Invasive fungal infections in the pediatric population

Keywords::

• children
• diagnosis
• epidemiology
• mycoses
• treatment

Invasive fungal infections (IFIs) are increasing in incidence and constitute an important cause of morbidity and mortality in immunocompromised pediatric patient populations, including, but not limited to, preterm neonates, children and adolescents with hematologic malignancies, and those undergoing hematopoietic stem cell transplantation (HSCT) [1–3]. Although children and adults are similarly vulnerable to IFIs, important differences between these two patient groups have to be considered. These include epidemiology, diagnostic approaches, as well as pharmacokinetics (PK) and adverse effects of antifungal agents, all of which have an impact on antifungal management strategies. In order to optimize prevention and treatment of IFIs in children, all specialists involved in the care of pediatric patients have to be familiar with these specifics of pediatric care.

Populations at risk & epidemiology of pediatric fungal infections

Although children and adults are similarly vulnerable to IFIs, important differences exist in host responses, the capacity of immune reconstitution after chemotherapy, and comorbidities, all of which influence the risk and outcome of IFI. For example, compared with older children and adults, neutrophils in the neonatal period have impaired chemotaxis and bactericidal activity [4,5], and T-cell regeneration following intensive chemotherapy, both in number and T-cell repertoire, critically depends on the age of the patient [6]. It is therefore not surprising that the epidemiology of IFI differs between children and adults. In comparison to adults, the incidence of invasive candidiasis is higher in the pediatric age group, with the highest risk in neonates [7,8]. Whereas prolonged rupture of membranes, the use of third-generation cephalosporins or H₂-blockers, the need for artificial ventilation, and colonization with Candida spp. at more than one site are well-described risk factors for invasive candidiasis in neonates, the risk factors for invasive Candida infections in older children are more similar to those in adults (e.g., immunosuppression and central venous lines). Importantly, in children aged younger than 1 year, the incidence of Candida parapsilosis is considerably higher than that of Candida glabrata, whereas in adolescents, the incidence of C. glabrata may exceed the incidence of C. parapsilosis[9]. Overall, the rate of mortality due to invasive candidiasis is lower in children compared with adults [10].

In contrast to Candida infections, invasive aspergillosis (IA) is rare in preterm and term neonates. A retrospective study revealed that corticosteroid therapy, neutropenia, immunosuppressive therapy, malignancy and allogeneic HSCT were the most common risk factors for IA in the pediatric age group [11]. Notably, almost all patients included in this analysis had at least one risk factor. The overall fatality rate of IA in this study was 53%, which is similar to that seen adult patients [11]. Surprisingly, 46% of the children received at least three concomitant antifungal agents for at least 3 days, in most cases a lipid formulation of amphotericin B and voriconazole; however, no superiority of any one antifungal in terms of mortality was identified. IA also significantly contributes to the mortality of children with acute lymphoblastic and myeloid leukemia, lymphoma, allogeneic HSCT and solid organ transplantion; in a retrospective cohort study using a national database of hospital inpatient stays during 2000, 18% (122 of 666) of children with IA died in the hospital, compared with 1% (1736 of 151,537) of similarly immunocompromised children without IA [12].

Relatively little is known regarding zygomycosis in children. A systematic literature review including reports back to 1939 identified a total of 157 reported children with zygomycosis [13]. Whereas prematurity was the most common risk factor in pediatric patients, diabetes and underlying malignancy are seen in both children and adults developing invasive zygomycosis. Compared with children, the mortality of zygomycosis appeared to be lower in adults, which might be due to a lower rate of dissemination [14].

Diagnostic procedures for pediatric fungal infections

In the pediatric population, published data on specificity and sensitivity of diagnostic approaches such as the Aspergillus galactomannan test or CT scans are quite limited [15]. There are several reasons for this, including the fact that many clinical trials enroll adult patients only and also that sub-analyses of pediatric data from larger trials enrolling both pediatric and adult patients, as well as prospective studies in children, are limited in their interpretability by small patient numbers. For example, one study analyzed galactomannan in 3294 serum samples from a total of 728 patients. While the specificity in the entire study population was 94.8%, it was significantly lower in the 42 children included in the study (47.6%) [16]. In contrast to these findings, the specificity of the galactomannan assay was 97.5% in a recent prospective study in 64 children undergoing HSCT [17]. Therefore, this important assay needs to be further validated in a large-scale format dedicated to pediatric patients. Similarly, the diagnostic sensitivity and specificity of β-D-glucan for the diagnosis of candidiasis seems to be good in adult patients, whereas the value in the pediatric population is not clear at all. Notably, a recent study evaluated β-glucan levels in children specifically not at risk for IFI and reported higher baseline levels of the assay in children compared with adults [18].

Computed tomography is another important tool in the diagnosis of IFI. Whereas both halo-sign and air-crescent sign are common and highly suggestive for invasive mold infection in adult patients [19], retrospective studies have demonstrated that CT scans are less specific in children. In this patient population, findings including segmental and multilobar consolidation, peripheral infiltrates, multiple small nodules and larger peripheral nodular masses are common, whereas the halo-sign is rarely present [20–23].

Antifungal therapy for pediatric fungal infections

Owing to the dramatic changes of the ratio between body surface area and bodyweight from birth to adolescence, a consistent body surface area- or bodyweight-related dosage of drug is not appropriate in the pediatric population. In addition, the age-dependent functional characteristics of hepatic and/or renal function have to be considered with regard to both metabolism and elimination of the drug. Despite considerable achievements, the prevention and treatment of IFI in the pediatric population is still limited by the fact that not all antifungal agents are approved in the pediatric population, that the appropriate dosage of these drugs has not been established for all age groups and that postmarketing data providing information on safety and efficacy of approved agents under real life circumstances are scant. For example, posaconazole, a novel broad-spectrum triazole, is widely used in the adult setting as it has been demonstrated to decrease the incidence of IFI and to impact upon overall survival in adults undergoing induction therapy for acute myeloid leukemia or adult HSCT recipients with severe graft-versus-host disease [24,25]. Unfortunately, however, the appropriate dosage of posaconazole in children younger than 13 years of age has not been established to date.

On the other hand, the strategies of how safety and efficacy of a compound are evaluated may differ for pediatric and adult patients. In this regard, the regulations and guidelines by both the US FDA and the European Medicines Agency [101] recognize certain features unique to pediatric studies, including: the potential for extrapolation of efficacy from studies in adults to pediatric patients or from older to younger pediatric patients when a medicinal product is to be used for the same indication(s); the disease process or target sensitivity is similar; and the outcome of therapy is likely to be comparable. In such cases, PK studies in all the age ranges of pediatric patients likely to receive the medicinal product, together with safety studies, may provide adequate information for use by allowing selection of pediatric doses that will produce blood levels similar to those observed in adults. In situations where the comparability of the disease course or outcome of therapy is expected to be similar, but the appropriate blood levels are not clear, a PK/pharmacodynamics (PD) approach combined with safety and other relevant studies could avoid the need for larger clinical efficacy studies [102]. However, the regulations and guidelines also stress the particular importance of postmarketing surveillance studies because of the usual limited pediatric database at the time of approval [102].

Prime examples for this approach in the field of antifungal pharmacology include the successful clinical development of caspofungin [26–28] and micafungin [29–31] through an ordered set of systematic investigations in Phase I–III clinical trials for definition of pediatric doses, collection of limited safety and efficacy data in the target indications that support the feasibility of extrapolation of safety and efficacy from large randomized adult clinical trials [31,32], supplemented by population PK studies [33], PK/PD analyses and establishment of a postmarketing surveillance system. Pharmacologically more complex drugs such as voriconazole, however, may require more focused efforts in pediatric populations with an unmet medical need [34–36], as do premature neonates, in whom PK and PD often need separate study.

Future perspective

In order to better define pediatric populations at risk for IFI, the use of diagnostic tools in an evidence-based manner and implementing proper development of antifungal drugs for pediatric patients, not only regulations and guidelines, but also the orchestration of clinical research and international collaboration, are required. There have been several promising developments in recent years, including the establishment of the International Pediatric Fungal Network that will serve as a platform for interventional and postmarketing studies, the US Pediatric Pharmacology Research Unit Network, the European Network of Paediatric Research and initiatives linking the administrative efforts of both the FDA and the European Medicines Agency in this area. To this end, these activities together with an increasing awareness of the special needs of children might result in a better standard of care when preventing and treating IFIs in preterm and term neonates, children and adolescents.

Financial & competing interests disclosure

Thomas Lehrnbecher has received a grant from Gilead, is a consultant to Astellas, Gilead, Merck, Sharp & Dohme and Schering-Plough, and has served on the speakers’ bureau for Gilead, Merck/MSD, Pfizer and Schering-Plough. Andreas H Groll has received grants from Gilead and Merck, Sharp & Dohme, is a consultant to Astellas, Gilead, Merck, Sharp & Dohme and Schering-Plough, and has served on the speakers’ bureau for Astellas, Gilead, Merck/MSD, Pfizer, Schering-Plough and Zeneus/Cephalon. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.