Invasive fungal infections in critically ill children: epidemiology, risk factors and antifungal drugs

Introduction

Invasive fungal infections (IFIs) pose a significant threat to critically ill children, particularly those with compromised immune systems. Among the most prevalent fungal pathogens are species of Candida, Aspergillus, Zygomycetes, and Fusarium, with Candida leading as the primary cause of fungal infections. The widespread empirical use of antifungal drugs has contributed to the emergence of some of these infections.

Among critically ill pediatric patients, invasive candidiasis infections (ICIs) and invasive aspergillosis infections (IAIs) are the most frequently encountered IFIs. ICIs, particularly caused by Candida albicans, are more commonly observed in the general pediatric intensive care unit (PICU) population. On the other hand, IAIs tend to occur more often in children with underlying conditions, such as hematological malignancies or solid tumors. IFIs, especially IAIs, are associated with higher mortality rates compared to ICIs, making early detection and treatment critical for improving patient outcomes.

This review aims to explore the epidemiology of IFIs in paediatric patients, particularly in the context of intensive care, and provides an updated overview of antifungal medications, their dosing strategies, and potential adverse effects in this vulnerable population. Understanding these aspects is crucial for improving outcomes in critically ill children facing these life-threatening infections.

Methods

A PubMed search was performed using Clinical Queries and the key terms “antifungal”, “children”, “critical care” AND “paediatric intensive care”. The search strategy included meta-analyses, clinical trials and observational studies, randomized controlled trials, and reviews and was restricted to the English language and paediatric population.

Review

In the PICU, children with severe diseases like hematological disorders or malignancies face a 5% incidence of invasive fungal infections (IFIs), with a high mortality rate of 60%. The rise in IFIs over the past 20 years is due to increased survival of children undergoing aggressive treatments such as chemotherapy, immunosuppressive therapy, and stem cell transplants. Candida and Aspergillus are the most common fungal pathogens. Risk factors include chemotherapy, transplants, neutropenia, immunosuppression, central lines, infections, surgery, mechanical ventilation, and prolonged PICU stays.

ICIs in critically ill children

The distribution of invasive candidiasis infections (ICIs) and Candida species in PICUs varies due to differences in institutional practices, geographical factors, and antifungal protocols. A French study found a 15% infection rate in PICUs, with ICIs making up 4.4% of infections. Studies from Greece and Spain reported incidences of 6.4 and 6.9 cases per 1000 PICU admissions, respectively. Lower rates were seen in the USA (3.5/1000 admissions) and Egypt (3/1000 inpatient days). Candida albicans is the most common cause, but non-albicans species account for 10-15% of cases. Risk factors include central venous lines (CVL), surgery, prolonged hospitalization, and mechanical ventilation.

In PICU patients, Candida colonization is common, and the risk of infection increases with the duration of a CVL. The Infectious Diseases Society of America recommends removing CVLs if candidaemia occurs. Some studies suggest prophylactic antifungal use if candidaemia risk exceeds 10%. Additionally, patients with underlying malignancies, chemotherapy, or immunosuppression face a higher risk of ICIs, with infections contributing significantly to mortality in children with leukemia.

IAIs in critically ill children

Data on invasive aspergillosis infections (IAIs) in children are limited and varied. Over the past decade, IAIs have increased three- to four-fold due to improved management of immunocompromised patients. In the USA, IAIs occurred in 0.4% of hospitalized immunocompromised children in 2006, primarily affecting those with malignancies. The median time from malignancy diagnosis to IAI was 8.5 months, with a notable incidence in acute myeloid leukemia (5.35%) and acute lymphocytic leukemia (1.5%). Mortality from IAIs in these cases was 37.5%.

Common fungal strains include Aspergillus species, with A. flavus and A. fumigatus being the most prevalent. A. niger can be found in septic granulomatous disease. IAIs often affect the lungs and skin, with up to 41% of skin lesions associated with aspergillosis. Risk factors for IAIs include hematological malignancies, bone marrow transplantation, high steroid use, and prolonged antibiotic treatment.

Mortality of ICIs and IAIs

Mortality rates differ between invasive fungal infections (IFIs) due to underlying conditions. Candidaemia increases hospital stay by 21 days with mortality rates of 30% in children and 43-54% in infants. Candidaemia with central venous lines (CVL) and invasive candidiasis (ICI) in PICU patients are linked to higher mortality.

Overall, mortality rates for pediatric IAIs and ICIs are around 70% and 20-30%, respectively. IAIs have seen a 357% increase in deaths over the past decade in the USA, with a 20% higher mortality rate and 13-fold increase in risk compared to non-IAI patients. Mortality for treated IAIs can be as high as 52.5%, and even higher (85-88%) in severe cases like central nervous system involvement or bone marrow transplantation.

In children with leukemia, mortality rates for IAIs increase significantly, with a 14-fold increase for acute lymphocytic leukemia (ALL) and a 5-fold increase for acute myeloid leukemia (AML). Central nervous system aspergillosis has a high mortality rate of 80%, though it has decreased since 1990 due to improved care.

Antifungal medications

The choice of antifungal medication and dosing depends on several factors, including risk stratification, spectrum of activity, mechanism of action, pharmacokinetics, pharmacodynamics, and potential adverse effects. Emerging drug resistance is a global health concern.

Four main classes of antifungal agents are used. The below Table details the available formulations of these drugs

Table 2: Summary of the formulations available.

Here’s a brief overview of each class of antifungal medications:

Azoles: Azoles inhibit lanosterol 14-α-demethylase, disrupting ergosterol biosynthesis and damaging the fungal cell membrane. Imidazoles (e.g., clotrimazole, ketoconazole) and triazoles (e.g., fluconazole, voriconazole) differ in their ring structure and pharmacokinetics. Triazoles are generally preferred for systemic infections due to better safety profiles and efficacy. Azoles are effective against many fungi but have drug interaction concerns due to CYP450 metabolism.

Polyenes: The oldest antifungals, polyenes like amphotericin B, bind to ergosterol in the fungal cell membrane, causing cell death. Amphotericin B is used for severe systemic fungal infections but can cause significant nephrotoxicity and other side effects. Lipid formulations (e.g., liposomal amphotericin B) reduce nephrotoxicity and are used in patients with pre-existing kidney issues.

Antifungal Antimetabolites: Flucytosine (5-FC) interferes with DNA and protein synthesis in fungi by being converted to 5-fluorouracil inside cells. It’s used primarily in combination with amphotericin B for serious Candida infections and cryptococcosis. Resistance develops quickly if used alone, and it has notable side effects like bone marrow suppression and gastrointestinal issues.

Echinocandins: This newer class of antifungals inhibits (1,3)-β-D-glucan synthesis, compromising fungal cell wall integrity. Echinocandins (e.g., micafungin, caspofungin) are effective against Candida and some Aspergillus species. They are generally safe with fewer severe side effects but lack oral formulations. Mild side effects include fever, rash, and phlebitis.

Drug interactions

Drug Interactions: Azole antifungals, such as itraconazole and ketoconazole, can significantly interact with other medications due to their role as both substrates and inhibitors of CYP3A4. This can lead to increased drug concentrations when combined with immunosuppressants, chemotherapeutics, calcium channel blockers, antidepressants, benzodiazepines, macrolides, and SSRIs. In contrast, echinocandins generally have minimal drug–drug interactions.

Antifungal Prophylaxis in PICU: Prophylaxis should be tailored based on individual risk factors and local epidemiology. Hand hygiene is crucial for infection control, supported by properly designed sinks and alcohol gel dispensers. Structured care bundles and checklists can ensure adherence to infection control policies. Routine antifungal prophylaxis is not recommended except for critically ill oncology and immunocompromised patients. Fluconazole is the first-line pre-emptive treatment for Candida spp., with alternatives including micafungin and liposomal amphotericin B.

We propose a flowchart for the management of IFIs (Figure 1). Pre-emptive therapy and recommendations have been well defined in IAIs.9 The real challenge is the identification of critically ill patients with a high risk of ICIs in the PICU so that targeted antifungal prophylaxis can be started pre-emptively to reduce IFI-associated comorbidities and mortality

Figure 1: Flowchart for the management of invasive fungal infections.