it in NICU with a prevalence higher than 5% of IC in babies <1,000 g at birth at a dose of 3-6 mg/kg twice weekly i.v. or orally [14]. Also, the Latino American working group of invasive fungal infections recommends fluconazole prophylaxis 3 mg/kg twice a week, in newborn weighing < 1,000 g for 6 weeks in NICU with prevalence of IC > 5% [15] (AI). In NICU with a prevalence < 5% fluconazole prophylaxis should be individualized and considered only in preterm neonates with multiple risk factors for IC (<1,000 g, need for a prolonged central vascular central and broad-spec- trum antibiotics (CII) [14]. Fluconazole prophylaxis is a safe strategy, and although isolates of Candida spp. with reduced susceptibility to azoles have been described, there is no evidence of development of clinical emergence of resistance to azoles in newborns after prolonged exposure. Although there are few studies with longterm follow-up, there is no evidence for any relationship with neurocognitive impairment, blindness, deafness or cerebral palsy at 24 months of life, nor impact on growth. Even though fluconazole may lead to increased liver enzymes, significant liver toxicity is uncommon with prophylaxis dosages [12]. Filamentous fungi are infrequent in the neonatal period, and have only rarely been reported in preterm babies, including Aspergillus spp. and Rhizopus spp., albeit associated with a very high mortality [16]. Micafungin is approved in newborns including preterm but its activity against moulds is limited. Voriconazole use has been anecdotical, although it is not approved below 2 years of age [16, 17]. Due to its potential retinal toxicity in particular in the immature preterm retina, no clinical trials are planned in this age group [18]. Thus, specific AFP against moulds in this patient group is not recommended [2]. 2.- ANTIFUNGAL PROPHYLAXIS IN THE PAEDIATRIC INTENSIVE CARE SETTING Indications for primary prophylaxis in non-immunocom- promised critically ill children are not clear. Despite a relatively high incidence of IFI in patients admitted at the Pediatric Intensive Care Unit (PICU), evidence for primary and/or secondary AFP in non-immunocompromised critically ill children is lacking. In the intensive care setting, by far the predominant IFI are due to Candida spp., being filamentous fungi anecdotical, and therefore, AFP if considered, should be targeted only against yeasts. Some authors, based on different prediction scores, recommend AFP in adults for invasive candidiasis, with fluconazole (CII), or as an alternative an echinocandin like caspofungin in non-immunocompromised high-risk patients, although the grade of recommendation is low (CIII) [19, 20]. Risk factors for invasive candidiasis identified in this population include: abdominal surgery with recurrent perforations, intubated patients for more than 48 h and expected to be ventilated for another 72 hours, multiple Candida spp. colonization, systemic antibiotics, central venous catheters, transfusion Clinical practice update of antifungal prophylaxis in immunocompromised childrenJ. T. Ramos, et al. Rev Esp Quimioter 2019;32(5): 410-425 413 matological and oncologic conditions (i.e. tyrosine kinase inhibitors], and it remains unclear if AFP is indicated in these cases [34]. Table 4 presents the different antifungal agents used for AFP. Azoles are the preferred drugs for prevention of IFI, considering anti-mould active agents in high-risk patients. Caution is advised for concomitant use of triazoles with chemotherapy metabolized by cytochrome P450 isoenzymes. Options include itraconazole (AII); posaconazole for patients ≥13 years of age (AII) and voriconazole for patients >2 years of age (AII). Echinocandins and liposomal amphotericin B represent alternatives when azoleing fever despite proper antibiotic treatment. In the absence of microbiological confirmation nor clinical response, therapy should be maintained no more than 4 or 5 days [1]. In adults, daily bathing of the patients admitted in the intensive care units in chlorhexidine has been studied in one trial for its role as a protective factor for Candida spp. bloodstream infections [28]. Even though significant impact on Candida spp. infection is not proven, the measure is easy, inexpensive and may be beneficial. The impact in paediatric intensive care units is still to be determined. In conclusion, current recommendations about prophylaxis should be individualized considering the PICU epidemiology, as well as the individual predisposition and colonization (CII). The balance between overuse of antifungal agents with emerging resistance and efficacy is yet to be determined and better evidence in the paediatric intensive care setting has to be collected. 3.- CANCER PATIENTS AND STEM CELL TRANSPLANT RECIPIENTS 3.1 Risk factors for invasive fungal disease Children receiving treatment for cancer or undergoing haematopoietic stem cell transplant (HSCT) have a significant risk of developing IFI, with high morbidity and mortality. Risk factors for IFI in these patients are conditioned by the breakdown in natural barriers, defects in cell-mediated immunity and mainly deficient the presence of profound and persistent neutropenia (table 1) [29, 30]. Primary AFP is generally recommended for those children whose risk is greater than 10% (table 2) [29, 31, 32]. However, in the choice of an appropriate AFP strategy it is important to consider some modifiers like the local epidemiology, comorbidities or specific treatment modalities. New therapies such as tyrosine kinase inhibitors and other immunomodulatory therapies (i.e. CAR T-cell therapy [33] broad the spectrum of patients at risk for IFI [34], so the assessment of risk should be individualized. 3.2 Primary antifungal prophylaxis Whereas pharmacokinetic/pharmacodynamic (PK/PD) and safety of the different antifungal agents are targeted in paediatric studies; the evidence for efficacy may need to be extrapolated from studies in adult population. Although there are only few antifungal agents currently approved for AFP in children, an increasing number of reports describe safety and suggest efficacy of agents given to prevent IFI in the pediatric population. In addition, most studies do not address the optimal dosage of an antifungal agent to prevent IFI. The final choice of an antifungal drug for prophylaxis should be individualized based on the patient risk, the agent activity, the toxicity profile, and the PK/PD data [29, 32]. The specific recommendations for AFP are summarized in table 3 based on the different risk groups. There are not specific prophylaxis recommendations for the new drug classes for hae- Clinical factors Severe and persistent neutropenia a Lymphopenia Mucosal damage Central venous catheters Previous fungal colonization Graft versus host disease (GVHD) in HSCT CMV infection in HSCT Pharmacological factors Steroids in high-doses b Anti-tumour necrosis factors agents Alemtuzumab Nucleoside analogues CAR T-cell therapy Table 1 Risk factors for IFI IFI: invasive fungal infection, HSCT: haematopoietic stem cell transplant, CMV: cytomegalovirus, CAR: chimeric antigen receptor a Absolute neutrophil count of ≤500 cells/μL for >7-10 days b Steroids in pharmacological doses (≥0.3 mg/kg per day prednisone or equivalent) High-risk (≥ 10%) Acute myeloid leukemia Recurrent or high-risk acute lymphoblastic leukemia Allogeneic HSCT a Severe aplastic anemia Low-risk (≤ 5%) Standard-risk acute lymphoblastic leukemia Autologous HSCT b Non-Hodgkin’s lymphoma Sporadic Pediatric solid tumors Brain tumors Hodgkin’s lymphoma Table 2 Stratification of risk for IFI HSCT: Haematopoietic Stem Cell Transplant. GVHD: Graft versus Host Disease. IFI: invasive fungal infection. a Pre-engraftment phase or with associated GVHD. b In the neutropenic phase it could be considered intermediate-risk. Clinical practice update of antifungal prophylaxis in immunocompromised childrenJ. T. Ramos, et al. Rev Esp Quimioter 2019;32(5): 410-425 414 3.3 Secondary antifungal prophylaxis Despite the scant data in children, secondary AFP or continued antifungal treatment after an episode of invasive mould infection is recommended based on the high rate of relapse (30–50%) [31]. The drug of choice should be active against the previous fungal pathogen. Secondary AFP should continue for as long as the patient is neutropenic or immunosuppressed (AII), e.g. allogeneic HSCT (early phase), chemotherapy resulting in severe neutropenia (i.e. <500/mL and at least for 7 days), acute GVHD > stage II, extensive chronic GVHD, or T-cell suppressing therapy, including steroids. Currently evidence is based regimes are contraindicated or not tolerated. Options include liposomal amphotericin B (BII); micafungin (BII); and, with less strength of evidence, aerosolized liposomal amphotericin B (CII) and caspofungin (CII) [31, 34, 35]. In the absence of GvHD, AFP may be continued after engraftment until discontinuation of immunosuppression and signs of immune recovery. In the presence of GvHD requiring augmented immunosuppression (including steroids in therapeutic dosages or anti-inflammatory antibodies), prophylaxis against IA and other relevant IFI is recommended (AII) [2]. Newer agents, such as isavuconazole, are under study in children, and have poor evidence to be recommended for AFP. Underlying condition Cancer Comments Children undergoing allogeneic HSCT with no GVHD AFP is recommended during the neutropenic phase until engraftment (BII) AFP is recommended after engraftment until discontinuation of immune suppression and immune recovery (no grading) Fluconazole (AI) Itraconazole (BI) Voriconazole (BI) Micafungin (CI) Liposomal amphotericin B (CIII) Posaconazole (no grading) Only active against yeasts TDM recommended TDM recommended For children ≥13 years TDM recommended Children undergoing allogeneic HSCT in the presence of GVHD (acute grade II–IV or chronic extensive) treated with augmented immunosuppression AFP against mould and yeast infections is recommended while the immunosuppression is maintained (AII) Posaconazole (BI) Voriconazole (BI) Itraconazole (CIII) Liposomal amphotericin B (no grading) Micafungin (no grading) For children ≥13 years TDM recommended TDM recommended TDM recommended Autologous HSCT with anticipated neutropenia >7 days AFP should be considered (BI) until immune recovery Fluconazole (AI) Micafungin (AII) Any mould active agent (DIII) Paediatric de novo or recurrent leukemia patients AFP should be considered in high risk patients (BII). No evidence-based recommendations can be made on the duration in patients with persisting neutropenia in this group Itraconazole (BI) Posaconazole (BI) Liposomal amphotericin B (BII) Fluconazole (CI) Other options include: Voriconazole (no grading) Micafungin (no grading) TDM recommended For children ≥13 years TDM recommended Active only against yeast Table 3 Antifungal primary prophylaxis in children with cancer: recommendations based on risk groups [31, 32, 34-39] AFP: Antifungal prophylaxis. TDM: Therapeutic Drug Monitoring. HSCT: Haematopoietic Stem Cell Transplant. GVHD: Graft versus Host Disease Clinical practice update of antifungal prophylaxis in immunocompromised childrenJ. T. Ramos, et al. Rev Esp Quimioter 2019;32(5): 410-425 415 minimize toxicity. This is important in children, because of their pharmacokinetic variability, and especially in hematology-on- cology patients who have multiple conditions (associated with their underlying disease and its treatment) that affects the absorption, distribution, metabolism and clearance of antifungal medications [44]. TDM is generally recommended during prophylaxis with itraconazole, voriconazole and posaconazole (AII). Recommended plasma target ranges are summarized in table 5 [40, 45]. Usually, the first sample should be acquired lacking regarding the minimal duration of the therapy before the continuation of anticancer treatment of the conditioning regime for allogeneic HSCT [31, 40]. 3.4 Practical aspects 3.4.1 Therapeutic drug monitoring (TDM) The objective of monitoring the plasma levels of antifungals is to optimize their dose, in order to improve efficacy and Antifungal agent and dosing Dosing Spectrum Comments Fluconazole 6–12 mg/kg/day QD IV/PO (maximum 400mg/day) Only against yeast Itraconazole 5 mg/kg/day BD PO (>2 years of age) Both yeasts and moulds Not approved in patients <18 years. TDM required Voriconazole 2 to <12 years or 12–14 years and <50 kg: 16 mg/kg/day BD IV/PO (first day: 18 mg/kg/day IV/PO BD) >15 years or 12–14 years and >50 kg: 8 mg/kg/day BD IV/PO (first day: 12 mg/kg/day BD IV; 400 mg/day BD PO) Both yeasts and moulds (no against Zygomycetes ) Not approved in patients <2 years. TDM required. Increased risk of phototoxicity. Posaconazole 600 mg/day TDS PO (suspension) in patients >13 years [41] 300 mg/day QD PO (3 x 100 mg delayed-release tablets). First day: 600 mg/day BD. 300 mg/day QD IV (first day: 300 mg/ day BD) Both yeasts and moulds Limited PK data in patients <13 years. Not approved in the European Union in patients <18 years. TDM required. Coverage for most fungi, including Zygomycetes. Delayed released tablet formulation presents better PD data. Taken with food. Liposomal amphotericin B 1 mg/kg IV every other day or 2.5 mg/kg IV twice weekly Both yeasts and moulds Still not approved for prophylaxis in children [32, 42]. Optimal dose of alternate administration is still unknown. Alternative when azole based regime is contraindicated or not tolerated. Caspofungin 50 mg/m 2 /day QD IV (first day: 70 mg/ m 2 /day QD IV) (maximum 70 mg/day) Both yeasts and moulds Caspofungin does not have a label for the prophylactic Indication [43]. Micafungin 1 mg/kg/day (if >50kg : 50mg) QD IV Both yeasts and moulds Approved for AFP of Candida spp. infections in granulocytopenic children. Less interactions than azoles with other drugs. Considerably higher drug clearance in children 4 months to 5 years compared to older children. Table 4 Agents and antifungal dosing recommended in haemato-oncological or HSCT paediatric patients [31, 32, 37, 40]. QD: once daily. BD: twice a day. TDS = three times a day. AFP: antifungal prophylaxis. For interactions, see table 6. Clinical practice update of antifungal prophylaxis in immunocompromised childrenJ. T. Ramos, et al. Rev Esp Quimioter 2019;32(5): 410-425 416 on the type of transplanted organ and the receptor risk factors to develop an IFI. There are no recommendations in the pediatric field due to the limited published information, so that most of them are adapted from those published in the adult population. In general, patients at high risk (expected incidence higher than 10%) should receive prophylaxis against filamentous fungi (AII). The drug of choice will depend on the type of transplant organ and the population studied [53]. 4.1. Prophylaxis against yeasts Liver, pancreas and bowel recipients have the highest risk to develop an invasive candidiasis, thereby potentially benefiting from AFP. Liver transplant recipients need to meet at least two risk factors [54, 55] (table 7). Fluconazole or echinocandins are the most recommended drugs [56], considering amphotericin B when patients have risk factors for filamentous fungi (AIII). The most recommended duration is 4 weeks in the liver transplant and at least 4 weeks in the pancreas and bowel transplant. In kidney recipients, invasive candidiasis is the most frequent IFI, although its incidence is low, so prophylaxis is not recommended (DIII) [54]. 4.2 Prophylaxis against Pneumocystis jirovecii (PJ) The incidence of PJ pneumonia in a study made in adult population in United Kingdom was 5.8% in lung or cardiopulmonary transplants, 5.5% in heart, 1.2% in liver and 0.3% in the kidney recipients [57]. Prophylaxis against PJ during the first months after the transplantation is recommended in several guidelines for adults and children [58]. Trimethoprim sulfamethoxazole (TMP-SMX) is the drug of choice [57, 59]. In case of intolerance to cotrimoxazole, dapsone is the second line drug more used for prophylaxis, although less effectivity has been observed in some pediatric studies [60]. There is little experience with atovaquone and pentamidine (inhaled or intravenous). The duration of PJ prophylaxis is not established, ranging between 3 and 12 months after the transplantation according to different scientific societies [59, 61]. Its indication should be prolonged after graft rejection or higher steroid needs (over 20 mg of prednisolone or ≥0.3 mg/kg or equivalent for more than 4 weeks). It has also been proposed to keep it indefinitely in lung or bowel transplant, in patients with chronic CMV infections and in those with a history of a previous infection by PJ (BII) [57]. 4.3 Prophylaxis against filamentous fungi Invasive aspergillosis (IA) is one of the most relevant fungal infections in SOT recipients, with an overall incidence reported of 1-15%, being higher in lung transplant in surveillance studies (44%) [51], and reported mortality rates of apwithin 5-7 days of starting therapy (2-5 days for voriconazole) and repeated until steady-state level in the therapeutic range is confirmed, if there are changes in the patient’s clinical condition, concomitant medications, or suspected toxicity [40]. 3.4.2 Side effects and drug-drug interactions The main side effects of the antifungals used in prophylaxis and relevant interactions for hematology-oncology patients are summarized in table 6. 3.4.3 Monitoring of fungal biomarkers Serum galactomannan (GM) screening should not be performed in neonates and children at low risk for IA (DIII). Serum GM should not be used as a screening test in asymptomatic patients undergoing AFP; several studies have shown that it has a low positive predictive value in these cases (BII) [46-48]. Therefore, given the low pre-test risk of IA in the context of effective anti-mould prophylaxis, the result of the test would be either negative or false positive in asymptomatic patients, leading to unnecessary diagnostic tests and treatments. The test remains useful to assist the diagnosis of patients with a clinical suspicion of IFI during prophylaxis [40, 46, 47, 49, 50]. 4.- SOLID ORGAN TRANSPLANTATION (SOT) Patients who received a SOT have a higher risk of IFI, being an important cause of morbidity and mortality. Candida spp. are the most frequent IFI, followed by filamentous fungi, especially Aspergillus spp. [51]. Not all recipients are at the same risk of IFI. The multicenter epidemiological study TRANSNET, conducted in adult population, shows the highest incidence of IFI in small bowel transplant recipients (11.6%), followed by lung (8.6%), liver (4.7%), heart (4%) and pancreas (3.4%) [51]. Data in children are still scarce, but a recent study, conducted in pediatric population revealed an IFI global incidence of 2%, cardiopulmonary and lung transplant showing the highest incidence (12.5% and 11.4% respectively) [52]. AFP in SOT pediatric recipients can decrease colonization, and therefore, the subsequent development of IFI. Nevertheless, universal AFP is not recommended, and its use will depend Antifungal Prophylaxis plasma range Treatment plasma range Quality of evidence Itraconazole 0.5-4 mg/L 1-4 mg/L AII efficacy BII toxicity Voriconazole 1-6 mg/L (optimal 2-5 mg/L) AII efficacy AII toxicity Posaconazole >0.7 mg/L >1 mg/L BII efficacy (prophylaxis) AII efficacy (treatment) Table 5 Recommended plasma target ranges for antifungal drugs Clinical practice update of antifungal prophylaxis in immunocompromised childrenJ. T. Ramos, et al. Rev Esp Quimioter 2019;32(5): 410-425 417 mould activity may also be used for IA prevention. The effectiveness and safety of voriconazole prophylaxis has been studied in lung transplant recipients [2]. The IDSA guidelines recommends itraconazole or voriconazole in patients colonized by Aspergillus spp., in those with a proven fungal infection in the removed organ, sinusal aspergillosis or in those who have received a unipulmonary transplant [35]. Duration of prophylaxis is unclear, but at least 3- to 4-week treatment or until resolution of risk factors seems appropriate [2]. In lung and high-risk heart transplanted children a more prolonged prophylaxis (3-12 months) is warranted. The drug of choice remains controversial. Lipid amphotericin B has shown proximately 22% despite novel treatment modalities. In lung transplant recipients, invasive pulmonary disease has an even higher mortality rate (67–82%) [59]. AFP against Aspergillus spp. is recommended in lung transplant recipients (AIII) and in those children exhibiting a high-risk profile (e.g. Model for End Stage Liver Disease score >30, liver failure, renal failure, reintervention) (BIII) [2]. Data of IA in heart recipients are scarce. Reduction of IFI has been observed in those patients with prophylaxis, but no consensus exists. Some authors recommend AFP only in patients with risk factors [2, 54]. Inhaled lipid formulations of amphotericin B are the most studied option, although its optimal dose, formulation and duration has not been defined in adult population. Systemic azoles with anti- Antifungal Adverse effects Interactions Fluconazole Gastrointestinal disorders Elevation of transaminase levels Cyclosporine, ifosfamida, irinotecan, vincristine, fentanyl, omeprazole, ondansetron, cotrimoxazole, prednisone, dexamethasone Itraconazole Gastrointestinal disorders Elevation of transaminase levels Periferal neuropathy Negative inotropic effect (less frequent) Cyclosporine, ifosfamida, irinotecan, methotrexate, etoposide, vincristine, fentanyl, deferasirox, omeprazole, ondansetron, ranitidine, dexamethasone, prednisone Voriconazole Gastrointestinal disorders Elevation of transaminase levels Visual disturbances Hallucinations Headache Rash Long QT-syndrome Ciclosporin, etoposide, ifosfamida, irinotecan, vincristine, fentanyl, cotrimoxazole, ibuprofen, omeprazole, ondansetron, dexamethasone, prednisone Posaconazol Gastrointestinal disorders Elevation of transaminase levels Headache Dizziness Periferal neuropathy Electrolyte alterations Long QT syndrome (less frequent) Cyclosporine, etoposide, ifosfamida, irinotecan, vincristine, fentanyl, omeprazole, ranitidine, dexamethasone, prednisone Micafungin Gastrointestinal disorders Headache Phlebitis Elevation of transaminase levels Electrolyte alterations Sirolimus, nifedipine, itraconazole Amphotericin B Hypokalemia Nephrotoxocity Headache Elevation of transaminase levels Infusion reactions Cyclophosphamide, cisplatin, cytarabine, etoposide, hydroxyurea, ifosfamide, irinotecan, mercaptopurine, methotrexate, temozolamide, vincristine, vinorelbine, dexamethasone, prednisone cyclosporine, aminoglycosides, pentamidine Table 6 Side effects and drug interactions of antifungals used in prophylaxis Clinical practice update of antifungal prophylaxis in immunocompromised childrenJ. T. Ramos, et al. Rev Esp Quimioter 2019;32(5): 410-425 418 of underlying immune disorders and PID must always be considered in those patients. There are several PID that may present with both invasive and mucocutaneous fungal infections, caused by moulds and/or yeasts [63, 64]. Neutrophil defects, (severe) combined immunodeficiencies and diseases caused by mutations altering relevant cytokine pathways are among the list of PID that may present with severe fungal infections. Thus, primary or secondary AFP is recommended for most of the diseases below listed (table 9). However, evidence regarding the most appropriate medication, duration, dosing schedule, drug monitoring and dose adjustment is scarce and often extrapolated from adults and/or the onco-haematologic setting (table 4). Chronic granulomatous disease (CGD) is the PID with the highest risk for IFI, particularly IA with incidences ranging from 26% to 45%. Additionally, IA is the most common infectious cause of death. Prevention of IA plays a central role in the clinical management of children with CGD and consists of reducing environmental exposure to moulds and the prophylactic use of antifungals. Itraconazole prophylaxis has shown to significantly reduce IFD in CGD patients and is recommended as prophylaxis (AII). Posaconazole is a a significant reduction of invasive fungal infections without a mortality reduction but is limited by its potential for nephrotoxicity. Echinocandins are not nephrotoxic, and promising results have been published in preventive studies focusing on high-risk liver transplant recipients [2]. In paediatric kidney transplant recipients AFP to prevent filamentous fungi is not recommended (DIII) [54]. In small bowel and pancreas recipients transplant, only patients are risk are candidates for prophylaxis against moulds. Table 8 summarized the indications about AFP in pediatric population after SOT [32]. 5.- PRIMARY IMMUNODEFICIENCIES Patients with primary immunodeficiencies (PID) are often prone to develop recurrent and/or severe infections, autoimmune disorders and malignancies. Infection site, causative pathogens, clinical course and outcome depend on a number of factors such as the underlying gene defect, patients’ age, existence of comorbidities and also environmental factors potentially related to pathogen exposure [62]. IFI are a hallmark Fungal infection Solid organ transplant Risk factors Candida species Liver Retrasplant Post-transplant renal failure More than one episode of acute rejection during the first month, requiring the use of steroids or monoclonal antibodies Colonization by Candida spp. Aspergillus species Liver Retrasplant Post-transplant renal failure requiring dyalisis Pretransplant fulminant liver failure Surgical re-intervention Intestine-pancreas Immunosupression Acute graft rejection Hemodyalisis Initial graft rejection Anastomosis related issues Post-transplant need of laparotomy Infection by cytomegalovirus Heart Post-transplant hemodyalisis Surgical reintervention Colonization or previous infection by Aspergillus spp. before or after transplantation Infection by cytomegalovirus Acute graft rejection Table 7 Risk factors to IFI in children with SOT SOT: Solid Organ Transplantation Clinical practice update of antifungal prophylaxis in immunocompromised childrenJ. T. Ramos, et al. 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